David B Arciniegas - The American Psychiatric Association Publishing Textbook of Neuropsychiatry and Clinical Neurosciences-American Psychiatric Association Publishing (2018)

The American Psychiatric Association Publishing
TEXTBOOK OF
NEUROPSYCHIATRY
and CLINICAL
NEUROSCIENCES
SIXTH EDITION
The American Psychiatric Association Publishing
TEXTBOOK OF
NEUROPSYCHIATRY
and CLINICAL
NEUROSCIENCES
SIXTH EDITION
EDITED BY
David B. Arciniegas, M.D.
Stuart C. Yudofsky, M.D.
Robert E. Hales, M.D., M.B.A.
Note: The authors have worked to ensure that all information in this book is
accurate at the time of publication and consistent with general psychiatric and
medical standards, and that information concerning drug dosages, schedules, and
routes of administration is accurate at the time of publication and consistent with
standards set by the U.S. Food and Drug Administration and the general medical
community. As medical research and practice continue to advance, however,
therapeutic standards may change. Moreover, specific situations may require a
specific therapeutic response not included in this book. For these reasons and
because human and mechanical errors sometimes occur, we recommend that
readers follow the advice of physicians directly involved in their care or the care of
a member of their family.
Books published by American Psychiatric Association Publishing represent the
findings, conclusions, and views of the individual authors and do not necessarily
represent the policies and opinions of American Psychiatric Association Publishing
or the American Psychiatric Association.
If you wish to buy 50 or more copies of the same title, please go to
www.appi.org/specialdiscounts for more information.
Copyright © 2018 American Psychiatric Association Publishing
ALL RIGHTS RESERVED
Sixth Edition
Manufactured in the United States of America on acid-free paper
22 21 20 19 18 5 4 3 2 1
American Psychiatric Association Publishing
800 Maine Ave. SW
Suite 900
Washington, DC 20024-2812
www.appi.org
Library of Congress Cataloging-in-Publication Data
Names: Arciniegas, David B. (David Brian), 1967- editor. | Yudofsky, Stuart C.,
editor. | Hales, Robert E., editor. | American Psychiatric Association Publishing,
publisher.
Title: The American Psychiatric Association Publishing textbook of neuropsychiatry
and clinical neurosciences / edited by David B. Arciniegas, Stuart C. Yudofsky,
Robert E. Hales.
Other titles: American Psychiatric Publishing textbook of neuropsychiatry and
behavioral neurosciences. | Textbook of neuropsychiatry and clinical
neurosciences | Neuropsychiatry and clinical neurosciences
Description: Sixth edition. | Washington, DC : American Psychiatric Association
Publishing, [2018] | Preceded by The American Psychiatric Publishing textbook
of neuropsychiatry and behavioral neurosciences / edited by Stuart C. Yudofsky,
Robert E. Hales. 5th ed. c2008. | Includes bibliographical references and index.
Identifiers: LCCN 2018012379 (print) | LCCN 2018012739 (ebook) | ISBN
9781615371877 (ebook) | ISBN 9781585624874 (hc : alk. paper)
Subjects: | MESH: Mental Disorders | Nervous System Diseases—psychology
|Diagnostic Techniques, Neurological | Neuropsychiatry—methods
Classification: LCC RC341 (ebook) | LCC RC341 (print) | NLM WM 140 | DDC
616.8—dc23 LC record available at https://lccn.loc.gov/2018012379
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.
Contents
Contributors
Preface
1 Neurobiological Bases of Cognition, Emotion,

and Behavior
C. Edward Coffey, M.D.
Jeffrey L. Cummings, M.D., Sc.D.
2 Neuropsychiatric Assessment
Fred Ovsiew, M.D.
3 Neuropsychological Assessment
Laura A. Flashman, Ph.D., ABPP
Fadi M. Tayim, Ph.D.
Robert M. Roth, Ph.D., ABPP
4 Neuroimaging in Neuropsychiatry
Robin A. Hurley, M.D., FANPA
Shiv S. Patel, M.D.
Katherine Taber, Ph.D., FANPA
5 Diagnostic Neurophysiology in Neuropsychiatry

Kerry L. Coburn, Ph.D.
Nash N. Boutros, M.D.
Samuel D. Shillcutt, Pharm.D., Ph.D.
Ali S. Gonul, M.D.
6 Attention-Deficit/Hyperactivity Disorder
Jeffrey H. Newcorn, M.D.
Tina Gurnani, M.D.
Anil Chacko, Ph.D.
7 Autism Spectrum Disorder Throughout the Life

Span
Alya Reeve, M.D., M.P.H.
Cynthia Y. King, M.D.
8 Delirium
Marie A. DeWitt, M.D.
Larry E. Tune, M.D., M.A.S.
9 Poisons and Toxins

Shreenath V. Doctor, M.D., D.D.S., Ph.D.
10 Epilepsy and Seizures

David K. Chen, M.D.
W. Curt LaFrance Jr., M.D., M.P.H.
11 Cerebrovascular Disorders
Ricardo Jorge, M.D.
Sergio Starkstein, M.D., Ph.D.
12 Traumatic Brain Injury

Hal S. Wortzel, M.D.
Lisa A. Brenner, Ph.D.
Jonathan M. Silver, M.D.
13 Hypoxic-Ischemic Brain Injury

C. Alan Anderson, M.D.
Christopher M. Filley, M.D.
Infectious Diseases of the Central Nervous
14 System
Joseph S. Kass, M.D., J.D.
Alicia S. Parker, M.D.
Rohini D. Samudralwar, M.D.
15 Brain Tumors
Alasdair G. Rooney, M.B.Ch.B., M.D.
16 Endocrine Disorders
Maria Rueda-Lara, M.D.
Charles B. Nemeroff, M.D., Ph.D.
17 Sleep and Sleep-Wake Disorders

Sudha Tallavajhula, M.D.
Joshua J. Rodgers, M.D.
Jeremy D. Slater, M.D.
18 Multiple Sclerosis
Melanie Selvadurai, B.H.Sc., M.B.A.
Omar Ghaffar, M.D., M.Sc., FRCPC
19 Alcohol and Other Substance Use Disorders

Thomas R. Kosten, M.D.
Colin N. Haile, M.D., Ph.D.
Steven Paul Woods, Psy.D.
Thomas F. Newton, M.D.
Richard De La Garza II, Ph.D.
20 Alzheimer’s Disease
Marissa C. Natelson Love, M.D.
David S. Geldmacher, M.D.
21 Neurocognitive Disorders With Lewy Bodies:
DEMENTIA WITH LEWY BODIES AND PARKINSON’S DISEASE
Mohammed Sheikh, M.D.
James E. Galvin, M.D., M.P.H.
22 Huntington’s Disease
Karen E. Anderson, M.D.
23 Frontotemporal Dementia
Geoffrey A. Kerchner, M.D., Ph.D.
Michael H. Rosenbloom, M.D.
24 Psychosis
David L. Bachman, M.D.
Nicholas J. Milano, M.D.
25 Mood Disorders
Sarah E. Dreyer-Oren, B.A.
Larry D. Mitnaul Jr., M.D., M.P.H., M.S.
Paul E. Holtzheimer III, M.D., M.S.
26 Anxiety Disorders
Isabelle M. Rosso, Ph.D.
Dan J. Stein, M.D., Ph.D.
Scott L. Rauch, M.D.
Index
Contributors
Vice-Chair of Education, Department of Neurology, Education and
Training Coordinator, Marcus Institute for Brain Health; Professor of
Neurology, Psychiatry, and Emergency Medicine, University of
Colorado School of Medicine, Aurora, Colorado

Associate Professor, Psychiatry and Neurology, Georgetown
University, Washington, D.C.

Chief Medical Officer, Center for Mental Health, Montrose, Colorado;
Director of Education, Marcus Institute for Brain Health; Clinical
Professor of Neurology and Psychiatry, University of Colorado
School of Medicine, Aurora, Colorado

Professor Emeritus, Department of Neurology, Medical University of
South Carolina, Charleston

Professor and Chairman, Department of Psychiatry, University of
Missouri, Kansas City, Missouri

Director, Rocky Mountain Mental Illness Research Education and
Clinical Center; Professor of Physical Medicine and Rehabilitation,
Neurology, and Psychiatry, University of Colorado Anschutz Medical
Campus, Denver
Anil Chacko, Ph.D.

Associate Professor, Department of Applied Psychology, New York
University, New York
David K. Chen, M.D.

Associate Professor of Neurology, Baylor College of Medicine;
Director, Neurophysiology Services, Michael E. DeBakey VA Medical
Center, Houston, Texas

Professor of Psychiatry and Neurology, Menninger Department of
Psychiatry and Behavioral Sciences, Baylor College of Medicine,
Houston, Texas

Professor of Psychiatry and Neurology, Department of Psychiatry
and Behavioral Sciences, Mercer University School of Medicine,
Macon, Georgia

Director, Cleveland Clinic Lou Ruvo Center for Brain Health, Las
Vegas, Nevada

Professor, Department of Psychiatry, Michael E. DeBakey VAMC and
Baylor College of Medicine, Houston, Texas

Program Director, Geriatric Psychiatry Fellowship Program; Assistant
Clinical Professor, Wayne State University School of Medicine; Staff
Psychiatrist, John Dingell VA Medical Center, Detroit, Michigan
Private Practice of Neuropsychiatry, Bellaire, Texas

Graduate Student, Department of Psychology, Miami University,
Oxford, Ohio

Director, Behavioral Neurology Section, Senior Scientific Advisor,
Marcus Institute for Brain Health; Professor of Neurology and
Psychiatry, University of Colorado School of Medicine, Aurora,
Colorado

Professor of Psychiatry, Neuropsychology Program, Department of
Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New
Hampshire

Professor of Integrated Medical Sciences and Associate Dean for
Clinical Research, Charles E. Schmidt College of Medicine,
Professor of Nursing and Medical Director of the Christine E. Lynn
College of Nursing, and Executive Director of the Institute for Healthy
Aging and Lifespan Studies, Florida Atlantic University, Boca Raton

Warren Family Endowed Chair in Neurology and Director, Division of
Memory Disorders and Behavioral Neurology, Department of
Neurology, University of Alabama at Birmingham

Medical Head, Neuropsychiatry Services, Ontario Shores Centre for
Mental Health Sciences, Department of Psychiatry, University of
Toronto, Ontario, Canada
Ali S. Gonul, M.D.
Professor, Department of Psychiatry, Ege University School of
Medicine, Bornova, Izmir, Turkey
Tina Gurnani, M.D.

Staff Child Psychiatrist, Meridian Behavioral Healthcare, Inc.,
Gainesville, Florida

Research Associate Professor and Director of Operations, UH
Animal Behavior Core Facility, Texas Institute for Measurement,
Evaluation and Statistics, Department of Psychology, University of
Houston, Houston, Texas

Distinguished Professor of Clinical Psychiatry, University of
California, Davis School of Medicine

Associate Professor of Psychiatry and Surgery and Director of Mood
Disorders Service, Department of Psychiatry, Geisel School of
Medicine at Dartmouth, Hanover, New Hampshire

Professor, Departments of Psychiatry and Radiology, Wake Forest
School of Medicine, Winston-Salem, North Carolina; Clinical
Professor, Department of Psychiatry, Baylor College of Medicine,
Houston, Texas; Associate Chief of Staff for Research and
Education, W.G. (Bill) Hefner VA Medical Center, Salisbury, North
Carolina; Associate Director for Education, Mid-Atlantic (VISN 6)
Mental Illness Research, Education and Clinical Center (MIRECC),
Salisbury, North Carolina
Ricardo Jorge, M.D.

Professor of Psychiatry and Behavioral Sciences, Beth K. and Stuart
C. Yudofsky Division of Neuropsychiatry, Baylor College of Medicine,
Houston, Texas

Associate Professor of Neurology, Psychiatry and Medical Ethics;
Vice Chair for Education, Department of Neurology; and Associate
Dean of Student Affairs, Baylor College of Medicine; Chief of
Neurology, Ben Taub General Hospital, Houston, Texas

Adjunct Clinical Associate Professor of Neurology and Neurological
Sciences, Stanford University School of Medicine, Stanford,
California

Associate Professor of Psychiatry, University of New Mexico,
Albuquerque

J.H. Waggoner Professor, Department of Psychiatry, Michael E.
DeBakey VAMC and Baylor College of Medicine, Houston, Texas

Associate Professor of Psychiatry and Neurology, Brown University;
Director, Neuropsychiatry and Behavioral Neurology, Rhode Island
Hospital; Staff Physician, Providence VA Medical Center,
Providence, Rhode Island

Assistant Professor, Department of Neurology, University of Alabama
at Birmingham

Assistant Professor, Department of Neurology, Medical University of
South Carolina, Charleston

Adjunct Professor of Psychiatry, Geisel School of Medicine at
Dartmouth, Dartmouth-Hitchcock Medical Center, Hanover, New
Hampshire; Child/Adolescent Psychiatrist, Via Christi Behavioral
Health Center, Wichita, Kansas

Leonard M. Miller Professor and Chairman, Director, Center on
Aging, and Chief of Psychiatry, Jackson Memorial Hospital; Chief of
Psychiatry, University of Miami Hospital, and Associate Director—
M.D./ Ph.D. Program, Leonard M. Miller School of Medicine,
University of Miami, Florida

Associate Professor of Psychiatry and Pediatrics, Department of
Psychiatry, Icahn School of Medicine at Mount Sinai, New York

Fred Ovsiew, M.D.

Professor of Clinical Psychiatry and Behavioral Sciences,
Northwestern University Feinberg School of Medicine, Chicago,
Illinois

Assistant Professor of Neurology, University of Texas Health San
Antonio, San Antonio, Texas
Shiv S. Patel, M.D.

Assistant Professor, Edward Via College of Osteopathic Medicine,
Blacksburg, Virginia; Staff Radiologist and Radiology Graduate
Medical Education Site Director, W.G. (Bill) Hefner VA Medical
Center, Salisbury, North Carolina

Professor, Department of Psychiatry, Harvard Medical School;
President, Psychiatrist in Chief, and Rose-Marie and Eijk van
Otterloo Chair of Psychiatry, McLean Hospital, Belmont,
Massachusetts

Emeritus Professor of Psychiatry, University of New Mexico,
Albuquerque; Medical Director, United Counseling Service,
Bennington, Vermont

Assistant Professor of Psychiatry and Behavioral Sciences, Baylor
College of Medicine; Staff Psychiatrist, The Menninger Clinic,
Houston, Texas

ST6 in General Adult Psychiatry, NHS Lothian; Honorary Fellow,
University of Edinburgh, Edinburgh, Scotland

Clinical Director, HealthPartners Center for Memory and Aging and
Chair HealthPartners, Department of Neurology; Assistant Professor
of Neurology, University of Minnesota, Saint Paul

Director, Anxiety and Traumatic Stress Disorders Laboratory,
McLean Hospital, Belmont, Massachusetts
Associate Professor of Psychiatry, Neuropsychology Program,
Department of Psychiatry, Geisel School of Medicine at Dartmouth,
Lebanon, New Hampshire

Assistant Professor of Psychiatry, Department of Psychiatry and
Behavioral Sciences, Leonard M. Miller School of Medicine,
University of Miami, Florida

Fellow, Center for Neuroimmunology and Neuroinfectious Diseases,
Washington University School of Medicine in St. Louis, St. Louis,
Missouri

Research Student, Neuropsychiatry Services, Ontario Shores Centre
for Mental Health Sciences, Department of Psychiatry, University of
Toronto; DeGroote School of Business, McMaster University,
Hamilton, Ontario, Canada

Clinical Trials Coordinator, Center for Cognitive Neurology, NYU
Langone Medical Center, New York

Professsor, Department of Psychiatry and Behavioral Sciences,
Mercer University School of Medicine, Macon, Georgia

Clinical Professor of Psychiatry, New York University School of
Medicine, New York

Professor, Department of Neurology and Kraft W. Eidman
Development Board Professor in the Medical Sciences, University of
Texas Houston Medical School, Houston, Texas

Professor of Psychiatry and Clinical Neurosciences, The University
of Western Australia, Crawley, Western Australia, Australia

Professor and Chair, Department of Psychiatry, University of Cape
Town, Cape Town, South Africa

Research Professor, Edward Via College of Osteopathic Medicine,
Blacksburg, Virginia; Research Health Scientist, W.G. (Bill) Hefner
VA Medical Center, Salisbury, North Carolina; Assistant Director for
Education, Mid-Atlantic (VISN 6) Mental Illness Research, Education
and Clinical Center (MIRECC), Salisbury, North Carolina

Assistant Professor, Division of Epilepsy, Department of Neurology,
University of Texas Houston Medical School; Medical Director, TIRR
Memorial Hermann Neurological Sleep Disorders Center, Houston,
Texas

Postdoctoral Fellow in Neuropsychology, Department of Psychiatry,
Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire

Professor, Department of Psychiatry and Behavioral Sciences and
Department of Neurology, Emory University School of Medicine,
Atlanta, Georgia

Director of Neuropsychiatric Consultation Services, Rocky Mountain
Mental Illness Research Education and Clinical Center; Michael K.
Cooper Professor of Neurocognitive Disease and Associate
Professor of Psychiatry, Neurology, and Physical Medicine and
Rehabilitation, University of Colorado School of Medicine, Denver

Distinguished Service Professor and Chairman and Drs. Beth K. and
Stuart C. Yudofsky Presidential Chair of the Menninger Department
of Psychiatry and Behavioral Sciences, Baylor College of Medicine;
Chairman Department of Psychiary, Houston Methodist Hospital,
Houston, Texas
Disclosure of Interests
The following contributors to this book have indicated a financial
interest in or other affiliation with a commercial supporter, a
manufacturer of a commercial product, a provider of a commercial
service, a nongovernmental organization, and/or a government
agency, as listed below:
C. Alan Anderson, M.D. Salary support: Participation in a clinical
trial of PFO closure in stroke from St. Jude Medical.
David S. Geldmacher, M.D. Research support: From Baxter,

Elan/Transition, Eisai, GSK, and Lundbeck paid to Dr. Geldmacher’s
institution for conduct of clinical trials.
W. Curt LaFrance Jr., M.D., M.P.H. Editor’s royalties: Cambridge

University Press for Gates and Rowan’s Nonepileptic Seizures,
copyright 2010; Author’s royalties: Oxford University Press for Taking
Control of Your Seizures: Workbook, copyright 2014, and Treating
Nonepileptic Seizures: Therapist Guide, copyright 2014; Consultant:
University of Colorado Denver Departments of Psychiatry and
Neurology to establish a NES clinic; Medico-legal consulting; Grant:
American Epilepsy Society, Epilepsy Foundation, NINDS, and Siravo
Foundation.
Marissa C. Natelson Love, M.D. Ongoing research support: NIA

2R01 AG021927 Marson (PI) 07/01/2010–06/30/2015, “Functional
Change in Mild Cognitive Impairment” (COINS-2 Study). This R01
renewal project longitudinally investigates MRI neuroimaging
variables in relation to financial capacity in patients with amnestic
MCI, develops a short-form financial capacity measure for clinical
and research use, and continues to develop predictor models for
clinical progression and conversion from MCI to dementia, Role:
Coinvestigator. NIH/University of California, Marson (PI) 09/30/2013–
08/31/2015, Alzheimer’s Disease Neuroimaging Initiative-2 (ADNI-2)
ADC-039. The overall goal of this project is to determine the
relationships among the clinical, cognitive, imaging, genetic, and
biochemical biomarker characteristics of the entire spectrum of
Alzheimer’s disease (AD), as the pathology evolves from normal
aging through very mild symptoms, to mild cognitive impairment
(MCI), to dementia. ADNI-2 continues the currently funded AD
Neuroimaging Initiative (ADNI1), a public/private collaboration
between academia and industry to study biomarkers of AD. ADNI will
inform the neuroscience of AD, identify diagnostic and prognostic
markers, identify outcome measures that can be used in clinical
trials, and help develop the most effective clinical trial scenarios;
Role: Coinvestigator. NIH/Washington University in St. Louis,
Roberson (PI) 10/2014–2018, a Phase II/III randomized, double-
blind, placebo-controlled multicenter study of two potential disease-
modifying therapies in individuals at risk for and with dominantly
inherited Alzheimer’s disease (DIAN-TU-001). The overall goal is to
assess the safety, tolerability, and biomarker efficacy of
Gantenerumab and Solanezumab in subjects who are known to
have an Alzheimer’s disease-causing mutation by determining if
treatment with the study drug improves primary and secondary
outcome diseaserelated biomarkers; Role: Coinvestigator. Clinical
trials contracts: CERE-110-03, Geldmacher (PI) 06/11/2009–
06/30/2014, Alzheimer’s Disease Cooperative Study/ National
Institute on Aging (ADCS/NIA), and Ceregene, Inc., a double-blind,
placebo-controlled (sham surgery), randomized, multicenter study
evaluating CERE-110 gene delivery in subjects with mild to
moderate Alzehimer’s disease. The purpose of this study is to
evaluate the effect of CERE-110 on cognition and to examine the
safety of the administration of CERE-110 in subjects with mild to
moderate Alzheimer’s disease. EISAI, Inc., Geldmacher (PI)
06/18/2013–06/17/2018, a placebocontrolled, double-blind, parallel-
group, Bayesian adaptive randomization design and dose regimen-
finding study to evaluate safety, tolerability and efficicy of BAN2401
in subjects with early AD; Role: Coinvestigator. Elan Pharma
International, Geldmacher (PI) 02/13/2013–02/ 12/2016, a
prospective, randomized, double-blind, placebo-controlled, Phase 2
efficacy and safety study of oral ELNDl005 for treatment of agitation
and aggression in patients with moderate to severe AD; Role:
Coinvestigator. Elan Pharma International, Geldmacher (PI)
09/01/2013– 08/30/2018, a 12-week safety extension study of oral
ELND005 for treatment of agitation and aggression in patients with
moderate to severe AD; Role: Coinvestigator. H. Lundbeck A/S
(Lundbeck), Geldmacher (PI) 02/26/2014–02/25/2019, randomzied,
double-blind parallel-group, placebo-controlled, fixed-dose study of
Lu AE58054 in patients with mild to moderate AD treated with
donepezil; Study 1; Role: Coinvestigator.
Charles B. Nemeroff, M.D., Ph.D. Research grants: National

Institutes of Health (NIH); Consulting: Xhale, Takeda, SK Pharma,
Shire, Roche, Lilly, Allergan, Mitsubishi Tanabe Pharma
Development America, Taisho Pharmaceutical, Inc., Lundbeck,
Prismic Pharmaceuticals (2014), Clintara LLC; Stockholder: CeNeRx
BioPharma, PharmaNeuroBoost, Revaax Pharma (2014), Xhale,
Celgene, Seattle Genetics, Abbvie, Titan Pharmaceuticals; Scientific
advisory boards: American Foundation for Suicide Prevention
(AFSP), CeNeRx BioPharma (2012), National Alliance for Research
on Schizophrenia and Depression (NARSAD), Xhale,
PharmaNeuroBoost (2012), Anxiety Disorders Association of
America (ADAA), Skyland Trail.
Jeffrey H. Newcorn, M.D. Advisor/Consultant: Alcobra,

Biobehavioral Diagnostics, GencoSciences, Ironshore, Lupin,
Neurovance, Shire, Sunovion (DSMB), Klingenstein Third
Generation Foundation; Research support: Shire.
Thomas F. Newton, M.D. Owner: Medications Discovery Texas,

Inc., company sponsoring a trial of carisbamate as a treatment for
alcohol use disorder.
Scott L. Rauch, M.D. Research participant: Research funded by

Cyberonics and Medtronic.
Michael H. Rosenbloom, M.D. Site investigator: Elan HARMONY

Trial and Merck MK-8931 study.
Jonathan M. Silver, M.D. Associate Editor: Journal Watch

Psychiatry and UpToDate.
Dan J. Stein, M.D., Ph.D. Research grants and/or consultancy

honoraria: AMBRF, Biocodex, Cipla, Lundbeck, National
Responsible Gambling Foundation, Novartis, Servier, and Sun.
Steven Paul Woods, Psy.D. Royalties: Oxford University Press for
Neuropsychological Aspects of Substance Use Disorders: Evidence-
based Perspectives; Grant recipient: National Institutes of Health
(MH073419, DA034497, MH098607, DA031098, DA026306); Grant
co-investigator: National Institutes of Health (MH084794,
MH062512).
Hal S. Wortzel, M.D. Private practice: Forensic neuropsychiatry.
The following contributors to this book have indicated no competing

interests to disclose during the year preceding manuscript
submission:

Anil Chacko, Ph.D.
David K. Chen, M.D.
Tina Gurnani, M.D.
Ricardo Jorge, M.D.
Preface
Neuropsychiatry: Back to the Future
I recall the precise moment of conception of The American

Psychiatric Press Textbook of Neuropsychiatry. It was early in 1984,
and I was in my tiny office on the 12th floor of the Neurological
Institute of Columbia Presbyterian Medical Center.
The telephone call came from Allen Frances. Although not in the
same class, we had both done our psychiatry residency training at
Columbia.
Allen: Stu, I have to be brief, so don’t interrupt me.

Stuart: O.K.
Allen: Please don’t interrupt me anymore. I’m in a hurry.
As I think you know, I’m coeditor of the Annual Review of
Psychiatry of the American Psychiatric Association (APA). We
choose about five topics each year to review, and our next volume is
going to be great. There are six chapters for each topic, and so far,
we have Joe Coyle as section editor for neurotransmitters and
neuroreceptors; David Kupfer on sleep disorders; Joel Yager on
eating disorders; and John Docherty on psychotherapy treatment
outcome.
I know you have been running an inpatient neuropsychiatry
service for a few years. I have two questions for you:
First of all, do you think that there is enough material to do a
section on neuropsychiatry?
Second, do you think anybody would be interested in reading
about neuropsychiatry?
Stuart: Yes, there is plenty of material to fill five chapters.
However, I really am not certain about the amount of interest of the
readership. There should be interest, however. Neuropsychiatric
disorders are quite common, and when these conditions do occur,
they are highly disabling. And, oftentimes, patients and their families
are uncertain about where to go for help. Neurologists send these
patients to psychiatrists, and psychiatrists refer them to neurologists.
Patients with neuropsychiatric conditions often fall through the
cracks of our health care system.
Allen: I thought I told you I was in a hurry, Stu. I guess we’ll go
forward with a section on neuropsychiatry.
In a few days, my coeditor for the Annual Review, Bob Hales, will
be calling you to tell you about the logistics. You’ll work with him on
your section.
Stuart: Who’s Bob Hales?
Allen: He’s a young up-and-comer in national psychiatry. Even
though he’s only an assistant professor at the military’s Uniformed
Services University of the Health Sciences, he’s chairperson of the
APA’s Scientific Program Committee, which runs the annual meeting.
He’s a West Point graduate and a colonel in the army. He’ll keep you
in line, Stu.
Bob Hales turned out to be an extraordinary editor for the
neuropsychiatry section. We worked closely and efficiently together
to choose the topics for the chapters and the chapter authors and to
review and edit the chapters when submitted. It was the beginning of
a long and wonderful relationship—both professionally and
personally.
In that era, the individual sections of the Annual Review were
featured seminars—one on each day of the corresponding annual
meeting of the APA. The first author of each chapter gave a 1-hour
presentation. The largest room in the venue was reserved for this
purpose. To everyone’s surprise, there was an overflow crowd for the
neuropsychiatry section’s presentations, and the subsequent ratings
were among the highest of the entire meeting that year.
It was clear to Bob Hales and to me that our colleagues were
eager for more information about neuropsychiatry, and we
understood why. For much of the nineteenth century, the approach to
disorders of mind and brain that we now refer to as neuropsychiatric
was the predominant, organizing focus of psychiatry. The advent and
increasing prominence of psychoanalysis in the first seven decades
of the twentieth century, however, led our profession to focus more
on the psychological and psychosocial aspects of psychiatry than on
its neurobiological bases.
As I wrote in the introduction to the update section,
Psychiatrists are intrigued as well as troubled by boundaries. We attempt to
define the line between normal and abnormal behavior. We search to
understand which symptomatologies stem from a patient’s biology and which
from his life experiences. We struggle to know what is mind and what is brain,
what is psychiatry and what is neurology….Neither psychiatry nor neurology
“really” exists, but each is a conceptual tool, an invention of man. To take too
seriously the boundary between psychiatry and neurology is, therefore, to take
ourselves and our inventions too seriously….Consequently, the authors of this
section intentionally do not focus upon the boundaries between psychiatry and
neurology; but, rather, upon the interfaces between these disciplines. We
have chosen the title “Neuropsychiatry” in order to emphasize the inevitable
inseparability of these two specialties. (Yudofsky 1985, p. 104)
Given the success of the neuropsychiatry section in the Annual

Review, Bob proposed that he and I coedit a textbook on
neuropsychiatry, with American Psychiatric Press, Inc. (APPI)
serving as our publisher. Our dear mentor, friend, and colleague
Shervert Frazier, then Editorin-Chief of APPI, immediately agreed,
with the strong support of another great friend and colleague, John
Talbott, then President of the APA.
At that time, English neuropsychiatrist William Alwyn Lishman’s
singleauthor classic textbook Organic Psychiatry: The Psychological
Consequences of Cerebral Disorder was the leading textbook in the
largely forgotten subspecialty of neuropsychiatry. Bob Hales and I
reasoned that a multiauthor textbook would provide a practical and
useful option to Lishman’s masterful tome. We said,
If Lishman’s textbook of neuropsychiatry is an elegant Rolls Royce, we will
produce an American Jeep that will take the reader rapidly and safely to
where our patients need to go.
Many of the chapter authors whom we selected for our first edition
were quite young at the time, and they later became important
leaders in American psychiatry, neuropsychiatry, and
neuropsychology. A sampling of this group includes the following:
Richard Abrams, John Black, Jean Cadet, Steven Dubovsky, David
Forrest, Richard Frances, Michael Franzen, Mark Gold, Lawrence
Gross, David Kupfer, James Lohr, Mark Lovell, Maurice Martin, John
Morihisa, Samuel Perry, Richard Pleak, Charles Reynolds III, Robert
Robinson, Frederick Sierles, Jonathan Silver, David Spiegel, James
Stevenson, Alan Stoudemire, Carl Rollyn Sullivan, Michael Taylor,
Troy Thompson II, Daniel Williams, and Michael Wise.
The first edition of The American Psychiatric Press Textbook of
Neuropsychiatry was well received from the perspectives of sales
and scholarly reviews. It was also the first textbook that APPI
published. Bob then boldly proposed that he and I edit, along with
John Talbott, a textbook of general psychiatry, the APPI Textbook of
Psychiatry, which also sold well and was positively reviewed. In the
five subsequent editions of both the Textbook of Psychiatry and the
Textbook of Neuropsychiatry, Bob took leadership of the former and I
of the latter. The exception is this latest edition of the Textbook of
Neuropsychiatry and Clinical Neurosciences, for which David B.
Arciniegas is lead editor.
One year after the 1987 publication of the first edition of the APPI
Textbook of Neuropsychiatry, the Journal of Neuropsychiatry and
Clinical Neurosciences came into being—with me as editor and Bob
Hales as deputy editor. That same year, the American
Neuropsychiatric Association (ANPA) was established, and not long
after, the Journal of Neuropsychiatry and Clinical Neurosciences
became ANPA’s official journal. A healthful and generative symbiosis
was created and has thrived for nearly three decades among these
three entities, with members of ANPA being regular and constructive
contributors to both the textbook and the journal.
Upon contemplating the sixth editions for both the Textbook of
Neuropsychiatry and Clinical Neurosciences and the Textbook of
Psychiatry, Bob Hales and I realized that the time had come to plan
for our successors as editors. We regard ourselves as unfathomably
fortunate to be succeeded—and no doubt surpassed—by two
extraordinary academic psychiatrists and leaders. Laura Roberts,
who is Chair of the Department of Psychiatry at Stanford and who
succeeded Bob Hales as Editor-in-Chief of American Psychiatric
Association Publishing, will be lead editor of the Textbook of
Psychiatry in its next edition. Consummate neuropsychiatrist David
Arciniegas, who developed the neuropsychiatry programs at the
University of Colorado School of Medicine and the Baylor College of
Medicine and who is one of the architects of the modern
subspecialty of behavioral neurology & neuropsychiatry, has
succeeded me as editor of the Journal of Neuropsychiatry and
Clinical Neurosciences and lead editor of the sixth edition of the
Textbook of Neuropsychiatry and Clinical Neurosciences.
In his first year as editor of the journal, David has made
transformational additions and improvements in its structure,
content, and access and presentations through electronic media.
Concurrently— driven principally by a shift in textbook development
adopted over the last several years by American Psychiatric
Association Publishing that emphasizes brevity, recency, and content
alignment with other works in the publisher’s catalog— David, Bob,
and I reviewed and revised the structure and content of this edition
of the textbook.
The prior editions of the textbook provided chapters on
neuropsychiatric assessment, neuropsychiatric symptoms,
neuropsychiatric syndromes, and neuropsychiatric treatments. The
present version also begins with an overview of the principles of
structural and functional neuroanatomy and the principles of
neuropsychiatric assessment. Thereafter, however, the previously
separate considerations of neuropsychiatric symptoms, syndromes,
and treatments are integrated into chapters addressing the
neuropsychiatry of neurodevelopmental disorders, acquired
neurological conditions, neurodegenerative disorders, and primary
psychiatric disorders. Much as we did in the early editions of the
textbook, we engaged senior members of our field as well as “rising
stars” in behavioral neurology & neuropsychiatry to contribute these
chapters. The present volume thereby offers a modern
reconsideration of the core concepts, conditions, and approaches in
neuropsychiatry that, in many respects, reiterates the century-old
foundations of our field—taking us back to the future.
Thirty years and six editions as editors of this textbook have been
both a great privilege and a great responsibility for Bob Hales and
me. From the bottoms of our hearts, Bob Hales and I thank the many
chapter authors and superlative staff of American Psychiatric
Association Publishing who have forged and formed the primary
foundation, substance, and spirit of each edition. With David, we also
gratefully acknowledge the excellent contributions, considerable
patience, and unwavering dedication of the authors and production
team of the present edition. We especially thank our dear colleagues
and readers who have faithfully and indefatigably supported us
during all the years that we have been editors. We also thank our
families, without whose support our work would not be possible. It is
our fondest hope that through these past and present works, we
have helped students and clinicians learn more about
neuropsychiatry, and with the present edition of this volume, they will
be empowered to alleviate the suffering of the many among us with
neuropsychiatric disorders.
Stuart C. Yudofsky, M.D., on behalf and with the collaboration of
David B. Arciniegas, M.D. and
Reference
Yudofsky SC: Neuropsychiatry: introduction, in Psychiatry Update: American
Psychiatric Association Annual Review, Vol 4. Edited by Hales, RE, Frances
AJ. Washington, DC, American Psychiatric Press, 1985, p 104
CHAPTER 1
Neurobiological Bases of Cognition, Emotion,

and Behavior
That brain and behavior are inseparable and that mental events are brain events are the physicalist
philosophical foundations of neuropsychiatry (Arciniegas et al. 2006). Biological, social, and
environmental factors, as well as their reciprocal interactions, are appreciated as influences on brain
function in health and disease, and neuropsychiatrists recognize all of these factors as necessary
elements of any account of mental (i.e., neuropsychiatric) function. Their influences on cognition,
emotion, and behavior and the combined mechanisms by which they engender neuropsychiatric
disorders, however, are understood and described in terms of their effects on brain structure and
function.
The Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric
Association and the Society for Behavioral and Cognitive Neurology (Arciniegas et al. 2006) directs
subspecialists in Behavioral Neurology & Neuropsychiatry (BNNP) to elicit and construct
comprehensive patient histories that emphasize neurodevelopmental and environmental influences on
cognition, emotion, behavior, and elementary neurological function. Clinical assessment of these
neuropsychiatric functions requires that practitioners understand brain-behavior relationships and
possess the assessment skills needed to apply that understanding in clinical practice. The clinical
assessment in BNNP employs, and is made systematic by, the use and interpretation of standardized,
validated, and reliable metrics of neuropsychiatric function. Neuropsychological testing, neuroimaging,
and electrophysiological and other laboratory measures that clarify the structural and functional
neuroanatomy of illness, refine differential diagnostic considerations, and inform prognosis, treatment
selection, and treatment response expectations are also employed, where appropriate (see Chapters
2 through 5). Interpreting clinical signs, symptoms, and syndromes in relation to structural and
functional neuroanatomy (i.e., the neurobiological bases of behavior) therefore supersedes
conventional (i.e., Diagnostic and Statistical Manual of Mental Disorders [DSM]–based) psychiatric
diagnoses. This neuropsychiatric approach to clinical assessment and treatment is designed to avoid
the practice of “mindless neurology” and “brainless psychiatry” that was pervasive during much of the
twentieth century (Abraham 1999). It also eschews the historical dichotomization of clinical conditions
into strict “psychiatric” or “neurological” types in favor of a more integrative approach. A
comprehensive account of neuropsychiatric health and disease therefore demands a detailed
understanding of the neurobiological bases of cognition, emotion, and behavior.
A life span, or neurodevelopmental, perspective adds another dimension to understanding
behavior: brain structure and function change dramatically with age—from fetal development through
infancy, childhood, adolescence, adulthood, and old age. Physiological functions vary more widely in
elderly people than in young people, tolerance of injury and potential for recovery are diminished in
elderly patients, and the neurobehavioral consequences of brain dysfunction often differ as a function
of the age of the patient.
This chapter is intended to introduce readers of this volume to the neuroanatomical and
neurochemical bases of cognition, emotion, and behavior. First, we present a synoptic model of
behavioral neuroanatomy as a framework for the remaining discussion. The model divides the
nervous system into three behaviorally relevant zones: an inner zone surrounding the ventricular
system, a middle zone encompassing the basal ganglia and limbic system, and an outer zone
composed primarily of the neocortex. We present the anatomy of each zone and describe the
behavioral consequences of injury to each. Next, we describe two distributed systems; these cross
the three zones to allow information to enter the brain (thalamocortical system) and allow impulses
mediating action to exit the brain (frontal-subcortical circuits). We also present neuropsychiatric
syndromes associated with abnormalities of these systems. Finally, we integrate the biochemical
bases of neuropsychiatric function with structural and functional neuroanatomy. Readers seeking
complementary and comprehensive syntheses of this information intended specifically for
subspecialists in BNNP are referred to recent reviews (Arciniegas et al. 2013; Hart 2016).
A Model of Behavioral Neuroanatomy

Paul Yakovlev developed a comprehensive model of the nervous system in terms relevant to
behavior (Yakovlev 1948, 1968; Yakovlev and Lecours 1967). He adopted an evolutionary perspective
and noted that the brain consists of three general regions: a median zone surrounding the ventricular
system, containing the hypothalamus and related structures; a paramedian-limbic zone consisting
primarily of limbic system structures, basal ganglia, and parts of the thalamus; and a supralimbic zone
containing the neocortex.
In this chapter, we present the Yakovlev approach—updated with information from more recent
anatomical studies (Benarroch 1997; Filley 2012; Hart 2016; Mesulam 2000)—as a foundation for
understanding brain-behavior relationships (Figure 1–1). The median zone is immediately adjacent to
the central canal, is poorly myelinated, and has neurons with short axons that synapse on nearby
cells, as well as on cells with longer axons that project to more distant nuclei. The median zone
contains the hypothalamus, medial thalamus, and periventricular gray matter of the brain stem as well
as functionally related areas of the amygdala and insular cortex. The system mediates energy
metabolism, homeostasis, peristalsis, respiration, and circulation. The median zone contains the
reticular activating system and the thalamocortical projections that maintain consciousness and
arousal in the awake state and that participate in sleep initiation and maintenance. No lateralization of
function is evident in the median zone. This system is fully functional at birth and is responsible for the
early survival of the infant.
FIGURE 1–1. Updated version of Yakovlev’s model of the nervous system demonstrating the median zone
(yellow), paramedian-limbic zone (blue), and supralimbic zone (red).
See Plate 1 to view this image in color.
Source. Based on Yakovlev and Lecours 1967.
The paramedian-limbic zone contains neurons that are more fully myelinated than those of the
median zone. Neurons here are grouped in nuclear structures that are connected in series. Many of
the thalamic nuclei, the basal ganglia, cingulate gyrus, insula, orbitofrontal region, hippocampus, and
parahippocampal gyri are included in this zone. The paramedian-limbic zone includes the structures
composing the limbic system (Papez 1937). Structures of this zone mediate posture, are essential for
generation and expression of emotion, and contribute to emotional experience. There is little lateral
specialization of the paramedian structures. Phylogenetically, this level of brain development is
present in reptiles (MacLean 1990). The paramedian-limbic zone is partially functional at birth, and its
emerging integrity becomes evident in smiling and crawling. Disorders of motivation, mood, and affect
are associated with paramedian-limbic dysfunction, and this zone is the anatomic site of structures
involved in many neuropsychiatric disorders. Parkinson’s disease, with its depression, apathy,
akinesia, masked facies, hypophonic voice, and marked postural changes, is an example of a
common disease of elderly people affecting the paramedian-limbic zone.
The supralimbic zone is outermost in the brain and includes the neocortex and the lateral thalamic
nuclei. The neurons of this zone have long, well-myelinated axons that project via white matter tracts
to more distant targets. The supralimbic neocortex contains the neurons mediating higher cortical
(association) functions, as well as the pyramidal neurons that project to limbs, lips, and tongue. It
mediates highly skilled, fine-motor movements evident in human speech and hand control.
Ontogenetically, this zone first finds expression in the pincer grasp and articulate speech.
Phylogenetically, the supralimbic zone first appears in mammals and is most well developed in
humans (MacLean 1990). The supralimbic zone is expressed in human cultural achievements,
including art, manufacture, speech, writing, and science. The supralimbic zone exhibits lateralized
specialization of structure and function, with marked differences between the functions supported by
each cerebral hemisphere.
The supralimbic zone is vulnerable to some of the most common neurological disorders associated
with aging, including stroke and Alzheimer’s disease. For example, the expansion of the neocortex
has been at the expense of a secure vasculature. The enlarged association areas have created
border zones between the territories of the major intracranial blood vessels that are at risk of stroke
because of limited interconnections and poor collateral flow; reduced cerebral perfusion with carotid
artery disease or cardiopulmonary arrest regularly results in border zone infarctions at the margins
between these vascular territories. In addition, penetrating branches form arterial end zones that have
no collateral supply as they project through the white matter to the borders of the ventricles. This
vascular anatomy creates an area of vulnerability to ischemia at the margins of the lateral ventricles.
Periventricular brain injury has been associated with depression (Smagula and Aizenstein 2016;
Sneed et al. 2008), “vascular cognitive impairment, no dementia” (VCIND; Stephan et al. 2009; see
also Duncombe et al. 2017), vascular neurocognitive disorder (Kirshner 2009; Tomimoto 2015), and
Binswanger’s disease (Filley 2012). Along with the hippocampus, the supralimbic zone is the major
site of pathological changes in Alzheimer’s disease (Savioz et al. 2009). Focal lesions of the
neocortex also result in neurobehavioral domain–restricted deficits such as aphasia (language),
apraxia (skilled purposeful movements, i.e., praxis), and agnosia (recognition).
This model of behavioral neuroanatomy provides an ontogenetic life span perspective showing the
emerging function of these structures in early life and their disease-related vulnerability in later life.
The model reflects an evolutionary perspective of the brain, emphasizing its development through
time and its increasing complexity in response to evolutionary pressures. From a clinical point of view,
the median zone is responsible for basic life-sustaining functions; accordingly, disturbances in this
zone are reflected in disorders of consciousness and abnormalities of metabolism, respiration, and
circulation. By contrast, most neuropsychological deficit syndromes, such as disorders of language,
prosody, praxis, recognition, visuospatial function, calculation, and executive function, are associated
with disturbances of the structure and/or function the supralimbic neocortex. Disorders of emotion
(i.e., mood disorders, disorders of affect), anterograde amnesia (impairments in new learning),
disorders of motivation, and personality alterations are more likely to occur with abnormalities in the
paramedian-limbic zone or disturbed interactions between this zone and the median and supralimbic
zones (Arciniegas 2013a; Gardini et al. 2009; Javitt 2007; Mayberg 2003). Thus, neuropsychiatric
disturbances occur in characteristic patterns that correspond to brain evolution, development,
structure, and function.
Neocortex (Supralimbic Zone)
Histological Organization of the Cortex and Behavior

Brodmann’s maps remain the classic guide to the histological organization of the cerebral mantle.
Within Brodmann’s areas (abbreviated BA followed by the number of the area), three types of cortex
relevant to understanding behavior have been identified: a three-layered allocortex, a six-layered
neocortex, and an intermediate paralimbic cortex. The limbic system cortex (e.g., the hippocampus)
has a three-layered allocortical structure, whereas the sensory, motor, and association cortices of the
hemispheres have a six-layered structure (Mesulam 2000). In the neocortex, layer I is outermost and
consists primarily of axons connecting local cortical areas; layers II and III have a predominance of
small pyramidal cells and serve to connect one region of cortex with another; layer IV has mostly
nonpyramidal cells, receives most of the cortical input from the thalamus, and is greatly expanded in
primary sensory cortex; layer V is most prominent in motor cortex and has large pyramidal cells that
have long axons descending to subcortical structures, brain stem, and spinal cord; and layer VI is
adjacent to the hemispheric white matter and contains pyramidal cells, many of which project to the
thalamus (Mesulam 2000) (Figure 1–2). Layers II and IV have the greatest cell density and the
smallest cells; conversely, layers III and V have the lowest density and the largest cells. Cell size
correlates with the extent of dendritic ramification, implying that cells of layers III and V projecting to
other cortical regions have the largest dendritic domains (Schade and van Groenigen 1961).
FIGURE 1–2. Histological structure of six-layered neocortex in a 5-year-old male (NeuN immunostain).
Roman numerals along each band correspond to the following layers: I–plexiform (molecular); II–external granular; III–
pyramidal; IV–internal granular; V–ganglionic; VI–multiform (polymorphous).
Source. Micrograph courtesy of Bette K. Kleinschmidt-DeMasters, M.D., University of Colorado School of Medicine.
Functional Organization of the Neocortex

The neocortex is highly differentiated into primary motor and sensory areas and unimodal and
heteromodal association regions (Mesulam 2000) (Table 1–1). Figures 1–3 through 1–5 illustrate the
anatomical distributions of the different cortical types in the cerebral hemispheres. Primary motor and
sensory areas account for only 16% of the neocortex (Figure 1–3), whereas unimodal and
heteromodal association cortices collectively occupy 84% of the human neocortex (Figures 1–4 and
1–5). The differences in these proportions reflect the marked importance of association cortex in the
functions that are characteristic of higher mammalian brains and particularly human functions like
language, executive function, humor, and creativity (Rapoport 1990). The neocortex is organized in a
mosaic of cortical columns, and local circuit neurons (confined to the cortex) compose approximately
25% of the cellular population (Rapoport 1990). Cortical regions receive and send information via
white matter tracts.
TABLE 1–1. Structure and function of different types of cerebral cortex

Cortex Layer number Brain regions Relevant behaviors
Neocortex
Primary cortex
Koniocortex 6 Primary sensory cortex Vision, hearing, somatic
(parietal) sensation
Macropyramidal cortex 6 Primary motor cortex Movement
(motor cortex)
Unimodal association 6 Secondary association Modality-specific
cortex (parietal, temporal, processing of vision,
occipital cortex) hearing, and somatic
sensation
Heteromodal association 6 Multimodal association Higher-order association
cortex (inferior parietal lobule,
prefrontal cortex)
Allocortex
Archicortex 3 Hippocampus Memory
Paleocortex 3 Piriform cortex Olfaction
Paralimbic cortex 4, 5 Orbitofrontal cortex, Emotional behavior
(mesocortex) insula, temporal pole,
parahippocampal
gyrus, cingulate gyrus
FIGURE 1–3. Primary motor (green) and sensory (blue) cortex.
Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.
FIGURE 1–4. Unimodal association cortex (red).
FIGURE 1–5. Heteromodal association cortex (pink).
Primary motor cortex occupies the motor strip in the posterior frontal lobe and serves as the origin
of the pyramidal motor system (Figure 1–3, green). Lesions of the motor cortex produce contralateral
weakness, particularly of the leg flexors and arm extensors; hyperreflexia; and an extensor plantar
response. Primary somatosensory cortex is located in the postcentral gyrus in the anterior parietal
lobe, primary auditory cortex occupies Heschl’s gyrus in the superior temporal lobe anterior to
Wernicke’s area, and primary visual cortex is situated in the calcarine region of the occipital lobe
(Figure 1–3, blue). Lesions of these regions typically result in contralateral hemisensory deficits (the
auditory system is an exception). Primary sensory cortices mediate first-level cortical information
processing in the brain (i.e., perception).
Unimodal association areas mediate second-level information processing in the cerebral cortex
after the primary sensory cortex (i.e., association; phenomenologically, recognition). Unimodal
somatosensory association cortex is located in the superior parietal lobule, unimodal auditory
association cortex is situated in the superior temporal gyrus immediately anterior to Wernicke’s region
in the left hemisphere and the equivalent area of the posterior superior temporal cortex of the right
hemisphere, and unimodal visual cortex occupies peristriate, midtemporal, and inferotemporal cortical
regions (Figure 1–4). Lesions of these regions produce recognition deficits confined to the affected
cortical sensory modality; the syndromes associated with dysfunction of these regions—that is,
agnosias—reflect deficits at this level of cortical information processing (i.e., stimuli in the affected
sensory modality are perceived but not recognized). For example, lesions of the auditory association
cortex not involving Wernicke’s area or its nondominant hemisphere homologue produce auditory
agnosia: pure word deafness (inability to recognize language auditorily), auditory agnosia (inability to
recognize sounds), or various forms of amusia (inability to recognize music). Lesions of the unimodal
visual association cortex produce visual agnosias (e.g., visual object agnosia, prosopagnosia, and
environmental agnosia) (Kirshner 1986; Mesulam 2000).
The highest level of information processing in the cerebral hemispheres occurs in the heteromodal
association cortices, including posterior (tertiary) heteromodal association cortex and anterior
(quaternary) cortex (Figure 1–5). Dysfunction of these areas produces complex behavioral deficits
that transcend single modalities.
Posterior (tertiary) heteromodal association cortex reflects the highest level of cortical processing of
incoming sensory information. It is primarily in this region that sensory information from primary
sensory and unimodal association cortex is integrated cross modally (i.e., linking visual, auditory,
somatosensory, olfactory, and gustatory information together into coherent multimodal
representations), as well as with limbic and paralimbic input (Mesulam 2000). Lesions of the posterior
heteromodal association cortex produce complex impairments of information integration (e.g., the
angular gyrus, or Gerstmann, syndrome, with alexia, agraphia, acalculia, right-left disorientation,
finger agnosia, anomia, and constructional disturbances) (Benson and Cummings 1982). Right-sided
inferior parietal lesions produce visuospatial deficits affecting constructional ability, spatial attention,
and body-environment orientation. Anterior (quaternary) heteromodal association provides integrative
functions between sensory and motor systems, enabling complex, flexible, and adaptive action
(Arciniegas 2013b; Mesulam 2000). Disturbances of the anterior heteromodal association cortices
produce impairments in motor programming, memory retrieval, abstraction, and judgment and
contribute to deficits in organizational and executive behaviors (Arciniegas 2013b; Stuss and Benson
1986; Tekin and Cummings 2002).
Wernicke’s area (BA22, adjacent areas of heteromodal cortex in BA39/40, and, perhaps, parts of
the middle temporal gyrus) is a particularly interesting example of heteromodal cortex: it serves as a
temporoparietal transmodal (heteromodal) gateway for lexical/semantic processing of language
(Mesulam 2000). Wernicke’s area lesions produce fluent aphasia (fluent output with impaired
comprehension, repetition, and naming). Lesions of the right-sided homologue of Wernicke’s area
produce the inability to understand the linguistic and emotional prosodic elements of language
(Wildgruber et al. 2006).
Thus, a behavioral neuroanatomy can be discerned in the organization of the cerebral cortex.
Information processing proceeds through progressively more complicated levels of analysis and
integration and is then translated into action through a series of executive processes (using anterior
heteromodal cortex and a series of cortical-subcortical circuits) and finally through supplementary and
primary motor cortices. Each cortical region carries on specific types of information processing
activities, and regional injury or dysfunction produces a signature syndrome. From a clinical
perspective, neurobehavioral and neuropsychological abnormalities such as aphasia, aprosodia, and
agnosia are products of dysfunction of neocortical association cortex or connecting pathways.
Although each region has unique functions, each also contributes to more complex integrative
processes required for human experience and behavior.
White Matter Connections

The cerebral white matter links cortical areas with each other and with subcortical structures
through multiple discrete bundles of myelinated axons, or fiber pathways. These pathways are
essential for the function of the distributed neural networks that subserve sensorimotor function,
cognition, emotion, and behavior. Within these neural networks are five general types of white matter
fiber pathways that emanate from every neocortical area: 1) cortico-cortical association fibers; 2)
corticostriatal fibers; 3) commissural fibers connecting the cerebral hemispheres; and cortico-
subcortical pathways that project to 4) the thalamus and 5) the pontocerebellar system, brain stem,
and/or spinal cord (Schmahmann et al. 2008). The principal projection tracts include the efferent
corticostriatal projections; corticothalamic connections; corticobulbar, corticopontine, and corticospinal
fibers; and the afferent thalamocortical radiations. There are also short and long association fibers.
The short association or, “U,” fibers connect adjacent sulci; the long association fibers form large
tracts connecting more distant regions within each hemisphere (Figure 1–6).
FIGURE 1–6. Brain dissection showing short corticocortical connections and intrahemispheric connections.
The main long association tracts are the following (Schmahmann et al. 2007):
The uncinate fasciculus connecting the orbital and medial prefrontal region with the rostral
temporal region, enabling interactions between emotion and cognition, self-regulation, and visual
learning
The arcuate fasciculus and also the extreme capsule, which project between superior temporal
areas and the superior and dorsal prefrontal cortex and which are involved in linking posterior and
anterior language areas as well as integrating sound localization with spatial attention
The first superior longitudinal fasciculus (SLF-I) linking the superior parietal lobule, which is
involved in appreciating limb and trunk location in space, with premotor areas engaged in higher
aspects of motor behavior and the supplementary motor area for intention and initiation of motor
activity
The second superior longitudinal fasciculus (SLF-II) connecting the caudal inferior parietal lobule
and posterior prefrontal cortices in the service of spatial attention
The third superior longitudinal fasciculus (SLF-III) linking the rostral inferior parietal lobule with
the supramarginal gyrus, ventral premotor area, and ventral prefrontal areas, which, collectively,
support gestural aspects of language as well as orofacial working memory
The frontal-occipital fasciculus, which supports visuospatial processing
The middle longitudinal fasciculus, which courses rostrocaudally in the white matter of the
superior temporal gyrus and which links associative and paralimbic cortices in the parietal,
cingulate, parahippocampal, and prefrontal regions with the heteromodal cortices of the superior
temporal region
The inferior longitudinal fasciculus connecting the occipital and temporal lobes, which supports
object recognition, discrimination, and memory, as well as face recognition
The cingulum bundle, linking the caudal cingulate gyrus with the hippocampus and
parahippocampus (for memory) as well as with the dorsolateral prefrontal cortices (BA9 and BA46)
for executive function and working memory and the rostral (anterior) cingulate gyrus for motivation
and drive
The commissural fibers are situated in the massive corpus callosum interconnecting all lobes of
one hemisphere with areas of the contralateral hemisphere and in the more diminutive anterior
commissure interconnecting the olfactory regions and the middle and inferior temporal gyri of the
hemispheres.
Intact cerebral function depends on the integrity of the axons of the white matter, as well as on the
activity of the neurons of the gray matter. White matter diseases with diffuse or multifocal
demyelination produce memory abnormalities, dementia, depression, mania, delusions, and
personality alterations. Focal lesions of white matter tracts produce a number of disconnection
syndromes that arise when critical neuronal areas are uncoupled by an intervening injury (Geschwind
1965; Kirshner 1986; Schmahmann et al. 2007, 2008). Table 1–2 summarizes the principal
disconnection syndromes.
TABLE 1–2. Fiber tracts and related disconnection syndromes of the cerebral hemispheres
Fiber type Tract Symptoms
Commissural Corpus callosum Left-hand tactile anomia, left-hand agraphia,
lefthand apraxia, inability to match hand
postures or tactile stimuli of the two
hands, reduced constructional skills in the
right hand
Splenium Alexia without agraphia (this syndrome
occurs when there is a left occipital injury
and right homonymous hemianopsia in
addition to the splenial lesion)
Association Arcuate fasciculus Conduction aphasia
Arcuate fasciculus Parietal apraxia
Inferior longitudinal fasciculus Prosopagnosia, environmental agnosia
(right)
Inferior longitudinal fasciculus Visual object agnosia
(bilateral)
Projection Corticospinal tract Locked-in syndrome
Disruption of commissural fibers by stroke, surgery, or trauma disconnects the left and right
hemispheres, and several commissural or callosal syndromes are recognized clinically. With an
anterior callosal lesion, the right hemisphere controlling the left hand becomes disconnected from the
left hemisphere; thus, the left hand no longer has access to the verbal and motor skills of the left
hemisphere, and callosal apraxia, left-hand tactile anomia, and left-hand agraphia result. When the
splenium of the corpus callosum is damaged in association with injury to the left occipital cortex
(usually from a left posterior cerebral artery occlusion), the visual information available to the right
hemisphere cannot be transferred to the left for semantic decoding, and alexia without agraphia
ensues.
Disconnection syndromes also occur with lesions of association fiber tracts. Lesions of the right
inferior longitudinal fasciculus produce prosopagnosia and environmental agnosia, whereas bilateral
inferior longitudinal fasciculus damage causes visual object agnosia. Hemisensory deficits and
homonymous hemianopsia result from lesions affecting the thalamocortical projections, and
hemimotor syndromes occur with lesions of the descending corticospinal projections. The locked-in
syndrome occurs with bilateral lesions of descending corticobulbar and corticospinal projection tracts
at the pontine level.
The complex histological organization of the cerebral cortex, with its different cytoarchitectonic
areas subsuming different processing tasks (as described above), is reflected in the complex
connectivity of the cerebral white matter. White matter tracts connect specialized cortical regions, and
neuropsychological syndromes may reflect focal cortical injury or disconnection of the cortical regions
through injury to the white matter connections. Disconnection syndromes occur with lesions of
commissural, long association, or projection fibers. Discrete neurobehavioral syndromes have been
identified and occur primarily when lesions of callosal or association fibers disconnect unimodal
association areas (e.g., interruption of visual processing in the agnosias or motor activities in the
apraxias).
Hemispheric Specialization, Laterality, and Dominance

Anatomic Asymmetries
The cerebral hemispheres, although grossly symmetrical, differ from one another in some aspects
of development, structure, and biochemical composition. Differences between the right and left
hemispheres have been shown in both the upper surface of the temporal lobes (the planum
temporale) and the inferolateral surface of the frontal lobe (Tzourio-Mazoyer 2016). The temporal lobe
area corresponding to Wernicke’s area (in 65% of cases) and the frontal region corresponding to
Broca’s area are both larger than the corresponding right-brain regions (in 83% of cases) (Falzi et al.
1982; Galaburda et al. 1978). The superior temporal surface is longer, and the total area is
approximately one-third larger in the left hemisphere. The sylvian fissure is longer and more horizontal
on the left, but it is curved upward on the right (Galaburda et al. 1978; Lyttelton et al. 2009).
Cytoarchitectonic differences correspond to these morphological asymmetries: there is a larger region
corresponding to Wernicke’s area on the left compared with that on the right.
Other gross asymmetries of the human brain include a wider and longer left occipital lobe, wider
right frontal lobe, larger left occipital horn of the lateral ventricular system, and a tendency for the left
descending pyramidal tract to decussate before the right in the medulla (Galaburda et al. 1978).
Asymmetries of neurotransmitter concentrations also have been identified: cortical choline
acetyltransferase activity is greater in the left than in the right temporal lobe (Amaducci et al. 1981).
Cerebral asymmetries do not occur in the brains of nonprimates, but they are present in gorillas,
chimpanzees, and orangutans, as well as in humans (LeMay 1976). Studies of endocasts of fossil
skulls reveal that brain asymmetries similar to those of modern humans were evident in the brains of
Neanderthal people 40,000 years ago and may have been present as early as 400,000 years ago in
Peking man (Galaburda et al. 1978) (or even earlier if more recent dating is taken into account).
Investigations of asymmetries between the two hemispheres have identified differences at the
gross morphological level, in the cytoarchitectonic structure of the hemispheres, in the shape of the
brain, in the shape of specific aspects of the ventricular system, and in the concentrations of
neurotransmitters. The magnitude of these differences is relatively small and does not explain the
marked differences in hemispheric function. The means by which the dramatic differences in function
of the two hemispheres are achieved remain enigmatic. The advantage of hemispheric specialization
and lateralized development of functional capacities is that the capacity of the human brain is nearly
doubled (Levy 1977). The principal disadvantage is that reduced redundancy exaggerates the effects
of lateralized cerebral injury; in humans, a unilateral lesion often has devastating behavioral
consequences because of the limited compensatory capability of the contralateral hemisphere.
Asymmetric Cognitive Function of the Hemispheres

Hemispheric specialization refers to the differential functions of the two hemispheres. All domains
of neuropsychiatric function—cognition, emotion, behavior, sensation, and motor ability—are
subserved by both hemispheres. Nevertheless, the two hemispheres differ substantially in their
relative subspecialization for these functions and, in particular, for their many subdomains. Numerous
attempts have been made to identify antinomies of function that characterize the right and left
hemispheres (i.e., verbal versus nonverbal, propositional versus appositional, holistic versus analytic);
none of these have been entirely successful, and it is unlikely that the brain is organized along such
polar dimensions. A more accurate approach is to acknowledge that the two hemispheres perform
different but not necessarily correlated or complementary roles. Table 1–3 lists capacities mediated to
a significantly different extent by the two hemispheres.
TABLE 1–3. Abilities mediated primarily by the right or left hemisphere and corresponding clinical deficits
resulting from lateralized lesions
Hemispheric function Correlated clinical deficit

Left hemisphere
Language Aphasia
Execution Nonfluent aphasia
Comprehension Comprehension defect
Reading Alexia
Writing Agraphia
Verbal memory Verbal amnesia
Verbal fluency (word list generation) Reduced verbal fluency
Mathematical abilities Anarithmetia
Praxis Apraxia
Musical rhythm (execution) Impaired rhythm in singing
Contralateral spatial attention Right-sided neglect
Contralateral motor function Right hemiparesis
Contralateral sensory function Right hemisensory loss
Contralateral visual field perception Right homonymous hemianopia
Right hemisphere
Speech prosody Aprosodia
Executive prosody Executive aprosodia
Receptive prosody Receptive aprosodia
Nonverbal memory Nonverbal amnesia
Design fluency (novel figure generation) Reduced design fluency
Elementary visuospatial skills
Depth perception Reduced depth perception
Angle discrimination Reduced angle discrimination
Complex visuospatial skills
Familiar face recognition Prosopagnosia
Familiar place recognition Environmental agnosia
Unfamiliar face discrimination Impaired facial discrimination
Visuomotor abilities
Constructional ability Constructional disturbance
Dressing (body-garment orientation) Dressing disturbance
Musical melody (perception and execution) Amusia
Contralateral spatial attention Left-sided neglect
Contralateral motor function Left hemiparesis
Contralateral sensory function Left hemisensory loss
Contralateral visual field perception Left homonymous hemianopia
Miscellaneous
Familiar voice recognition Phonagnosia
Language is the most well-known and among the most thoroughly characterized examples of a
lateralized neuropsychiatric function. The left perisylvian region and the association cortices to which
it is connected subserve the syntactic and semantic elements of language (i.e., fluency,
comprehension, repetition, naming), whereas the homologous regions of the right hemisphere
mediate the affective prosodic elements of language. The left hemisphere is specialized for symbolic
communication, including communication using words (verbal and written), mathematical symbols,
symbolic gesture, and verbal memory. The left hemisphere is dominant for language in nearly all right-
handed individuals and in most left-handed people. However, lateralization of language functions is
not complete, and rudimentary language skills are present in the right brain. The left hemispheric
dominance for language is predicated on interhemispheric communication through the corpus
callosum, the absence of which results in language development delays like those observed in
persons with autism (Hinkley et al. 2016).
Praxis refers to the ability to execute skilled purposeful movements on command. Like language,
with which it is nearly always colateralized, praxis is typically a function of the left hemisphere
(Vingerhoets et al. 2013). It has been suggested that the colateralization of language and praxis
networks (both forms of complex learned movement in their outputs) represents an evolutionary
remnant of a neural system out of which protosign and protospeech coevolved (Vingerhoets et al.
2013). As a result of this pattern of development and hemispheric lateralization, most instances of
apraxia occur in patients with left hemispheric brain injury or degeneration and frequently co-occur
with aphasias (Leiguarda and Marsden 2000; Vingerhoets et al. 2013).
The right hemisphere is dominant for visuospatial functions, but the left hemisphere has
considerable visuospatial ability, and left hemisphere injuries frequently produce at least minor
visuospatial deficits. The most marked and enduring visuospatial abnormalities occur with lesions of
the posterior right hemisphere. Elementary visuoperceptual skills (e.g., judging line orientation, depth
perception), complex visual discrimination and recognition abilities (e.g., discriminating between two
unfamiliar faces, recognizing familiar faces), and visuomotor skills (e.g., drawing, copying, dressing)
are mediated primarily by the right hemisphere (Kimura and Durnford 1974; Mesulam 2000).
Limbic System (Paramedian Zone)

Limbic system structures compose a critical neuroanatomic substrate for emotion, memory, and
motivation, among other functions. Limbus means edge, fringe, or border, and limbic was first used in
an anatomical context by P.P. Broca, the French anatomist, to describe the structures that lie beneath
the neocortex and that surround the brain stem (Isaacson 1974). In 1937, J.W. Papez authored the
landmark article “A Proposed Mechanism of Emotion,” in which he hypothesized that these structures
surrounding the upper brain stem formed a functional system mediating human emotion (Papez
1937). Since then, research and clinical observations have largely confirmed the idea that limbic
structures are involved in the mediation of behaviors and experiences that share the common feature
of having an emotional component.
As it is currently conceived, the limbic system—composed of limbic and paralimbic structures—
includes the entorhinal-hippocampal complex, fornix, mammillary body, olfactory bulb and piriform
cortex, caudal orbitofrontal cortex, insula, temporal pole, parahippocampal gyrus, cingulate gyrus,
amygdala, orbitofrontal cortex, septal nuclei, nucleus accumbens, hypothalamus, and selected
thalamic nuclei (Arciniegas 2013a; Carpenter 1991; Mesulam 2000) (Figure 1–7). The limbic system
is poised between the hypothalamus with its neuroendocrine control systems of the internal milieu and
the neocortex mediating action on the external environment. Within this system, the entorhinal-
hippocampal complex, as well as its outflow through the forniceal-mammillo-thalamic tract, is an
essential element of the brain networks involved in declarative new learning and memory
consolidation. Localized injury to the hippocampus or its outflow tract produces an amnestic disorder
with deficient storage of new information. This syndrome has been described with hippocampal
damage secondary to stroke, anoxia, trauma, early Alzheimer’s disease, and herpes encephalitis. The
paralimbic elements of the limbic system include brain regions critical to emotional control, social
judgment, civility, and motivated behavior. Lesions of the orbitofrontal cortex produce marked
personality changes with disinhibition, impulsiveness, loss of tact, and coarsened behavior. Cingulate
dysfunction results in marked apathy with disinterest and loss of motivation (Cummings 1993).
FIGURE 1–7. Limbic and paralimbic cortex (purple).

Portions of the basal ganglia also are included in the limbic system, at least from a functional
perspective. The head of the caudate nucleus consists of ventromedial and dorsolateral portions. The
ventromedial section has major limbic system connections and receives projections from the
hippocampus, amygdala, cingulate cortex, and the orbitofrontal cortex. The dorsolateral portion, in
contrast, receives projections from the lateral prefrontal cortex and has little limbic input (Nauta 1986).
The globus pallidus is divided similarly into dorsal-nonlimbic portions and ventral-limbic portions. As
predicted by these anatomic observations, basal ganglia diseases are commonly accompanied by
emotional dysfunction and psychopathology.
Limbic and Paralimbic Structure and Function in Relation to Emotion

With respect to the structural and functional anatomy of emotion, two general hypotheses dominate
the literature: the lateralization hypothesis, in which, to a greater or lesser extent, the right hemisphere
is regarded as the “emotional” hemisphere and is contrasted with the left hemisphere as the “‘logical”
hemisphere; and the valence-related hypothesis, which generally posits that both hemispheres
process emotion but differ with respect to the role of each hemisphere in emotions of particular
valences.
There are three variations of the valence-related neuroanatomic hypothesis. The first suggests that
the left hemisphere is dominant for positive emotions and the right hemisphere is dominant for
negative emotions. The second variation suggests that lateralization of emotion is linked more
strongly to approach (left anterior) and avoidance (right anterior) behaviors rather than valence per se.
Despite their conceptual differences, the only major point of disagreement between these first two
variations of the valence-related hypothesis is their hemispheric assignment of anger; although
colloquially regarded as a negative emotion, anger is often, even if sometimes maladaptively,
associated with approach behaviors. The third variation suggests that both hemispheres are involved
in a valence-general manner and that only minor differences in lateralized activation occur in relation
to specific valences.
The era of advanced neuroimaging and meta-analytic approaches has yielded important evidence-
based insights that inform usefully on the neuroanatomic bases of emotion.
A meta-analysis of 105 neuroimaging studies using the emotional faces paradigm (or variants
thereof) in 1,600 healthy subjects (Fusar-Poli et al. 2009) failed to support the hypothesis of overall
right-lateralization of emotional processing of faces, although it could not preclude preferential right
hemisphere activation for emotions provoked by stimuli other than human faces (e.g., animals,
figures). The authors observed that all emotional conditions, irrespective of stimulus valence,
produced bilateral activations of the parahippocampal gyrus and amygdala, posterior cingulate,
middle temporal gyrus, inferior frontal and superior frontal gyri, fusiform gyrus, lingual gyrus,
precuneus, and inferior and middle occipital gyrus. A valence-specific lateralization to the left
amygdala during processing of negative emotions was observed, as was a “left/approach” and
“right/withdrawal” pattern of imaging activation to emotional faces. This neuroimaging-based meta-
analysis of emotional processing favors the valence-specific hypothesis but suggests that emotional
processing is a complex phenomenon that may be understood most usefully by integrating elements
of the right hemisphere hypothesis and both variations of the valence-specific hypothesis.
A subsequent meta-analysis of 397 functional magnetic resonance imaging (fMRI) and positron
emission tomography (PET) studies—collectively comprising 6,827 participants and 914 experimental
contrasts—extended the above observations by assessing the evidentiary support for three
hypotheses of the neuroanatomy of emotion: the bipolarity hypothesis (i.e., positive and negative
emotion are supported by a neural network that increases or decreases monotonically along the
valence dimension), the bivalent hypothesis (i.e., positive and negative affect are supported by
independent networks in the brain), and the affective work space hypothesis (i.e., positive and
negative affect are supported by a flexible set of valence-general regions) (Lindquist et al. 2016). The
evidence did not support either the bipolarity or bivalent hypotheses. Instead, and consistent with the
findings of Fusar-Poli et al. (2009), the evidence favored the valence-general hypothesis: that is, at
the level of fMRI-measurable brain activity, affect is represented across its various forms in valence-
general limbic and paralimbic brain regions.
Kirby and Robinson (2017) used activation likelihood estimation (ALE) to quantify convergence of
neuroimaging-demonstrated neural activations across studies within seven categories of emotion:
anger, anxiety, disgust, fear, happiness, humor, and sadness. The ALE maps demonstrated consistent
cross-hemispheric limbic-paralimbic, cortical, and cerebellar activations for all categories of emotion.
Within the median and paramedian-limbic zones, structures activated across emotions included the
insula, reflecting its role in autonomic arousal associated with emotions and emotional judgment, as
well as the amygdala, hippocampus, basal ganglia, and thalamus. Within the supralimbic zone, all
emotion categories were associated with dorsolateral prefrontal cortex (BA9/46, BA44/45, and BA47)
activation. Activation within BA9 and BA46 may reflect engagement of cortical areas involved in
processing emotion and emotion- and reward-related decision making, whereas activation of BA44/45
(Broca’s area) may reflect engagement of structures connecting with language and affective prosody.
The involvement of BA47 across multiple emotions may also implicate a role in affective components
of language processing as well as emotion-related episodic memory. Convergence of emotional
processing in prefrontal areas may reflect interactions between limbic-paralimbic (i.e., emotion
generating) and higher cognitive (i.e., emotion integration and regulation) functions, with the prefrontal
areas serving as a network hub for such integrative interactions. Collectively, these findings reinforce
the modern view that emotion engages bihemispherically distributed networks, the specific elements
of which vary somewhat between emotions but do not fully lateralize specific emotions, or emotions
more generally, to either cerebral hemisphere.
With regard to the experiential aspects of emotion, Damasio and colleagues (2000), using 15O PET,
studied the neural correlates of happiness, sadness, fear, and anger using a personal life–episodes
recall paradigm in 41 healthy individuals. Although there were individual variations in the specific brain
regions activated during subjects’ experiences of these emotions, all involved activation of bilateral
structures in limbic, paralimbic, somatosensory, prefrontal, brain stem, and cerebellar areas. Taken
together with the aforementioned meta-analytic and ALE studies, these observations suggest that
both the expressed and experiential aspects of emotion are mediated by complex, typically bilateral,
limbic-cortical and limbic–brain stem systems.
Asymmetric Neurochemical Anatomy of the Limbic System

Although emotion is bihemispherically represented and modulated neurochemically in both
hemispheres, neurotransmitter asymmetries may underlie the differential occurrence of mood
disorders and anxiety, with lesions of the left and right hemispheres. Asymmetries of subcortical
structures are less marked than are asymmetries of cortical regions, but the left globus pallidus, right
medial geniculate nucleus of the thalamus, and left lateral posterior nucleus of the thalamus have
been found to be larger than the corresponding nuclei of the contralateral hemisphere (Eidelberg and
Galaburda 1982; Kooistra and Heilman 1988). Asymmetries of neurotransmitter concentrations in
limbic system structures have been identified. The content of dopamine and choline acetyltransferase
(a marker of cholinergic function) is increased in the left globus pallidus compared with their content in
the right (Glick et al. 1982); norepinephrine concentrations are greater in the left pulvinar and in the
right somatosensory nuclei of the thalamus (Oke et al. 1978); and choline acetyltransferase activity is
greater in the left than in the right temporal lobe (Amaducci et al. 1981).
Neuropsychiatric Disorders Associated With Limbic and Paralimbic
Disturbances
The limbic system serves no single unifying function, but disorders involving the limbic system
frequently involve some manner of altered emotional or social function. Disorders involving limbic and
paralimbic structures therefore produce a wide range of disturbance in thought, emotion, and behavior
(Cummings 1985; Doane 1986) (Table 1–4). Importantly, conditions with isolated involvement of the
“traditional” limbic system described by Papez (1937) tend to produce little intellectual impairment
except for impairments in declarative new learning associated with lesions to or degeneration of the
entorhinal-hippocampal-forniceal-mammillo-thalamic pathway. Instead, these conditions are often,
although not invariably, associated with “productive” disorders of emotional function with the new
appearance of positive neuropsychiatric symptoms.
TABLE 1–4. Neuropsychiatric disorders with evidence of limbic system dysfunction
Neuropsychiatric Limbic and paralimbic structures
disorder implicated Diseases affecting structure
Amnesia Hippocampus, hypothalamus Stroke, anoxia, trauma, tumors, herpes encephalitis
Psychosis Temporal cortex Epilepsy, stroke, tumors, herpes encephalitis,
Alzheimer’s disease
Striatum Huntington’s disease, idiopathic basal ganglia
calcification, lacunar state, schizophrenia
Depression Striatum, thalamus, insula, medial Stroke, Huntington’s disease, Parkinson’s disease,
orbitofrontal cortex idiopathic basal ganglia calcification, idiopathic
depression
Mania Striatum Huntington’s disease, idiopathic basal ganglia
calcification
Thalamus Stroke
Right basotemporal cortex Stroke, trauma
OCD Lateral orbitofrontal cortex, nucleus Idiopathic OCD
accumbens, basal ganglia, thalamus
Striatum, globus pallidus Huntington’s disease, Sydenham’s chorea, PEPD,
manganese intoxication, carbon monoxide
intoxication
Personality Orbitofrontal cortex Trauma, tumors, degenerative disorders
alterations
Temporal cortex Epilepsy
Amygdala Herpes encephalitis, trauma
Anxiety Amygdala PTSD, social phobia, specific phobia
Insula Idiopathic anxiety
Rostral anterior cingulate, ventral medial PTSD
prefrontal cortex
Temporal cortex, basal ganglia Alzheimer’s disease, Parkinson’s disease, stroke,
trauma
Apathy Anterior cingulate, ventral striatum, Stroke, trauma, tumors, degenerative disorders
nucleus accumbens, thalamus
Hyposexuality Temporal cortex Epilepsy (interictal)
Hypothalamus Trauma (surgical)
Hypersexuality Orbitofrontal cortex Tumors, trauma
Temporal cortex Epilepsy (ictal)
Amygdala Herpes encephalitis, trauma
Septal nuclei Trauma
Paraphilias Hypothalamus Tumors, trauma, encephalitis
Addictions Septal nuclei, anterior cingulate, Idiopathic addictive behavior
orbitofrontal cortex, nucleus
accumbens, hypothalamus
Note. OCD=obsessive-compulsive disorder; PEPD=postencephalitic Parkinson’s disease; PTSD=posttraumatic stress
disorder.
Mood disorders are associated with limbic system dysfunction (Arciniegas 2013a), although current
models of depression incorporate a large set of limbic-paralimbic-cortical-subcortical interactions
(Arciniegas 2013a; Mayberg 2003). Depression occurs with basal ganglia dysfunction in stroke,
movement disorders, and idiopathic depressive disorders (Baxter et al. 1985; Cummings 1992;
Starkstein et al. 1987, 1988a). Manic behavior has been associated with disorders affecting the
caudate nuclei, thalamus, and basotemporal areas (Bogousslavsky et al. 1988; Cummings and
Mendez 1984; Folstein 1989; Oster et al. 2007; Starkstein et al. 1988b).
Anxiety is a core feature of many psychiatric conditions and a common consequence of brain
disorders. Relatively heightened amygdala activation is observed in response to disorder-relevant
stimuli in posttraumatic stress disorder, social phobia, and specific phobia, and activation in the insular
cortex appears to be heightened in many of the anxiety disorders (Shin and Liberzon 2010). Unlike
other anxiety disorders, posttraumatic stress disorder also features diminished responsivity in the
rostral anterior cingulate cortex and adjacent ventral medial prefrontal cortex (Shin and Liberzon
2010). Anxiety has been associated with temporal lobe and basal ganglia disorders, including
Parkinson’s disease and Alzheimer’s disease (Reisberg et al. 1989; Stein et al. 1990), and is a
common but less conclusively localized problem following stroke or trauma (Carota et al. 2002; Jorge
et al. 2004).
Psychosis occurs with lesions of the temporal lobes and subcortical limbic system structures, as
well as with abnormal interactions between limbic and other cortical and brain stem systems (Javitt
2007; Arciniegas 2015). The schizophrenia-like disorder of epilepsy occurs almost exclusively in
patients with seizure foci in the temporolimbic cortex (Perez et al. 1985). Stroke, tumors, herpes
encephalitis, and Alzheimer’s disease are other disorders that affect the temporal cortex and produce
psychotic features in the elderly (Arciniegas 2015). At the subcortical limbic level, Huntington’s
disease, idiopathic basal ganglia calcification, and lacunar state are examples of conditions with
pathology of the limbic system and increased frequencies of psychosis (Arciniegas 2015).
Investigation of idiopathic obsessive-compulsive behavior has revealed aberrant regulation of
limbic and paralimbic structures involved in reward (orbitofrontal cortex and nucleus accumbens),
error detection (anterior cingulate), activation of motor and behavioral programs (basal ganglia), and
storage of information regarding behavioral sequences (prefrontal cortices) (Huey et al. 2008).
Imaging, surgical, and lesion studies suggest that the orbitofrontal and anterior cingulate cortices, in
particular, in addition to the basal ganglia and thalamus, are involved in the genesis of obsessive-
compulsive disorder (Baxter et al. 1987; Huey et al. 2008) and that focal lesions and neurological
disorders producing obsessive-compulsive behavior frequently involve the caudate nucleus or globus
pallidus (Cummings and Cunningham 1992).
A variety of personality alterations have been correlated with limbic system lesions. Orbitofrontal or
orbitofrontal-subcortical circuit lesions produce disinhibited, impulsive, and tactless behavior;
temporolimbic epilepsy has been associated with a rigid, viscous demeanor with hypergraphia,
circumstantiality, hyposexuality, and hyperreligiosity (Brandt et al. 1985); and bilateral amygdala
lesions produce behavioral placidity as part of the Klüver-Bucy syndrome (Lilly et al. 1983).
Disorders of sexual function also may reflect limbic system disturbances. Diminished libido has
been associated with hypothalamic injury and with the interictal state of patients with temporal lobe
seizure foci. Hypersexuality, including new-onset pedophilic hypersexual behavior, has been observed
in patients with orbitofrontal injury (Burns and Swerdlow 2003) or trauma to the septal region and also
as an ictal manifestation in the course of temporal lobe seizures (Gorman and Cummings 1992).
Paraphilic behavior, including pedophilia, transvestism, sadomasochistic behavior, and exhibitionism,
has been observed in patients with temporal lobe injury and epilepsy, basal ganglia disorders, and
brain tumors involving limbic (including orbitofrontal) structures (Burns and Swerdlow 2003;
Cummings 1985; Mendez et al. 2000; Miller et al. 1986). Drug addictions appear to be mediated in
part by alterations of reward circuitry, including anterior cingulate and orbitofrontal interactions with the
nucleus accumbens (Kalivas and Volkow 2005).
In contrast to the tendency for limbic system disorders to generate “productive” symptoms and
syndromes (i.e., excesses of normal function), apathy—a disorder of diminished motivation—is a
deficit syndrome associated with damage to or degeneration of key limbic-paralimbic-subcortical
network structures. The core features of the syndrome of apathy are reductions in goal-directed
cognition, emotion, and behavior (Marin 1991). This syndrome varies in severity from mild loss of
interest and reduced involvement in previous affairs (i.e., diminished motivation) to an akinetic mute
state with markedly reduced movement, speech, and intellectual content (Marin and Wilkosz 2005).
The syndrome most commonly results from lesions of the anterior cingulate cortex or related
structures of the cingulate-subcortical circuit, including nucleus accumbens, globus pallidus, and
thalamus (Cummings 1993; Lavretsky et al. 2007).
Neuropsychiatric Disorders Associated With Lateralized Limbic and Paralimbic

Disturbances
Studies of patients with unilateral lesions tend to favor a relative lateralization of emotional
disturbance after neurological injury. It has long been recognized that patients with left hemisphere
lesions are more likely to experience pathological crying, catastrophic reactions, depression, and
anxiety; patients with right hemisphere lesions evidence more indifference and tend to joke about,
minimize, or deny their disability (Gainotti 1972; Sackeim et al. 1982). Investigations of stroke patients
have found a higher prevalence of severe depression among patients with left frontal lobe lesions,
whereas patients with right-brain lesions exhibited more undue cheerfulness or, occasionally, frank
mania (Jorge et al. 2004; Oster et al. 2007; Robinson 2006).
Van Lancker (1991) observed that many functions of the right hemisphere subserve determination
of the personal relevance of environmental stimuli, and Weintraub and Mesulam (1983) reported that
children who sustained right-brain injury characteristically had interpersonal difficulties, shyness, and
impaired prosody and gesture. An impaired ability to comprehend personally relevant information or to
execute interpersonal cues appropriately may lead to difficulties in establishing interpersonal
relationships and to subsequent social isolation. In elderly individuals, right hemisphere dysfunction
may contribute to the disengagement and interpersonal abnormalities evident in many patients with
right-brain strokes and dementia syndromes. Table 1–5 summarizes the neuropsychiatric syndromes
associated with lateralized brain dysfunction.
TABLE 1–5. Neuropsychiatric disorders associated with lateralized brain dysfunction

Neuropsychiatric disorder Predominant laterality of associated lesion
Disorders of personal relevance
Unilateral hemispatial neglect Right
Prosopagnosia (inability to recognize familiar faces) Right
Environmental agnosia (inability to recognize familiar Right
places)
Phonagnosia (inability to recognize familiar voices) Right
Affective aprosodia (inability to inflect one’s language to Right
communicate emotion or to comprehend the emotion
communicated in the inflections of others)
Emotional disorders
Secondary depression Left
Catastrophic reaction Left
Pathological crying Left
Secondary mania Right
Secondary euphoria Right
Eutonia Right
Pathological laughing Right
Another avenue for investigating the hemisphericity of emotion is to search for evidence of lateral
brain dysfunction in idiopathic psychiatric disorders. Early neuroimaging studies, generally employing
measures of regional cerebral blood flow, sometimes identified lateralized dysfunction in association
with mood disorders (Baxter et al. 1985; Delvenne et al. 1990; Dolan et al. 1992; Drevets et al. 1992;
George et al. 1996; Sackeim et al. 1990). Consistent with the findings of Fusar-Poli et al. (2009),
Lindquist et al. (2016), and Kirby and Robinson (2017), however, current models of the neurology of
emotion and emotional regulation (in healthy individuals and those with idiopathic depression) favor a
ventral-dorsal dichotomy for emotion generation and regulation and do not rest on a lateralized view
of emotion (Arciniegas 2013a; Mayberg 2003; Mesulam 2000; Seminowicz et al. 2004). A meta-
analysis of the neuroimaging data used to construct these models reveals that the function of right
and left BA9 (an element of the dorsolateral prefrontal cortex and of these models of idiopathic
depression) is highly intercorrelated, and their replacement by one another in these models produces
similarly robust results (Seminowicz et al. 2004). Similarly, in deep brain stimulation of the subgenual
cingulate gyrus among patients with refractory depression, treatment effect does not differ as a
function of laterality of stimulation (Hamani et al. 2009). Collectively, clinically derived models of
emotion generation and regulation suggest that these are bilaterally mediated functions of limbic-
cortical and limbic–brain stem systems.
Marshall et al. (1997) reported excessive activity of the right anterior cingulate and right
orbitofrontal cortex (in a patient with conversion disorder involving unilateral limb paralysis) in a single-
case report (“hysterical paralysis”). Spence et al. (2000) observed hypofunction of the left dorsolateral
prefrontal cortex in three individuals with unilateral hysterical paralysis regardless of the side of their
conversion symptoms. A subsequent study involving a group of seven subjects failed to find a
lateralized association with conversion paralysis; instead, deficient activation of striatothalamocortical
circuits subserving sensory motor function and voluntary motor behavior contralateral to the side of
conversion paralysis was noted. Contrary to earlier views on the laterality of conversion symptoms,
and in accord with the more recent studies on the anatomy of emotion and emotional disturbances,
current evidence suggests that conversion disorder involving limb paralysis is associated with
aberrant function of and/or interactions between paralimbic-subcortical circuits and sensorimotor
systems in a manner that is not predictably lateralized (Voon et al. 2016).
In contrast to the lateralization of neuropsychiatric syndromes are the consequences of anomalous
(or neurodevelopmentally diminished) cerebral asymmetry. This aberrancy of interhemispheric
asymmetry has been observed in a number of psychiatric disorders, including schizophrenia (Crow
2008; Gregório et al. 2009; Kawasaki et al. 2008; Wilson et al. 2007), in which it is a well-replicated
finding; bipolar disorder (Reite et al. 2009; Wilson et al. 2007); autism (Chiron et al. 1995); dyslexia
(Leonard and Eckert 2008; Zadina et al. 2006); women with eating disorders (Eviatar et al. 2008); and
psychopathy (Mayer and Kosson 2000). These observations suggest the possibility that failure to
develop (or a subsequent neurodevelopmental loss of) normal cerebral asymmetry may play a role in
the development of neuropsychiatric disorders featuring prominent impairments of limbic system–
dependent neurobehavioral functions.
Reticular Formation (Median Zone)

The median zone contains the reticular formation, including the ascending reticular activating
system, the vasopressor and respiratory mechanisms, and the central components of the sympathetic
and parasympathetic nervous systems (Carpenter 1991). The reticular formation is a dense network
of neurons with short and long axons that form nuclei in the periventricular gray areas surrounding the
cerebral aqueduct in the midbrain, is adjacent to the floor of the fourth ventricle in the pons, and
extends into the medulla. The ascending reticular activating system projects to the intralaminar nuclei
of the thalamus, and these in turn project to the cerebral cortex. The intralaminar nuclei project
primarily to layer I of the cortex, the layer composed of parallel fibers whose stimulation results in local
cortical activation (Figure 1–8).
FIGURE 1–8. Cortical projections from the thalamus (blue).

The thalamic reticular nucleus is a unique structure that forms a thin shell around the anterior
aspects of the thalamus and governs cortical arousal. It receives projections from the cerebral cortex,
dorsal intralaminar nucleus, and dorsal specific sensory nuclei. It has no projections to the cerebral
cortex but projects back to the dorsal thalamic nuclei. The thalamic reticular nucleus is positioned to
serve as a gate, modifying and censoring information projected from thalamus to cortex, and its
principal effect is to inhibit cortical activity (Carpenter and Sutin 1983; Plum and Posner 1980).
Increased input from the brain stem reticular activating system reduces the tonic inhibition of the
reticular nucleus and activates the cortex by disinhibiting the cortical projections of other thalamic
nuclei (Plum and Posner 1980). The ascending reticular activating system is responsible for the
maintenance of consciousness, and disturbances of the system result in impaired arousal varying
from drowsiness to obtundation, stupor, and coma.
Nuclei of the reticular formation also are involved in control of heart rate, blood pressure, and
respiratory rhythms (Carpenter 1991). Dysfunction of these nuclei results in alterations in blood
pressure, cardiac arrhythmias, and respiratory irregularities. The hypothalamus is contained in the
median zone, and abnormalities of basic life functions (e.g., appetite, libido, sleep) may occur in
individuals who sustain hypothalamic injury. The hypothalamus influences endocrine function via its
connections with the pituitary gland, and endocrine abnormalities are produced by hypothalamic
lesions.
Cortical-Subcortical Connections
The entry pathway into cortical information processing systems is via thalamocortical afferents,
which receive sensory information from peripheral sensory afferent pathways and convey the data to
the cortex. The principal exit pathway from cortical information processing systems is via the
descending corticospinal tracts, particularly the pyramidal system. Thus, the flow of information is from
sensory pathways to the thalamus to the primary sensory cortex, then to unimodal association cortex,
and then to heteromodal association cortex. From there, the long association fibers connect the
posterior heteromodal cortex to the anterior (prefrontal) heteromodal association cortex that in turn,
connects to the subcortical nuclei. After being processed through frontal-subcortical circuits and
undergoing executive formatting, information flows to the primary motor cortex and then to bulbar and
spinal effector mechanisms. The thalamocortical afferents and frontal-subcortical efferents are
distributed systems that include portions of both paramedian (limbic) and supralimbic (neocortical)
zones. Activation of brain structures is not limited to the sequence described above; there is
simultaneous activation of many brain regions, as well as feedback mechanisms from ongoing activity.
Thalamocortical Interactions
The thalamus plays several crucial roles in human brain function. Specific thalamic nuclei receive
input from a relatively restricted number of sources and project to layers III and IV of the cortex. The
specific nuclei include sensory nuclei that process all incoming sensory information except olfaction
(ventral posterior, medial geniculate, and lateral geniculate); nuclei that participate in the motor
pathways (ventral anterior and ventral lateral); association nuclei that have major connections with
frontal (medial dorsal nuclei) or temporoparietal (lateral nuclei) association cortex; and nuclei that are
included in the limbic circuits (anterior and medial nuclei) (Carpenter and Sutin 1983; Mesulam 2000;
Nauta and Feirtag 1986; Shipp 2003). Table 1–6 represents a functional classification of thalamic
nuclei with their principal afferents and efferents.
TABLE 1–6. Function and anatomical relationships of the thalamic nuclei
Nuclei Input Output Function
Limbic nuclei
Anterior and Mammillary body Posterior cingulate, retrosplenial Learning and memory
laterodorsal area, entorhinal-hippocampal
complex
Motor nuclei
Ventroanterior Globus pallidus Frontal cortex Modulation of motor function
Ventrolateral Cerebellum Frontal cortex Modulation, coordination, and
learning of movement
Sensory nuclei
Ventral Sensory tracts from Parietal sensory cortex Somatosensory function
posterolateral body
Ventral Sensory tracts from Parietal sensory cortex Facial sensation
posteromedial face
Solitary tract Cortical gustatory area and Taste
anterior insula
Lateral geniculate Optic tracts Occipital cortex Vision
Medial geniculate Inferior colliculi Temporal cortex Hearing
Association nuclei
Medial dorsal Globus pallidus, Prefrontal cortex Executive function, memory,
amygdala, social cognition, emotion
temporal and
frontal cortex
Lateral nuclear Frontal, parietal, Frontal, parietal, temporal, and Coordinates intra- and cross-
group (pulvinar) temporal, and occipital cortex modal cortical information
occipital cortex processing
Nonspecific nuclei
Midline Hypothalamus Amygdala, cingulate, Visceral function
hypothalamus
Intralaminar Reticular formation, Striatum, cortex Activation
precentral and
premotor cortex
Reticular Thalamic nucleus Dorsal thalamic nuclei Samples, gates, and focuses
and cortex thalamocortical output
A number of distinctive behavioral disorders have been associated with dysfunction of the
associative and sensory thalamic nuclei. Disorders of the associative medial dorsal nuclei produce
amnesia and a “frontal lobe”–type syndrome (Cummings 1993; Stuss et al. 1988). Apathy also is
common after dorsal medial nuclear injury. Lesions of the specific thalamic sensory nuclei cause
deficits in primary sensation. Ventral posterior nuclear lesions disrupt all sensory abilities of the
contralateral limbs, trunk, and face. In some cases, spontaneous disabling pain of the affected side
occurs (Dejerine-Roussy syndrome) (Adams and Victor 1981). Lesions of the lateral geniculate bodies
produce a contralateral visual field defect. Mania has been observed in several patients with right-
sided thalamic lesions involving the paramedian thalamic nuclei (Bogousslavsky et al. 1988;
Cummings and Mendez 1984; Starkstein et al. 1988b).
Frontal-Subcortical Circuits
The frontal lobe is the origin of executive processes that guide action. The output from the frontal
lobe is through subcortical circuits that eventually reach motor pathways. Five circuits connecting the
frontal lobes and subcortical structures are currently recognized: a motor circuit originating in the
supplementary motor area, an oculomotor circuit with origins in the frontal eye fields, and three
circuits originating in prefrontal cortex (dorsolateral prefrontal cortex, lateral orbital cortex, and anterior
cingulate cortex) (Alexander and Crutcher 1990; Alexander et al. 1986, 1990; Arciniegas 2013b;
Lichter and Cummings 2001). The prototypic structure of all circuits is an origin in the frontal lobes,
projection to striatal structures (caudate, putamen, or nucleus accumbens), connections from striatum
to globus pallidus and substantia nigra, projections from these two structures to specific thalamic
nuclei, and a final link back to the frontal lobe (Figure 1–9).
FIGURE 1–9. Organization of the prefrontal-subcortical circuits.

The prefrontal cortical regions (dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate) project to specific striatal
regions (green) that in turn project to globus pallidus and substantia nigra (blue). These structures project to the thalamic
nuclei (in blue, projections from globus pallidus interna to thalamus and from globus pallidus externa to subthalamic
nucleus (in green, from subthalamic nucleus to globus pallidus interna) that subsequently connect to the frontal lobe
(green), completing the circuit.
The motor circuit originates from neurons in the supplementary motor area, premotor cortex, motor
cortex, and somatosensory cortex (Alexander and Crutcher 1990; Alexander et al. 1986; Arciniegas
2013b; Lichter and Cummings 2001). Throughout the circuit, the discrete somatotopic organization of
movement-related neurons is maintained. Distinct types of motor disturbances are associated with
lesions at different sites in the motor circuit. Motor initiation abnormalities (akinesia) are associated
with supplementary motor area lesions; parkinsonism and dystonia are observed with putaminal
dysfunction; and choreiform movements occur with caudate and subthalamic nucleus damage.
The oculomotor circuit originates in the frontal eye fields, as well as in the prefrontal and posterior
parietal cortex. Acute lesions of the cortical eye fields produce ipsilateral eye deviation, whereas more
chronic lesions produce ipsilateral gaze impersistence. Lesions in other areas of the circuit produce
supranuclear gaze palsies such as those seen in Parkinson’s disease, progressive supranuclear
palsy, and Huntington’s disease.
Three distinct frontal lobe neurobehavioral syndromes are recognized, and each corresponds to a
region of origin of one of the three prefrontal-subcortical circuits: the dorsolateral prefrontal circuit, the
lateral orbitofrontal circuit, and the anterior cingulate circuit (Figure 1–10) (Arciniegas 2013b;
Cummings 1993; Lichter and Cummings 2001). Dysfunction of any of the member structures of the
circuits results in similar circuit-specific behavioral complexes, and these frontal-subcortical circuits
compose major anatomic axes governing behavior. The dorsolateral prefrontal circuit originates in the
convexity of the frontal lobe and projects primarily to the dorsolateral head of the caudate nucleus.
This caudate region connects to globus pallidus and substantia nigra, and pallidal and nigral neurons
of the circuit project to the medial dorsal thalamic nuclei that in turn project back to the dorsolateral
prefrontal region. The dorsolateral prefrontal syndrome is characterized primarily by executive
function deficits. Abnormalities include developing poor strategies for solving visuospatial problems or
learning new information and reduced ability to shift sets. Such behavioral changes are observed in
patients with dorsolateral prefrontal lesions, as well as in those with caudate, globus pallidus, and
thalamic dysfunction.
FIGURE 1–10. Prefrontal cortical origins of the dorsolateral (blue), anterior cingulate (pink), and lateral
orbitofrontal (green) circuits.
The lateral orbitofrontal circuit contains primarily limbic system structures. It begins in the
inferolateral prefrontal cortex and projects to the ventromedial caudate nucleus (Figure 1–10). This
caudate region projects to the pallidum and substantia nigra. Pallidum and nigra connect to medial
portions of the ventral anterior and medial dorsal thalamic nuclei that project back to the orbitofrontal
cortex. Disorders involving cortical or subcortical structures of the orbitofrontal circuit feature marked
changes in personality, including a tendency to be more outspoken, more irritable, and more tactless
and a tendency to worry less and have an elevated mood.
The anterior cingulate circuit begins in the cortex of the anterior cingulate gyrus (BA24) and
projects to the ventral striatum (also known as the limbic striatum), which includes the nucleus
accumbens and the ventromedial portions of the caudate and putamen (Figure 1–10). The most
dramatic cases of anterior cingulate injury involve akinetic mutism. The patients are profoundly
apathetic: they typically have their eyes open, do not speak spontaneously, answer questions in
monosyllables if at all, and are profoundly indifferent. Apathy also has been associated with lesions of
the nucleus accumbens, globus pallidus, and thalamus, the principal subcortical members of the
anterior cingulate circuit. Table 1–7 summarizes the behaviorally relevant frontal-subcortical circuits,
including the anatomical structures involved, the behavioral disturbances observed with circuit
dysfunction, and the common diseases affecting each circuit.
TABLE 1–7. Behavioral abnormalities associated with frontal-subcortical circuit disorders

Obsessive-
Personality compulsive Neuropsychological
Disease change Mania Depression disorder impairment
Prefrontal cortical disorders
Dorsolateral prefrontal syndrome No No Yes Yes Yes
Lateral orbitofrontal syndrome Yes Yes Yes Yes No
Anterior cingulate syndrome Yes Yes Yes Yes Yes
Caudate disorders
Parkinson’s disease Yes No Yes No Yes
Progressive supranuclear palsy Yes No Yes Yes Yes
Huntington’s disease Yes Yes Yes Yes Yes
Sydenham’s chorea Yes No No Yes Yes
Wilson’s disease Yes Yes Yes No Yes
Neuroacanthocytosis Yes Yes Yes Yes Yes
Fahr’s disease UD Yes Yes No Yes
Infarction Yes No Yes Yes Yes
Globus pallidus disorders
Postencephalitic Parkinson’s Yes Yes Yes Yes Yes
disease
Manganese toxicity Yes UD UD Yes Yes
Carbon monoxide toxicity Yes No No Yes Yes
Infarction Yes UD UD No Yes
Thalamic disorders
Infarction Yes Yes No No Yes
Degeneration Yes UD UD UD Yes
Note. UD=undetermined.
Disturbances of the frontal-subcortical circuits are involved in many neuropsychiatric disorders. In

addition to personality alterations (e.g., apathy, disinhibition), mood disorders are associated with focal
brain lesions affecting these circuits. Depression occurs with lesions of the dorsolateral prefrontal
cortex and the head of the caudate nucleus, particularly when the left hemisphere is affected (Jorge et
al. 2004; Robinson 2006; Robinson et al. 1984; Starkstein et al. 1987, 1988a). Current models of the
neurocircuitry of depression (Mayberg 2003; Seminowicz et al. 2004) identify roles for all three of
these circuits in idiopathic major depression as well as secondary depressive disorders. Lesions
producing secondary mania also involve nuclei and connections of frontal-subcortical circuits. Mania
has been observed with lesions of the medial orbitofrontal cortex, diseases of the caudate nuclei such
as Huntington’s disease, and injury to the right thalamus (Bogousslavsky et al. 1988; Cummings and
Mendez 1984; Folstein 1989; Oster et al. 2007; Starkstein et al. 1988b).
Both acquired and idiopathic obsessive-compulsive disorders have been related to dysfunction of
frontal-subcortical circuits. Obsessive-compulsive behavior has been observed in patients with
caudate dysfunction in Huntington’s disease and after Sydenham’s chorea (Cummings and
Cunningham 1992; Swedo et al. 1989), as well as with globus pallidus lesions in postencephalitic
Parkinson’s disease, progressive supranuclear palsy, manganese-induced parkinsonism, and after
anoxic injury (Laplane et al. 1989; Mena et al. 1967; Schilder 1938). Idiopathic obsessive-compulsive
disorder involves disturbances across the three neurobehaviorally salient frontal-subcortical circuits,
with current models (Huey et al. 2008) identifying roles for the orbitofrontal cortex (in reward), the
anterior cingulate cortex (in error detection), the basal ganglia (in threshold setting for motor and
behavioral program activation), and the dorsolateral prefrontal cortex (in storing memories of
behavioral sequences).
Frontal-subcortical circuits are affected in patients who have diseases of the basal ganglia. The
high frequency of neuropsychological alterations, the increased prevalence of personality and mood
disturbances, the occurrence of obsessive-compulsive disorder, and the similarity between the
behaviors of patients with basal ganglia diseases and patients with frontal lobe injury are attributable
to dysfunction of multiple frontal-subcortical circuits in basal ganglia disorders.
Neurochemistry and Behavior

The anatomical organization of the brain is complemented by an equally complex neurochemical
organization. Many behavioral disorders reflect biochemical dysfunction, and the most effective
interventions available are neurochemical in nature. Neurobehavioral deficits stemming from focal
cortical lesions (e.g., aphasia, apraxia) have limited available remediable neurochemical treatments;
neuropsychiatric disorders associated with limbic system dysfunction are frequently modifiable
through neurochemical interventions.
There are two types of cerebral transmitters: 1) projection, or extrinsic, transmitters that originate in
subcortical and brain stem nuclei and project to brain targets and 2) local, or intrinsic, transmitters that
originate in neurons of the brain and project locally to adjacent or nearby cells. Projection transmitters
or their synthetic enzymes must be transported within neurons for long distances from subcortical
nuclei to distant regions and therefore are vulnerable to disruption by stroke, tumors, and other
processes. Transmitters are highly conserved from an evolutionary point of view, and many function
locally in some neuronal systems and function as projection transmitters in others. The classic
neurotransmitters have served neuronal communication for 600 million years of evolution (Rapoport
1990). Table 1–8 summarizes the origins and destinations of the extrinsic transmitters.
TABLE 1–8. Origins and destinations of the major extrinsic transmitter projections
Neurotransmitter Origin Destination
Acetylcholine
Basal forebrain system Nucleus basalis and nucleus of Neocortex, hippocampus, hypothalamus,
diagonal band of Broca and amygdala
Reticular system Reticular formation Thalamus
Dopamine
Nigrostriatal system Substantia nigra Putamen and caudate nucleus
Mesolimbic system Ventral tegmental area Nucleus accumbens, septal nucleus, and
amygdala
Mesocortical system Ventral tegmental area Medial temporal and frontal lobes and
anterior cingulate cortex
Histamine Posterior hypothalamus Entire brain
GABA Zona incerta Neocortex, basal ganglia, and brain stem
Caudate and putamen Globus pallidus and substantia nigra
Globus pallidus and substantia nigra Thalamus
Glutamate Neocortex Caudate, putamen, thalamus, and nucleus
accumbens
Subthalamic nucleus Globus pallidus
Thalamus Neocortex
Hippocampus and subiculum Septal region
Entorhinal cortex Hippocampus
Norepinephrine
Dorsal pathway Locus coeruleus Thalamus, amygdala, basal forebrain,
hippocampus, and neocortex
Ventral pathway Locus coeruleus Hypothalamus and midbrain reticular
formation
Serotonin Raphe nuclei Entire brain
Note. GABA=γ-aminobutyric acid.
The effects of neurotransmitters are mediated by receptors to which the transmitter binds after it
has been released into the synaptic cleft. Receptors may be located on the presynaptic or
postsynaptic terminal. Presynaptic receptors (autoreceptors) regulate neurotransmitter synthesis or
release. Postsynaptic receptors mediate the effects of the neurotransmitter on the postsynaptic cell.
Heteroreceptors (receptors for neurotransmitters other than those produced by the neuron) also
regulate synaptic activity. Binding of a neurotransmitter to a receptor results either in opening of an ion
channel (ionotropic receptors) or initiation of second messenger cascades via guanosine
triphosphate–binding (G) proteins (metabotropic receptors). The neurotransmitter is removed from the
synapse (either before or after binding to a receptor) either by enzymatic degradation or by active
reuptake into the presynaptic terminal by a high-affinity transporter protein. Behavioral effects can
rarely be assigned to alterations in a single transmitter, but some aberrant behaviors are associated
with changes that affect predominantly one type of transmitter. Table 1–9 presents the principal
transmitter-behavior relationships currently identified.
TABLE 1–9. Behavioral alterations associated with transmitter disturbances
Neurotransmitter Reduced function Increased function
Acetylcholine Memory impairment, apathy, delirium, Depression, aggression
delusions
Dopamine
Motor function Parkinsonism Chorea, tics
Behavior Cognitive impairment (especially inattention), Hallucinations, delusions, elation, obsessive-
apathy, depression compulsive behavior, paraphilias
GABA Seizures, anxiety Amnesia, incoordination, sedation
Glutamate Cognitive impairment (especially amnesia), Seizures, excitotoxicity
psychosis, apathy
Norepinephrine Cognitive impairment (especially inattention), Anxiety
depression, dementia
Serotonin Depression, anxiety, suicide, aggression Confusion, hypomania, agitation, myoclonus
Note. GABA=γ-aminobutyric acid.
There are several discrete cholinergic nuclei that project from subcortical sites to the brain. In the
brain stem, the laterodorsal tegmental and pedunculopontine nuclei reside in the reticular formation
and project via the dorsal tegmental pathway to the thalamus. This pathway is the essential
component of the ascending reticular activating system (Arciniegas 2011; Nieuwenhuys 1985;
Salmond et al. 2005). The cholinergic cell groups of the basal forebrain are the principal sources of
cerebral acetylcholine (Perry et al. 1999; Salmond et al. 2005; Selden et al. 1998). Cholinergic
projections in the septal nucleus and the vertical limb of the diagonal band of Broca project via the
fornix to the hippocampus. The cells of the horizontal limb of the diagonal band of Broca supply the
olfactory bulb. The neurons composing the nucleus basalis of Meynert project in several discrete
bundles to the amygdala, to the cingulate and orbitofrontal cortices, to the insula and opercular
cortices, and also to the rest of the neocortex (Figure 1–11). The afferents to nucleus basalis are
primarily from cortical and subcortical limbic system structures establishing the nucleus basalis as a
relay between the limbic system afferents and efferents to the neocortex (Mesulam and Mufson 1984).
FIGURE 1–11. Cholinergic projections from the nucleus basalis (red).
Cholinergic function is mediated by either nicotinic (ionotropic) or muscarinic (metabotropic)

receptors. The muscarinic receptors are classified pharmacologically as M1 (located on the
postsynaptic neuron) or M2 (located on the presynaptic neuron) and have different distributions
throughout the brain. Cholinergic systems mediate a wide range of behaviors. Disruption of central
cholinergic function (e.g., through the administration of cholinergic receptor–blocking agents such as
scopolamine) produces amnesia (Bartus et al. 1982), and intoxication with anticholinergic compounds
produces delirium and delusions. Alzheimer’s disease is one major disorder associated with
cholinergic deficiency. This disease produces atrophy of the nucleus basalis with consequent
reduction in the synthesis of choline acetyltransferase, the enzyme that synthesizes acetylcholine;
loss of synthetic activity leads to interruption of cortical cholinergic function (Katzman and Thal 1989).
Increasing evidence indicates that some of the neuropsychiatric disturbances of Alzheimer’s disease
—hallucinations, apathy, disinhibition, purposeless behavior—are produced by the cholinergic deficit
(Cummings and Kaufer 1996). Cholinergic deficits are also characteristic of dementia with Lewy
bodies and Parkinson’s disease dementia. Cholinergic hyperactivity has been posited to play a role in
the genesis of depression (Dilsaver and Coffman 1989), and in some species, cholinergic stimulation
of limbic system structures produces aggression (Valzelli 1981).
There are three main dopaminergic projections from the brain stem to the cerebral hemispheres: 1)
a nigrostriatal projection arising from the compact portion of the substantia nigra and projecting to the
putamen and caudate, 2) a mesolimbic projection originating in the ventral tegmental area and
projecting to limbic system structures, and 3) a mesocortical system beginning in the ventral
tegmental area and projecting to frontal and temporal areas (Nieuwenhuys 1985) (Figure 1–12).
Targets of the mesolimbic dopaminergic projection include the nucleus accumbens, septal nucleus,
and amygdala. The mesocortical projections terminate primarily in the medial frontal lobe, medial
temporal lobe, and the anterior cingulate region. Less robust projections are distributed to the
neocortex.
FIGURE 1–12. Nigrostriatal and mesocortical dopaminergic projections arising from the substantia nigra and
ventral tegmental area, respectively (green).
Dopaminergic function is mediated by metabotropic receptors that can be classified
pharmacologically as D1-like (stimulate cyclic adenosine monophosphate [cAMP]) or D2-like (inhibit
cAMP). These receptors have different distributions throughout the brain. The D2 receptors are
blocked by neuroleptics, and it is possible that subtypes of the D2 receptor differentially mediate the
motor and mental effects of dopaminergic drugs.
Dopamine plays a key role in motoric functions and behavior. Dopamine deficiency or blockade
leads to parkinsonism; dopamine excess produces chorea, dyskinesia, or tics. Behaviorally, dopamine
deficiency causes at least mild cognitive impairment and may contribute to the depression that
commonly accompanies Parkinson’s disease and other parkinsonian syndromes. Dopamine excess
leads to psychosis, elation or hypomania, and confusion. Dopamine hyperactivity may contribute to
the pathophysiology of schizophrenia, obsessive-compulsive behavior, anxiety, and some paraphilic
behaviors (Cummings 1985, 1991).
The locus coeruleus and adjacent nuclei constitute the origin of the noradrenergic projection
system. A dorsal noradrenergic bundle courses in the dorsal brain stem to the septum, thalamus,
amygdala, basal forebrain, hippocampus, and neocortex (Nieuwenhuys 1985) (Figure 1–13). A ventral
noradrenergic bundle projects to the hypothalamus and midbrain reticular formation. Adrenergic
function is mediated by metabotropic receptors that can be classified pharmacologically as α (inhibit
cAMP) or β (stimulate cAMP) receptors. α-Adrenergic receptors can be further subtyped as α1 or α2;
the former are located postsynaptically and the latter presynaptically and postsynaptically. These
receptors have different distributions throughout the brain. Effective treatment for depression is
associated with decreased numbers (downregulation) of β-adrenergic receptors. Noradrenergic
hypofunction has been linked to depression, dementia, and diminished alertness and concentration
(Agid et al. 1987). Increased noradrenergic activity has been linked to anxiety (Lechin et al. 1989).
FIGURE 1–13. Noradrenergic projections from the locus coeruleus (pink).
Serotonergic neurons are located almost exclusively in the median and paramedian raphe nuclei of
the medulla, pons, and midbrain (Figure 1–14). The projection of these serotonergic neurons is a
complex, highly branched, fiber system that embraces virtually the entire central nervous system
(Nieuwenhuys 1985). Serotonergic function is mediated by multiple metabotropic receptors (e.g., 5-
HT1, 5-HT2, 5-HT4) and to a lesser extent by ionotropic receptors (i.e., 5-HT3). These receptors have
different distributions throughout the brain. Serotonin deficiency has been hypothesized to play a
major role in suicide, depression, anxiety, and aggression (Agid et al. 1987), and excesses of cerebral
serotonin may produce confusion, hypomania, agitation, and myoclonus (Isbister and Buckley 2005).
5-HT2A receptors are implicated in the pathophysiology of psychosis.
FIGURE 1–14. Serotonergic projections (blue).
γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter present in both projection systems

and local neuronal circuits. The principal GABA projection system begins in the zona incerta and
projects bilaterally to the entire neocortex, basal ganglia, and brain stem (Lin et al. 1990). In
subcortical regions, one projection system originates in the caudate and putamen and projects to the
globus pallidus and substantia nigra, and another begins in the globus pallidus and substantia nigra
with projections to the thalamus (Alexander and Crutcher 1990; Nieuwenhuys 1985). Local circuit
neurons using GABA are found in the raphe nuclei, reticular nucleus of the thalamus, and basal
ganglia. Local circuit neurons of the cerebral cortex also use GABA as their principal neurotransmitter
(Rapoport 1990). GABA function is mediated by ionotropic (GABAA) and metabotropic (GABAB)
receptors, the former being of special interest to neuropsychiatry because they contain the binding
sites for alcohol, anticonvulsants, and benzodiazepines. These receptors have different distributions
throughout the brain. GABA concentrations are decreased in the basal ganglia of patients with
Huntington’s disease, and the GABA deficiency may contribute to dementia, mood disorder,
obsessive-compulsive disorder, and psychosis occurring with increased frequency in this condition
(Morris 1991).
Glutamate is an excitatory neurotransmitter that is used in the massive projection from the
neocortex to the ipsilateral caudate, putamen, and nucleus accumbens. Glutamate is the principal
neurotransmitter of projections from cortex to thalamus, from thalamus to cortex, and from one region
of cortex to another. Glutamatergic neurons also project from subthalamic nucleus to globus pallidus.
Glutamate functions in several hippocampus-related projections, including the perforant pathway
projecting from entorhinal cortex to hippocampus and the pathways originating in the hippocampus
and adjacent subiculum and projecting to the septal region (Alexander and Crutcher 1990;
Nieuwenhuys 1985). Glutamatergic function is mediated by ionotropic and metabotropic receptors,
with subtypes of the former (e.g., N-methyl-D-aspartate (NMDA) receptor) having been implicated in
learning, excitotoxicity, and the psychotomimetic effects of phencyclidine (PCP). These receptors
have different distributions throughout the brain. The behavioral consequences of alterations in
glutamate function are substantial. Antagonism of NMDA receptors induced by PCP or ketamine is a
useful pharmacological model for schizophrenia in that it results in the positive (e.g., hallucination,
delusion, behavioral dyscontrol) symptoms, negative symptoms (e.g., alogia, anhedonia, inanition),
and the cognitive impairments of this condition (Javitt 2007). Noncompetitive NMDA antagonists such
as memantine improve cognition in Alzheimer’s disease, implicating a role for this transmitter system
in cognition. Glutamatergic excesses are implicated in the ictogenesis (development of seizures) in
general and particularly in mesial temporal lobe epilepsy (Eid et al. 2008).
Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers
studying the rodent central nervous system (de Lecea et al. 1998; Sakurai et al. 1998). One group
(Sakurai et al. 1998) named it orexin, from orexis, meaning “appetite” in Greek; the other group (de
Lecea et al. 1998) named it hypocretin, because it is produced in the hypothalamus and bears a weak
resemblance to secretin. Although often used interchangeably, hypocretin is now used to refer to
protein precursor products of the gene HCRT on chromosome 17 (i.e., hypocretin neuropeptide
precursor protein yields hypocretin-1 and -2), and orexin refers to the mature excitatory neuropeptides
(orexin-A and -B). There are approximately 70,000 orexin-producing neurons in the lateral and
posterior hypothalamus. These neurons project to the brain stem, diencephalic, and basal forebrain
nuclei involved in the modulation of wakefulness. Through this modulation, orexin facilitates
integration of metabolic, circadian, and sleep debt influences in a manner that directs wakefulness
and/or sleep.
The tuberomammillary nucleus (TMN), which is located in the hypothalamus, is the only site of
neuronal histamine synthesis in the adult mammalian brain and is the source of histaminergic
projections to all major parts of the brain (Nieuwenhuys 1985). Histaminergic neurons of the TMN
have the most wake-selective firing pattern of all known neurons. They become active during the
“wake” cycle, firing at approximately 2 Hz; during slow-wave sleep, this firing rate decreases to 0.5 Hz;
these neurons stop firing entirely during REM sleep. Histamine release from TMN neurons (e.g., by
orexin) promotes wakefulness by activating (at least) basal forebrain cholinergic neurons, raphe
serotonergic neurons, and thalamic neurons through H1 receptors. H1 receptor antagonists that cross
the blood-brain barrier are therefore sedating (diminish arousal). H3 receptor antagonists (acting as
inverse agonists) increase wakefulness by promoting the release of histamine and other
neurotransmitters.
Glycine is an inhibitory transmitter that may function in local circuit neurons in the substantia nigra,
caudate, and putamen. Substance P is present in the projection from caudate and putamen to the
substantia nigra, and enkephalin-containing neurons project from caudate and putamen to the globus
pallidus (Alexander and Crutcher 1990; Nieuwenhuys 1985). Vasoactive intestinal peptide neurons
are intrinsic to the cortex and participate in local neuronal circuits (Nieuwenhuys 1985).
Conclusion
The brain consists of a median zone mediating arousal and basic life-sustaining functions, such as
respiration, digestion, circulation, and neuroendocrine function; a paramedian-limbic zone mediating
extrapyramidal function and many aspects of emotional experience; and a supralimbic-neocortical
zone mediating instrumental cognitive functions such as language and praxis (Table 1–10). Injury of
the supralimbic-neocortical zone is associated with neurobehavioral deficit syndromes, such as
aphasia and apraxia; dysfunction of the paramedian-limbic zone correlates with neuropsychiatric
disorders, including mood disorders, psychoses, anxiety, and obsessive-compulsive disorder. Within
each zone, behavioral disorders are associated with dysfunction of one or multiple neurotransmitters.
This model of behavioral neuroanatomy provides a comprehensive framework for understanding
brain-behavior relationships and the disturbances of those relationships that are observed in clinical
practice.
TABLE 1–10. Summary of the anatomy, functions, and syndromes of the median, paramedian-limbic, and
supralimbic-neocortical zones of the brain
Neuronal Behavioral
Zone Myelination connectivity/anatomyOntogeny Function syndromes
Median Poor Feltwork; reticular Functional at Arousal Disturbances of
birth arousal,
neuroendocrine
control,
respiration,
circulation
Paramedian- Intermediate Series; limbic Functional Emotion; Neuropsychiatric
limbic system and within first extrapyramidal disorders;
basal ganglia few function movement
months disorders
Supralimbic- Complete Parallel; neocortex Functional in Instrumental Neurobehavioral
neocortical adulthood cognitive disorders
functions (e.g.,
language,
praxis)
References
Abraham J: Neurosciences: a neurosurgeon’s perspective. Neurol India 47(1):3–7, 1999 10339700
Adams RD, Victor M: Principles of Neurology, 2nd Edition. New York, McGraw-Hill, 1981
Agid Y, Ruberg M, Dubois B, et al: Anatomoclinical and biochemical concepts of subcortical dementia, in Cognitive
Neurochemistry. Edited by Stahl SM, Iversen SD, Goodman EC. New York, Oxford University Press, 1987, pp 248–271
Alexander GE, Crutcher MD: Functional architecture of basal ganglia circuits: neural substrates of parallel processing.
Trends Neurosci 13(7):266–271, 1990 1695401
Alexander GE, DeLong MR, Strick PL: Parallel organization of functionally segregated circuits linking basal ganglia and
cortex. Annu Rev Neurosci 9:357–381, 1986 3085570
Alexander GE, Crutcher MD, DeLong MR: Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor,
“prefrontal” and “limbic” functions. Prog Brain Res 85:119–146, 1990 2094891
Amaducci L, Sorbi S, Albanese A, Gainotti G: Choline acetyltransferase (ChAT) activity differs in right and left human
temporal lobes. Neurology 31(7):799–805, 1981 7195501
Arciniegas DB: Cholinergic dysfunction and cognitive impairment after traumatic brain injury, Part 1: the structure and
function of cerebral cholinergic systems. J Head Trauma Rehabil 26(1):98–101, 2011 21209567
Arciniegas DB: Emotion, in Behavioral Neurology & Neuropsychiatry. Edited by Arciniegas DB, Anderson CA, Filley CM.
Cambridge, UK, Cambridge University Press, 2013a, pp 266–298
Arciniegas DB: Executive function, in Behavioral Neurology & Neuropsychiatry. Edited by Arciniegas DB, Anderson CA,
Filley CM. Cambridge, UK, Cambridge University Press, 2013b, pp 225–249
Arciniegas DB: Psychosis. Continuum: Lifelong Learning in Neurology Behavioral Neurology and Neuropsychiatry
21(3):715–736, 2015 26039850
Arciniegas DB, Kaufer DI; Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric
Association; Society for Behavioral and Cognitive Neurology: Core curriculum for training in behavioral neurology and
neuropsychiatry. J Neuropsychiatry Clin Neurosci 18(1):6–13, 2006 16525065
Arciniegas DB, Anderson CA, Filley CM (eds): Behavioral Neurology & Neuropsychiatry. Cambridge, UK, Cambridge
University Press, 2013
Bartus RT, Dean RL 3rd, Beer B, Lippa AS: The cholinergic hypothesis of geriatric memory dysfunction. Science
217(4558):408–414, 1982 7046051
Baxter LR Jr, Phelps ME, Mazziotta JC, et al: Cerebral metabolic rates for glucose in mood disorders. Studies with
positron emission tomography and fluorodeoxyglucose F 18. Arch Gen Psychiatry 42(5):441–447, 1985 3872649
Baxter LR Jr, Phelps ME, Mazziotta JC, et al: Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A
comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry 44(3):211–218, 1987
3493749
Benarroch EE: Central Autonomic Network: Functional Organization and Clinical Correlations. Armonk, NY, Futura, 1997
Benson DF, Cummings JL: Angular gyrus syndrome simulating Alzheimer’s disease. Arch Neurol 39(10):616–620, 1982
7125973
Bogousslavsky J, Ferrazzini M, Regli F, et al: Manic delirium and frontal-like syndrome with paramedian infarction of the
right thalamus. J Neurol Neurosurg Psychiatry 51(1):116–119, 1988 3258356
Brandt J, Seidman LJ, Kohl D: Personality characteristics of epileptic patients: a controlled study of generalized and
temporal lobe cases. J Clin Exp Neuropsychol 7(1):25–38, 1985 3920238
Burns JM, Swerdlow RH: Right orbitofrontal tumor with pedophilia symptom and constructional apraxia sign. Arch Neurol
60(3):437–440, 2003 12633158
Carota A, Staub F, Bogousslavsky J: Emotions, behaviours and mood changes in stroke. Curr Opin Neurol 15(1):57–69,
2002 11796952
Carpenter MB: Core Text of Neuroanatomy, 4th Edition. Baltimore, MD, Williams & Wilkins, 1991
Carpenter MB, Sutin J: Human Neuroanatomy, 8th Edition. Baltimore, MD, Williams & Wilkins, 1983
Chiron C, Leboyer M, Leon F, et al: SPECT of the brain in childhood autism: evidence for a lack of normal hemispheric
asymmetry. Dev Med Child Neurol 37(10):849–860, 1995 7493719
Crow TJ: The ‘big bang’ theory of the origin of psychosis and the faculty of language. Schizophr Res 102:31–52, 2008
18502103
Cummings JL: Clinical Neuropsychiatry. New York, Grune & Stratton, 1985
Cummings JL: Behavioral complications of drug treatment of Parkinson’s disease. J Am Geriatr Soc 39(7):708–716, 1991
2061539
Cummings JL: Depression and Parkinson’s disease: a review. Am J Psychiatry 149(4):443–454, 1992 1372794
Cummings JL: Frontal-subcortical circuits and human behavior. Arch Neurol 50(8):873–880, 1993 8352676
Cummings JL, Cunningham K: Obsessive-compulsive disorder in Huntington’s disease. Biol Psychiatry 31(3):263–270,
1992 1532132
Cummings JL, Kaufer D: Neuropsychiatric aspects of Alzheimer’s disease: the cholinergic hypothesis revisited. Neurology
47(4):876–883, 1996 8857712
Cummings JL, Mendez MF: Secondary mania with focal cerebrovascular lesions. Am J Psychiatry 141(9):1084–1087,
1984 6465386
Damasio AR, Grabowski TJ, Bechara A, et al: Subcortical and cortical brain activity during the feeling of self-generated
emotions. Nat Neurosci 3(10):1049–1056, 2000 11017179
de Lecea L, Kilduff TS, Peyron C, et al: The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc
Natl Acad Sci USA 95(1):322–327, 1998 9419374
Delvenne V, Delecluse F, Hubain PP, et al: Regional cerebral blood flow in patients with affective disorders. Br J Psychiatry
157:359–365, 1990 2245265
Dilsaver SC, Coffman JA: Cholinergic hypothesis of depression: a reappraisal. J Clin Psychopharmacol 9(3):173–179,
1989 2661605
Doane BK: Clinical psychiatry and the physiodynamics of the limbic system, in The Limbic System: Functional
Organization and Clinical Disorders. Edited by Doane BK, Livingston KE. New York, Raven, 1986, pp 285–315
Dolan RJ, Bench CJ, Brown RG, et al: Regional cerebral blood flow abnormalities in depressed patients with cognitive
impairment. J Neurol Neurosurg Psychiatry 55(9):768–773, 1992 1402966
Drevets WC, Videen TO, Price JL, et al: A functional anatomical study of unipolar depression. J Neurosci 12(9):3628–
3641, 1992 1527602
Duncombe J, Kitamura A, Hase Y, et al: Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive
impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive
impairment and dementia. Clin Sci (Lond) 131(19):2451–2468, 2017 28963120
Eid T, Williamson A, Lee TS, et al: Glutamate and astrocytes: key players in human mesial temporal lobe epilepsy?
Epilepsia 49 (suppl 2):42–52, 2008 18226171
Eidelberg D, Galaburda AM: Symmetry and asymmetry in the human posterior thalamus, I: cytoarchitectonic analysis in
normal persons in the posterior thalamus. Arch Neurol 39(6):325–332, 1982 7046701
Eviatar Z, Latzer Y, Vicksman P: Anomalous lateral dominance patterns in women with eating disorders: clues to
neurobiological bases. Int J Neurosci 118(10):1425–1442, 2008 18788027
Falzi G, Perrone P, Vignolo LA: Right-left asymmetry in anterior speech region. Arch Neurol 39(4):239–240, 1982 7073534
Filley CM: The Behavioral Neurology of White Matter, 2nd Edition. New York, Oxford University Press, 2012
Folstein SE: Huntington’s Disease: A Disorder of Families. Baltimore, MD, Johns Hopkins University Press, 1989
Fusar-Poli P, Placentino A, Carletti F, et al: Laterality effect on emotional faces processing: ALE meta-analysis of evidence.
Neurosci Lett 452(3):262–267, 2009 19348735
Gainotti G: Emotional behavior and hemispheric side of the lesion. Cortex 8(1):41–55, 1972 5031258
Galaburda AM, LeMay M, Kemper TL, Geschwind N: Right-left asymmetrics in the brain. Science 199(4331):852–856,
1978 341314
Gardini S, Cloninger CR, Venneri A: Individual differences in personality traits reflect structural variance in specific brain
regions. Brain Res Bull 79(5):265–270, 2009 19480986
George MS, Ketter TA, Kimbrell TA, et al: What functional imaging has revealed about the brain basis of mood and
emotion. Advances in Biological Psychiatry 2:63–113, 1996
Geschwind N: Disconnection syndromes in animals and man. Brain 88:237–294, 585–644, 1965
Glick SD, Ross DA, Hough LB: Lateral asymmetry of neurotransmitters in human brain. Brain Res 234(1):53–63, 1982
6120746
Gorman DG, Cummings JL: Hypersexuality following septal injury. Arch Neurol 49(3):308–310, 1992 1536635
Gregório SP, Sallet PC, Do KA, et al: Polymorphisms in genes involved in neurodevelopment may be associated with
altered brain morphology in schizophrenia: preliminary evidence. Psychiatry Res 165(1-2):1–9, 2009 19054571
Hamani C, Mayberg H, Snyder B, et al: Deep brain stimulation of the subcallosal cingulate gyrus for depression:
anatomical location of active contacts in clinical responders and a suggested guideline for targeting. J Neurosurg
111(6):1209–1215, 2009 19480538
Hart J Jr: The Neurobiology of Cognition and Behavior. Oxford, UK, Oxford University Press, 2016
Hinkley LB, Marco EJ, Brown EG, et al: The contribution of the corpus callosum to language lateralization. J Neurosci
36(16):4522–4533, 2016 27098695
Huey ED, Zahn R, Krueger F, et al: A psychological and neuroanatomical model of obsessive-compulsive disorder. J
Neuropsychiatry Clin Neurosci 20(4):390–408, 2008 19196924
Isaacson RL: The Limbic System. New York, Plenum, 1974
Isbister GK, Buckley NA: The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and
treatment. Clin Neuropharmacol 28(5):205–214, 2005 16239759
Javitt DC: Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate
interactions. Int Rev Neurobiol 78:69–108, 2007 17349858
Jorge RE, Robinson RG, Moser D, et al: Major depression following traumatic brain injury. Arch Gen Psychiatry 61(1):42–
50, 2004 14706943
Kalivas PW, Volkow ND: The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry
162(8):1403–1413, 2005 16055761
Katzman R, Thal L: Neurochemistry of Alzheimer’s disease, in Basic Neurochemistry, 4th Edition. Edited by Siegel GJ,
Agranoff BW, Albers RW, et al. New York, Raven, 1989, pp 827–838
Kawasaki Y, Suzuki M, Takahashi T, et al: Anomalous cerebral asymmetry in patients with schizophrenia demonstrated by
voxel-based morphometry. Biol Psychiatry 63(8):793–800, 2008 17936725
Kimura D, Durnford M: Normal studies on the function of the right hemisphere in vision, in Hemisphere Function in the
Human Brain. Edited by Dimond SJ, Beaumont JG. London, Elek Science, 1974, pp 25–47
Kirby LAJ, Robinson JL: Affective mapping: An activation likelihood estimation (ALE) meta-analysis. Brain Cogn 118:137–
148, 2017 26074298
Kirshner HS: Behavioral Neurology. A Practical Approach. New York, Churchill Livingstone, 1986
Kirshner HS: Vascular dementia: a review of recent evidence for prevention and treatment. Curr Neurol Neurosci Rep
9(6):437–442, 2009 19818230
Kooistra CA, Heilman KM: Motor dominance and lateral asymmetry of the globus pallidus. Neurology 38(3):388–390, 1988
3347342
Laplane D, Levasseur M, Pillon B, et al: Obsessive-compulsive and other behavioural changes with bilateral basal ganglia
lesions. A neuropsychological, magnetic resonance imaging and positron tomography study. Brain 112(Pt 3):699–725,
1989 2786440
Lavretsky H, Ballmaier M, Pham D, et al: Neuroanatomical characteristics of geriatric apathy and depression: a magnetic
resonance imaging study. Am J Geriatr Psychiatry 15(5):386–394, 2007 17463189
Lechin F, van der Dijs B, Amat J, et al: Central neuronal pathways involved in anxiety behavior: experimental findings, in
Neurochemistry and Clinical Disorders: Circuitry of Some Psychiatric and Psychosomatic Syndromes. Edited by Lechin
F, van der Dijs B. Boca Raton, FL, CRC Press, 1989, pp 49–64
Leiguarda RC, Marsden CD: Limb apraxias: higher-order disorders of sensorimotor integration. Brain 123(Pt 5):860–879,
2000 10775533
LeMay M: Morphological cerebral asymmetries of modern man, fossil man, and nonhuman primate. Ann N Y Acad Sci
280:349–366, 1976 827951
Leonard CM, Eckert MA: Asymmetry and dyslexia. Dev Neuropsychol 33(6):663–681, 2008 19005910
Levy J: The mammalian brain and the adaptive advantage of cerebral asymmetry. Ann N Y Acad Sci 299:264–272, 1977
280207
Lichter DC, Cummings JL: Introduction and overview, in Frontal-Subcortical Circuits in Psychiatric and Neurological
Disorders. Edited by Lichter DG, Cummings JL. New York, Guilford, 2001, pp 1–43
Lilly R, Cummings JL, Benson DF, Frankel M: The human Klüver-Bucy syndrome. Neurology 33(9):1141–1145, 1983
6684248
Lin C-S, Nicolelis MAL, Schneider JS, Chapin JK: A major direct GABAergic pathway from zona incerta to neocortex.
Science 248(4962):1553–1556, 1990 2360049
Lindquist KA, Satpute AB, Wager TD, et al: The brain basis of positive and negative affect: evidence from a meta-analysis
of the human neuroimaging literature. Cereb Cortex 26(5):1910–1922, 2016 25631056
Lyttelton OC, Karama S, Ad-Dab’bagh Y, et al: Positional and surface area asymmetry of the human cerebral cortex.
Neuroimage 46(4):895–903, 2009 19345735
MacLean PD: The Triune Brain in Evolution. New York, Plenum, 1990
Marin RS: Apathy: a neuropsychiatric syndrome. J Neuropsychiatry Clin Neurosci 3(3):243–254, 1991 1821241
Marin RS, Wilkosz PA: Disorders of diminished motivation. J Head Trauma Rehabil 20(4):377–388, 2005 16030444
Marshall JC, Halligan PW, Fink GR, et al: The functional anatomy of a hysterical paralysis. Cognition 64(1):B1–B8, 1997
9342933
Mayberg HS: Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based
algorithms for diagnosis and optimised treatment. Br Med Bull 65:193–207, 2003 12697626
Mayer AR, Kosson DS: Handedness and psychopathy. Neuropsychiatry Neuropsychol Behav Neurol 13(4):233–238, 2000
11186158
Mena I, Marin O, Fuenzalida S, Cotzias GC: Chronic manganese poisoning. Clinical picture and manganese turnover.
Neurology 17(2):128–136, 1967 6066873
Mendez MF, Chow T, Ringman J, et al: Pedophilia and temporal lobe disturbances. J Neuropsychiatry Clin Neurosci
12(1):71–76, 2000 10678516
Mesulam M-M: Behavioral neuroanatomy: large-scale networks, association cortex, frontal syndromes, the limbic system,
and hemispheric specializations, in Principles of Cognitive and Behavioral Neurology. Edited by Mesulam M-M. Oxford,
UK, Oxford University Press, 2000, pp 1–120
Mesulam M-M, Mufson EJ: Neural inputs into the nucleus basalis of the substantia innominata (Ch4) in the rhesus
monkey. Brain 107(Pt 1):253–274, 1984 6538106
Miller BL, Cummings JL, McIntyre H, et al: Hypersexuality or altered sexual preference following brain injury. J Neurol
Neurosurg Psychiatry 49(8):867–873, 1986 3746322
Morris M: Psychiatric aspects of Huntington’s disease, in Huntington’s Disease. Edited by Harper PS. Philadelphia, PA,
WB Saunders, 1991, pp 81–126
Nauta WJH: Circuitous connections linking cerebral cortex, limbic system, and corpus striatum, in The Limbic System:
Functional Organization and Clinical Disorders. Edited by Doane BK, Livingston KE. New York, Raven, 1986, pp 43–54
Nauta WJH, Feirtag M: Fundamental Neuroanatomy. New York, WH Freeman, 1986
Nieuwenhuys R: Chemoarchitecture of the Brain. New York, Springer-Verlag, 1985
Oke A, Keller R, Mefford I, Adams RN: Lateralization of norepinephrine in human thalamus. Science 200(4348):1411–
1413, 1978 663623
Oster TJ, Anderson CA, Filley CM, et al: Quetiapine for mania due to traumatic brain injury. CNS Spectr 12(10):764–769,
2007 17934381
Papez JW: A proposed mechanism of emotion. Arch Neurol Psychiatry 38:725–743, 1937
Perez MM, Trimble MR, Murray NMF, Reider I: Epileptic psychosis: an evaluation of PSE profiles. Br J Psychiatry
146:155–163, 1985 3978333
Perry E, Walker M, Grace J, Perry R: Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends
Neurosci 22(6):273–280, 1999 10354606
Plum F, Posner JB: The Diagnosis of Stupor and Coma. Philadelphia, PA, FA Davis, 1980
Rapoport SI: Integrated phylogeny of the primate brain, with special reference to humans and their diseases. Brain Res
Brain Res Rev 15(3):267–294, 1990 2289087
Reisberg B, Franssen E, Sclan SG, et al: Stage specific incidence of potentially remediable behavioral symptoms in aging
and Alzheimer’s disease. Bull Clin Neurosci 54:95–112, 1989
Reite M, Teale P, Rojas DC, et al: MEG auditory evoked fields suggest altered structural/functional asymmetry in primary
but not secondary auditory cortex in bipolar disorder. Bipolar Disord 11(4):371–381, 2009 19500090
Robinson RG: The Clinical Neuropsychiatry of Stroke, 2nd Edition. Cambridge, UK, Cambridge University Press, 2006
Robinson RG, Kubos KL, Starr LB, et al: Mood disorders in stroke patients. Importance of location of lesion. Brain 107(Pt
1):81–93, 1984 6697163
Sackeim HA, Greenberg MS, Weiman AL, et al: Hemispheric asymmetry in the expression of positive and negative
emotions. Neurologic evidence. Arch Neurol 39(4):210–218, 1982 7041863
Sackeim HA, Prohovnik I, Moeller JR, et al: Regional cerebral blood flow in mood disorders, I: comparison of major
depressives and normal controls at rest. Arch Gen Psychiatry 47(1):60–70, 1990 2294857
Sakurai T, Amemiya A, Ishii M, et al: Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-
coupled receptors that regulate feeding behavior. Cell 92(4):573–585, 1998 9491897
Salmond CH, Chatfield DA, Menon DK, et al: Cognitive sequelae of head injury: involvement of basal forebrain and
associated structures. Brain 128(Pt 1):189–200, 2005 15548553
Savioz A, Leuba G, Vallet PG, Walzer C: Contribution of neural networks to Alzheimer disease’s progression. Brain Res
Bull 80(4-5):309–314, 2009 19539730
Schade JP, van Groenigen W: Structural organization of the human cerebral cortex, 1: maturation of the middle frontal
gyrus. Acta Anat (Basel) 47:74–111, 1961 14497900
Schilder P: The organic background of obsessions and compulsions. Am J Psychiatry 94:1397–1416, 1938
Schmahmann JD, Pandya DN, Wang R, et al: Association fibre pathways of the brain: parallel observations from diffusion
spectrum imaging and autoradiography. Brain 130(Pt 3):630–653, 2007 17293361
Schmahmann JD, Smith EE, Eichler FS, Filley CM: Cerebral white matter: neuroanatomy, clinical neurology, and
neurobehavioral correlates. Ann N Y Acad Sci 1142:266–309, 2008 18990132
Selden NR, Gitelman DR, Salamon-Murayama N, et al: Trajectories of cholinergic pathways within the cerebral
hemispheres of the human brain. Brain 121(Pt 12):2249–2257, 1998 9874478
Seminowicz DA, Mayberg HS, McIntosh AR, et al: Limbic-frontal circuitry in major depression: a path modeling
metanalysis. Neuroimage 22(1):409–418, 2004 15110034
Shin LM, Liberzon I. The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology 35(1):169–191,
2010 19625997
Shipp S: The functional logic of cortico-pulvinar connections. Philos Trans R Soc Lond B Biol Sci 358(1438):1605–1624,
2003 14561322
Smagula SF, Aizenstein HJ: Brain structural connectivity in late-life major depressive disorder. Biol Psychiatry Cogn
Neurosci Neuroimaging 1(3):271–277, 2016 27430029
Sneed JR, Rindskopf D, Steffens DC, et al: The vascular depression subtype: evidence of internal validity. Biol Psychiatry
64(6):491–497, 2008 18490003
Spence SA, Crimlisk HL, Cope H, et al: Discrete neurophysiological correlates in prefrontal cortex during hysterical and
feigned disorder of movement. Lancet 355(9211):1243–1244, 2000 10770312
Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical lesions in the production of poststroke
mood disorders. Brain 110(Pt 4):1045–1059, 1987 3651794
Starkstein SE, Robinson RG, Berthier ML, et al: Differential mood changes following basal ganglia vs thalamic lesions.
Arch Neurol 45(7):725–730, 1988a 3390026
Starkstein SE, Boston JD, Robinson RG: Mechanisms of mania after brain injury. 12 case reports and review of the
literature. J Nerv Ment Dis 176(2):87–100, 1988b 3276815
Stein MB, Heuser IJ, Juncos JL, Uhde TW: Anxiety disorders in patients with Parkinson’s disease. Am J Psychiatry
147(2):217–220, 1990 2301664
Stephan BC, Matthews FE, Khaw KT, et al: Beyond mild cognitive impairment: vascular cognitive impairment, no dementia
(VCIND). Alzheimers Res Ther July 9, 1(1):4, 2009 19674437
Stuss DT, Benson DF: The Frontal Lobes. New York, Raven, 1986
Stuss DT, Guberman A, Nelson R, Larochelle S: The neuropsychology of paramedian thalamic infarction. Brain Cogn
8(3):348–378, 1988 3214590
Swedo SE, Rapoport JL, Cheslow DL, et al: High prevalence of obsessive-compulsive symptoms in patients with
Sydenham’s chorea. Am J Psychiatry 146(2):246–249, 1989 2912267
Tekin S, Cummings JL: Frontal-subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res
53(2):647–654, 2002 12169339
Tomimoto H: White matter integrity and cognitive dysfunction: Radiological and neuropsychological correlations. Geriatr
Gerontol Int 15 (suppl 1):3–9, 2015 26671151
Tzourio-Mazoyer N: Intra- and inter-hemispheric connectivity supporting hemispheric specialization, in Micro-, Meso- and
Macro-connectomics of the Brain (Research and Perspectives in Neurosciences). Edited by Kennedy H, Van Essen
DC, Christen Y. Springer Nature, 2016, pp 129–146
Valzelli L: Psychobiology of Aggression and Violence. New York, Raven, 1981
Van Lancker D: Personal relevance and the human right hemisphere. Brain Cogn 17(1):64–92, 1991 1781982
Vingerhoets G, Alderweireldt AS, Vandemaele P, et al: Praxis and language are linked: evidence from co-lateralization in
individuals with atypical language dominance. Cortex 49(1):172–183, 2013 22172977
Voon V, Cavanna AE, Coburn K, et al; on behalf of the American Neuropsychiatric Association Committee for Research:
Functional neuroanatomy and neurophysiology of functional neurological disorders (conversion disorder). J
Weintraub S, Mesulam M-M: Developmental learning disabilities of the right hemisphere. Emotional, interpersonal, and
cognitive components. Arch Neurol 40(8):463–468, 1983 6870605
Wildgruber D, Ackermann H, Kreifelts B, Ethofer T: Cerebral processing of linguistic and emotional prosody: fMRI studies.
Prog Brain Res 156:249–268, 2006 17015084
Wilson TW, Rojas DC, Teale PD, et al: Aberrant functional organization and maturation in early-onset psychosis: evidence
from magnetoencephalography. Psychiatry Res 156(1):59–67, 2007 17728112
Yakovlev PI: Motility, behavior and the brain; stereodynamic organization and neural coordinates of behavior. J Nerv Ment
Dis 107(4):313–335, 1948 18913439
Yakovlev PI: Telencephalon “impar”, “semipar” and “totopar”. (Morphogenetic, tectogenetic and architectonic definitions).
Int J Neurol 6(3-4):245–265, 1968 5759636
Yakovlev PI, Lecours A-R: Myelogenetic cycles of regional maturation of the brain, in Regional Development of the Brain in
Early Life. Edited by Minkowski A. Oxford, UK, Blackwell Scientific, 1967, pp 3–65
Zadina JN, Corey DM, Casbergue RM, et al: Lobar asymmetries in subtypes of dyslexic and control subjects. J Child
Neurol 21(11):922–931, 2006 17092456
CHAPTER 2
Neuropsychiatric Assessment
Fred Ovsiew, M.D.
In this chapter, the tools offered by history taking and

examination for discovering the contribution of cerebral dysfunction
to psychological abnormality and behavioral disturbance are
reviewed. The focus is on methods of filling in a matrix of clinical
information; clinical correlates of the symptoms and signs discussed
are mentioned but not comprehensively reviewed. The focus also is
on the manifestations of cerebral disease rather than on systemic
disorders and the signs to which they may give rise in the general
physical examination.
A focus on the phenomenology of cerebral disease should not be
mistaken for a commitment to a localizationist paradigm of cerebral
function. Focal neurobehavioral syndromes are clinical facts and
have been of substantial heuristic value in the cognitive
neurosciences (D’Esposito 2003). The power of the cognitive
neurosciences is being brought to bear on the deconstruction of
psychiatric syndromes into disruptions of well-understood normal
cognitive processes, the discipline of cognitive neuropsychiatry (see
Halligan and David 2001 and Pantelis and Maruff 2002). This likely
will lead to expansion of the mutual territory of psychiatry and the
cognitive neurosciences, a welcome development.
Taking the History

Obtaining a history is an active process on the part of the
interviewer, who must have in mind a matrix to be filled in with
information. Drawing on interview of the patient and knowledgeable
informants as well as review of medical records and other data
sources, the clinician constructs a history of present illness; past
medical, surgical, psychiatric, and substance use histories; current
medicines and medication history; social history, including
development, academic strengths and weaknesses, employment,
military history, legal history, relationships and present marital status,
financial status, and health insurance; family history; and review of
systems, with particular emphasis on cognitive, emotional,
behavioral, and elementary neurological function.
The excuse “the patient is a poor historian” has no place in
neuropsychiatry. The examiner must realize that he or she, and not
the patient, is the “historian,” responsible for gathering information
from all necessary sources and forming a coherent narrative.
Discovering that the patient is unable to give an adequate account of
his or her life and illness should prompt a search, first, for other
informants and, second, for an explanation of the incapacity.
It also must be realized from the start that in neuropsychiatry—as
in all of medicine—the clinical assessment is an element of
treatment and may be psychologically therapeutic. The interest and
concern shown by the examiner, the rapport formed with the patient
and the family, and the laying on of hands all form the basis of
subsequent treatment. These effects must be attended to from the
beginning of the consultation.
Who should be present for the diagnostic inquiry? Usually, it is
necessary to interview others who are knowledgeable about a
patient’s history, symptoms and signs, and everyday function.
Frequently, one discovers that a family member has misjudged the
nature or severity of the patient’s impairment. Examining the patient
in front of the family to show impairments allows consensual
validation and mutual discussion. Examining a patient in this manner
requires tact and occasionally requires that the examination be
discontinued or continued with the patient alone.
Birth
The neuropsychiatric history begins with events that took place
even before the birth of the patient. Maternal illness in pregnancy
and the process of labor and delivery should be reviewed for
untoward events associated with fetal maldevelopment, including
bleeding and substance abuse during pregnancy, the course of
labor, low birth weight, and fetal distress at birth and in the
immediate postnatal period. Obstetric complications are associated
with schizophrenia and probably other psychiatric syndromes,
potentially including mood disorder and anorexia nervosa (Verdoux
and Sutter 2002).
Development
At times, the historian can gather information from the first
minutes of extrauterine life; for example, when Apgar scores are
available in hospital records. More commonly, parental recollection
of milestones must be relied on. The ages at which the child walked,
spoke words, spoke sentences, went to school, and so on often can
be elicited from parents. Parents may be able to compare the patient
with a “control” sibling. The infant’s temperament—shy, active,
cuddly, fussy, and so on—may give clues to persisting traits. School
performance is an important marker of both the intellectual and the
social competence of the child and often is the only information
available about premorbid intellectual level. Of particular interest is
an anomalous pattern of intellectual strengths and weaknesses.
Relative weakness in reading (dyslexia) is well recognized. Low
capacities in nonverbal skills along with arithmetic impairment
suggest a nonverbal learning disability (Volden 2013). Childhood
illness, including febrile convulsions, head injury, and central nervous
system infection, is sometimes the precursor of adult
neuropsychiatric disorder (Koponen et al. 2004; Leask et al. 2002).
Handedness
Assessment of handedness provides an essential bedside clue to
cerebral organization. Several questionnaires are available (Peters
1998). Fortunately, a few simple inquiries—asking the patient which
hand he or she uses to write, throw, draw, and to hold scissors or a
toothbrush—serve well to establish handedness. With some
nonverbal patients (e.g., those with severe intellectual disabilities),
watching the patient catch and throw a ball or a crumpled piece of
paper is a simple examination for handedness. The “torque test” of
drawing circles (Demarest and Demarest 1980), examination of the
angle formed by the opposed thumb and the little finger (Metzig et al.
1975), and observation of handwriting posture (Duckett et al. 1993)
have advocates as ways to establish cerebral dominance at the
bedside.
Ictal Events
Many “spells” or “attacks” occur in neuropsychiatric patients, and
taking the history of a paroxysmal event has certain requirements
regardless of the nature of the event. Beginning an inquiry about
seizures by asking if the patient has just one sort of spell or more
than one reduces confusion as history taking proceeds with a patient
who has both focal and generalized seizures. Some patients with
psychogenic nonepileptic seizures will say that they have epileptic
spells and then another sort that happens when they are upset. The
clinician should track through the phases of the paroxysm, starting
with the prodrome, then the aura, then the remainder of the ictus (the
aura being the onset or core of the ictus), and then the aftermath.
For any attack disorder, how frequent and how stereotyped the
events are should be determined. Rapidity of onset and cessation;
disturbance of consciousness or of language; occurrence of
autochthonous sensations, ideas, and emotions and of lateralized
motor or cognitive dysfunction; purposefulness and coordination of
actions; injury sustained during the attack; memory for the spell; and
duration of the recovery period should be ascertained.
Laughing (gelastic) and crying (dacrystic) seizures are unusual
ictal events but ones that should be considered when patients
present with episodes involving both altered consciousness and
altered affect (Wortzel et al. 2009). Gelastic epilepsy is associated
with hypothalamic hamartomas and left-sided lesions (Arroyo et al.
1993), and dacrystic epilepsy is associated with right-sided lesions
(Sackeim et al. 1982). Although crying is more common than
laughter in pathological affect, laughing seizures are more common
than crying seizures (Sackeim et al. 1982). Weeping (rather than
stereotyped crying) during an ictus, in fact, suggests psychogenic
nonepileptic seizures (Walczak and Bogolioubov 1996).
Adverse changes in emotion commonly occur on the days
preceding a seizure. Some of the abnormal experiences that are well
known in temporal lobe epilepsy occur in mood disorders, in other
psychiatric states, and in some putatively healthy individuals
(Persinger and Makarec 1993; Silberman et al. 1985). These
phenomena in nonepileptic populations are associated with markers
of brain injury, such as a history of perinatal hypoxia, fever with
delirium, neurotrauma, and childhood abuse as well as schizotypical
personality structure and nonpsychotic paranormal beliefs. The
phenomena of the voluminous mental state can be elicited by
questions about déjà vu and jamais vu, depersonalization and
derealization, autoscopy, micropsia and macropsia,
metamorphopsia, other visual illusions, paranormal experiences
such as clairvoyance or precognition or a sensed presence, and
other paroxysmal experiences.
Traumatic Brain Injury

Discerning the role of cerebral dysfunction in posttraumatic states
is a common diagnostic challenge. The length of the anterograde
amnesia, from the moment of trauma to the recovery of the capacity
for consecutive memory, can be learned either from the patient by
retrospective interview or from hospital records (when prospective
assessments of such have been performed). The patient can state
what the last memories before the injury are; from last memory to
injury is the period of retrograde amnesia. The lengths of these
intervals are correlated with the severity of injury and are useful
predictors of cognitive and functional outcomes after traumatic brain
injury (Frey et al. 2007). The characteristics of the neurotrauma as
well as the psychosocial setting for its occurrence and whether pre-
injury psychiatric and/or behavioral issues were contributing factors
should be learned.
Alcohol and Substance Use

A substance use history is taken from all patients. Questions
about vocational, family, and medical impairment attributable to
abuse; shame and guilt over abuse and efforts to control it; morning
or secret drinking; blackouts; and other familiar issues help the
clinician identify pathological behavior in this sphere. Cocaine and
alcohol abuse in particular are associated with a variety of
neuropsychiatric consequences, including cognitive impairment,
movement disorders, seizures, and stroke (Marshall 1999).
Cognitive Impairment
Screening for cognitive complaints, their character, and their
course is a routine element of the neuropsychiatric assessment.
While these may be the presented complaint for some patients and
be overt elements of the clinical presentation, the character and
course of such problems in other cases are relatively subtle. Many
patients with mild cognitive disturbance do not meet criteria for a
diagnosis of dementia (or major neurocognitive disorder, as it is
described in Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition [DSM-5]; American Psychiatric Association 2013), and
are, instead, better described as having mild cognitive impairment
(MCI), or mild neurocognitive disorder (American Psychiatric
Association 2013). Familiarity with the criteria for these conditions,
the domains of cognition that they typically affect (addressed in the
“Mental Status Examination” subsections of this chapter), and the
differences in the functional import of cognitive problems associated
with mild versus major neurocognitive disorders is necessary to
frame accurately additional history taking and cognitive examination.
The clinician must also remain mindful that cognitive impairment is
not necessarily a progressive problem: unlike those whose MCI is a
prodromal stage of dementia—for example, the amnestic prodome of
Alzheimer’s disease or the dysexecutive prodrome of vascular
dementia—some patients present with mild cognitive impairments
that are chronic and stable; traumatic brain injury, particularly when
moderate or severe, commonly produces this state (Dikmen et al.
2009).
Appetitive Functions
Appetitive functions include sleeping, eating, and sexual interest
and performance. Disturbed sleep is common in patients with
psychiatric disorders of any origin and in the general population as
well. The clinician inquires about the pattern of disturbance: early
waking in depressive illness, nighttime wakings related to pain or
nocturnal myoclonus, excessive daytime sleepiness in narcolepsy
and sleep apnea, sleep attacks in narcolepsy, and periodic
excessive somnolence in Kleine-Levin syndrome and related
disorders. Simple observation of a hospitalized patient by night
nursing staff, or at home by family members, can identify snoring,
apneas, or abnormal movements.
Sexual interest, sexual performance, and reproductive health are
commonly disturbed in brain disease. A change in a person’s
habitual sexual interests, either quantitative or qualitative, occurring
de novo in adult life, suggests neurological disease (Cummings
1999). Hyposexuality is reportedly a feature of epilepsy, and either
antiepileptic drugs or epilepsy itself may disturb sex hormones, in a
fashion that may depend on the laterality of the seizure focus.
Patterns of abnormal eating behavior in neuropsychiatric
disorders include the hyperphagia of medial hypothalamic disease,
in which food exerts an irresistible attraction, or reduced eating with
lateral hypothalamic lesions; the gourmand syndrome of right
anterior brain injury; the mouthing and eating of nonfood objects in
bilateral amygdalar disease (part of the Klüver-Bucy syndrome); and
the impulsive stuffing of food into the mouth irrespective of hunger in
frontal disease. While diminished appetite is a common feature in
many neurological, medical, and psychiatric conditions, the full
syndromal picture of anorexia nervosa results rarely from
neurological disease, usually involving right frontal and temporal
regions (Uher and Treasure 2005).
Aggression
Patterns of aggressive behavior in brain disease relate to the
locus of injury. Commonly, the injury or degeneration is of the
anterior and ventrolateral frontal regions and the networks in which
they participate. Features of aggressive behavior such as its onset
and cessation; the patient’s mental state and especially clarity of
consciousness during the violent period; the patient’s capacity for
planned, coordinated, and well-organized action as shown in the act;
the patient’s regret, or otherwise, afterward; and any associated
symptoms may yield clues about the contribution of cerebral
dysfunction to the behavior.
Personality Change
Changes in sexual preference with onset in adult life have already
been mentioned as pointers to organic mental disorder. Persisting
alterations in or exaggerations of other personality traits, if not
related to an abnormal mood state or psychosis, may be important
indicators of the development of cerebral disease. Lability and
shallowness of emotion, irritability, aggressiveness, loss of sense of
humor, and coarsening of the sensibilities are often mentioned.
A set of personality traits said to be distinctive for temporal lobe
epilepsy includes hypergraphia, mystical or religious interests,
“humorless sobriety,” tendency toward rage, interpersonal stickiness
or “viscosity,” and hyposexuality. Whether these traits are related to
epilepsy, to the temporal lobe injury underlying epilepsy, or merely to
psychopathology remains controversial (Blumer 1999; Devinsky and
Najjar 1999).
Occupation
Exposures to heavy metals or volatile hydrocarbons and repeated
blows to the head in boxers are examples of occupational causes of
neuropsychiatric illness. Apart from gathering etiological information,
the clinician needs to know about the patient’s work to gauge
premorbid capacities and to assess disability.
Family History
Genetic contributions to many neuropsychiatric illnesses are well
delineated (e.g., Huntington’s disease); in other illnesses, the
contribution is probable but its nature less clear (e.g., Tourette
syndrome). Inquiry about the family history of neuropsychiatric
illness is most rewarding when pursued relative by relative, while
constructing a family tree.
Neurological Examination
The usual elements of the neurological examination are outlined
in Table 2–1. The sensitivity and specificity of many neurological
examination findings are unknown, even for signs that are routine or
traditional in the clinical examination. Too often, the clinical
examination proceeds by ritual. The clinician who asks the patient
with right hemisphere stroke to interpret proverbs but not to copy
figures, or asks him or her to remember three words but not three
shapes, is bowing to tradition and ignoring the physiology of the
brain disease. Moreover, the tasks may lack discernible relation to
cognitive or anatomical systems: What underlies the ability to recall
the names of the last four presidents? Probes of mental function
should be chosen with reference to the structure of the mind, as best
understood.
TABLE 2–1. The neurological examination
Section Elements
Cranial nerves I: Olfaction (use items such as coffee, mint, vanilla,
cinnamon)
II: Visual fields, visual acuity, and pupillary responses,
and fundus (i.e., retina, disc, macula)
III, IV, VI: Pupillary responses to light and
accommodation and extraocular movements (up,
down, lateral, and convergent gaze, smooth
pursuit eye movements and saccades, and
observation for nystagmus)
V: Facial sensation and masseter strength
VII: Facial motor function
VIII: Hearing and vestibular function
IX, X: Palatal elevation
XI: Sternocleidomastoid and trapezius strength
XII: Tongue protrusion
Motor – Part I Resistance to passive manipulation, including
assessment of intrinsic tone and assessment for
paratonia
Observation of muscle bulk and symmetry as well as
for abnormal involuntary movements
Reflexes Stretch reflexes, including those at biceps, triceps,
brachioradialis, patellar, and Achilles tendons;
responses graded as 0 (absent), 1+ (diminished,
may require evocation maneuvers), 2+ (active), 3+
(brisk, often with spread to other groups), and 4+
(very brisk, with spread and clonus)
When clinically appropriate, additional brain stem
reflexes (e.g., corneal, oculovestibular, gag) not
already evaluated in the cranial nerve
examination, other stretch reflexes, and cutaneous
reflexes assessed
Section Elements
Assessment for primitive reflexes, including glabellar,
snout, suck, palmomental, and finger grasp;
among persons with more severe neurological
conditions, foot grasp, self-grasp, and rooting
responses assessed as well.
Motor – Part II Strength testing of bilateral upper and lower
extremities proximally and distally; responses
graded as 0 (no muscle movement), 1 (visible or
palpable muscle contraction), 2 (full range of
motion with gravity eliminated but not against
gravity), 3 (movement against gravity but not
added resistance), 4 (movement against
resistance but subnormal), and 5 (normal strength)
Sensory Pain (pin prick), temperature
Light touch
Vibration, proprioception (including finger-to-nose with
eyes closed and Romberg tests)
Coordination Finger-nose-finger, fine finger movements, finger-
thumb opposition
Rapid repetitive movement, rapid alternating
movement
Heel-to-shin movement
Gait Posture, station
Walking, including initiation, stride length, arm swing,
turning, toe walking, and heel walking
Tandem gait
Corticospinal signs Response to plantar stimulation (assessment for
Babinski sign) and related maneuvers
Assessment for Hoffmann’s sign
Source. Adapted from Arciniegas DB: “Medical Evaluation,” in Management of
Adults With Traumatic Brain Injury. Edited by Arciniegas DB, Zasler ND,
Vanderploeg RD, Jaffee MS. Washington, DC, American Psychiatric Publishing,
2013, pp 35–72. Copyright © 2013 American Psychiatric Publishing. Used with
permission.
Sometimes, clinicians attempt to elicit not signs of brain disease
but so-called positive signs of nonorganic states. Vibratory sensation
that shows lateralized deficit on the sternum is an example. Most
such signs are of limited utility, not because they are uncommon in
functional neurological disorders (i.e., conversion disorders or,
formerly, “hysteria”) but because suggestibility is common in organic
mental states as well (Fishbain et al. 2003). These signs cannot be
relied on for differential diagnosis. However, the Hoover, abductor,
and “drift without pronation” signs may offer more specificity (Daum
and Aybek 2013; Sonoo 2004; Stone et al. 2002).
Asymmetry and Minor Physical Anomalies

Abnormal development of a hemisphere may be betrayed by
slight differences in the size of the thumbs or thumbnails. A
postcentral location of cortical lesions causing asymmetry is
characteristic (Penfield and Robertson 1943). Other physical
anomalies are stable through childhood and give clues to abnormal
neurodevelopment even in adulthood. The Waldrop scale is in
common use, but minor anomalies not included in that scale may be
relevant (Ismail et al. 1998). They may occur in healthy individuals,
and only an excessive number, not an individual anomaly, correlates
with psychopathology. The deviant development can be traced to the
first 4 months of fetal life, and either genetic or environmental factors
can give rise to the disturbance of gestation (Compton et al. 2011).
Presumably, the relation of the anomalies to the brain disorder lies in
a disturbance of contemporaneous cerebral development.
Head circumference, however, differs from the other anomalies,
both in its having significance as a sole finding and in the timing of its
occurrence. Both microcephaly and macrocephaly are of clinical
significance, the latter especially in the instance of autism spectrum
disorders (Sacco et al. 2015). Such anomalies are associated with
schizophrenia (McNeil et al. 2000), even late-onset schizophrenia
(Lohr et al. 1997). The evidence less conclusively associates them
with other neuropsychiatric disorders (Ovsiew 2017). Thus, they are
best regarded as a nonspecific indicator of abnormal
neurodevelopment that may interact with psychosocial factors in the
genesis of psychopathology.
Dysmorphic features in an individual with intellectual or other
developmental disabilities should prompt investigations to identify
the cause of those disabilities (Ryan and Sunada 1997). In particular,
subtelomeric deletion should be considered, as it is a recognized
cause of nonsyndromal intellectual and developmental disability (de
Vries et al. 2001).
Olfaction
Hyposmia or anosmia can be detected in Alzheimer’s disease,
Parkinson’s disease, normal aging, schizophrenia, multiple sclerosis,
subfrontal tumor, human immunodeficiency virus (HIV) infection,
migraine, and traumatic brain injury (Martzke et al. 1997). The most
common cause of hyposmia, however, is local disease of the nasal
mucosa, and the examiner must exclude local disease before
regarding the finding as having neuropsychiatric significance.
Stimuli that cause trigeminal irritation (such as ammonia) are not
suitable for testing for anosmia. Floral and musk odors provide the
greatest sensitivity. More sophisticated equipment is available for
clinical use (Savic et al. 1997).
Eyes
Dilated pupils associated with anticholinergic toxicity may be a
clue to the cause of delirium, and small pupils associated with opiate
intoxication may be a clue to substance abuse. Argyll Robertson
pupils—bilaterally small, irregular, and reactive to accommodation
but not to light—characteristically accompany neurosyphilis but also
may be observed among patients with sarcoidosis, Lyme disease,
and other conditions (Dacso and Bortz 1989). Pupillary abnormalities
other than Argyll Robertson pupils, such as bilateral tonic pupils, also
may occur in neurosyphilis. A Kayser-Fleischer ring is nearly always
present when Wilson’s disease affects the brain (Brewer 2005). This
brownish-green discoloration of the cornea begins at the limbus, at
12 o’clock and then at 6 o’clock, spreading from each location
medially and laterally until a complete ring is formed. It can be
difficult to discern in patients with dark irises, so slit-lamp
examination should supplement bedside inspection.
Visual Fields
When lesions disrupt the white matter of the temporal lobe, a
homonymous superior quadrantanopsia or even a full homonymous
hemianopsia can result from involvement of Meyer’s loop, the portion
of the optic radiation that dips into the temporal lobe. The finding can
be an important pointer to an otherwise neurologically silent temporal
lobe lesion. In cases of delirium from posterior cerebral or right
middle cerebral artery infarction, hemianopsia may be the only
indicator of a structural, rather than toxic-metabolic, cause (Devinsky
et al. 1988).
Blinking
The normal response to regular one-per-second taps on the
glabella (with the examiner behind the patient so that the striking
finger is not within the patient’s visual field and the patient is not
responding to visual threat) is blinking to the first few taps, followed
by habituation and no further blinking. Failure to habituate to
glabellar tap (Myerson’s sign) is seen in a wide range of conditions
affecting frontal-subcortical-thalamo-cerebellar circuits (Schneck
2013).
The normal spontaneous blink rate increases through childhood
but is stable in adulthood at a rate of about 16±8 per minute. The
matter is of particular interest because the rate of spontaneous
blinking is quite insensitive to peripheral stimuli (ambient light,
humidity, even deafferentation of the fifth nerve) but is under
dopaminergic control (Elsworth et al. 1991). Clinically, dopaminergic
influence produces a low blink rate in parkinsonism and an increase
in blink rate with effective levodopa treatment (Karson et al. 1984).
Thus, blink rate provides a simple quantitative index of central
dopamine activity.
Eye Movements
Abnormal eye movements are commonly observed among
persons with schizophrenia spectrum disorders. Gaze abnormalities,
abnormality in eye contact with the examiner (e.g., fixed staring or no
eye contact), impaired convergence movements, and abnormal
(irregular) smooth pursuit movements are among the most common
abnormal eye movements in such patients. Clinicians’ descriptions of
eye movements are often inferential (e.g., “looking at the voices”),
but an attempt at phenomenological description is useful (e.g.,
“unexplained episodic lateral glances”). However, abnormal eye
movements of these types are common and nonspecific findings in
many neuropsychiatric disorders and do not reliably distinguish
schizophrenic patients from healthy control subjects (Chen et al.
1995) or patients with other neuropsychiatric disorders (Schneck
2013).
Elucidating abnormalities of eye movement in neuropsychiatric
patients requires separate examination of voluntary eye movements
without fixation (“look to the left”), generation of saccades to a target
(“look at my finger, now back at my face”), and smooth pursuit
(“follow my finger”). Failure of voluntary downgaze is a hallmark of
progressive supranuclear palsy but is not always present early in the
course. Limitation of voluntary upgaze is common in the healthy
elderly. Slowed saccades and abnormal initiation of saccades (e.g.,
inability to make a saccade without moving the head or blinking) are
important early abnormalities in Huntington’s disease (Blekher et al.
2004). Slowed saccades are also a feature of early progressive
supranuclear palsy, although this finding can occur in other
parkinsonian syndromes (Lloyd-Smith Sequeira et al. 2017).
Abnormalities of eye movement (nystagmus, a sixth nerve palsy, or a
gaze palsy) in a confused patient may indicate Wernicke’s
encephalopathy.
When the head is moved in the same direction as the visual target
(e.g., the head is passively turned to the right as the examiner’s
hand moves from the midline to the patient’s right), the eyes follow
the visual target as instructed only when the patient is able to inhibit
the vestibulo-ocular reflex; failure to inhibit this reflex leads to eye
movements in the opposite direction (doll’s eyes) in supranuclear
disorders such as progressive supranuclear palsy and schizophrenia
(Warren and Ross 1998). Excessive synkinesia of head and eye
movement (i.e., the head moves involuntarily when the patient is
instructed to move only the eyes to a target) on voluntary initiation of
gaze occurs in schizophrenia and dementia (Chen et al. 1995).
Inability to inhibit reflexive saccades to a target is characteristic of
frontal disease and is seen inter alia in schizophrenia (Kennard et al.
1994); in its extreme, when any moving object captures the patient’s
gaze, this phenomenon is visual grasping (Ghika et al. 1995).
Subtler manifestations can be elicited by instructing the patient to
look at the examiner’s finger when the fist moves, and vice versa,
with one hand on each side of the patient—an antisaccade task
(Currie et al. 1991). A human face is a particularly potent stimulus to
visual grasping (Riestra and Heilman 2004), and this fact can be
applied in the inattentive patient by using one’s own face as a
fixation point in testing pursuit movements (i.e., moving one’s head
from side-to-side in front of the patient rather than just a hand).
Apraxia of gaze, like other apraxias, refers to a failure of voluntary
movement with the preserved capacity for spontaneous movement.
Congenital ocular motor apraxia (Cogan’s syndrome), in which
saccadic shifts of gaze are abnormal and often require initiation by
head thrusting, is often associated with other neurodevelopmental
abnormalities—notably, truncal ataxia and apraxia of speech.
Despite the customary term, congenital ocular motor apraxia is not
truly an apraxia because the nonvolitional saccadic system is
abnormal (Harris et al. 1996). This abnormality is commonly
associated with hypoplasia of the cerebellar vermis (Jan et al. 1998;
Sargent et al. 1997). In spasm of fixation, intentional saccades are
severely impaired, but the quick phase of vestibular nystagmus is
preserved, thus more exactly meeting the definition of apraxia.
Saccades can be performed more normally if fixation is eliminated.
Such cases are associated with bilateral frontoparietal lesions
(Pierrot-Deseilligny et al. 1997).
Apraxia of gaze is a feature in Balint’s syndrome, but here, too,
the term apraxia is questionable. Although visually guided saccades
are severely impaired, saccades to command may be intact (Pierrot-
Deseilligny et al. 1997). Psychic paralysis of gaze, Balint’s original
term, is a more accurate designation (Moreaud 2003). The
dysfunction relates to a disorder of spatial attention; classically,
although not necessarily, the patients show bilateral posterior
parietal lesions.
In so-called apraxia of eyelid opening, patients have difficulty in
initiating lid elevation. This disorder occurs in extrapyramidal disease
—notably, progressive supranuclear palsy (Grandas and Esteban
1994)—and as an isolated finding (Defazio et al. 1998). Eye closure
and reflex eye opening are normal. In apraxia of lid opening, as
distinct from blepharospasm, the orbicularis oculi are not excessively
contracted; in blepharospasm, the brows are lowered below the
superior orbital margins (Charcot’s sign) (Esteban et al. 2004).
Sensory tricks may be effective in initiating eye opening (Defazio et
al. 1998), probably an indicator of extrapyramidal dysfunction in the
disorder (thus making the term apraxia incorrect). Some (e.g.,
Esteban et al. 2004) but not all authors distinguish the phenomenon
from ptosis of cerebral origin, which occurs with frontal lesions,
especially right hemisphere infarction.
Supranuclear disorders of eyelid closure may occur with bilateral
frontal lesions, either structural or functional, as in the case of
progressive supranuclear palsy (Grandas and Esteban 1994).
Spontaneous blinking is intact, and other bulbar musculature often is
involved.
Facial Movement
A double dissociation in the realm of facial movement shows that
emotional movements and volitional movements are separately
organized. A paresis seen in movements in response to a command
(“show me your teeth”) is sometimes overcome in spontaneous
smiling; this indicates disease in pyramidal pathways. A severe
impairment of voluntary control of the bulbar musculature with
preservation of automatic movements is seen in bilateral opercular
lesions, the anterior opercular or Foix-Chavany-Marie syndrome
(Bakar et al. 1998). The inverse phenomenon—normal movement in
response to a command but asymmetry of spontaneous emotional
movements—is seen with disease in the supplementary motor area,
anterior thalamus, amygdala, striatum and internal capsule, and
brain stem. Emotional facial weakness is contralateral to the seizure
focus in temporal lobe epilepsy (Jacob et al. 2003).
Abnormalities of Movement
Weakness
A complete review of the findings associated with lesions of the
pyramidal tracts, spinal cord, peripheral nerves, and muscles is
beyond the scope of the present work. However, there are several
simple maneuvers that facilitate recognition of the motor effects of
cerebral lesions that merit description here (Teitelbaum et al. 2002).
Pronator drift is assessed by asking the patient to keep the arms
outstretched and supinated, with the fingers together and then with
the fingers apart. Abduction of the fingers in the first portion of the
test and pronation, elbow flexion, or lateral and downward drift in the
second portion indicate pyramidal disease. Testing should last at
least 30 seconds. Upward drift indicates a parietal lesion. (By asking
the patient to hold the arms pronated, the examiner can conveniently
observe for asterixis and tremor at this point in the examination.)
In the finger-rolling test, the patient is asked to rotate each index
finger around the other for 5 seconds in each direction. The
tendency for one finger to orbit the other indicates a subtle pyramidal
lesion on the stationary side. Fine finger movements are assessed
by asking the patient, with the hands supinated in the lap, to touch
the thumb to each of the other four fingers in turn, one hand at a
time. Mirror movements (discussed in the subsection “Synkinesia
and Mirror Movements” later in this chapter) are conveniently
observed incidentally at this point in the examination.
Greater awareness of the findings in nonpyramidal syndromes
may help the clinician identify neurobehavioral syndromes
associated with cerebral disease outside the primary motor regions.
Caplan et al. (1990) described the features of a “nonpyramidal
hemimotor” syndrome with caudate nucleus lesions. Patients show
clumsiness and decreased spontaneous use of the affected limbs;
associated movements are decreased as well. What appears at first
glance to be paresis proves to be a slow development of full
strength; if coaxed and given time, the patient shows mild weakness
at worst.
Freund and Hummelsheim (1985) explored the motor
consequences of lesions of the premotor cortex. They observed a
decrease in spontaneous use of the arm and attributed it to a failure
of postural fixation; when supported, the arm showed at worst mild
slowing of finger movements. The defect in elevation and abduction
of the arm was best demonstrated by asking the patient to swing the
arms in a windmill movement, both arms rotating forward or
backward; the same defect can be found in cycling movements of
the legs, especially backward cycling (Freund 1992). Movement
rapidly decomposed when such coordination was required.
Pyramidal signs—increased tendon jerks, Babinski’s sign, and
spasticity—may be absent in patients with these findings. In acute
parietal lesions, “motor helplessness” due to loss of sensory input is
sometimes seen.
Abnormality of Gait
Assessment of gait is a central feature of the neuropsychiatric
physical examination. Alterations in gait are common in subcortical
vascular disease, for example, and may provide crucial diagnostic
information. The examiner must scrutinize the patient’s rising from a
chair, standing posture, postural reflexes, initiation of gait, stride
length and base, and turning. Failures of gait ignition (initiation),
locomotion, and postural control should be identified as such,
whether alone or in combination.
In mild gait ignition failure, start hesitation and occasional freezing
are seen. In mild locomotion failure, slow and short strides on a
widened base are present, with mild unsteadiness. In postural
control failure, falling is seen in conjunction with turning impairment,
ultimately leading to an inability to stand unsupported. Stressed gait
(e.g., walking heel to toe or on the outer aspects of the feet) may
reveal asymmetric posturing of the upper extremity in patients
without other signs. Frontal gait disorder is characterized by short,
shuffling steps on either a wide or a narrow base, with hesitation at
starts and turns. Postural equilibrium is impaired, although not as
much as in Parkinson’s disease, and the trunk is held upright on stiff,
straight legs. Festination is not a feature, and the upper extremities
are unimpaired or far less affected. This is the gait disorder of
subcortical vascular dementia, and it must be distinguished from that
of Parkinson’s disease (FitzGerald and Jankovic 1989). A widened
base strongly points away from idiopathic Parkinson’s disease and
toward subcortical vascular disease or a parkinsonian-plus
syndrome.
Thalamic, basal ganglia, and cortical lesions can produce balance
disorders with falling and unfamiliar derangements of station and
gait, easily mistaken for psychogenic disorders. Falls also occur in
patients with dementia or delirious patients whose executive
dysfunction leads to carelessness with regard to walking rather than
specific gait impairment.
Contrariwise, cautious gait occurs in healthy people in
treacherous footing (e.g., on ice) or in the frail and anxious elderly.
Features of cautious gait include short stride length at a slow pace, a
widened base, excessive knee flexion, and decreased arm swing.
Such patients are often anxious and depressed and evince an
excess of extrapyramidal and frontal release signs—but not
pyramidal or cerebellar signs—as well as a reduction in muscle
strength (Giladi et al. 2005). Although anxiety may play an important
role in the genesis of the gait pattern, the organic factors must not be
ignored, even though the gait disorder is not a classically localizable
one.
Akinesia
Akinesia has several aspects: delay in the initiation of movement,
slowness in the execution of movement, and special difficulty with
complex movements. The disturbance is established by requiring the
patient to perform a repeated action, such as tapping thumb to
forefinger, or two actions at once. A decrement in amplitude or
freezing in the midst of the act is observed. When established,
akinesia is unmistakable in the patient’s visage and demeanor and in
the way he or she sits motionlessly and has trouble arising from the
chair. A distinction between parkinsonian akinesia and depressive
psychomotor retardation is not easy to make, but the associated
features of tremor, rigidity, and postural instability are generally
absent in depressive illness (Rogers et al. 1987).
Agitation
The term agitation is often misused to refer to the behavior of
aggression or the affect of anxiety. “The preferred definition of
psychomotor agitation is of a disorder of motor activity associated
with mental distress which is characterized by a restricted range of
repetitive, nonprogressive (‘to-and-fro’), non-goal directed activity”
(Day 1999, p. 95). In distinction from akathisia, the excessive
movement characteristically involves the upper extremities. Agitation
in the verbal sphere is manifested in repetitive questioning or
complaining, screaming, or attention seeking. In some patients with
Alzheimer’s disease, wandering is associated with depressive and
anxiety symptoms and may represent agitation in this cognitively
impaired population. Roaming, differentiated from wandering by
being purposeful and exploratory, is characteristic of frontotemporal
dementia.
Akathisia
Motor restlessness accompanied by an urge to move is referred
to as akathisia. Although akathisia is most familiar as a side effect of
psychotropic drugs, the phenomenon occurs often in idiopathic
Parkinson’s disease, occasionally in traumatic brain injury, herpes
simplex encephalitis, restricted basal ganglion lesions (even
occurring unilaterally with a contralateral lesion), after withdrawal
from dopamine-blocking drugs, or as a tardive movement disorder
(Sachdev 1995).
Eliciting the account of subjective restlessness from a psychotic
patient may be difficult. Complaints specifically referable to the legs
are more characteristic of akathisia than of anxiety. Although by
derivation the term refers to an inability to sit, its objective
manifestations are most prominent when the patient attempts to
stand still. The patient “marches in place,” shifting weight from foot to
foot. Seated, the patient may shuffle or tap his or her feet or
repeatedly cross his or her legs. When the disorder is severe, the
recumbent patient may show myoclonic jerks or a coarse tremor of
the legs.
Hypertonus
Three alterations of motor tone (or apparent motor tone) concern
the neuropsychiatrist: spasticity, rigidity, and paratonia.
In spasticity, tone is increased in flexors in the upper extremity
and extensors in the lower but not in the antagonists. The
hypertonus shows an increase in resistance followed by an
immediate decrease (the clasp-knife phenomenon) and depends on
the velocity of the passive movement. This is the typical hemiplegic
pattern of hemisphere stroke, universally called pyramidal, which
indicates a lesion actually not in the pyramidal tract but in the
corticoreticulospinal tract. However, clinicians should be aware that
striking variability in muscle tone (poikilotonia) can occur in the acute
phase of parietal stroke.
In rigidity, tone is increased in both agonists and antagonists
throughout the range of motion. Hypertonus of this type is not
dependent upon the velocity with which the affected muscle (usually
a limb muscle) is moved. This is the characteristic hypertonus of
extrapyramidal disease.
In paratonia (including mitgehen [“go with”] and gegenhalten
[“stop going”]), resistance to passive manipulation is erratic and
depends on the intensity of the imposed movement. This pattern of
hypertonus is usually related to frontosubcortical dysfunction
(Schneck 2013). The erratic quality is related to the presence of both
oppositional and facilitatory aspects of the patient’s motor
performance. Beversdorf and Heilman (1998) described a test for
facilatory paratonia: the patient’s arm is repeatedly flexed to 90° and
extended to 180° at the elbow, then the examiner’s hand is
withdrawn at the point of arm extension. In the abnormal response,
the patient lifts or even continues to flex and extend the arm.
A cogwheel feel to increased muscle tone is not intrinsic to the
hypertonus; the cogwheeling in parkinsonism is imparted by postural
(not rest) tremor superimposed on rigidity. In delirium and dementia,
the paratonia of diffuse brain dysfunction can be mistaken for
extrapyramidal rigidity when the examiner feels cogwheeling, which
actually indicates the additional presence of the common tremor of
metabolic encephalopathy or postural tremor of some other etiology.
Dystonia
Dystonia refers to sustained involuntary muscle contractions that
produce twisting and repetitive movements or abnormal postures.
The contractions may be generalized or focal. Typically, the dystonic
arm hyperpronates, with a flexed wrist and extended fingers; the
dystonic lower extremity shows an inverted foot with plantar flexion.
Several syndromes of focal dystonia are well recognized, such as
torticollis, writer’s cramp, and blepharospasm with jaw and mouth
movements (Meige syndrome).
A dystonic pattern of particular interest is oculogyric crisis, in
which forced thinking or other psychological disturbance
accompanies forced deviation of the eyes. Dystonic movements
characteristically worsen with voluntary action and may be evoked
only by very specific action patterns. Dystonic movements,
especially in an early stage or mild form of the illness, can produce
apparently bizarre symptoms, such as a patient who cannot walk
because of twisting feet and legs but who is able to run or a patient
who can do everything with his or her hands except write. Adding to
the oddness is the frequent capacity of the patient to reduce the
involuntary movement by using “sensory tricks” (le geste
antagoniste); in torticollis, for example, the neck contractions that are
forceful enough to break restraining devices may yield to the
patient’s simply touching the chin with his or her own finger. Eliciting
a history of such tricks or observing the patient’s use of them is
diagnostic.
Tremor
Tremors are rhythmic, regular, oscillating movements. The major
forms of tremor are rest tremor, postural tremor, intention (or kinetic)
tremor, and rubral (or midbrain) tremor.
In rest tremor, the movement is present distally when the limb is
supported and relaxed; action reduces the intensity of the tremor.
The frequency is usually low, about 4–8 cycles per second. This is
the well-known tremor of Parkinson’s disease. Because the
amplitude of the tremor diminishes with action, rest tremor is usually
less disabling than it might appear. In postural tremor, the
outstretched limb oscillates. At times, this can be better visualized by
placing a piece of paper over the outstretched hand. Postural tremor
is produced by anxiety, by certain drugs (e.g., caffeine, lithium,
steroids, adrenergic agonists), and by hereditary essential tremor. A
coarse, irregular, postural tremor is frequently seen in metabolic
encephalopathy. In intention tremor (also called kinetic tremor), the
active limb oscillates more prominently as the limb approaches its
target during goal-directed movements, but the tremor is present
throughout the movement. Rubral, or midbrain, tremor is a low-
frequency, large-amplitude, predominantly proximal, sometimes
unilateral tremor with rest, postural, and intention components.
Observing the patient with arms supported and fully at rest, then
with arms outstretched, and then with arms abducted to 90° at the
shoulders and bent at the elbows while the hands are held palms
down with the fingers pointing at each other in front of the chest, will
identify most upper-extremity tremors (Jankovic and Lang 2004). A
given patient’s organic tremor may vary in amplitude, for example,
with anxiety when the patient is aware of being observed. However,
anxiety and other factors do not alter tremor frequency. Thus, if the
patient’s tremor slows or accelerates when the examiner asks him or
her to tap slowly or quickly with the opposite limb, a functional tremor
should be suspected.
Chorea, Athetosis, Ballismus, and Dyskinesia

Chorea refers to brief, abrupt, irregular, unpredictable,
nonstereotyped movements, chiefly (but not exclusively) affecting
the limbs and face. When mild, choreic movements may falsely
appear purposeful and may suggest fidgeting or clumsiness. Chorea
may become more evident when elicited by gait or other activity, and
choreic movements may be incorporated, often involuntarily, into
motor acts that appear or are secondarily purposeful (i.e., a flitting
movement of the fingers and hand toward the head that transitions
into stroking or smoothing of the hair). Chorea is often, although not
invariably, accompanied by athetosis, a slow, sinuous, involuntary
writhing movement of the fingers, hands, toes, feet, arms, legs,
tongue, neck, and/or trunk; this combination of abnormal movements
is referred to as choreoathetosis. However, athetosis may occur in
the absence of chorea (e.g., Hammond’s disease). The differential
diagnosis of chorea is wide, including at least Huntington’s disease,
Fahr’s syndrome, Sydenham’s chorea, Wilson’s disease, systemic
lupus erythematosus, tardive dyskinesia, and adverse reactions to
antiepileptic drugs, antidepressants, lithium, levodopa, and
nonantipsychotic antidopaminergic drugs such as metoclopramide
and prochlorperazine. If the patient has psychosis, the clinician must
not assume that chorea is tardive dyskinesia but must consider a
differential diagnosis of diseases that can produce both chorea and
psychosis, including the schizophrenia spectrum disorders
themselves (McCreadie et al. 2005).
By contrast, predominantly proximal movements, large in
amplitude and violent in force, are called ballistic. Usually, ballism is
unilateral (hemiballism), but it can be bilateral. Despite the oft-cited
association of ballismus (especially hemiballismus) with a lesion in
the subthalamic nucleus, lesions elsewhere in the basal ganglia are
more frequently culpable (Postuma and Lang 2003).
Many elderly patients with oral dyskinesia are edentulous. In
edentulous dyskinesia, abnormality of tongue movement is minimal;
in contrast, vermicular (wormlike) movements of the tongue inside
the mouth are prominent in tardive dyskinesia. In Huntington’s
disease, impersistence of tongue protrusion is prominent, whereas in
tardive dyskinesia, voluntary protrusion of the tongue markedly
reduces the abnormal oral movements. Abnormal movements of the
upper face are much more prominent in Huntington’s disease than in
tardive dyskinesia (Jankovic and Lang 2004).
Myoclonus
Myoclonus comprises sudden, jerky, shock-like movements, which
can originate at various levels in the nervous system. Certain forms
of myoclonus are within normal experience; the hiccup and the jerk
that awakens one just as one drifts off to sleep (the hypnic jerk) are
myoclonic phenomena. Myoclonus does not show the continuous,
dance-like flow of movement that characterizes chorea. When
myoclonus is rhythmic, it differs from tremor in having an interval
between individual movements, a “square wave” rather than a “sine
wave.”
The distinction of myoclonus from tic is partly based on subjective
features: the tiqueur reports a wish to move, a sense of relief after
the movement, and the ability to delay the movement (albeit at the
cost of increasing subjective tension). Also, tics can be more
complex and stereotyped than myoclonic jerks.
Various psychoactive medicines, notably lithium, can cause
myoclonus. Myoclonus can be a prominent feature of Creutzfeldt-
Jakob disease (in which cortical myoclonus may be elicited by
auditory stimuli), dementia with Lewy bodies, and corticobasal
degeneration. Myoclonus can accompany dystonia, including tardive
dystonia, and tardive myoclonus without dystonia is also recognized.
Myoclonus occurring in a confused patient is usually a feature of
toxic-metabolic encephalopathy, but it should raise the question of
nonconvulsive status epilepticus, an easily overlooked condition
(Kaplan 2002). Gaze deviation, lateralized dystonic posturing, and
automatisms should be red flags for the latter condition.
Asterixis
Asterixis is the repeated momentary loss of postural tone that
produces a flapping movement of the outstretched hands, originally
described in the setting of liver failure but subsequently recognized
in many or all states of metabolic encephalopathy and in all muscle
groups. It may be elicited by asking the patient to dorsiflex the index
fingers for 30 seconds while the hands and arms are outstretched,
with the patient watching to ensure maximum voluntary contraction.
Physiologically, asterixis is the inverse of multifocal myoclonus,
with brief electromyographic silences amidst otherwise sustained
activity. The coarse tremor of delirium is a slower version of asterixis.
Bilateral asterixis is a valuable sign because it points reliably to a
toxic-metabolic confusional state. Asterixis, to our knowledge, has
never been described in the idiopathic psychoses and is thus
pathognomonic for an encephalopathy. Occasionally, asterixis is
unilateral and reflects a lesion of the contralateral thalamic, parietal,
or medial frontal structures (usually thalamic); rarely, bilateral
asterixis is of structural origin.
Startle
The normal reaction to an unexpected auditory stimulus invariably
includes an eye blink and then predominantly flexor muscle jerks that
are most intense cranially, tapering caudally. A rare, usually familial,
disorder in which this reflex is disturbed is called hyperexplexia. It
features hyperreflexia, hypertonus, and abnormal gait in infancy;
myoclonus; and exaggerated startle, frequently causing falls.
Abnormal startle reactions are also seen in posttraumatic stress
disorder, Tourette syndrome, some epilepsies, certain culture-bound
syndromes such as latah and the “jumping Frenchmen of Maine,”
brain stem encephalitis, postanoxic encephalopathy, and
hexosaminidase A deficiency.
Tics and Compulsions

Some of the key features of tics were described in the subsection
“Myoclonus” in differentiating tics from myoclonus. Tics are sudden
jerks, sometimes simple (e.g., a blink or a grunt) but sometimes as
complex as a well-organized voluntary movement (e.g., repeatedly
touching an object or speaking a word). In addition to the important
subjective differences noted previously, tics differ from many other
abnormal movements in that they may persist during sleep (Jankovic
and Lang 2004), as may some myoclonic disorders and some
dyskinetic movements (Sawle 1999). Despite the quasivoluntary
quality of some tics, electrophysiological evidence shows that tics
differ from identical movements produced voluntarily by the same
person in that they lack the readiness potential
(Bereitschaftspotential) that normally precedes a voluntary
movement.
Compulsions are repetitive behaviors or mental acts that an
individual feels driven to perform in response to an obsession (or
another source of anxiety) or according to rules that must be applied
rigidly. Compulsions (as well as obsessions) arising in the context of
neurological disorders are similar phenomenologically to those of
idiopathic obsessive-compulsive disorder (Berthier et al. 1996).
Some behaviors that appear to be compulsions represent utilization
behavior rather than activity driven by anxiety.
A distinction between complex tics and compulsions rests partly
on the subjective experience of the patient. While compulsions are
taken to be voluntary, the drive to action often is so strong that the
experience of the patient may not be one of full voluntary control
over the performance. Similarly, tics may be experienced as
deliberate responses to an urge (like scratching because of an itch)
or be given a post hoc meaning by the patient, so the distinction
between “voluntary” and “involuntary” movements and actions may
be obscured.
Stereotypy and Mannerism

Stereotypies are rhythmic, repetitive, fixed, predictable, but
purposeless movements, sometimes performed in lieu of other motor
activity and for long periods of time. Stereotypies include movements
such as crossing and uncrossing the legs, clasping and unclasping
the hands, picking at clothes or at the nails or skin, head banging,
and rocking. Stereotyped movements are seen in schizophrenia,
autism, mental retardation, Rett syndrome, Tourette syndrome,
neuroacanthocytosis, congenital blindness, and numerous other
psychopathological states. They are particularly characteristic of
frontotemporal dementia (Mendez et al. 2005).
Nonautistic children may show repetitive complex movements.
These are phenomenologically distinct from tics in that they are more
rhythmic, patterned, and prolonged; lack premonitory urges or
internal tension; are easily abolished by distraction but are not
disturbing to the child and thus are not intentionally controlled; and
start earlier, often before age 2 years (Mahone et al. 2004). They
may persist into adulthood and may be associated with obsessive
and compulsive symptoms (Niehaus et al. 2000). At times, especially
in those with intellectual and developmental disabilities, a distinction
of stereotypies from epileptic events may be difficult.
Many of the abnormal movements of tardive dyskinesia (e.g.,
chewing movements, pelvic rocking) are patterned and repetitive, not
random as is chorea, and they are best described as stereotypies.
Amphetamine intoxication is a well-recognized cause of stereotypy,
known in this setting as punding, a Swedish word introduced during
a Scandinavian epidemic of amphetamine abuse (Rylander 1972).
Similarly, cocaine and levodopa can cause stereotyped movements
(Evans et al. 2004). Stereotypies occur occasionally ipsilateral or
contralateral to a motor deficit during the acute phase of stroke
(Ghika-Schmid et al. 1997) and rarely with other focal lesions
affecting motor control systems (especially the basal ganglia).
Mannerisms are purposeful movements carried out in a peculiar
way. Mannerisms are typically evinced in task performance and tend
to be unique to the individual performing them. Although observed
among persons with neuropsychiatric disorders, they are common in
the general population as well.
Catatonia
Catatonia, the syndrome described by Kahlbaum in the nineteenth
century and absorbed into the concept of dementia praecox by
Kraepelin, occurs in a wide variety of neurological and medical
conditions as well as in the classic idiopathic psychoses (Taylor and
Fink 2003). Catatonia comprises a large number of motor and
behavioral abnormalities. Among these are motor signs such as
catalepsy, posturing, or waxy flexibility; signs of psychosocial
withdrawal and/or excitement such as mutism and negativism; and
bizarre or repetitive movements such as grimacing, stereotypies,
mannerisms, command automatism, echopraxia/echolalia,
verbigeration, and impulsiveness. Taylor and Fink (2003) proposed
formal criteria for the catatonia syndrome: 1) immobility, mutism, or
stupor of at least an hour’s duration accompanied by catalepsy,
automatic obedience, or posturing observed on two occasions or 2)
two or more observations of two or more of the following motor
features: stereotypy, echophenomena, catalepsy, automatic
obedience, posturing, negativism, gegenhalten, or ambitendency.
Such signs are common in severe mental disorders, including
schizophrenia spectrum disorders, bipolar disorder, and major
depressive disorder, as well as a large number of neurological and
medical conditions (van der Heijden et al. 2005). Many of the signs
are seen with frontosubcortical lesions (Northoff 2002), and
cataleptic postures can occur with contralateral parietal lesions
(Ghika et al. 1998). Several assessment scales have been devised
and validated; the most commonly used of these is the Bush-Francis
Catatonia Rating Scale (Bush et al. 1996).
Synkinesia and Mirror Movements

Excessive synkinesia—automatic movement accompanying
intended voluntary movement—occurs in a variety of
neuropsychiatric conditions. Obligatory, congenital bimanual
synkinesia (“mirror movements”) persisting into adulthood occurs
with cerebral palsy due to a lesion predating 24 weeks of gestation,
cervical spine disease (such as Klippel-Feil syndrome), agenesis of
the corpus callosum, and Kallmann’s syndrome. To observe the
phenomenon, the examiner asks the patient to touch, repeatedly and
in turn, the fingers of the right hand to the right thumb, and then the
left fingers to the left thumb, as the hands rest supine in front of the
patient; in addition to watching the active hand for fine motor
coordination, the examiner watches the contralateral hand for mirror
movements. The pathophysiology involves abnormal ipsilateral
motor pathways or diminished transcallosal inhibition (Ueki et al.
2005). Asymmetric parkinsonism also gives rise to mirror
movements (Espay et al. 2005). However, it is not uncommon that
no definite malformation, injury, or degenerative condition can be
identified in association with such movements (Rasmussen 1993).
Primitive Reflexes
The various signs collectively referred to as primitive reflexes
differ in their sensitivity and specificity for brain disease, and, in most
instances, the presence of a single primitive reflex may not be
clinically significant (Schneck 2013). By contrast, the presence of
multiple primitive reflexes that fail to habituate on repeated
stimulation more reliably suggests pathology (Di Legge et al. 2001;
Owen and Mulley 2002). Thus, the examiner should place little
weight on a single primitive reflex, especially if it fatigues on
repeated stimulation. The exception is the grasp reflex, which in the
two studies just cited was present in no healthy subject and in only
rare patients with vascular disease but not dementia—and which
thus reliably indicates disease when present.
The received wisdom is that the primitive reflexes listed in Table
2–2 are brought about by cortical disease, especially frontal injury or
degeneration, which disinhibits primitive movement patterns. In light
of that received wisdom, these signs are often described as “frontal
release signs.” However, the localizing value of these signs is
variable, and, with rare exception, their presence localizes to fronto-
subcortico-thalamo-ponto-cerebellar networks rather than to the
frontal lobe alone (Schneck 2013). A possible exception to this rule
is the grasp reflex, which appears to be a genuine frontal sign: in a
study of 491 patients, grasping was never associated with a
postcentral lesion (De Renzi and Barbieri 1992). A similar response
may be elicited in the sole of the foot, but the plantar grasp is
present only when the palmar grasp is present, so its diagnostic
utility is limited. Awareness of the plantar grasp reflex, however, may
keep the examiner from missing an extensor plantar response when
this is masked by the plantar grasp.
TABLE 2–2. Primitive reflexes, their examination, and interpretation of
findings
Primitive Normal Abnormal

reflexes Examination maneuver response response
Glabellar Examiner taps 10 times Blinking in Partial or full
on the glabella (area response blinking in
just above and to first few response to
between eyebrows) taps then each tap
at rate of one per habituation
second. and no
further
blinks
Grasp Examiner places two No grasp Patient grasps
fingers in patient’s examiner’s
hand and strokes fingers
across palm or
along fingers.
Self-grasp Examiner grasps No grasp Patient grasps
patient’s arm and, own
with webbing contralateral
between the forearm
patient’s thumb and
fingers as the point
of contact, strokes
the patient’s
contralateral ulnar
surface.
Foot grasp Examiner places his or No response Plantar flexion
her hand on the and
plantar surface of adduction of
the distal part of the the toes
patient’s foot and
toes.
Palmomental Examiner strokes palm No movement Ipsilateral
from lateral aspect mentalis
of hypothenar (chin)
eminence to thenar muscle
eminence. contracts
Primitive Normal Abnormal
reflexes Examination maneuver response response
Rooting Examiner uses his No movement Patient turns
finger to stroke head toward
patient’s cheek side being
(from mouth toward stroked
temporomandibular
joint).
Snout Examiner uses his or No movement Lips pucker
her finger to lightly
tap on patient’s lips
(finger oriented
perpendicular to
lips); alternatively,
and to determine
the presence of any
asymmetry of
response, examiner
taps above the
upper lip just lateral
to the philtrum on
each side.
Suck Examiner places No movement Sucking motion
gloved knuckle
between patient’s
lips; alternatively, a
cotton tip applicator
is placed
simultaneously
across the patient’s
tongue and lower
lip.
Some authors have included the Babinski, Hoffmann, or

Rossolimo signs in the category of primitive reflexes. To be sure,
these pyramidal signs reflect disinhibition of early motor synergies,
but because of their specificity for the pyramidal tract, it is
reasonable to consider them separately from primitive reflexes.
Subtle Neurological Signs
Subtle neurological signs (also known historically as “neurological
soft signs”) are a varied set of disturbances of sensorimotor
integration and motor control. Unfortunately, the many studies of
these signs have not used the same test batteries (Sanders and
Keshavan 1998). Among them, the Neurological Evaluation Scale
(Buchanan and Heinrichs 1989) is the most widely used in
psychiatric and neuropsychiatric research (Bombin et al. 2013).
Schizophrenia spectrum disorders are unquestionably associated
with an excess of abnormal neurological examination findings
(Arciniegas et al. 2007). These findings are independent of
neuroleptic treatment and are present in first-episode cases.
Although the bulk of studies have examined the occurrence of subtle
neurological signs in schizophrenia, these signs are not specific to
this disorder, being found in a wide range of psychiatric and
neurological conditions. However, the pattern of abnormal findings
may differ among disorders (Arciniegas et al. 2007; Boks et al. 2004;
Wortzel et al. 2009). Subtle neurological signs therefore should be
considered to provide a nonspecific index of altered brain structure
or function across a broad range of neuropsychiatric disorders
(Schneck 2013).
Mental Status Examination

The neuropsychiatric mental status examination is outlined in
Table 2–3, including the typical elements of the general mental
status examination as well as the core components of the cognitive
examination. A comprehensive review of the mental status
examination in neuropsychiatry is presented elsewhere (Arciniegas
2013c); as in the preceding sections of this chapter, the present
focus is on methods of filling in a matrix of clinical information, rather
than a detailed description of the examination itself, with an
emphasis on cognitive assessment.
TABLE 2–3. Outline of the mental status examination
Section Elements
Appearance and Arousal, apparent age, body habitus and other
behavior physical characteristics, position and posture,
attire and grooming, personal hygiene, voluntary
and involuntary motor activity, eye contact,
comportment (demeanor, attitude), motivation,
engagement with examiner
Emotion and feeling Mood (pervasive and sustained emotion and
emotional feelings; the emotional “climate”) and
affect (moment-to-moment emotion and emotional
feelings; the emotional “weather”)
Communication Voice, speech, language, and paralinguistics (i.e.,
prosody, kinesics)
Thought process Style (flow) and structure (organization) of thought;
“how” an individual thinks
Thought content Perception (e.g., illusions, hallucinations, other
perceptual distortions), ideas (e.g., confabulations,
delusions, obsessions), concerns (e.g., intrusive
memories, worries, phobias), themes, and lethality
(e.g., thoughts of violence toward self, others,
and/or objects); “what” an individual thinks about
Cognition Arousal, attention, processing speed, working
memory, recognition, language and prosody,
declarative memory, praxis, visuospatial function,
calculation, and executive function
Insight Self-awareness and understanding of the thoughts
and actions of others (e.g., social cognition, theory
of mind)
Judgment Ability to reason soundly and draw conclusions
rationally
Source. Adapted from Arciniegas DB: “Medical Evaluation,” in Management of
Vanderploeg RD, Jaffee MS. Washington, DC, American Psychiatric Publishing,
2013, pp 35–72. Copyright © 2013 American Psychiatric Publishing. Used with
permission.
Appearance and Behavior
Observing and documenting appearance and behavior, including
level of arousal (wakefulness), physical characteristics,
comportment, and interactions with the examiner and the
environment (i.e., people, objects), is an essential element of the
mental status examination.
The patient’s apparent age (and its concordance, or not, with
chronological age), body habitus (size and shape), and other
noteworthy physical characteristics (e.g., physical anomalies or
deformities, scars, tattoos, piercings) are noted. Body position and
posture, attire, grooming, and hygiene are noted. Behaviors,
including excesses and/or deficits in voluntary motor function as well
as involuntary movements (as described earlier in this chapter) are
observed throughout the clinical encounter. Eye contact,
comportment, gestures, and associated movements made (or not)
merit particular attention (discussed further in the “Communication”
subsection of this chapter) and may provide information about the
patient’s emotional, motivational, and social-cognitive status.
Comportment refers to the patient’s social conduct, including attitude
(dispositions, opinions, feelings, and beliefs that underlie behavior),
demeanor (behavior toward other people), propriety (adherence to
conventional expectations regarding social conduct), and the overall
character of interpersonal interactions. Motivation—goal-directed
thoughts, feelings, and behaviors—contributes to comportment and
influences the patient’s conduct throughout the entire clinical
encounter (disorders of which are discussed later in this chapter).
Emotion
Assessment of emotion expression and its regulation is performed
by the clinician as a natural part of observing the patient during the
examination; in addition, the examiner asks questions about the
patient’s emotional experience. Questions and observations also
should seek to characterize mood (pervasive and sustained
emotional expression and experience; the emotional “climate”) and
affect (moment-to-moment emotion expression and experience; the
emotional “weather”) (American Psychiatric Association 2013;
Arciniegas 2013a). Toward that end, nothing substitutes for extended
and sensitive conversation.
Persistent and excessive sadness (expressed and experienced) is
a cardinal feature of major depressive episodes, and persistent and
excessive euphoria, irritability, and expansiveness (expressed and
experienced) are cardinal features of manic episodes. Although
these mood disorders are well known to most clinicians across
medical specialties, less well known are the disturbances of emotion
that typify neuropsychiatric illness.
Euphoria, a persistent and unreasonable sense of well-being
without the increased mental and motor rates of a manic state, is
often alluded to in connection with multiple sclerosis. Actually,
euphoria is unusual, and its occurrence almost always signals
extensive disease and cognitive impairment (Ron and Logsdail
1989). Pathological affect refers to brief, uncontrollable, stereotyped
paroxysms of emotional expression due to an underlying
neurological disorder, the prototypical forms of which are
pathological laughing and pathological crying (Wortzel et al. 2008).
Although such episodes may occur without concurrent and
concordant changes in emotional experience, disturbances of
emotional experience during the episodes of pathological affect are
common but often of lesser intensity than the emotional expression
or of a valence contrary to it (i.e., feeling mirth while crying, feeling
sad while laughing) (Olney et al. 2011; Wilson 1924). Pathological
affect may be on a continuum with the affective dyscontrol, lability,
and shallowness that occur in frontal disease or dementia. This latter
state, also called emotionalism, comprises increased tearfulness (or,
more rarely, laughter) and sudden, unexpected, and uncontrollable
tears. So defined, pathological affect and emotionalism are common
among patients with neurological disorders, commonly associated
with cognitive impairment, and related to left frontal and temporal
lesions. Rating scales for pathological affect are available (Robinson
et al. 1993; Smith et al. 2004).
Form of Thought
Thought Disorder
Features of thought disorder in the idiopathic psychoses—poverty
of speech, pressure of speech, derailment, tangentiality,
incoherence, and so on—have been carefully defined (Andreasen
1979), and both executive and semantic dysfunction may participate
in the pathogenesis of formal thought disorder (Barrera et al. 2005).
Cutting and Murphy (1988) differentiated among intrinsic thinking
disturbances, including loose associations, concreteness,
overinclusiveness, and illogicality; disorders of the expression of
thought, including disturbed pragmatics of language; and deficits in
real-world knowledge, which can produce odd conversational
interchange. They argued that the distinctive pattern of
schizophrenic thought is suggestive of right hemisphere dysfunction.
However, the group of schizophrenic patients with thought disorder
may be heterogeneous (Kuperberg et al. 2000), and lesions
elsewhere may produce abnormal expression of thought (Chatterjee
et al. 1997).
Many authors have noted the similarity between the “negative”
features of thought disorder and the characteristics of the frontal lobe
syndrome. Cutting (1987) contrasted the “positive” features of
thought disorder in schizophrenia with the thinking process of
delirious patients. The latter was prominently illogical or slowed and
impoverished in output; more distinctively, delirious patients gave
occasional irrelevant replies amid competent responses.
Vorbeireden (Vorbeigehen)
The symptom of approximate answers, vorbeireden
(vorbeigehen), is the defining feature of the Ganser state (Dwyer and
Reid 2004). The patient’s responses show that he or she
understands the questions, however, the lack of knowledge implied
by the mistaken replies is implausible (e.g., the patient reports that a
horse has three legs). The remainder of the syndrome includes
confusion, hallucinations, and conversion symptoms. This
phenomenon is rare, and whether it rests on organic foundations has
been controversial from the outset. Ganser (1898) described three
patients (of four he had seen); two had experienced head injury, and
one was recovering from typhus. Subsequently, some regarded the
behavior as dissociative (Feinstein and Hattersley 1988), and others
emphasized the neuropsychological underpinnings (Cutting 1990).
Content of Thought
Delusions
Complex psychotic phenomena, such as first-rank symptoms, are
often associated with preservation of cognitive capacity (Almeida et
al. 1995; Cutting 2015), whereas patients with neurocognitive
disorders more commonly develop unsystematized abnormal beliefs
or nonbizarre delusions that often arise ad hoc from situations of
cognitive failure. Malloy and Richardson (1994) argued that
delusions confined to a single topic suggest frontal lobe disorder, but
by no means can neurological disease always be identified, and
such delusions are observed in patients with idiopathic psychotic
disorders (American Psychiatric Association 2013). By contrast,
misidentification syndromes, such as Capgras and Frégoli
syndromes, and states seemingly related to misidentification, such
as the phantom boarder syndrome, occur in schizophrenia spectrum
disorders as well as acquired and degenerative neurological
disorders but are more common in the latter contexts (Anderson and
Filley 2016). The presence of persecutory delusions before the
advent of misidentification speaks against evident organic factors
(Fleminger and Burns 1993).
When delusions—be they monothematic or polythematic,
mundane or bizarre—arise in the context of neurological disorders,
they tend to be associated with right hemisphere lesions or right
hemispheric network dysfunction (Darby and Prasad 2016; Gurin
and Blum 2017). This association appears to evince the role of the
right hemisphere in pragmatic communication, perceptual
integration, attentional surveillance, anomaly/novelty detection, and
belief updating (Gurin and Blum 2017), which, when disrupted by
lesion or degeneration, provides the foundation for the development
of fixed false beliefs.
Hallucinations
Visual hallucinations occur commonly in idiopathic schizophrenia,
but visual hallucinations in the absence of auditory hallucinations are
strongly suggestive of neurological disease. Elementary visual
hallucinations may arise from ocular disease or occipital disease;
migraine auras or migraine accompaniments without headache are a
common cause. Complex, or formed, visual hallucinations arise from
a variety of pathological bases, including narcolepsy, epilepsy, and
deafferentation of the visual system due to stroke. Visual
hallucinations developing early in the course of other symptoms
suggesting a neurodegenerative dementia imply underlying diffuse
Lewy body disease (Ballard et al. 1999). A lilliputian character is
present in visual hallucinations of various etiologies without apparent
specificity. Palinopsia refers to persisting or recurrent visual images
after the stimulus of which they are copies is gone. Responsible
lesions are typically parieto-occipital, perhaps related to a role for
abnormal parietal spatial representations in pathogenesis. The
physiology of this phenomenon may be epileptic or disinhibition of
the short-term visual memory system (Maillot et al. 1993).
The Charles Bonnet syndrome—visual hallucinations without
other psychopathology, usually in the presence of ocular disease
with visual loss—is common, especially in the elderly. The
hallucinations are usually vivid images of animals or human beings
or of faces, and the patient is aware of their unreality. The visual
experience exceeds veridical perception in clarity. Characteristically,
patients with these symptoms do not report them spontaneously.
Visual hallucinations in a hemifield blind from cerebral disease
(release hallucinations) occur with occipital strokes or occasionally
other posterior lesions. Because the pathogenesis of hallucinations
in ocular disease may differ from that in occipital disease, the
eponym probably is best reserved for hallucinations associated with
peripheral visual impairment.
Vivid, elaborate, and well-formed visual hallucinations may occur
with disease in the upper brain stem or thalamus (peduncular
hallucinosis). Such hallucinations often worsen in the evening
(crepuscular) or when the patient is sleepy, and again the patient is
generally aware of their unreality. A dreamlike state may accompany
the hallucinosis. Similar hallucinations occur as hypnagogic
phenomena in narcolepsy and in response to dopaminergic drugs in
Parkinson’s disease, and the brain stem mechanism may be related.
Auditory hallucinations are characteristic of idiopathic psychiatric
disorders but occur in association with a broad range of neurological
disorders as well. Similarly to peduncular visual hallucinations,
auditory hallucinations may arise from pontine lesions as well as
from lesions in the temporal lobes (Braun et al. 2003). Although
musical hallucinations may develop in patients with idiopathic
psychiatric disorders, they characteristically are associated with
progressive hearing impairment (analogous to Bonnet
hallucinations), including unilateral hearing impairment (in which they
are ipsilateral to the deaf, or more deaf, ear). Analogous to
pallinopsia, palinacousis refers to persisting or recurrent auditory
“images” after the stimulus they echo is gone and is associated with
temporal lobe lesions.
Olfactory hallucinations, often taken to imply epilepsy or temporal
lobe disease, are common in idiopathic psychiatric disorders. Rarely,
the olfactory reference syndrome—a patient’s belief that he or she
emits an aversive odor, with accompanying social withdrawal—may
develop as a consequence of neurological disorders, perhaps
especially right hemisphere lesions (Lochner and Stein 2003).
Cognitive Examination
At what point in the interview should the cognitive examination be
done? If the initial few minutes of history taking give reason to
suspect substantial cognitive difficulty, one may wish to do at least
some of the testing promptly. Not all of the cognitive examination
needs to be done at once. Fatigue is an important factor in the
cognitive performance of many patients, and long examinations may
not elicit their best performance. For this reason, short periods of
probing may yield new perspectives on a patient’s capacities.
Shorter periods of questioning also may help prevent adverse
emotional and behavioral reactions when a patient’s capacities are
exceeded. When such reactions occur, the patient is often unable to
engage effectively in tasks that would otherwise be within his or her
capacities, yielding data collected at such times that, at best, are of
limited value.
A common difficulty for beginners is how to introduce the formal
cognitive inquiry. All too often, one hears the examiner apologize for
the “silly but routine” questions he or she is about to ask. (One never
hears a cardiologist apologize for the silly but routine instrument
being applied to the patient’s precordium.) This is rarely the best way
to gain the patient’s full cooperation and best effort. Most of the time,
patients report symptoms that can lead naturally (i.e., naturally from
the patient’s point of view) to a cognitive examination. For example,
a patient with depressive symptoms may report trouble
concentrating. If the examiner then says, “Let me ask you some
questions to check your concentration,” the patient is more likely to
collaborate and less likely to be offended. Nearly any tasks can then
be introduced.
Attention and Working Memory

Full alertness with normal attention lies at one end of a
continuum, the other end of which is coma. Where the patient is on
this continuum can be assessed by observing the reaction to a
graded series of probes: entering the room, speaking the patient’s
name, touching the patient without speaking, shouting, and so on
through painful stimulation. The proper recording of the response is
by specific notation of the probe and the reaction (e.g., “makes no
response to examiner’s entrance but orients to examiner’s voice;
speaks only when shaken by the shoulder”). Deficits occur in the
capacity to maintain attention to external stimuli (vigilance), the
capacity to attend consistently to internal stimuli (concentration), and
the capacity to shift attention from one stimulus to another.
Vigilance can be assessed by the patient’s capacity to carry out a
continuous-performance task; such tasks have been extensively
used in the psychological laboratory. In a bedside adaptation, the “A
test,” the patient is presented with a string of letters, one per second,
and is required to signal at each occurrence of the letter A. A single
error of omission or of commission is considered an abnormal
response.
Concentration can be assessed by the patient’s capacity to recite
the numbers from 20 to 1 or to give the days of the week or the
months of the year in reverse order. A pathognomonic error is the
intrusion of the ordinary forward order: “20, 19, 18, 17, 18, 19,...”
This amounts to a failure to inhibit the intrusion of the more familiar
“set.”
Digit span is a classic psychological test of working memory,
easily performed at the bedside. The examiner recites strings of
numbers, slowly, clearly, and without phrasing into chunks. The
patient is required to repeat them immediately. Subsequently, the
patient can be asked to repeat strings of digits after reversing them
in his or her head. The normal forward digit span is usually
considered to be a minimum of five. The backward digit span is a
variation of this task that employs executive control of working
memory (i.e., reverse ordering of information held in working
memory). A related task of working memory is asking the patient to
alphabetize the letters of the word world (Leopold and Borson 1997).
Neglect
Hemispatial inattention, or neglect, describes a patient who is
densely inattentive to the nondominant hemispace, typically the left
side of his or her body—one of the most dramatic clinical
phenomena in neuropsychiatry. The bedside clinician can readily
identify the patient who leaves his or her left arm out of the sleeve of
a gown, leaves the left side of breakfast uneaten, and so on. Neglect
can be recognized further during a line-bisection task (the patient
must place an X at the midpoint of a line drawn by the examiner) or a
cancellation task (in which the patient crosses out letters or other
items for which he or she must search in an array). However, careful
attention to neglect in behavior—grooming, dressing, moving about,
acknowledgment of left limbs—is even more sensitive than paper-
and-pencil tasks (Azouvi et al. 2002).
Neglect may occur not only in external space but also in
“representational space” (i.e., the patient may neglect the left half of
an imagined object). Indeed, representational and perceptual neglect
doubly dissociate (Ortigue et al. 2003). Mesulam (1999) constructed
a network theory in which the parietal cortex, frontal cortex, and
cingulate cortex interact to generate attention to the opposite side of
space. Lesions in these cortices produce distinguishable
contralateral sensory neglect, directional hypokinesia, and reduced
motivational value, respectively. Rarely, neglect occurs not on the
left-right axis but on a vertical or radial (near-far) axis (Adair et al.
1995).
An inverse syndrome of “acute hemiconcern” was described as
occurring after right parietal stroke producing pseudothalamic
sensory loss without neglect. The patients transiently concentrated
attention on the left side of the body and manipulated it actively
(Bogousslavsky et al. 1995).
Memory
Bedside testing of verbal memory can be undertaken briefly and
validly. Because memory failure is a sensitive indicator of attentional
dysfunction, in which case the basis is not in memory systems
proper, assessing and interpreting attentional function is a
prerequisite to the evaluation of memory. That done, recall of a name
and an address or three words after several minutes is simple and
satisfactory (Bowers et al. 1989). Addition of a cueing procedure at
the learning stage as well as at the retrieval stage in memory testing
adds specificity to the diagnosis of memory impairment by controlling
for attention and semantic processing. At presentation of target
words for recall, the examiner can provide a category cue, to be
used several minutes later if free recall fails. Failure at this point
strongly suggests impairment in hippocampal memory systems. The
improvement of verbal recall with semantic cues is suggestive of a
disorder of retrieval mechanisms, such as is seen in frontal-
subcortical disease.
Similar testing of figural memory at the bedside is also easily
done. For example, Weintraub and Mesulam’s “three words–three
shapes” test (Weintraub 2000) quickly and simply compares verbal
and figural memory side by side, as well as revealing failure at the
encoding or retrieval stages of memory processing.
Orientation
Disorientation is a nonspecific indicator of altered cerebral
function and/or structure. Disorientation to person, to place, to time,
and to situation differs with regard to the types and severities of
other cognitive disturbances with which the disorientation is typically
associated. Accordingly, the pattern of disorientation can have
diagnostic importance. A patient may be unable to give the date or
place because of impairment in attention, memory, language, or
content of thought. The neuropsychiatrist probes these potential
mechanisms of disorientation by using more specific cognitive tasks.
Communication
Communication refers to the conveyance of information by verbal
and nonverbal means. Speech refers specifically to the use of the
orofacialpharyngeal musculature to articulate words. It is distinct
from language, which is a systematic means of communicating that
uses conventionalized symbols (i.e., signs, sounds, gestures, or
marks) with specific meanings to convey information. Speaking and
writing are the most common forms of linguistic communication, and,
in most patients, the assessment of speech and language are
undertaken concurrently. Among patients with congenital or acquired
impairments in voice, speech, hearing, writing, and/or reading,
however, linguistic communication may be accomplished through the
use of signing, Braille, or other (sometimes idiosyncratic) methods.
Recognizing that language may be conveyed through speech but is
not equivalent to it reduces the likelihood of mistaking disturbances
of speech (dysarthrias) and/or writing (dysgraphias) for disturbances
of language (aphasias).
Speech and Dysarthria
Disorders of speech are difficult to describe, although they often
are easily recognized when heard. In pyramidal disorders, the
speech output is slow, strained, and slurred. Often accompanying
the speech disorder are other features of pseudobulbar palsy,
including dysphagia, drooling, and disturbance of the expression of
emotions. Usually, the causative lesions are bilateral. By contrast,
bulbar, or flaccid, dysarthria is marked by breathiness and nasality,
as well as impaired articulation. Signs of lower motor neuron (brain
stem) involvement can be found in the bulbar musculature. Scanning
speech is a characteristic sign of disease of the cerebellum and its
connections; the rate of speech output is irregular, with equalized
stress on the syllables. In parkinsonism and in depression, speech is
hypophonic and monotonous, often tailing off with longer phrases.
Darley et al. (1975) described in detail a scheme for examining
the motor aspects of speech. It begins with assessment of the
elements of speech production (e.g., facial musculature, tongue,
palate) at rest and during voluntary movement. The patient is asked
to produce the vowel “ah” steadily for as long as possible; the
performance is assessed for voice quality, duration, pitch,
steadiness, and loudness. Production of strings of individual
consonants (e.g., “puh-puh-puh-puh”) and alternated consonants
(e.g., “puh-tuh-kuh-puh-tuh-kuh”) is assessed for rate and rhythm.
Impairment of the more complex alternation of sounds with intact
production of individual sounds suggests apraxia of speech.
Language, Aphasia, and Discourse

Symbolic communication may be assessed with respect to four
principal components: naming, fluency, repetition, and
comprehension. Assessment generally encompasses both oral and
written language; these domains are germane to the assessment of
individuals whose primary mode of symbolic communication is
through sign language or Braille as well. An impairment in
confrontation naming, even without concurrent impairments in
fluency, repetition, syntax, or comprehension, is sufficient to merit
a diagnosis of aphasia (i.e., anomic aphasia).
Attending to the patient’s spontaneous speech and responses to
questions throughout the interview enables qualitative assessment of
fluency and comprehension. Fluency is operationally defined as
phrase lengths that, on average, are of six or more words and are
without undue pauses or agrammatisms. Written fluency requires
specific testing and typically entails asking the patient to write a
complete sentence or a brief narrative. Agraphia is a constant
accompaniment of aphasic syndromes, so the writing sample is a
good screening test of language function (assuming premorbid
literacy). Similarly, comprehension of written language requires
specific testing. This can be accomplished by asking the patient to
give yes/no responses (to minimize the factor of apraxia) to
progressively more complex questions (e.g., “Am I wearing a hat?”
“Does a stone sink in water?” “Does Monday come before
Tuesday?”). Patients with anterior aphasia often have mild disorders
of comprehension of syntactically complex material. This can be
observed by asking patients to interpret sentences in which the
passive voice and similarly difficult constructions are used (e.g., “The
lion was killed by the tiger. Which animal was dead?”).
Alexia can be present with no other abnormality of language
(alexia without agraphia or pure alexia), although this is a relatively
rare problem. More commonly, problems with reading identified
during the examination reflect literacy issues.
Repetition and naming require specific testing. Repetition is tested
by offering the patient phrases of increasing length and grammatical
complexity. For example, one may start with single words and
continue with simple phrases, then invert the phrases into questions,
and then use phrases made up of grammatical function words (e.g.,
“no ifs, ands, or buts”). Confrontation naming can be tested by using
items at hand: a watch and its parts; parts of the body; shirt, sleeve,
and cuff; and so on. Naming is dependent on the frequency of
occurrence of the target word in the vocabulary, so testing must
employ less frequently used items to detect mild but clinically
meaningful deficits. Some patients have extraordinary domain-
specific dissociations in naming ability (category-specific anomia); for
example, the ability to name vegetables may be intact while the
ability to name animals is devastated (Gainotti 2000).
Patients who do not have elementary disorders of language,
nonetheless, may have macrolinguistic deficits. When words and
sentences—lexicon and syntax —are normal, paragraphs and
discourse may not be. Patients with right hemisphere disease,
despite the adequacy of their lexical-semantic and syntactical
performance, have deficits in the capacity to tell a story or recognize
the point of a joke (Brownell and Martino 1998; Paradis 1998). These
patients rarely give “I don’t know” responses; rather, they contrive
some answer even if implausible; they fail to draw appropriate
inferences, especially from emotional data, so that incongruity is not
recognized; and their sense of humor is impaired. Temporal lobe
epilepsy and traumatic brain injury are associated with deficits in
planning, producing, and monitoring discourse; patients’ narratives
may be verbose and inefficient or contain insufficient or irrelevant
information, requiring the listener to expend extra effort to
understand them (Biddle et al. 1996; Field et al. 2000). These
findings emphasize the value of open-ended inquiries (e.g., “What
brings you to the hospital?”), with attention to the patient’s discourse
taken as a whole as a sign of cerebral function. Disorders at the level
of discourse are well recognized phenomenologically in psychiatry.
Patients who experienced attachment disorganization in childhood
show disturbances of the form of thought when discussing
emotionally powerful material; this may relate to the characteristic
vagueness and inconsistency of the medical accounts provided by
hysterical patients (Ovsiew 2006).
Mutism
The term mutism should be reserved for the situation in which a
person does not speak and does not make any attempt at spoken
communication despite preservation of an adequate level of
consciousness. The first order of business in assessing an alert
patient who does not speak is to examine phonation, articulation,
and nonspeech movements of the relevant musculature (e.g.,
swallowing, coughing) to determine whether the disorder is due to
elementary sensorimotor abnormalities involving the apparatus of
speech. A restricted disturbance of verbal communication also must
be distinguished from a more global disorder of the initiation of
activity. At its extreme, the latter is the state of akinetic mutism.
If an elementary disorder is not at fault, the examination proceeds
to a search for specific disturbances of verbal communication. Does
the patient make any spontaneous attempt at communication
through means other than speech? Does the patient gesture? Can
the patient write, or, if hemiplegic, can he or she write with the
nondominant hand? Can he or she arrange cut-out paper letters or
letters from a child’s set of spelling toys? Or, if familiar with sign
language, can he or she sign? Some patients with acute vascular
lesions restricted to the lower primary motor cortex and the adjacent
frontal operculum have transient mutism and then recover through
severe dysarthria without agrammatism, a disorder known as
aphemia (Fox et al. 2001). The same syndrome can arise from right
hemisphere disease, testifying to its nature as an articulatory rather
than a language disorder (Mendez 2004; Vitali et al. 2004).
Transcortical motor aphasia features a prominent disturbance of
spontaneous speech, occasionally beginning as mutism. Mutism
also commonly develops in patients with frontotemporal dementia or
primary progressive aphasia (Snowden et al. 1992).
Stuttering and Cluttering

Common developmental stuttering, or stammering, is familiar to
everyone’s ear. Rhythm of speech is disturbed by repetition,
prolongation, or arrest of sounds. In developmental but not acquired
stuttering, involuntary movements of the face and head resembling
those of cranial dystonia—such as excessive blinking, forced eye
closure, clonic jaw movements, and head tilt—are characteristically
seen. Alternatively, such movements can be interpreted as being
akin to tics; this view is supported by an increased prevalence of
obsessive-compulsive behaviors in persons with developmental
stuttering (Abwender et al. 1998). Rarely, developmental stuttering
that had been overcome returns after brain injury, or developmental
stuttering disappears after brain injury (Helm-Estabrooks et al.
1986).
Acquired stuttering, subtly different from the developmental variety
(Van Borsel and Taillieu 2001), is unusual but can be caused by
stroke, traumatic brain injury, extrapyramidal disease, and
antipsychotic medications. Although ictal or postictal stuttering
occurs rarely in epilepsy, the more common occurrence is in
psychogenic nonepileptic seizures (Chung et al. 2004; Vossler et al.
2004). Psychogenic stuttering—marked by dramatic response to
psychological treatment, atypical or “bizarre” speech features,
multiple concurrent pseudoneurological complaints, and variability or
situation specificity in presentation—may occur with or without
concomitant structural neurological disease (Duffy and Baumgartner
1997).
Cluttering is a disorder of fluency in which discourse, rather than
purely articulation, is disturbed by a range of deficits in speech
pragmatics, motor control, and attention (Daly and Burnett 1999).
Speech output is abnormal because of rapid rate, disturbed prosody,
sound transpositions or slips of the tongue, poor narrative skills, and
impaired management of the social interaction encompassing
speech. Thoughts may be expressed in fragments; words or phrases
may be repeated. In sharp contrast to developmental stuttering,
patients with cluttering are characteristically unconcerned about their
impairment. Stuttering may be mistakenly diagnosed or occur in
association with cluttering. Some features of the disorder are
replicated by festinant speech in parkinsonism (Lebrun 1996), and
rare instances of acquired cluttering have been reported (Thacker
and De Nil 1996).
Echolalia
In echolalia, the patient repeats the speech of another person
automatically, without communicative intent or effect. Often, the
speech repeated is that of the examiner, and the phenomenon is
immediately apparent without being specifically elicited. At times,
other verbalizations in the environment are repeated. Sometimes the
patient repeats only the last portion of what he or she hears,
beginning with a natural break in the utterance. Sometimes
grammatical corrections are made when the examiner deliberately
utters an ungrammatical sentence. The patient may reverse
pronouns (e.g., “I” for “you”) in the interlocutor’s utterance, altering
the sentence in a grammatically appropriate way. These corrections
and alterations evince intactness of the patient’s syntactic
capabilities. Speaking to the patient in a foreign language may elicit
obviously automatic echolalic speech.
Echolalia is a normal phenomenon in the learning of language in
infancy. Echolalia in transcortical aphasia marks the intactness of
primary language areas in the frontal and temporal lobes, with
syntax thus unimpaired but disconnected from control by other
language functions. Other neuropsychiatric disorders in which
echolalia may occur include autism, Tourette syndrome, dementia of
the frontal type and other degenerative disorders, catatonia, and
startle-reaction disorders (McPherson et al. 1994). In all these
situations, it may represent an environmental-dependency reaction,
in which verbal responding is tightly stimulus bound, echolalia
representing the converse of failure of normal initiation of speech
much as perseveration represents the converse of impersistence.
Palilalia
Palilalia is the patient’s automatic repetition of his or her own word
or phrase. Commonly, the volume of the patient’s voice trails off and
the rate of speech is festinant; less frequently, in palilalie atonique,
repetitions of the utterance without acceleration alternate with
silence. Despite claims to the contrary, repetition need not be
confined to elements at the end of the utterance (Van Borsel et al.
2001). Palilalia occurs most commonly among patients with
extrapyramidal diseases, including progressive supranuclear palsy,
postencephalitic parkinsonism, and idiopathic parkinsonism, but it
may be observed in association with Tourette syndrome, epilepsy,
traumatic brain injury, thalamic lesions, and neurosyphilis as well.
Blurting
The speech of some patients is marked by impulsive utterances of
stereotyped or simple responses with no aphasic or echolalic
features—blurting. For example, an elderly woman had the clinical
features of progressive supranuclear palsy with no elementary
cognitive abnormality. When questioned, she often replied “yes, yes”
or “no, no” even before the questioner finished speaking and
regardless of her intended answer to the question. She could then
correct herself and give the reply she wished to give and was unable
to explain the behavior. This phenomenon (also described as
“echoing approval” and “yes-no reversals”) seems to be related to
echolalia and palilalia as well as to the environment-driven, impulsive
(but not stereotyped) utterances of patients with disorders involving
the frontostriatal circuitry (Ovsiew 2003).
Prosody and Affective Aprosodia

Lesions of the right hemisphere may disturb prosody, the “melody
of language,” which conveys both propositional and affective
information. Such lesions interfere with the production and/or
recognition of affective elements of verbal communication. Ross
(1981) schematized these syndromes—the affective aprosodias—as
mirror images of left hemisphere aphasic syndromes. Less
commonly, left hemisphere lesions also may produce prosodic
abnormalities along with aphasia and cortical dysarthria (Wertz et al.
1998).
Often, appropriate test materials also disclose disturbed
recognition of the affective component of material presented visually
to patients with right hemisphere lesions. Unless the primary
prosodic alteration is recognized, the abnormality may appear to lie
in mood or social relatedness. The examiner should listen to
spontaneous speech for prosodic elements; ask the patient to
produce statements in various emotional tones, such as anger,
sadness, surprise, and joy; produce such emotional phrasings
himself or herself, using a neutral sentence (e.g., “I am going to the
store”) while turning his or her face away from the patient, and ask
the patient to identify the emotion; and ask the patient to reproduce
an emotional phrasing the examiner has generated (Ross 1993).
Praxis and Apraxia

Praxis refers to the ability to perform skilled purposeful
movements on demand. Inability to do so in the absence of
elementary sensory or motor dysfunction that explain that inability or
language comprehension problems that preclude understanding of
the requested act is known as apraxia. Limb-kinetic apraxia amounts
to cortical clumsiness, especially of finger coordination. Ideomotor
apraxia refers to impaired ability to perform skilled transitive
movements (i.e., action on an imagined object). A screening
examination should use several tasks that differ with respect to their
transitive versus intransitive, meaningful versus nonmeaningful,
outward-directed versus self-directed, single versus repetitive, or
novel versus overlearned character, as well as their focus on
oromotor, limb, or axial movement. Disorders of performing
pantomimed transitive movements predominantly occur in patients
with left hemisphere lesions and commonly co-occur with aphasias.
As with other tasks in the cognitive examination, errors in performing
skilled movements are more telling than simple failures, and the
patient who shows how to hammer with a flat palm is unequivocally
apraxic. For some forms of apraxia, patients do not complain of
apraxic deficits and are not disabled by them because the deficits do
not appear in a natural context. However, this may not always be so,
and exploration of the motor performance deficit across contexts is
appropriate (Hanna-Pladdy et al. 2003). The phenomenon of
ideational apraxia is the incapacity to carry out a sequential or
ordered set of actions toward a unitary goal in the presence of the
necessary objects.
Signs of Callosal Disconnection

Simple maneuvers suffice to elicit many of the crucial elements of
the callosal disconnection syndromes. On examination, the patient
with callosal lesions shows an inability to name odors presented to
the right nostril. In visual field testing, a hemianopsia appears to be
present in each hemifield alternately, opposite to the hand the patient
uses to point to stimuli. Thus, when the patient is using the right
hand, he or she responds only to stimuli in the right hemifield, but
when the patient is using the left hand, he or she responds only to
stimuli in the left hemifield.
Callosal apraxia, which typically involves apraxia of only the left
hand in a left hemisphere–dominant individual, can be shown by the
usual testing maneuvers. This problem arises as a result of impaired
transfer of motor engrams that guide praxic actions from the left
hemisphere to the right hemisphere (which controls the left hand) by
a callosal lesion. Similarly, writing with the left hand is impossible.
For reciprocal reasons, the right hand shows a visuo-constructional
disorder. The patient has an anomia for unseen objects felt with the
left hand. If the examiner places one of the patient’s hands (again
unseen) into a given posture, the patient is unable to match the
posture with the other hand. Similarly, the patient cannot touch with
the left thumb the finger of the left hand that corresponds to the
finger of the right hand touched by the examiner, and vice versa.
No doubt the most dramatic feature of callosal disconnection is
behavioral conflict between the hands or the patient’s sense that the
left hand behaves in an “alien” fashion. Brion and Jedynak (1972)
described “le signe de la main étrangère,” translated in the English
summary of the article as the “strange hand sign” but subsequently
(and better) as the “alien hand sign.” The original description clearly
conveyed a sensory phenomenon, akin to neglect and one which
Brion and Jedynak considered a hemisomatagnosia specific for
touch. The authors emphasized the unawareness specifically of
ownership of the hand, that is, the sense of “strangeness” or
alienation and the association of this phenomenon with posterior
callosal lesions.
Many subsequent patients with intermanual conflict have had
lesions in various positions in the callosum. However, not all patients
with the alien hand phenomenon have callosal disconnection. The
phenomenon of directed though unwilled behavior by the hand—the
“anarchic hand”—is associated with frontal lobe pathology. Other
patients without callosal lesions may have the alien hand syndrome
through a combination of deficits involving praxis and proprioception
(MacGowan et al. 1997). The alien hand seen in corticobasal
degeneration (Fisher 2000) may fit this pattern in some instances; in
others, it may be more closely akin to the levitation of the upper
extremity seen with contralateral parietal lesions (Gondim et al.
2005).
Recognition and Agnosia

The bedside clinician can seek evidence of relatively intact
elementary visual processing (e.g., copying the picture of an object
may be possible). Although the patient’s language is intact (e.g., he
or she is able to name the object in the picture from a description or
from tactile data), his or her capacity to recognize the object visually
—either by naming it or by demonstrating its use—is strikingly
abnormal. Such patients are often markedly impaired in activities of
daily living. Visual agnosia results from a ventral lesion of the “what”
stream of processing.
Alert to the patient’s and family’s reports and equipped with
photographs of a few famous people, the bedside examiner can
identify clinical cases of prosopagnosia, an acquired defect of face
recognition. The lesion is ventral occipitotemporal, either on the right
or bilaterally. Disordered recognition not of facial identity but of
features such as gaze direction or expression may be associated
with more dorsal lesions. Some prosopagnostic patients show not
only an inability to recognize specific faces (while knowing that they
are looking at a face) but also an inability to recognize individual
exemplars of other classes of items; such patients may not be able
to identify their own car or farm animal.
Simultanagnosia, the inability to discern more than one object at a
time, is detected by asking the patient to describe a visually complex
array; the Cookie Theft picture from the Boston Diagnostic Aphasia
Examination (Goodglass and Kaplan 1983) is suitable.
Simultanagnosia is a rare and incompletely characterized defect,
and its association with optic ataxia and psychic paralysis of gaze is
inconstant. These disorders result from dorsal lesions of the “where”
processing stream. Focal cortical degenerations or Alzheimer’s
disease may produce dysfunction of posterodorsal or posteroventral
cortices, with disturbed spatial processing or object recognition
(Caselli 2000).
Visuospatial Function and Dysfunction

The traditional probes for impairment with regard to spatial
relations are drawing and copying tasks. Copying a Greek cross,
intersecting pentagons, a figure from the Bender-Gestalt test (Lesak
2012), or the figures in Mesulam and Weintraub’s three-shapes test
(Weintraub 2000) or drawing a clock face serves as a suitable
screen; more subtle abnormality may be identified with use of the
Rey Complex Figure test (Lesak 2012). The complexity of the Rey
figure offers the opportunity to assess not only the final performance
but also the patient’s strategy. Having the patient change the color of
ink several times during the copying process shows the steps taken
to produce the final drawing. Both left-sided and right-sided lesions
impair copying performance, although differently. The difference
between a piecemeal approach (the patient slavishly copies element
by element) and a gestalt approach (the patient grasps the major
structures, such as the large rectangle) can be noted, with the former
suggesting right-sided disease. As noted earlier in this chapter,
neglect of the left side of the figure likewise strongly suggests right
hemisphere disease.
Other tasks probe visuospatial analysis without the same output
demand. Elements of neuropsychological instruments can be used,
for example, in asking the patient to discern overlapping figures or to
identify objects photographed from noncanonical views. Even if
vision is impaired, it is possible to test related functions by
topographical skills: “If I go from Chicago to New York, is the Atlantic
Ocean in front of me, behind me, or to my left or right?” Isolated
defects of topographical skill occur, although the usual patient with
trouble finding his or her way around home or hospital unit has a
broader right hemisphere syndrome (Barrash 1998). The focal cases
generally show either an agnosia for landmarks or scenes, related to
a ventral lesion, or an inability to orient in egocentric space despite
preserved recognition, a dorsal deficit.
Executive Function and Dysfunction

Executive function refers to a complex set of processes that
manage and control other, relatively basic, cognitive functions and
that support purposeful goal-directed behaviors (Arciniegas 2013b).
Executive function includes information retrieval and generation, set
shifting, inhibitory control, environmental autonomy, planning and
organization, pattern recognition, categorization, problem solving,
and abstraction (i.e., intrinsic executive functions) as well as the
management and control of “basic” aspects of cognition (i.e.,
executive control of attention, working memory, declarative memory,
language, praxis, visuospatial information). Executive function
provides for conscious decision making and purposive action; the
initiation, maintenance, and cessation of behaviors that increase the
likelihood of achieving a desired end; self-monitoring and outcome
monitoring, including evaluating success of a previously decided
behavior sequence in relation to the goal of that behavior; “mental
flexibility,” including the ability to see beyond the concrete aspects of
a thing or situation, to integrate new information into such schemas,
to consider alternate schemas or actions, and to shift set; and
reasoning, including the capacity to assess the current situation and
potential future action options and to assign outcome probabilities to
those options and pursue the one that best fits the short- and long-
term goals and the judgment that arises from such reasoning, among
other similar complex cognitive functions. Executive function is
engaged most fully when confronting novel problems or situations for
which no previously established routines exist, and it enables an
individual to respond flexibly and adaptively to the challenges of
everyday life.
Deficits in executive function compromise an individual’s ability to
meet the demands of everyday life in a flexible and adaptive manner,
even when basic cognitive functions are relatively preserved.
Concrete thinking, impaired reasoning and decision making,
impersistence, loss of environmental autonomy, and perseveration
are among the many examples of executive dysfunction arising from
developmental, acquired, or degenerative conditions affecting the
dorsolateral prefrontal-subcortical circuit and its integration into the
large-scale distributed neural networks required for executive
function.
The assessment of executive cognitive dysfunction is of
paramount importance in neuropsychiatry, and in all neuropsychiatric
patients an examination of cognition is incomplete without attention
to this domain. Among the most useful measures for briefly
assessing executive function are the Executive Interview (EXIT;
Royall et al. 1992), the Behavioral Dyscontrol Scale (BDS, or its
second version, the BDS-2; Grigsby et al. 1992, 1998), and the
Frontal Assessment Battery (FAB; Dubois et al. 2000). Among these,
the FAB—which assesses conceptualization and abstraction
(similarities task), mental flexibility (lexical fluency task), complex
motor sequencing (Luria hand task, “fist-edge-palm”), sensitivity to
interference (conflicting instructions task), inhibitory control (go–no
go task), and environmental autonomy (prehension behavior and
response to social ambiguity)—has become among the most widely
accepted and useful bedside assessments of executive function
(Arciniegas 2013b; Daffner et al. 2015).
Insight and Unawareness of Deficits

Insight refers to the capacity for understanding one’s own mental
processes, problems, and circumstances (i.e., self-awareness), as
well as the ability to understand the mental processes of others and
the significance of events or actions. The capacity for self-awareness
and insight into the minds and actions of others are related but
psychologically distinct functions that are characterized by
substantial inter-individual differences even among healthy
individuals. The patient who lacks awareness of a deficit obvious to
everyone else is a common phenomenon in neuropsychiatry, one
with important implications for treatment.
The demented patient with Alzheimer’s disease often lacks
awareness of the reason his or her spouse wants to visit the doctor.
In Anton’s syndrome, the patient is unaware of blindness, typically
cortical blindness. Patients with tardive dyskinesia are often unaware
of the abnormal movements. The classical—and common—example
of unawareness of illness is right hemisphere injury and
unawareness of a left hemiparesis. However, disturbances of
awareness depend on the combination of parietal and frontal lesions
(Pia et al. 2004) and particularly the frontal polar areas (Ramnani
and Owen 2004). A range of states can be seen, from minimization
of the gravity of the deficit (anosodiaphoria) through simple
unawareness (anosognosia) to bizarre denial of ownership of the
affected body part or delusional beliefs about it (somatoparaphrenia).
Surprisingly (from the perspective of currently dominant paradigms),
not only the denial but also the presumably elementary sensory
impairment may depend on operations in the patient’s inner
representational world, including defensive operations (Bottini et al.
2002; Solms and Turnbull 2002). Such defensive processes appear
to contribute to lack of insight in psychosis, along with cognitive
impairment (Subotnik et al. 2005). A purely motivational explanation
of anosognosia is inadequate, however, as is shown by the rarity of
denial of illness when the lesion is peripheral and by the lack of
denial of other deficits in the patient with anosognosia for
hemiplegia. As Vuilleumier (2004, p. 13) put it, “Some particular brain
states seem required to permit anosognosia.” However, the
disordered brain state may not always consist of denial; disturbances
of discovery of anomalous functioning (because of neglect or
deafferentation) or of the formation of beliefs in circumstances of
uncertainty may lie at the root of anosognosia.
Standardized Cognitive and Noncognitive

Assessments in Neuropsychiatry
Cognitive Screening Instruments
Over the last 40 years, a multitude of cognitive screening
measures have been developed and promulgated with varying
degrees of usefulness and acceptance in both primary care and the
clinical neuroscience specialties (Cordell et al. 2013; Lin et al.
2013a, 2013b). Among them, the Mini-Mental State Examination
(MMSE; Folstein et al. 1975) and the Montreal Cognitive
Assessment (MoCA; Nasreddine et al. 2005) are the most widely
used. Although each of these measures has its advantages and
disadvantages, both are unidimensional measures (Bernstein et al.
2011; Jones and Gallo 2000)—contrary to the appearance given in
each measure by the labeling of test items under specific cognitive
domain headings. Additionally, performance on both measures is
strongly influenced by age, education, and language/culture (Crum
et al. 1993; Rossetti et al. 2011), and interpretation of performance
using commonly recommended raw score cutoffs yields high rates of
misclassification (Crum et al. 1993; Kenny et al. 2013; Rossetti et al.
2011). For example, the commonly used raw cutoff score of 26 on
the MoCA misclassifies more than 66% of healthy adults as
cognitively impaired (Rossetti et al. 2011).
Accordingly, the recommendations of the American
Neuropsychiatric Association Committee on Research (Malloy et al.
1997) on cognitive screening instruments in neuropsychiatry applies
to the MMSE and extends to the MoCA: these measures serve only
as minimum screening assessments for cognitive impairment, must
be interpreted using age- and education-normative corrections, and
should be supplemented with specific measures appropriate to the
clinical presentation of any particular patient (e.g., delayed memory,
visuospatial function, executive function). These instruments (i.e.,
MMSE or MoCA plus additional domain-specific assessments) can
provide a brief, quantititative, and repeatable cognitive examination.
Population-based normative data are available for both the MMSE
and MoCA (Crum et al. 1993; Kenny et al. 2013; Rossetti et al. 2011;
each database drawn from community samples of more than 2,600
individuals) with which z scores (i.e., standard deviations from the
mean) can be calculated and performance interpreted.
Performances yielding z scores of –2 or lower (i.e., ≥2 standard
deviations below age- and education-adjusted performance
expectations) reflect cognitive impairment of a severity consistent
with major neurocognitive disorder; performances yielding z scores
of –1 to –2 (i.e., 1–2 standard deviations below age- and education-
adjusted performance expectations) reflect mild cognitive
impairments at a level consistent with mild neurocognitive disorder
(American Psychiatric Association 2013). A more conservative, and
empirically established, threshold for mild cognitive impairment is
z=–1.5, which represents a reasonable compromise for making a
diagnosis of mild cognitive impairment (or mild neurocognitive
disorder) clinically meaningful (Knopman et al. 2015), provided that
everyday functional performance comports with that diagnosis as
well.
Domain-Specific Cognitive Measures

Importantly, the MMSE, MoCA, and other similar brief measures
are intended for use, and should serve only, as cognitive screening
measures. They are not appropriate instruments with which to render
diagnoses of neurocognitive disorders. When a patient performs
below expectations on such a measure, the next step in the
evaluation of a possible neurocognitive disorder is the administration
and interpretation of one or more domain-specific cognitive
measures relevant to the diagnosis in question.
Indeed, the DSM-5 criteria for disorders in which cognitive
impairment is the principal feature require the use of domain-specific
assessment in the service of diagnosing such conditions (American
Psychiatric Association 2013). DSM-5 describes six general domains
of clinical relevance to these diagnoses, under which attention
(selective, sustained, and divided), processing speed, declarative
memory, language, visuospatial function, visuo-constructional
abilities, praxis, recognition (gnosis), executive function, and social
cognition are subsumed. For each of these domains, DSM-5
provides examples of symptoms or observations consistent with mild
or major neurocognitive disorder, and suggested assessments are
provided (American Psychiatric Association 2013, pp. 593–595).
Normative interpretation of performance on measures assessing
these aspects of cognition is a required element of the evaluation for
neurocognitive disorders, as is ascertainment of the functional
consequences of any cognitive impairments identified.
In the DSM-5 era, then, knowledge and skilled use of domain-
specific cognitive tests as well as their normative interpretation is an
expectation of clinicians rendering neurocognitive disorder
diagnoses. Complementary recommendations and guidance are
provided by the Behavioral Neurology Section of the American
Academy of Neurology (Daffner et al. 2015), which conducted
evidence-based reviews of frequently used tests of attention,
executive function, memory, language, and spatial cognition from
which a clinically useful cognitive examination could be constructed.
Their reviews focused on suitability for office-based clinical practice,
emphasizing relatively brief administration times, availability of
normative data (echoing the aforementioned recommendations on
the use of such in everyday practice), and measures in the public
domain. Their review yielded a list of 19 domain-specific measures
that can be readily applied to clinical practice and must supplant
cognitive screening measures like the MMSE and MoCA when
performing diagnostic evaluations for neurocognitive disorders.
Standardized Neuropsychiatric Assessments

There are a great many standardized, valid, and reliable
diagnostic, syndrome-specific, and symptom-specific asessments of
neuropsychiatric status, a complete review of which is beyond the
scope of the present chapter (see Arciniegas 2013c). Among these,
the Neuropsychiatric Inventory (NPI) and the Neurobehavioral Rating
Scale—Revised (NRS-R) provide for valid, reliable, broad, and
relatively rapid assessment for neuropsychiatric disturbances in
patients with neurological disorders.
The NPI (Cummings et al. 1994) comprises assessments of up to
14 categories of neuropsychiatric disturbances that are common
among patients with neurologic disorders: delusions, hallucinations,
agitation, aggression, dysphoria, anxiety, elation/euphoria,
apathy/indifference, disinhibition, irritability/lability, aberrant motor
disturbance, sleep disorders, and appetite and eating disorders and
aberrant vocalizations. An informant-based interview approach is
used, which screens across these domains, using 10 screening
questions to invoke supplementary questions to rate frequency and
severity. Validated modifications of this measure allow for its use as
a questionnaire for relatives or caregivers (Neuropsychiatric
Inventory—Questionnaire [NPI-Q]; Kaufer et al. 2000) and for more
frequent assessments in institutional settings (Neuropsychiatric
Inventory—Nursing Home version [NPI-NH]; Wood et al. 2000). A
more recent modification is the couples informant-based assessment
of neuropsychiatric status with clinician-based ratings
(Neuropsychiatric Inventory—Clinician version [NPI-C]; de Medeiros
et al. 2010).
The NRS-R (McCauley et al. 2001) is a modification of the well-
known Brief Psychiatric Rating Scale (Overall and Gorham 1962),
with the addition of items thought relevant for a population with head
injuries but also appropriate for patients with dementia and other
disorders (Sultzer et al. 1995). In contrast to the informant-based
approach of the NPI, the NRS-R combines clinical interview and
observation of the patient across 29 items assessing five domains of
neuropsychiatric function: cognition, positive symptoms, negative
symptoms, mood and affect, and oral/motor function. Completing the
interview portion of the NRS-R typically requires only 15–20 minutes.
During the interview, structured clinical observations are made and
then supplemented by collateral data gathered from reliable
informants on the patient’s day-to-day functioning. This relatively
brief assessment thereby provides the clinician with a useful method
of initial symptom identification, diagnostic formulation, and serial
assessment, as well as a means by which to resolve discrepancies
between the history provided by the patient and his or her
caregivers.
Conclusion
The “complete examination” is a figment of the imagination. No
practical examination can include all possible elements. The expert
clinician is constantly generating hypotheses and constructing an
examination to confirm or refute them. The diagnostician as historian
constantly strives to write the patient’s biography: How did this
person arrive at this predicament at this time? This biographical
endeavor is far more complex than attaching a DSM-5 (American
Psychiatric Association 2013) label to a patient. Diagnosis in
neuropsychiatry does not mean the search only for cause, or only for
localization, or only for functional capacity. It means, along with
those aims, constructing a pathophysiological and
psychopathological formulation from cause to effect, from etiological
factor to symptomatic complaint or performance. This formulation of
pathogenetic mechanisms provides a rational framework for
intervention. Cognitive examination is the traditional psychiatric
method for making a nonidiopathic mental diagnosis, and reliance on
hard signs on physical examination is the traditional neurological
method. The material reviewed in this chapter shows the broad array
of tools that can implicate brain impairment in the pathogenesis of
mental disorder. The clinician should maximize use of the means
available in this difficult task, ideally without interference from
disciplinary boundaries.
References
Abwender DA, Trinidad KS, Jones KR, et al: Features resembling Tourette’s
syndrome in developmental stutterers. Brain Lang 62(3):455–464, 1998
9593619
Adair JC, Williamson DJ, Jacobs DH, et al: Neglect of radial and vertical space:
importance of the retinotopic reference frame. J Neurol Neurosurg Psychiatry
58(6):724–728, 1995 7608675
Almeida OP, Howard RJ, Levy R, David AS: Psychotic states arising in late life
(late paraphrenia). The role of risk factors. Br J Psychiatry 166(2):215–228,
1995 7728366
American Psychiatric Association: Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition. Arlington, VA, American Psychiatric Association, 2013
Anderson CA, Filley CM: Delusional Misidentification Syndromes: Progress and
New Challenges. J Neuropsychiatry Clin Neurosci 28(3):160–161, 2016
27444049
Andreasen NC: Thought, language, and communication disorders. I. Clinical
assessment, definition of terms, and evaluation of their reliability. Arch Gen
Psychiatry 36(12):1315–1321, 1979 496551
Arciniegas DB: Emotion, in Behavioral Neurology & Neuropsychiatry. Edited by
Arciniegas DB, Anderson CA, Filley CM. Cambridge, UK, Cambridge University
Press, 2013a, pp 266–298
Arciniegas DB: Executive function, in Behavioral Neurology & Neuropsychiatry.
Edited by Arciniegas DB, Anderson CA, Filley CM. Cambridge, UK, Cambridge
University Press, 2013b, pp 225–249
Arciniegas DB: Mental status examination, in Behavioral Neurology &
Neuropsychiatry. Edited by Arciniegas DB, Anderson CA, Filley CM.
Cambridge, UK, Cambridge University Press, 2013c, pp 344–393
Arciniegas DB, Rojas DC, Kleman MR, et al: Neurological signs and cognitive
performance distinguish between adolescents with and without psychosis. J
Arroyo S, Lesser RP, Gordon B, et al: Mirth, laughter and gelastic seizures. Brain
116(Pt 4):757–780, 1993 8353707
Azouvi P, Samuel C, Louis-Dreyfus A, et al; French Collaborative Study Group on
Assessment of Unilateral Neglect (GEREN/GRECO): Sensitivity of clinical and
behavioural tests of spatial neglect after right hemisphere stroke. J Neurol
Bakar M, Kirshner HS, Niaz F: The opercular-subopercular syndrome: four cases
with review of the literature. Behav Neurol 11(2):97–103, 1998 11568407
Ballard C, Holmes C, McKeith I, et al: Psychiatric morbidity in dementia with Lewy
bodies: a prospective clinical and neuropathological comparative study with
Alzheimer’s disease. Am J Psychiatry 156(7):1039–1045, 1999 10401449
Barrash J: A historical review of topographical disorientation and its
neuroanatomical correlates. J Clin Exp Neuropsychol 20(6):807–827, 1998
10484692
Barrera A, McKenna PJ, Berrios GE: Formal thought disorder in schizophrenia: an
executive or a semantic deficit? Psychol Med 35(1):121–132, 2005 15842035
Bernstein IH, Lacritz L, Barlow CE, et al: Psychometric evaluation of the Montreal
Cognitive Assessment (MoCA) in three diverse samples. Clin Neuropsychol
25(1):119–126, 2011 21154110
Berthier ML, Kulisevsky J, Gironell A, Heras JA: Obsessive-compulsive disorder
associated with brain lesions: clinical phenomenology, cognitive function, and
anatomic correlates. Neurology 47(2):353–361, 1996 8757004
Beversdorf DQ, Heilman KM: Facilitory paratonia and frontal lobe functioning.
Neurology 51(4):968–971, 1998 9781514
Biddle KR, McCabe A, Bliss LS: Narrative skills following traumatic brain injury in
children and adults. J Commun Disord 29(6):447–468, quiz 468–469, 1996
8956102
Blekher TM, Yee RD, Kirkwood SC, et al: Oculomotor control in asymptomatic and
recently diagnosed individuals with the genetic marker for Huntington’s
disease. Vision Res 44(23):2729–2736, 2004 15358067
Blumer D: Evidence supporting the temporal lobe epilepsy personality syndrome.
Neurology 53(5) (suppl 2):S9–S12, 1999 10496229
Bogousslavsky J, Kumral E, Regli F, et al: Acute hemiconcern: a right anterior
parietotemporal syndrome. J Neurol Neurosurg Psychiatry 58(4):428–432,
1995 7738548
Boks MPM, Liddle PF, Burgerhof JGM, et al: Neurological soft signs discriminating
mood disorders from first episode schizophrenia. Acta Psychiatr Scand
110(1):29–35, 2004 15180777
Bombin I, Arango C, Buchanan RW: Assessment for subtle neurological signs, in
Behavioral Neurology & Neuropsychiatry. Edited by Arciniegas DB, Anderson
CA, Filley CM. Cambridge, UK, Cambridge University Press, 2013, pp 333–343
Bottini G, Bisiach E, Sterzi R, Vallar G: Feeling touches in someone else’s hand.
Neuroreport 13(2):249–252, 2002 11893919
Bowers D, White T, Bauer RM: Recall of three words after 5 minutes: its
relationship to performance on neuropsychological memory tests (abstract).
Neurology 39 (suppl 1):176, 1989
Braun CM, Dumont M, Duval J, et al: Brain modules of hallucination: an analysis of
multiple patients with brain lesions. J Psychiatry Neurosci 28(6):432–449, 2003
14631455
Brewer GJ: Neurologically presenting Wilson’s disease: epidemiology,
pathophysiology and treatment. CNS Drugs 19(3):185–192, 2005 15740174
Brion S, Jedynak CP: Troubles du transfert interhémisphérique (callosal
disconnection). A propos de trois observations de tumeurs du corps calleux. Le
signe de la main étrangére. [Disorders of interhemispheric transfer (callosal
disconnection). 3 cases of tumor of the corpus callosum. The strange hand
sign]. Rev Neurol (Paris) 126(4):257–266, 1972 4350533
Brownell H, Martino G: Deficits in inference and social cognition: the effects of right
hemisphere brain damage on discourse, in Right Hemisphere Language
Comprehension: Perspectives From Cognitive Neuroscience. Edited by
Beeman M, Chiarello C. Mahwah, NJ, Erlbaum, 1998, pp 309–328
Buchanan RW, Heinrichs DW: The Neurological Evaluation Scale (NES): a
structured instrument for the assessment of neurological signs in
schizophrenia. Psychiatry Res 27(3):335–350, 1989 2710870
Bush G, Fink M, Petrides G, et al: Catatonia, I: rating scale and standardized
examination. Acta Psychiatr Scand 93(2):129–136, 1996 8686483
Caplan LR, Schmahmann JD, Kase CS, et al: Caudate infarcts. Arch Neurol
47(2):133–143, 1990 2405818
Caselli RJ: Visual syndromes as the presenting feature of degenerative brain
disease. Semin Neurol 20(1):139–144, 2000 10874783
Chatterjee A, Yapundich R, Mennemeier M, et al: Thalamic thought disorder: on
being “a bit addled.” Cortex 33(3):419–440, 1997 9339327
Chen EYH, Shapleske J, Luque R, et al: The Cambridge Neurological Inventory: a
clinical instrument for assessment of soft neurological signs in psychiatric
patients. Psychiatry Res 56(2):183–204, 1995 7667443
Chung SJ, Im JH, Lee JH, Lee MC: Stuttering and gait disturbance after
supplementary motor area seizure. Mov Disord 19(9):1106–1109, 2004
15372607
Compton MT, Chan RC, Walker EF, Buckley PF: Minor physical anomalies:
potentially informative vestiges of fetal developmental disruptions in
schizophrenia. Int J Dev Neurosci 29(3):245–250, 2011 20974242
Cordell CB, Borson S, Boustani M, et al; Medicare Detection of Cognitive
Impairment Workgroup: Alzheimer’s Association recommendations for
operationalizing the detection of cognitive impairment during the Medicare
Annual Wellness Visit in a primary care setting. Alzheimers Dement 9(2):141–
150, 2013 23265826
Crum RM, Anthony JC, Bassett SS, Folstein MF: Population-based norms for the
Mini-Mental State Examination by age and educational level. JAMA
269(18):2386–2391, 1993 8479064
Cummings JL: Neuropsychiatry of sexual deviations, in Neuropsychiatry and
Mental Health Services. Edited by Ovsiew F. Washington, DC, American
Psychiatric Press, 1999, pp 363–384
Cummings JL, Mega M, Gray K, et al: The Neuropsychiatric Inventory:
comprehensive assessment of psychopathology in dementia. Neurology
44(12):2308–2314, 1994 7991117
Currie J, Ramsden B, McArthur C, Maruff P: Validation of a clinical antisaccadic
eye movement test in the assessment of dementia. Arch Neurol 48(6):644–
648, 1991 2039388
Cutting J: The phenomenology of acute organic psychosis. Comparison with acute
schizophrenia. Br J Psychiatry 151:324–332, 1987 3427288
Cutting J: The Right Cerebral Hemisphere and Psychiatric Disorders. Oxford, UK,
Oxford University Press, 1990
Cutting J: First-rank symptoms of schizophrenia: their nature and origin. Hist
Psychiatry 26(2):131–146. 2015 3427288
Cutting J, Murphy D: Schizophrenic thought disorder: a psychological and organic
interpretation. Br J Psychiatry 152:310–319, 1988 3167363
Dacso CC, Bortz DL: Significance of the Argyll Robertson pupil in clinical
medicine. Am J Med 86(2):199–202, 1989 2643871
Daffner KR, Gale SA, Barrett AM, et al: Improving clinical cognitive testing: report
of the AAN Behavioral Neurology Section Workgroup. Neurology 85(10):910–
918, 2015 26163433
Daly DA, Burnett ML: Cluttering: traditional views and new perspectives, in
Stuttering and Related Disorders of Fluency, 2nd Edition. Edited by Curlee RF.
New York, Thieme Medical Publishing, 1999, pp 222–254
Darby R, Prasad S: Lesion-related delusional misidentification syndromes: a
comprehensive review of reported cases. J Neuropsychiatry Clin Neurosci
28(3):217–222, 2016 26900740
Darley FL, Aronson AE, Brown JR: Motor Speech Disorders. Philadelphia, PA, WB
Saunders, 1975
Daum C, Aybek S: Validity of the “Drift without pronation” sign in conversion
disorder. BMC Neurol 13:31, 2013 23548051
Day RK: Psychomotor agitation: poorly defined and badly measured. J Affect
Disord 55(2-3):89–98, 1999 10628877
Defazio G, Livrea P, Lamberti P, et al: Isolated so-called apraxia of eyelid opening:
report of 10 cases and a review of the literature. Eur Neurol 39(4):204–210,
1998 9635470
Demarest J, Demarest L: Does the ‘torque test’ measure cerebral dominance in
adults? Percept Mot Skills 50(1):155–158, 1980 7367161
de Medeiros K, Robert P, Gauthier S, et al: The Neuropsychiatric Inventory–
Clinician rating scale (NPI-C): reliability and validity of a revised assessment of
neuropsychiatric symptoms in dementia. Int Psychogeriatr 22(6):984–994,
2010 20594384
De Renzi E, Barbieri C: The incidence of the grasp reflex following hemispheric
lesion and its relation to frontal damage. Brain 115(Pt 1):293–313, 1992
1559160
D’Esposito M: Neurological Foundations of Cognitive Neuroscience. Cambridge,
MA, MIT Press, 2003
Devinsky O, Najjar S: Evidence against the existence of a temporal lobe epilepsy
personality syndrome. Neurology 53(5) (suppl 2):S13–S25, 1999 10496230
Devinsky O, Bear D, Volpe BT: Confusional states following posterior cerebral
artery infarction. Arch Neurol 45(2):160–163, 1988 3341929
de Vries BBA, White SM, Knight SJL, et al: Clinical studies on submicroscopic
subtelomeric rearrangements: a checklist. J Med Genet 38(3):145–150, 2001
11238680
Dikmen SS, Corrigan JD, Levin HS, et al: Cognitive outcome following traumatic
brain injury. J Head Trauma Rehabil 24(6):430–438, 2009 19940676
Di Legge S, Di Piero V, Altieri M, et al: Usefulness of primitive reflexes in
demented and non-demented cerebrovascular patients in daily clinical practice.
Eur Neurol 45(2):104–110, 2001 11244273
Dubois B, Slachevsky A, Litvan I, Pillon B: The FAB: a frontal assessment battery
at bedside. Neurology 55(11):1621–1626, 2000 11113214
Duckett S, Gibson W, Salama M: Levy-Reid hypothesis. Brain Lang 45(1):121–
124, 1993 8353727
Duffy JR, Baumgartner J: Psychogenic stuttering in adults with and without
neurologic disease. J Med Speech-Lang Pathol 5:75–96, 1997
Dwyer J, Reid S: Ganser’s syndrome. Lancet 364(9432):471–473, 2004 15288747
Elsworth JD, Lawrence MS, Roth RH, et al: D1 and D2 dopamine receptors
independently regulate spontaneous blink rate in the vervet monkey. J
Pharmacol Exp Ther 259(2):595–600, 1991 1682479
Espay AJ, Li JY, Johnston L, et al: Mirror movements in parkinsonism: evaluation
of a new clinical sign. J Neurol Neurosurg Psychiatry 76(10):1355–1358, 2005
16170075
Esteban A, Traba A, Prieto J: Eyelid movements in health and disease. The
supranuclear impairment of the palpebral motility. Neurophysiol Clin 34(1):3–
15, 2004 15030796
Evans AH, Katzenschlager R, Paviour D, et al: Punding in Parkinson’s disease: its
relation to the dopamine dysregulation syndrome. Mov Disord 19(4):397–405,
2004 15077237
Feinstein A, Hattersley A: Ganser symptoms, dissociation, and dysprosody. J Nerv
Ment Dis 176(11):692–693, 1988 3183655
Field SJ, Saling MM, Berkovic SF: Interictal discourse production in temporal lobe
epilepsy. Brain Lang 74(2):213–222, 2000 10950915
Fishbain DA, Cole B, Cutler RB, et al: A structured evidence-based review on the
meaning of nonorganic physical signs: Waddell signs. Pain Med 4(2):141–181,
2003 12911018
Fisher CM: Alien hand phenomena: a review with the addition of six personal
cases. Can J Neurol Sci 27(3):192–203, 2000 10975531
FitzGerald PM, Jankovic J: Lower body parkinsonism: evidence for vascular
etiology. Mov Disord 4(3):249–260, 1989 2779595
Fleminger S, Burns A: The delusional misidentification syndromes in patients with
and without evidence of organic cerebral disorder: a structured review of case
reports. Biol Psychiatry 33(1):22–32, 1993 8420592
Folstein MF, Folstein SE, McHugh PR: “Mini-mental state”: a practical method for
grading the cognitive state of patients for the clinician. J Psychiatr Res
12(3):189–198, 1975 1202204
Fox RJ, Kasner SE, Chatterjee A, Chalela JA: Aphemia: an isolated disorder of
articulation. Clin Neurol Neurosurg 103(2):123–126, 2001 11516558
Freund H-J: Apraxia, in Diseases of the Nervous System/Clinical Neurobiology,
2nd Edition, Vol 1. Edited by Asbury AK, McKhann GM, McDonald WI.
Philadelphia, PA, WB Saunders, 1992, pp 751–767
Freund H-J, Hummelsheim H: Lesions of premotor cortex in man. Brain 108(Pt
3):697–733, 1985 3929994
Frey KL, Rojas DC, Anderson CA, Arciniegas DB: Comparison of the O-Log and
GOAT as measures of posttraumatic amnesia. Brain Inj 21(5):513–520, 2007
17522991
Gainotti G: What the locus of brain lesion tells us about the nature of the cognitive
defect underlying category-specific disorders: a review. Cortex 36(4):539–559,
2000 11059454
Ganser SJM: A peculiar hysterical state (1898), in Themes and Variations in
European Psychiatry. Edited by Hirsch SR, Shepherd M. Bristol, UK, John
Wright & Sons, 1974, pp 67–73
Ghika J, Tennis M, Growdon J, et al: Environment-driven responses in progressive
supranuclear palsy. J Neurol Sci 130(1):104–111, 1995 7650525
Ghika J, Ghika-Schmid F, Bogousslasvky J: Parietal motor syndrome: a clinical
description in 32 patients in the acute phase of pure parietal strokes studied
prospectively. Clin Neurol Neurosurg 100(4):271–282, 1998 9879853
Ghika-Schmid F, Ghika J, Regli F, Bogousslavsky J: Hyperkinetic movement
disorders during and after acute stroke: the Lausanne Stroke Registry. J Neurol
Sci 146(2):109–116, 1997 9077506
Giladi N, Herman T, Reider-Groswasser II, et al: Clinical characteristics of elderly
patients with a cautious gait of unknown origin. J Neurol 252(3):300–306, 2005
15726273
Gondim FA, Oliveira GR, Cruz-Flores S: Position-dependent levitation of the
dominant arm after left parietal stroke: an unreported feature of posterior alien
limb syndrome? Mov Disord 20(5):632–633, 2005 15726577
Goodglass H, Kaplan E: The Assessment of Aphasia and Related Disorders, 2nd
Edition. Philadelphia, PA, Lea & Febiger, 1983
Grandas F, Esteban A: Eyelid motor abnormalities in progressive supranuclear
palsy. J Neural Transm Suppl 42(suppl):33–41, 1994 7964695
Grigsby J, Kaye K, Robbins LJ: Reliabilities, norms and factor structure of the
Behavioral Dyscontrol Scale. Percept Mot Skills 74(3 Pt 1):883–892, 1992
1608726
Grigsby J, Kaye K, Baxter J, et al: Executive cognitive abilities and functional
status among community-dwelling older persons in the San Luis Valley Health
and Aging Study. J Am Geriatr Soc 46(5):590–596, 1998 9588372
Gurin L, Blum S: Delusions and the right hemisphere: a review of the case for the
right hemisphere as a mediator of reality-based belief. J Neuropsychiatry Clin
Neurosci 29(3):225–235, 2017 28347214
Halligan PW, David AS: Cognitive neuropsychiatry: towards a scientific
psychopathology. Nat Rev Neurosci 2(3):209–215, 2001 11256082
Hanna-Pladdy B, Heilman KM, Foundas AL: Ecological implications of ideomotor
apraxia: evidence from physical activities of daily living. Neurology 60(3):487–
490, 2003 12578932
Harris CM, Shawkat F, Russell-Eggitt I, et al: Intermittent horizontal saccade failure
(‘ocular motor apraxia’) in children. Br J Ophthalmol 80(2):151–158, 1996
8814747
Helm-Estabrooks N, Yeo R, Geschwind N, et al: Stuttering: disappearance and
reappearance with acquired brain lesions. Neurology 36(8):1109–1112, 1986
3736877
Ismail B, Cantor-Graae E, McNeil TF: Minor physical anomalies in schizophrenic
patients and their siblings. Am J Psychiatry 155(12):1695–1702, 1998 9842778
Jacob A, Cherian PJ, Radhakrishnan K, Sarma PS: Emotional facial paresis in
temporal lobe epilepsy: its prevalence and lateralizing value. Seizure 12(1):60–
64, 2003 12495652
Jan JE, Kearney S, Groenveld M, et al: Speech, cognition, and imaging studies in
congenital ocular motor apraxia. Dev Med Child Neurol 40(2):95–99, 1998
9489497
Jankovic J, Lang AE: Movement disorders: diagnosis and assessment, in
Neurology in Clinical Practice, 4th Edition, Vol 1. Edited by Bradley WG, Daroff
RB, Fenichel G, et al. Philadelphia, PA, Butterworth-Heinemann, 2004, pp 293–
322
Jones RN, Gallo JJ: Dimensions of the Mini-Mental State Examination among
community dwelling older adults. Psychol Med 30(3):605–618, 2000 10883716
Kaplan PW: Behavioral manifestations of nonconvulsive status epilepticus.
Epilepsy Behav 3(2):122–139, 2002 12609414
Karson CN, Burns RS, LeWitt PA, et al: Blink rates and disorders of movement.
Neurology 34(5):677–678, 1984 6231489
Kaufer DI, Cummings JL, Ketchel P, et al: Validation of the NPI-Q, a brief clinical
form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci
12(2):233–239, 2000 11001602
Kennard C, Crawford TJ, Henderson L: A pathophysiological approach to saccadic
eye movements in neurological and psychiatric disease. J Neurol Neurosurg
Psychiatry 57(8):881–885, 1994 8057107
Kenny RA, Coen RF, Frewen J, et al: Normative values of cognitive and physical
function in older adults: findings from the Irish Longitudinal Study on Ageing. J
Am Geriatr Soc 61 (suppl 2):S279–S290, 2013 23662720
Knopman DS, Beiser A, Machulda MM, et al: Spectrum of cognition short of
dementia: Framingham Heart Study and Mayo Clinic Study of Aging. Neurology
85(19):1712–1721, 2015 26453643
Koponen H, Rantakallio P, Veijola J, et al: Childhood central nervous system
infections and risk for schizophrenia. Eur Arch Psychiatry Clin Neurosci
254(1):9–13, 2004 14991373
Kuperberg GR, McGuire PK, David AS: Sensitivity to linguistic anomalies in
spoken sentences: a case study approach to understanding thought disorder in
schizophrenia. Psychol Med 30(2):345–357, 2000 10824655
Leask SJ, Done DJ, Crow TJ: Adult psychosis, common childhood infections and
neurological soft signs in a national birth cohort. Br J Psychiatry 181:387–392,
2002 12411263
Lebrun Y: Cluttering after brain damage. J Fluency Disord 21:289–295, 1996
Leopold NA, Borson AJ: An alphabetical ‘WORLD’: a new version of an old test.
Neurology 49(6):1521–1524, 1997 9409339
Lesak MD: Neuropsychological Assessment, 5th ed. New York, Oxford University
Press, 2012
Lin JS, O’Connor E, Rossom RC, et al: Screening for cognitive impairment in older
adults: a systematic review for the U.S. Preventive Services Task Force. Ann
Intern Med 159(9):601–612, 2013a 24145578
Lin JS, O’Connor E, Rossom RC, et al: Screening for Cognitive Impairment in
Older Adults: An Evidence Update for the U.S. Preventive Services Task Force.
Evidence Syntheses No 107. Report No 14-05198-EF-1. Rockville, MD,
Agency for Healthcare Research and Quality, 2013b
Lloyd-Smith Sequeira A, Rizzo J-R, Rucker JC: Clinical approach to supranuclear
brainstem saccadic gaze palsies. Front Neurol 8:429, 2017 28878733
Lochner C, Stein DJ: Olfactory reference syndrome: diagnostic criteria and
differential diagnosis. J Postgrad Med 49(4):328–331, 2003 14699232
Lohr JB, Alder M, Flynn K, et al: Minor physical anomalies in older patients with
late-onset schizophrenia, early-onset schizophrenia, depression, and
Alzheimer’s disease. Am J Geriatr Psychiatry 5(4):318–323, 1997 9363288
MacGowan DJL, Delanty N, Petito F, et al: Isolated myoclonic alien hand as the
sole presentation of pathologically established Creutzfeldt-Jakob disease: a
report of two patients. J Neurol Neurosurg Psychiatry 63(3):404–407, 1997
9328266
Mahone EM, Bridges D, Prahme C, Singer HS: Repetitive arm and hand
movements (complex motor stereotypies) in children. J Pediatr 145(3):391–
395, 2004 15343197
Maillot F, Belin C, Perrier D, Larmande P: Persévération visuelle et palinopsie: une
pathologie de la mémoire visuelle? [Visual perseveration and palinopsia: a
visual memory disorder?] Rev Neurol (Paris) 149(12):794–796, 1993 7997740
Malloy PF, Richardson ED: The frontal lobes and content-specific delusions. J
Malloy PF, Cummings JL, Coffey CE, et al: Cognitive screening instruments in
neuropsychiatry: a report of the Committee on Research of the American
Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 9(2):189–197,
1997 9144098
Marshall EJ: Neuropsychiatry of substance abuse, in Neuropsychiatry and Mental
Health Services. Edited by Ovsiew F. Washington, DC, American Psychiatric
Press, 1999, pp 105–148
Martzke JS, Kopala LC, Good KP: Olfactory dysfunction in neuropsychiatric
disorders: review and methodological considerations. Biol Psychiatry
42(8):721–732, 1997 9325566
McCauley SR, Levin HS, Vanier M, et al: The Neurobehavioural Rating Scale—
revised: sensitivity and validity in closed head injury assessment. J Neurol
McCreadie RG, Srinivasan TN, Padmavati R, Thara R: Extrapyramidal symptoms
in unmedicated schizophrenia. J Psychiatr Res 39(3):261–266, 2005 15725424
McNeil TF, Cantor-Graae E, Ismail B: Obstetric complications and congenital
malformation in schizophrenia. Brain Res Brain Res Rev 31(2-3):166–178,
2000 10719145
McPherson SE, Kuratani JD, Cummings JL, et al: Creutzfeldt-Jakob disease with
mixed transcortical aphasia: insights into echolalia. Behav Neurol 7(3):197–
203, 1994 24487337
Mendez MF: Aphemia-like syndrome from a right supplementary motor area
lesion. Clin Neurol Neurosurg 106(4):337–339, 2004 15297011
Mendez MF, Shapira JS, Miller BL: Stereotypical movements and frontotemporal
dementia. Mov Disord 20(6):742–745, 2005 15786492
Mesulam MM: Spatial attention and neglect: parietal, frontal and cingulate
contributions to the mental representation and attentional targeting of salient
extrapersonal events. Philos Trans R Soc Lond B Biol Sci 354(1387):1325–
1346, 1999 10466154
Metzig E, Rosenberg S, Ast M: Lateral asymmetry in patients with nervous and
mental disease. A preliminary study. Neuropsychobiology 1(4):197–202, 1975
1226229
Moreaud O: Balint syndrome. Arch Neurol 60(9):1329–1331, 2003 12975305
Nasreddine ZS, Phillips NA, Bédirian V, et al: The Montreal Cognitive Assessment,
MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc
53(4):695–699, 2005 15817019
Niehaus DJ, Emsley RA, Brink P, Stein DJ: Stereotypies: prevalence and
association with compulsive and impulsive symptoms in college students.
Psychopathology 33(1):31–35, 2000 10601825
Northoff G: What catatonia can tell us about “top-down modulation”: a
neuropsychiatric hypothesis. Behav Brain Sci 25(5):555–577, discussion 578–
604, 2002
Olney NT, Goodkind MS, Lomen-Hoerth C, et al: Behaviour, physiology and
experience of pathological laughing and crying in amyotrophic lateral sclerosis.
Brain 134(Pt 12):3458–3469, 2011 22155983
Ortigue S, Viaud-Delmon I, Michel CM, et al: Pure imagery hemi-neglect of far
space. Neurology 60(12):2000–2002, 2003 12821753
Overall JE, Gorham DR: Brief Psychiatric Rating Scale. Psychol Rep 10:799–812,
1962
Ovsiew F: Yes/no reversals (letter). Eur J Neurol 10(4):464, author reply 464, 2003
12823505
Ovsiew F: An overview of the psychiatric approach to conversion disorder, in
Psychogenic Movement Disorders: Neurology and Neuropsychiatry. Edited by
Hallett M, Fahn S, Jankovic J, et al. Philadelphia, PA, Lippincott Williams &
Wilkins, 2006, pp 115–121
Ovsiew F: Neuropsychiatric approach to the patient, in Comprehensive Textbook
of Psychiatry, 10th Edition. Edited by Sadock BJ, Sadock VA, Ruiz P.
Philadelphia, PA, Lippincott Williams & Wilkins, 2017, pp 448–474
Owen G, Mulley GP: The palmomental reflex: a useful clinical sign? J Neurol
Pantelis C, Maruff P: The cognitive neuropsychiatric approach to investigating the
neurobiology of schizophrenia and other disorders. J Psychosom Res
53(2):655–664, 2002 12169340
Paradis M: The other side of language: pragmatic competence. Journal of
Neurolinguistics 11:1–10, 1998
Penfield W, Robertson JSM: Growth asymmetry due to lesions of the postcentral
cerebral cortex. AMA Arch Neurol Psychiatry 50:405–430, 1943
Persinger MA, Makarec K: Complex partial epileptic signs as a continuum from
normals to epileptics: normative data and clinical populations. J Clin Psychol
49(1):33–45, 1993 8425933
Peters M: Description and validation of a flexible and broadly usable handedness
questionnaire. Laterality 3(1):77–96, 1998 15513076
Pia L, Neppi-Modona M, Ricci R, Berti A: The anatomy of anosognosia for
hemiplegia: a meta-analysis. Cortex 40(2):367–377, 2004 15156794
Pierrot-Deseilligny C, Gaymard B, Müri R, Rivaud S: Cerebral ocular motor signs.
J Neurol 244(2):65–70, 1997 9120498
Postuma RB, Lang AE: Hemiballism: revisiting a classic disorder. Lancet Neurol
2(11):661–668, 2003 14572734
Ramnani N, Owen AM: Anterior prefrontal cortex: insights into function from
anatomy and neuroimaging. Nat Rev Neurosci 5(3):184–194, 2004 14976518
Rasmussen P: Persistent mirror movements: a clinical study of 17 children,
adolescents and young adults. Dev Med Child Neurol 35(8):699–707, 1993
8335159
Riestra AR, Heilman KM: Visual facial grasp. Neurocase 10(5):363–365, 2004
15788274
Robinson RG, Parikh RM, Lipsey JR, et al: Pathological laughing and crying
following stroke: validation of a measurement scale and a double-blind
treatment study. Am J Psychiatry 150:286–293, 1993 8422080
Rogers D, Lees AJ, Smith E, et al: Bradyphrenia in Parkinson’s disease and
psychomotor retardation in depressive illness. An experimental study. Brain
110(Pt 3):761–776, 1987 3107750
Ron MA, Logsdail SJ: Psychiatric morbidity in multiple sclerosis: a clinical and MRI
study. Psychol Med 19(4):887–895, 1989 2594885
Ross ED: The aprosodias. Functional-anatomic organization of the affective
components of language in the right hemisphere. Arch Neurol 38(9):561–569,
1981 7271534
Ross ED: Nonverbal aspects of language. Neurol Clin 11(1):9–23, 1993 8441376
Rossetti HC, Lacritz LH, Cullum CM, Weiner MF: Normative data for the Montreal
Cognitive Assessment (MoCA) in a population-based sample. Neurology
77(13):1272–1275, 2011 21917776
Royall DR, Mahurin RK, Gray KF: Bedside assessment of executive cognitive
impairment: the executive interview. J Am Geriatr Soc 40(12):1221–1226, 1992
1447438
Ryan R, Sunada K: Medical evaluation of persons with mental retardation referred
for psychiatric assessment. Gen Hosp Psychiatry 19(4):274–280, 1997
9327256
Rylander G: Psychoses and the punding and choreiform syndromes in addiction to
central stimulant drugs. Psychiatr Neurol Neurochir 75(3):203–212, 1972
4625014
Sachdev P: Akathisia and Restless Legs. Cambridge, UK, Cambridge University
Press, 1995
Sackeim HA, Greenberg MS, Weiman AL, et al: Hemispheric asymmetry in the
expression of positive and negative emotions. Neurologic evidence. Arch
Neurol 39(4):210–218, 1982 7041863
Sacco R, Gabriele S, Persico AM: Head circumference and brain size in autism
spectrum disorder: A systematic review and meta-analysis. Psychiatry Res
234(2):239–251, 2015 26456415
Sanders RD, Keshavan MS: The neurologic examination in adult psychiatry: from
soft signs to hard science. J Neuropsychiatry Clin Neurosci 10(4):395–404,
1998 9813784
Sargent MA, Poskitt KJ, Jan JE: Congenital ocular motor apraxia: imaging
findings. AJNR Am J Neuroradiol 18(10):1915–1922, 1997 9403454
Savic I, Bookheimer SY, Fried I, Engel J Jr: Olfactory bedside test. A simple
approach to identify temporo-orbitofrontal dysfunction. Arch Neurol 54(2):162–
168, 1997 9041857
Sawle G: Movement disorders during sleep, in Movement Disorders in Clinical
Practice. Edited by Sawle G. Oxford, UK, Isis Medical Media, 1999, pp 159–
163
Schneck SA: Neurological examination, in Behavioral Neurology &
Neuropsychiatry. Edited by Arciniegas DB, Anderson CA, Filley CM.
Cambridge, UK, Cambridge University Press, 2013, pp 319–332
Silberman EK, Post RM, Nurnberger J, et al: Transient sensory, cognitive and
affective phenomena in affective illness. A comparison with complex partial
epilepsy. Br J Psychiatry 146:81–89, 1985 3978348
Smith RA, Berg JE, Pope LE, et al: Validation of the CNS emotional lability scale
for pseudobulbar affect (pathological laughing and crying) in multiple sclerosis
patients. Mult Scler 10(6):679–685, 2004 15584494
Snowden JS, Neary D, Mann DM, et al: Progressive language disorder due to
lobar atrophy. Ann Neurol 31(2):174–183, 1992 1575456
Solms M, Turnbull O: The Brain and the Inner World: An Introduction to the
Neuroscience of Subjective Experience. New York, Other Press, 2002
Sonoo M: Abductor sign: a reliable new sign to detect unilateral non-organic
paresis of the lower limb. J Neurol Neurosurg Psychiatry 75(1):121–125, 2004
14707320
Stone J, Zeman A, Sharpe M: Functional weakness and sensory disturbance. J
Neurol Neurosurg Psychiatry 73(3):241–245, 2002 12185152
Subotnik KL, Nuechterlein KH, Irzhevsky V, et al: Is unawareness of psychotic
disorder a neurocognitive or psychological defensiveness problem? Schizophr
Res 75(2-3):147–157, 2005 15885506
Sultzer DL, Berisford MA, Gunay I: The Neurobehavioral Rating Scale: reliability in
patients with dementia. J Psychiatr Res 29(3):185–191, 1995 7473295
Taylor MA, Fink M: Catatonia in psychiatric classification: a home of its own. Am J
Psychiatry 160(7):1233–1241, 2003 12832234
Teitelbaum JS, Eliasziw M, Garner M: Tests of motor function in patients suspected
of having mild unilateral cerebral lesions. Can J Neurol Sci 29(4):337–344,
2002 12463489
Thacker RC, De Nil LF: Neurogenic cluttering. J Fluency Disord 21:227–238, 1996
Ueki Y, Mima T, Oga T, et al: Dominance of ipsilateral corticospinal pathway in
congenital mirror movements. J Neurol Neurosurg Psychiatry 76(2):276–279,
2005 15654052
Uher R, Treasure J: Brain lesions and eating disorders. J Neurol Neurosurg
Psychiatry 76(6):852–857, 2005 15897510
Van Borsel J, Taillieu C: Neurogenic stuttering versus developmental stuttering: an
observer judgement study. J Commun Disord 34(5):385–395, 2001 11565960
Van Borsel J, Schelpe L, Santens P, et al: Linguistic features in palilalia: two case
studies. Clin Linguist Phon 15:663–677, 2001
van der Heijden FMMA, Tuinier S, Arts NJM, et al: Catatonia: disappeared or
under-diagnosed? Psychopathology 38(1):3–8, 2005 15714008
Verdoux H, Sutter AL: Perinatal risk factors for schizophrenia: diagnostic specificity
and relationships with maternal psychopathology. Am J Med Genet 114(8):898–
905, 2002 12457383
Vitali P, Nobili F, Raiteri U, et al: Right hemispheric dysfunction in a case of pure
progressive aphemia: fusion of multimodal neuroimaging. Psychiatry Res
130(1):97–107, 2004 14972372
Volden J: Nonverbal learning disability. Handb Clin Neurol 111:245–249, 2013
23622171
Vossler DG, Haltiner AM, Schepp SK, et al: Ictal stuttering: a sign suggestive of
psychogenic nonepileptic seizures. Neurology 63(3):516–519, 2004 15304584
Vuilleumier P: Anosognosia: the neurology of beliefs and uncertainties. Cortex
40(1):9–17, 2004 15070000
Walczak TS, Bogolioubov A: Weeping during psychogenic nonepileptic seizures.
Epilepsia 37(2):208–210, 1996 8635432
Warren S, Ross RG: Deficient cancellation of the vestibular ocular reflex in
schizophrenia. Schizophr Res 34(3):187–193, 1998 9850985
Weintraub S: Neuropsychological assessment of mental state, in Principles of
Cognitive and Behavioral Neurology, 2nd Edition. Edited by Mesulam M-M.
Oxford, UK, Oxford University Press, 2000, pp 121–173
Wertz RT, Henschel CR, Auther LL, et al: Affective prosodic disturbance
subsequent to right hemisphere stroke: a clinical application. Journal of
Neurolinguistics 11:89–102, 1998
Wilson SAK: Some problems in neurology: no. II—pathological laughing and
crying. J Neurol Psychopathol 4:299–333, 1924 21611529
Wood S, Cummings JL, Hsu MA, et al: The use of the neuropsychiatric inventory
in nursing home residents. Characterization and measurement. Am J Geriatr
Psychiatry 8(1):75–83, 2000 10648298
Wortzel HS, Oster TJ, Anderson CA, Arciniegas DB: Pathological laughing and
crying : epidemiology, pathophysiology and treatment. CNS Drugs 22(7):531–
545, 2008 18547124
Wortzel HS, Frey KL, Anderson CA, Arciniegas DB: Subtle neurological signs
predict the severity of subacute cognitive and functional impairments after
traumatic brain injury. J Neuropsychiatry Clin Neurosci 21(4):463–466, 2009
19996256
CHAPTER 3
Neuropsychological
Assessment
Clinical neuropsychologists are trained in the science of brain-

behavior relationships. They assess brain function by making
inferences based on an individual’s cognitive, sensorimotor,
emotional, and social behavior. The clinical neuropsychologist
specializes in the application of assessment and intervention
principles based on the scientific study of human behavior across the
life span as it relates to normal and abnormal functioning of the
central nervous system.
During the early history of neuropsychology, these assessments
were often the most direct measure of brain integrity. Whereas
neuropsychological measures remain the major diagnostic modality
for some conditions, advances in neuroimaging have permitted more
accurate localization of illness or injury and have resulted in a shift in
the focus of neuropsychological assessment from the localization of
possible brain damage to a better understanding of specific brain-
behavior relations and the psychosocial consequences of brain
dysfunction.
Qualifications for Performing

Neuropsychological Evaluations
Professionals in the field of neuropsychology typically have
backgrounds in clinical psychology, psychiatry, neurology, and
language pathology, to name the most common contributing
disciplines. Qualified individuals have expertise both in brain-
behavior relations and in skills in diagnostic assessment and in
counseling (Barth et al. 2003; Hannay 1998). Clinical
neuropsychology is a specialty that is formally recognized by the
American Psychological Association and the Canadian
Psychological Association. Education and training in clinical
neuropsychology have evolved along with the development of the
specialty itself. The Houston Guidelines were developed to
document a widely recognized and accepted model of integrated
education and training that is both programmatic and competency
based (Hannay 1998). Specialization begins at the doctoral level and
continues with an internship and a 2-year residency program, with
clinical, didactic, and academic training. A growing number of
neuropsychologists have qualified for proficiency in this subspecialty
area, earning the American Board of Professional Psychology’s
award of Diploma in Clinical Neuropsychology (Bieliauskas and
Matthews 1987), and as of 2014, subspecialty certification in
pediatric clinical neuropsychology is also recognized. Beginning in
2015, a board-certified neuropsychologist is required to complete
maintenance of certification (MOC) every 10 years. The MOC model
asserts that competence is established at the time of initial board
certification and is continuously updated through lifelong learning
(continuing education), ongoing participation in professional
activities, and self-evaluation related to core competencies.
Indications for a Neuropsychological Evaluation
Patients may be referred to a neuropsychologist for assessment
for a number of reasons. An evaluation can provide information
about the nature and severity of a patient’s cognition, emotional
status, personality characteristics, social behavior, and adaptation to
his or her conditions. A patient’s potential for independent living and
productive activity can be inferred from these data. Information about
his or her behavioral strengths and weaknesses provides a
foundation for treatment planning, vocational training, competency
determination, and counseling for both the patient and his or her
family. Neuropsychological assessment is often requested in cases
of Alzheimer’s disease and related dementing disorders and other
progressive diseases (e.g., Parkinson’s disease, Huntington’s
disease, multiple sclerosis), as well as for cerebrovascular disorders,
traumatic brain injury (TBI), tumors, seizures, developmental
disorders, infections, and psychiatric disorders (e.g., schizophrenia,
mood disorders, attention-deficit/hyperactivity disorder [ADHD]).
Specific referral questions may differ based on the setting in which
an individual is seen. In the inpatient setting, typical questions
involve issues related to an individual’s current cognitive status and
its impact on daily functioning, with an emphasis on identifying what
types of services might be appropriate while in the hospital as well
as in the community as a crucial part of discharge planning. In acute
care hospital settings, individuals who have neurological disorders or
who have recently had neurosurgical intervention may be referred to
a neuropsychologist for evaluation. Inpatient psychiatric referrals are
also common. Inpatient teams often have questions regarding
individuals’ safety (i.e., Can they be left alone in their home?),
functional independence (i.e., Are they able to live alone? Can they
manage their own money?), and employability (i.e., Can they work?
In what type of job would they be most likely to succeed?). Results of
the evaluation form part of the repertoire of data used by the
inpatient team to address these issues, and these evaluation results
can provide insights into what supports might be needed to provide
the least restrictive environment for the patient and/or what
accommodations can be made to maximize his or her success (e.g.,
in the workplace).
In subacute inpatient settings, referrals may be made to help
address issues related to recovery from an injury or psychiatric
episode or to help determine if there has been cognitive
improvement as a result of medication or other treatment
interventions. Data can be used as part of the determination of
disability. There are also various forensic and other legal purposes
for which neuropsychological data can serve an important purpose in
this population, such as contributing to the determination of decision-
making capacity (Moberg and Kniele 2006). Results of the
neuropsychological evaluation may result in referrals to other
specialists, such as cognitive rehabilitation professionals,
neurologists, vocational counselors, and educational services, to
further inform differential diagnosis and/or make sure any potentially
treatable problems are addressed. Finally, the recommendations of
the neuropsychologist regarding appropriate compensatory
strategies as well as environmental and other modifications are
made. Feedback can be provided to the patient, his or her family, the
inpatient providers, and community support services, including
outpatient providers. This team approach is very common in
inpatient settings and allows input from several sources (e.g.,
physician, neuropsychologist, occupational therapist, other
rehabilitation staff) in developing the most efficacious treatment plan.
Neuropsychological evaluations in outpatient settings may be
used to support or clarify a diagnosis, to aid in differential diagnosis
(especially when there are unusual symptoms or concerns regarding
comorbidities), and/or to provide a profile of cognitive strengths and
weaknesses to guide rehabilitation, educational, vocational, or other
services. Such an evaluation can document changes in functioning
since prior evaluation(s), address questions of decline over time, and
note the efficacy of treatment. Even in outpatient settings, the
interdisciplinary team model can be effective, with input provided by
various health care professionals to fully assess an individual, aid in
differential diagnosis, and maximize treatment planning. Similarly,
neuropsychologists can be integrated into specialty clinics working
with various populations (e.g., clinics for geriatric populations, clinics
for persons with TBI or developmental disabilities).
Other outpatient models include neuropsychology private practice.
In this case, the neuropsychologist receives referrals from various
physicians and neuropsychiatrists, performs a patient assessment,
and sends a report back to the referral source. In this model, there is
less interdisciplinary collaboration; there is a clearer separation
between the evaluation provided by the neuropsychologist and the
treatment provided by the physician. Finally, there are
neuropsychologists who develop forensic practices, in which their
primary focus involves the application of neuropsychological
assessment methods to the evaluation of criminal or civil litigants.
The approach and battery of tests used should be capable of
meeting legal standards, and there is often an increased emphasis
on collateral sources of information, assessment of response bias,
consideration of the individual’s level of effort, and/or issues of
malingering.
Regardless of the setting or the model, the type of referral
questions may vary somewhat depending on the situation. For
example, in the case of an individual with TBI, a neuropsychological
evaluation might be used both to provide evidence of brain
dysfunction and to describe the nature and severity of problems. A
person who has sustained a blow to the head from an automobile
accident that produces a brief loss of consciousness, even with no
apparent further neurological complications, might experience
disruption in cognitive efficiency. On returning to work after 1 week,
this individual might be unable to keep up with job demands. After
several weeks of on-the-job difficulties, the individual’s physician
may refer the him or her to a neuropsychologist. The
neuropsychologist might look for evidence of problems with divided
attention, sustained concentration and mental tracking, and memory,
all of which are common findings in the weeks or months following
mild head injury. The neuropsychologist can advise the patient that
these problems frequently occur after head injury and that
considerable improvement might be expected during the next month
or two. Recommendations about how to structure work activities to
minimize both these difficulties and the equally common problem of
fatigue provide both aid and comfort to the concerned patient.
The most common referral for neuropsychological evaluation of
older adults without obvious risk factors for brain disease, other than
age, is for early detection of progressive dementias such as
Alzheimer’s disease. Most persons have symptoms associated with
dementia for at least a year before they see a physician because the
problems initially are mild and easily attributed to factors such as
aging, concurrent illness, or emotional stress. The progression of
symptoms is insidious, especially because many patients have
“good” and “bad” days during the early stages of a dementing
disorder. Neuropsychological assessment is useful in evaluating
whether problems are age-related, attributable to factors such as
depression, or suggestive of early dementia.
One of the greatest challenges for a neuropsychologist is to
determine whether patients with psychiatric illness show evidence of
a separate underlying brain disorder. Many psychiatric patients
without neurological disease have cognitive disruptions, as well as
behavioral or emotional disturbances. Cognitive impairment is highly
prevalent in schizophrenia, particularly with respect to attention,
processing speed, memory, and executive function. Patients with
unipolar depression (Lee et al. 2012) or bipolar disorder (Mann-
Wrobel et al. 2011) may have difficulty with attention, memory, and
executive function even when euthymic. Conversely, patients with
neurological diseases can present with prominent psychiatric
features. Confabulations associated with undiagnosed neurological
illnesses, such as Korsakoff’s syndrome, may be misinterpreted as a
psychotic illness. Hallucinations may be an early feature of Lewy
body dementia and may occur with Parkinson’s disease, Alzheimer’s
disease, other neurodegenerative diseases, stroke, epilepsy,
migraine, and toxic metabolic encephalopathies.
Many medical conditions can affect brain function, including
systemic illnesses such as endocrinopathies; metabolic and
electrolyte disturbances associated with diseases of the kidney, liver,
and pancreas; and nutritional deficiencies. Vascular disorders,
cardiac and pulmonary diseases, anemia, and complications of
anesthesia or surgery can compromise blood supply to the brain and
thus disrupt cognition.
Age and health habits also must be taken into consideration when
evaluating a person’s behavioral alterations because they affect the
probability of cerebral disorder (Perfect and Maylor 2000). In
addition, certain medications can disrupt cognitive functioning. Such
considerations demonstrate the importance of the multifaceted
nature of training in neuropsychology, including a knowledge base in
psychology, psychiatry, and neurology, among other disciplines.
In cases with no known explanation for mental deterioration, it
becomes important to search for possible risk factors or other
reasons for brain disease through history taking, physical
examination, laboratory tests, and interviews with the patient’s family
or close associates. Should this search produce no basis for the
mental deterioration, a neuropsychological evaluation can be useful.
The neuropsychological evaluation of persons with or without known
risk factors for brain damage is diagnostically useful if it identifies
cognitive or behavioral deficits, particularly if those deficits occur in a
meaningful pattern. A pattern is considered meaningful when it is
specific to one or only a few diagnoses (e.g., a pattern suggestive of
a lateralized or focal brain disruption).
Neuropsychological signs and symptoms that are possible
indicators of a brain disorder are presented in Table 3–1. Confidence
in diagnoses based on neuropsychological evidence is greater when
risk factors for brain dysfunction exist or the patient shows signs and
symptoms of brain dysfunction than when neuropsychological
diagnoses rely solely on exclusion of other diagnoses.
TABLE 3–1. Neuropsychological signs and symptoms that may indicate a
pathological brain process
Functional class Symptoms and signs

Speech and Dysarthria
language
Dysfluency
Marked change in amount of speech output
Paraphasia
Word-finding problems
Academic skills Alterations in reading, writing, calculating, and
number abilities
Frequent letter or number reversals
Thinking Perseveration of speech
Simplified or confused mental tracking, reasoning,
and concept formation
Motor Weakness or clumsiness, particularly if lateralized
Impaired fine-motor coordination (e.g., changes in
handwriting)
Apraxia
Perseveration of action components
Memory Impaired recent memory for verbal and/or
visuospatial material
Disorientation
Perception Diplopia or visual field alterations
Inattention (usually left-sided)
Somatosensory alterations (particularly if lateralized)
Inability to recognize familiar stimuli (agnosia)
Visuospatial abilities Diminished ability to perform manual skills (e.g.,
mechanical repairs, sewing)
Spatial disorientation
Left-right disorientation
Impaired spatial judgment (e.g., angulation of
distances)
Functional class Symptoms and signs
Emotions Diminished emotional control with temper outburst
and antisocial behavior
Diminished empathy or interest in interpersonal
relationships
Affective changes
Irritability without evident precipitating factors
Personality change
Social behavior Altered appetites and appetitive activities
(comportment) Altered grooming habits (excessive fastidiousness or
carelessness)
Hyperactivity or hypoactivity
Social inappropriateness
Although neuropsychological assessment provides a measure of

the type and degree of cognitive disorder, it often cannot specify the
cause of the disturbance. Cognitive deficits appearing in an adult
patient who previously functioned well and had no history of
psychiatric illness or recent stress should raise suspicions of a
neurological disorder.
Role of the Referring Neuropsychiatrist

The referring neuropsychiatrist identifies patients who might
benefit from a neuropsychological evaluation, prepares the patient,
and formulates referral questions that best define the needed
information. A valid evaluation depends on obtaining the patient’s
best performance. It is nearly impossible to obtain satisfactory
evaluations of patients who are uncooperative, unmotivated,
severely fatigued, actively psychotic, seriously depressed, highly
anxious, or physically uncomfortable or who want to demonstrate
impaired performance for secondary gain. For example, seriously
depressed patients may appear to have dementia, and the
evaluation may underestimate the individual’s full potential (Yousef et
al. 1998). Whenever possible, patients with active psychiatric
symptoms should be referred after they have shown clinical
improvement, so that the findings are more representative of their
true ability uncontaminated by reversible emotional or behavioral
disturbances.
To obtain the patient’s cooperation and alleviate unnecessary
anxiety, the patient should understand the purpose and nature of the
evaluation. The explanation usually includes a statement that the
evaluation has been requested to assess how the brain is
functioning by looking at thinking abilities using paper and pencil
and/or computerized tests. In most cases, patients should know that
the examiner will look for cognitive and emotional strengths as well
as problem areas to obtain information that could assist with
differential diagnosis, treatment planning, and development of
compensatory strategies.
The more explicit the referral question, the more likely it is that the
evaluation will be conducted to ascertain the needed information.
The referral should include identifying information about the patient,
reasons for the evaluation request, description of the problem to be
assessed, and pertinent history. Because the neuropsychological
evaluation is designed specifically around the referral question, it
behooves the neuropsychiatrist to be as specific as possible about
what he or she and the patient are hoping to get from the evaluation.
Some referrals seek behavioral descriptions, such as, “Does this
individual with multiple sclerosis show evidence of cognitive deficits,
and, if so, what are they? Could they interfere with treatment
compliance?” Other referral questions may be framed around issues
with patient management (i.e., level of functional independence),
counseling, and educational or vocational planning.
Assessment Process
A comprehensive neuropsychological evaluation has several
components. Obtaining relevant background history is a vital building
block on which interpretation of the test results is built. Information is
obtained in part from a review of pertinent records (e.g., medical,
psychiatric, academic) and, as appropriate, consultation with other
practitioners involved with the patient’s care.
The clinical interview is another essential way to gain background
history, allowing one to elicit the patient’s and relevant collateral’s
(e.g., family) concerns with respect to the nature and course of
changes in cognitive, sensory, and motor skills; emotional
functioning; behavioral or personality changes; and ability to
complete basic and instrumental activities of daily life, as well as
functioning in academic, employment, and social settings. The
interview also affords the opportunity to confirm and update relevant
information, including medical, psychiatric, developmental,
educational, and occupational history. Furthermore, the interview
provides the neuropsychologist with an opportunity to directly
observe the patient’s appearance, attention, speech, thought
process and content, and motor abilities and to evaluate affect,
behavior, orientation, and judgment. The interview can help gauge
the patient’s insight into his or her own abilities. Patients with certain
conditions, such as Alzheimer’s disease, schizophrenia, and
acquired frontal lobe lesions, may demonstrate poor awareness of
their problems or minimize their significance (Flashman 2002). In the
extreme form, this may result in complete denial of an obvious
impairment, such as hemiplegia in a person with right-hemisphere
stroke. More often, patients may misattribute their difficulties—for
example, a person with dementia attributing his or her memory
problems to normal aging or a person with schizophrenia attributing
cognitive impairment to psychological stress.
Neuropsychologists use a variety of standardized tests and
measures to assess a patient’s functioning. For the majority of these,
normative data are used to aid in the interpretation of test results,
although qualitative aspects of performance are also highly
informative (e.g., how organized is a patient’s copy of a complex
figure rather than just the accuracy of the final drawing). The
selection of tests typically follows one of three primary approaches.
The fixed battery approach uses the same set of tests with every
individual, analogous to a physician conducting a standard physical
examination on all patients (e.g., Reitan and Wolfson 1985). This
approach usually entails several hours of testing but ensures that all
patients complete a fairly broad-based examination. The fixed
battery approach has several limitations, however, including risk of
failure to focus on specific areas of difficulty for a given patient; it
may overlook subtler problems, may not cover all areas relevant to
either a reliable diagnosis or practical counseling, and may not
resolve uncertainty about why performance is impaired without
additional testing. In contrast, the hypothesis-testing approach tailors
the neuropsychological evaluation to the patient’s requirements,
allowing the examiner to learn what is needed, with greater time and
cost efficiency (Bauer 2000). Hypotheses are generated about the
source(s) and nature of the brain dysfunction based on background
history and behavioral observations, and tests are selected to
address each hypothesis. Furthermore, hypothesis testing is
considered a dynamic process that continues throughout the
assessment, with results from a particular test or set of tests
potentially leading to new hypotheses being formulated and prior
ones being modified or refuted. For example, an elderly patient may
be referred to inform a differential diagnosis of depression versus
dementia, based on family reports of forgetfulness and lack of
motivation. Competing hypotheses can be tested to determine if
changes are due to depression, dementia, or a combination of the
two. The examiner may therefore include tests that are relatively
unstructured and require active initiation and organization, and he or
she may look at whether cuing and recognition memory testing aid in
retrieval of information from memory. Finally, most
neuropsychologists use a fixed-flexible approach (Bauer 2000) in
which the examiner starts the evaluation with a preferred core set of
measures that have demonstrated applicability to a variety of clinical
populations and usefulness for answering a wide range of clinical
questions. This core is then supplemented with other measures
based on a hypothesis-testing approach.
Clinical neuropsychological evaluations typically go beyond
assessing cognitive functioning; they commonly include measures of
emotional functioning and questionnaires assessing personality and
a variety of other symptoms, depending on the presenting
complaints and diagnosis at hand (e.g., fatigue and pain rating
scales). This is important regardless of diagnosis because mood,
personality, and other symptoms can impact test performance, as
has been seen in numerous neurological populations (e.g.,
Butterfield et al. 2010), and these factors may be important
contributors to the patient’s clinical presentation.
Nature of Neuropsychological Tests

Most tests of cognitive ability are designed with the expectation
that very few will obtain a perfect score and that most scores will
cluster in a middle range. The scores of many persons taking the
test can be plotted as a distribution curve. Most scores on tests of
complex learned behaviors fall into a characteristic bell-shaped
curve called a normal distribution curve. The statistical descriptors of
the curve are the mean, or average score; the degree of spread of
scores about the mean, expressed as the standard deviation; and
the range, or the distance from the highest to the lowest scores.
Most neuropsychological measures are designed so that all
individuals within a culture are expected to be able to perform the
tasks; thus, failure to do so may be suggestive of impairment.
The level of competence within different cognitive domains varies
from individual to individual and also varies within the same
individual at different times. This variability also has the
characteristics of a normal curve. Because of the normal variability of
performance on cognitive tests, any single score should be
interpreted as falling within a range and should not be taken as a
precise value. For this reason, many neuropsychologists are
reluctant to report exact scores; rather, they describe their findings in
terms of ability levels (e.g., average range, mildly impaired range).
See Table 3–2 for interpretations of ability levels expressed as
deviations from the mean of the normative sample. An individual’s
score is compared with normative data, often through calculation of a
standard or z score, which describes the individual’s performance in
terms of statistically regular distances (i.e., standard deviations) from
the mean relative to individuals of similar age, gender, and/or
educational level. For example, a performance in the below-average
direction that is greater than two standard deviations from the mean
is usually described as falling in the impaired range because 98% of
the normative sample taking the test achieve better scores.
TABLE 3–2. Normative data
z Score Percentile rank Descriptor
2.0 and above 98 and above Very superior
1.3 to 1.99 91 to 97 Superior
0.66 to 1.29 75 to 90 High average
–0.069 to 0.065 25 to 74 Average
–1.39 to –0.7 10 to 24 Low average
–2.09 to –1.4 2 to 9 Borderline
–2.1 and below 1.9 and below Extremely lowa
–2.69 to –2.1 0.38 to 1.89 Mildly impaired
–3.09 to –2.7 0.13 to 0.37 Moderately impaired
–3.1 and below 0.12 and below Severely impaired
Note. The respective cutoff values are expressed as z scores, along with their
percentile equivalents.
aThe extremely low range encompasses the mildly, moderately, and severely
impaired range performances.
Psychological tests should be constructed to satisfy both reliability

and validity criteria (American Educational Research Association et
al. 2014). The reliability of a test refers to the consistency of test
scores when the test is given to the same individual at different times
or with different sets of equivalent items. Tests have validity when
they measure what they purport to measure. For example, if a test is
designed to measure attention, then patient groups known to have
attention deficits should perform more poorly on the test than
persons from the population at large. To achieve reliability and
validity, tests are often constructed with large normative samples
composed of individuals with similar demographic characteristics,
such as age and education. For example, the Wechsler Adult
Intelligence Scale–IV (WAIS-IV; Wechsler 2008) has normative data
for 2,220 adults stratified by sex, race/ethnicity, geographic region,
and education.
Some neuropsychological tests detect subtle deficits better than
others; however, other factors such as depression, anxiety, medicine
side effects, and low energy level due to systemic illness also may
disrupt performance on these tests. Therefore, they are sensitive to
cognitive disruption but not specific to one type of cognitive
disturbance. The specificity of a test in detecting a disorder depends
on the overlap between the distributions of the scores for persons
who do not have and persons who have the disorder. In general, the
less overlap there is, the better the test can differentiate between
normal and abnormal performances. A test that is highly specific
purports to measure a defined cognitive construct and produces few
false positive findings. Many neuropsychological tests offer a trade-
off between sensitivity and specificity, and detailed information
regarding many tests can be found in books such as A Compendium
of Neuropsychological Tests (Strauss et al. 2006).
Interpretation: Principles and Cautions

Neuropsychological assessment relies on comparisons between
the patient’s test performance and normative data, as well as intra-
individual comparison of the patient’s current level of functioning
versus his or her known or estimated level of premorbid functioning.
Most healthy people perform within a statistically definable range on
cognitive tests, determined by normative data that typically take into
account demographic variables, and deviations below this expected
range raise the question of impairment. Impairment may also be
identified as a discrepancy between current test performance and
scores on estimates of premorbid functioning. Such estimates
typically involve mathematically based formulas that use
demographic information or performance on tests of functions less
likely to be affected by brain disorders, for example, fund of
information or reading vocabulary tests such as the Test of
Premorbid Functioning from the Advanced Clinical Solutions
(Wechsler 2009) and the Reading subtest from the Wide Range
Achievement Test (Wilkinson and Robertson 2006).
The assumption of impairment is valid in most instances in which
one or a set of scores fall significantly below expectations, although
even in healthy individuals, impairment may be seen on one or a few
scores across an extensive battery of measures (Schretlen et al.
2008). Impairment on multiple measures involving similar or related
abilities increases the examiner’s confidence in the findings. If similar
tasks do not elicit impairment, either the finding was spurious or the
tasks varied in important features that did not involve the patient’s
problem area.
For meaningful interpretations of neuropsychological functioning,
examiners not only rely on tests but also search for a performance
pattern that makes neuropsychological sense using test scores and
qualitative features of performance. Because there are few
pathognomonic findings in neuropsychology (or in most other
branches of medical science), the pattern of performance may
suggest several diagnoses but could also facilitate differential
diagnosis. For example, a cluster of mild impairments in processing
speed, concentration, and memory is a nonspecific finding
associated with several conditions, including mild TBI and
depression. Other patterns may be highly specific for certain
conditions. The finding of left-sided neglect and visuospatial
distortions is highly suggestive of brain dysfunction and specifically
occurs with right hemisphere damage. For many neuropsychological
conditions, typical deficit patterns are known, allowing the examiner
to evaluate the patient’s performances in light of these known
patterns.
The quality of a neuropsychological evaluation depends on many
factors. In general, one should beware of conclusions from
evaluations in which test scores alone (i.e., without information from
the history, interview, observations of examination behavior) are
used to make diagnostic decisions and of dogmatic statements
offered without strong supportive evidence. It is also important to
remember that neuropsychological tests do not measure “brain
damage.” Rather, the finding of impaired functioning implies an
underlying brain disorder; however, other possible interpretations
may exist that should be addressed in the evaluation (e.g., mood).
Furthermore, neuropsychological evaluations increasingly include
stand-alone and/or embedded measures of test-taking effort and
provide evidence about whether the assessment results should be
considered as a valid reflection of the patient’s current level of
functioning. While it is very difficult to clearly establish that a patient
has malingered on testing or to determine the reason(s) for failure on
measures of test-taking effort, one must be mindful of the validity of
test findings.
Major Test Categories

In this section, we present a selective review of tests used for
assessment of areas of cognition and personality. Many useful
neuropsychological tests are not described in this summary. Please
refer to texts such as Neuropsychological Assessment (Lezak et al.
2012) and A Compendium of Neuropsychological Tests (Strauss et
al. 2006) for more detailed information on other frequently used
tests.
Attention and Processing Speed

Attentional deficits and slowed processing speed are common
features of many disorders, for example, depression, schizophrenia,
and Parkinson’s disease. Several relevant measures of attention and
processing speed ability are included in the WAIS-IV (Wechsler
2008). For example, the Digit Span subtest is included in the
Working Memory Index (WMI). Immediate auditory attention is
assessed using Digit Span forward, which involves repetition of digits
in the order presented and has minimal working memory demand.
Processing speed is measured in the WAIS-IV and has its own
designated index, the Processing Speed Index (PSI). Digit Symbol
Coding is a task of visual attention, processing speed, and
psychomotor speed and requires integration of each to complete the
task successfully. Similarly, the Symbol Search subtest is a measure
of attention, processing speed, psychomotor speed, and visual
pattern discrimination. These tests, like many processing speed
measures, are susceptible to the effects of extraneous factors, such
as motor slowing, which could be due to peripheral factors such as
nerve or muscle damage, as well as to diminished visual acuity.
There are a variety of other measures of attention and processing
speed that differ in difficulty and processing demands, and these
measures can be incorporated into the assessment based on the
specific referral question or functional concern. Measures of
sustained auditory and visual attention are presumably more difficult
because of the increased cognitive demand required to focus on
relevant stimuli, while suppressing responding to irrelevant stimuli,
for a prolonged period of time. Many neuropsychological batteries
will include sustained attention tasks when diagnostic clarification is
requested for neurodevelopmental disorders related to attention,
such as ADHD. While neuropsychological assessment is not
required to make a diagnosis of ADHD, neuropsychological
measures provide objective data regarding the nature and extent of
associated cognitive problems. Sustained visual attention measures,
such as the Conners’ Continuous Performance Test (Conners 2004),
provide information regarding inattention, impulsivity, and
psychomotor speed and its consistency, as well as an individual’s
response style (e.g., emphasis on accuracy vs. speed). The Trail
Making Test (TMT; Reitan and Wolfson 1985) is a measure of visual
attention, and it relies heavily on intact psychomotor processing
speed, cognitive flexibility, and visual scanning abilities. The TMT is
divided into parts A and B. Part A requires the individual to connect a
sequence of numbers in ascending order and purports to measure
processing speed, visual attention, and visual scanning. Part B
requires the individual to sequence numbers and letters in an
ascending, alternating order and incorporates a cognitive flexibility
component to the aforementioned abilities. This test has been widely
used to detect brain damage, with longer completion time and/or
more errors being indicative of impairment.
Memory
Memory is frequently reported as the primary cognitive concern by
individuals seeking assessment. Memory may be divided into two
major subdomains. Implicit (or procedural) memory refers to
information that is automatized and thus typically not consciously
retrieved (e.g., buttoning a shirt, driving a car) and is not typically
assessed during the neuropsychological evaluation. Explicit (or
declarative) memory refers to information that is consciously
retrieved from previous experience. Furthermore, short-term memory
involves information that is held for a brief period of time (typically 30
seconds or less), while long-term memory involves the retention of
information for minutes, days, or even years. Long-term memory can
be divided into semantic memory and episodic memory. Semantic
(fact) memory refers to general knowledge about the world that we
learn throughout our lives, but it is not linked to a specific time,
person, or place. It is distinct from episodic memory, which is our
memory of specific events and experiences. For instance, semantic
memory might contain information about what a cat is, whereas
episodic memory might contain a specific memory of petting a
particular cat. Semantic memory may be assessed using the WAIS-
IV Vocabulary and Information subtests (Wechsler 2008), as well as
other tests such as category fluency (e.g., name all the animals one
can think of in a minute) and confrontation naming (i.e., object
naming).
Memory can be thought of as involving three stages: encoding,
consolidation, and retrieval. Encoding, also referred to as learning or
acquisition, involves the process of acquiring new information.
Consolidation of information occurs when recently encoded
information is manipulated and stored in a meaningful way for
increased accuracy during later recall. Retrieval is the expressed
recall of information that has been successfully encoded and
consolidated. All three episodic memory subprocesses provide
valuable information about the overall learning and memory abilities
of a patient, and this often guides the recommendations provided by
neuropsychologists. For example, if an encoding difficulty is
observed, a neuropsychologist may recommend that physicians and
staff working with the patient repeat information, write information
down, and incorporate the use of organization strategies to enhance
encoding and later recall.
The type of information presented in memory tests can vary
significantly. For example, verbal memory tests may use contextual
(e.g., information presented in a story) or noncontextual (e.g.,
information presented in a seemingly random word list) formats.
Similarly, visual information can be simple (e.g., basic geometric
figures) or more complex (e.g., geometrically detailed and
unnameable figures). A number of neuropsychological tests measure
these aspects of memory. The Wechsler Memory Scale—4th Edition
(Jorge et al. 2010) includes subtests assessing memory for different
types of information (e.g., story recall, word pairs, designs). The
California Verbal Learning Test–II provides valuable insight into
auditory-verbal noncontextual memory using a word-list format (Delis
et al. 2000). Measures of simple visual memory include the Brief
Visuospatial Memory Test (Benedict 1997), which uses an array of
simple geometric figures to measure visual learning and memory; a
more complex measure is the Rey Complex Figure Test (Meyers and
Meyers 1995). These tests, as well as many others, contain a similar
structure, with information presented during a single learning trial or
over the course of several learning trials. Depending on the
measure, request to recall the presented information can be
immediate, after a brief delay (typically less than 5 minutes), or after
a longer delay (usually 20–30 minutes). Recognition memory is a
key component of many memory measures and requires the
individual to discriminate between stimuli that were and were not
previously presented to them using a “yes” or “no” response format;
this helps determine whether memory deficits are related to retrieval
or consolidation of information.
Language
Evaluating language is an essential component of the
neuropsychological evaluation. Receptive language refers to the
ability to comprehend the symbolic communication of others. In
contrast, expressive language refers to the ability to produce
meaningful and coherent symbolic communication. A comprehensive
neuropsychological battery should include measures of both
receptive and expressive language, because these abilities often
frame the context in which results may be interpreted. For example,
an individual with impaired receptive language may demonstrate a
range of poor performances on cognitive measures as a result of not
adequately understanding task instructions.
Typical neuropsychological evaluations include a few measures of
language abilities such as confrontation naming (e.g., Boston
Naming Test, 2nd edition; Kaplan et al. 2001) and verbal fluency
(phonemic and semantic), which are sensitive to disruptions in
systems involved in language, especially involving the frontal and
temporal lobes. In certain circumstances, however, a more
comprehensive language assessment may be required to diagnose
and characterize language disorders, called aphasias. Aphasias can
involve language comprehension (receptive aphasia), expressive
language (expressive aphasia), repetition (conduction aphasia),
confrontation naming ability (anomic aphasia), and/or prosody,
depending on the location of the injury. The Boston Diagnostic
Aphasia Examination (Goodglass et al. 2001) and Multilingual
Aphasia Examination (Benton et al. 1994), for example, may aid in
differential diagnosis and treatment planning because of their wide
scope and sensitivity to different aphasias. Such batteries typically
include measures of spontaneous speech, speech comprehension,
word and sentence repetition, confrontation naming, reading, and
writing.
Visuospatial and Visuoconstruction Abilities

Deficits in visuospatial abilities can manifest as perceptual
distortions and/or impairments in object or facial recognition, mental
rotation, spatial memory, navigation and spatial orientation, visual
neglect, and representation of the size of and distance between
objects. The most commonly used measures to assess visuospatial
functioning involve visual discrimination (e.g., geometric forms,
angulation, faces, familiar objects) or the ability to integrate
fragmented, disarranged pieces into an identifiable whole object.
Additionally, spatial localization and visuoperception are integral
components of some widely administered measures, such as the
Clock Drawing Test, which requires correctly drawing a clock face
(i.e., shape and contour), placement and arrangement of the
numbers, and placement of and discrimination (i.e., size
differentiation) between the hour and minute hands. Notably, many
tests of visuospatial abilities also require visuoconstruction ability,
such as drawing or manually manipulating blocks. Thus, additional
testing may be needed to determine whether a patient has a purely
visuospatial impairment or whether impairment is the result of
difficulties with construction. For example, a patient with Parkinson’s
disease may show impairment on a test involving replicating a
design using blocks (e.g., WAIS-IV Block Design; Wechsler 2008),
but this may be due to poor construction secondary to motor slowing.
Use of similar tests that do not require a motor response could be
informative in such cases.
Processing of visuospatial information involves multiple brain
systems, although typically posterior areas of the right hemisphere
are involved. For example, identification of visuospatial information is
heavily reliant on intact right posterior temporal systems (the “what”
visual stream), whereas localization of visual information is
dependent on intact right posterior parietal systems (the “where”
visual stream) (Farah 2003).
Motor Abilities and Praxis

Motor abilities may be impaired in patients with a variety of
conditions that often prompt referral for neuropsychological
evaluation (e.g., Parkinson’s disease, multiple sclerosis). Commonly
employed measures, such as the Finger Tapping Test (Reitan and
Wolfson 1985), Grooved Pegboard (Reitan and Wolfson 1985), and
the Purdue Pegboard (Tiffin and Asher 1948), assess manual motor
speed and, to varying degrees, manual motor dexterity and
coordination. A hand dynamometer is often used to gauge grip
strength. Assessment of performance separately for each hand, as
well as discrepancies between scores obtained for a patient’s
dominant and nondominant hand, can provide valuable information
with respect to the possibility of a lateralized deficit (i.e., left or right
hemisphere), especially if the results are consistent with other
aspects of the assessment (e.g., discrepancy between verbal and
perceptual intellectual skills).
Apraxia, a type of motor impairment, is an inability to perform a
desired sequence of motor activities that is not a direct result of
motor weakness or paralysis. Rather, the primary deficit is in
planning and carrying out the required activities, and it is associated
with disruption of spatial location and the appropriate hand gestures
for completing actions (Haaland et al. 1999). Tests for apraxia
assess the patient’s ability to reproduce learned movements of the
face or limbs and may include, for instance, the use of objects (e.g.,
pantomiming the use of an object), conventional gestures (e.g.,
waving good-bye), and buccofacial and respiratory responses (e.g.,
pretending to blow out a candle). Assessment of praxis can provide
valuable information with regard to the cerebral lateralization of
abnormality based on the side of the apraxia (left- or right-side motor
skills), as well as to more specific brain regions based on the nature
of the apraxia (e.g., ideational).
Executive Function
Executive function is a category of cognition that comprises
interrelated self-regulatory control processes involved in the
selection, initiation, organization, execution, and monitoring of goal-
directed behavior (Roth et al. 2005; Stuss and Alexander 2000).
Executive function includes the ability to independently initiate
behaviors, inhibit impulses, select relevant task goals, plan and
organize a means to solve problems (especially when novel or
complex), think flexibly in response to changing circumstances,
regulate emotions, monitor and evaluate one’s behavior, and hold
information actively “online” (i.e., working memory) so that the
information may be manipulated and utilized in the service of
planning and guiding cognition and behavior. Accordingly, executive
function is essential for the highest levels of cognition such as
judgment, decision making, and self-awareness.
There are numerous tests designed to assess executive function,
and these vary widely in terms of the specific abilities required.
Working memory is most commonly assessed using span tasks such
as Digit Span Backward from the WAIS-IV, involving repeating digits
in reverse order. The Paced Auditory Serial Addition Test places
greater demand on working memory and processing speed, lasting
several minutes and requiring an individual to add consecutive pairs
of numbers presented at a fixed rate (e.g., a 3-second interval), with
increased difficulty achieved by presenting numbers at an increased
rate (e.g., a 2-second interval) (Gronwall 1977). The standard Stroop
Color-Word Interference Test (Golden 1978) presents color words in
incongruent colors (e.g., the word red written in blue ink) and
requires the individual to suppress the habitual tendency to read
words rather than say colors. Verbal fluency tests (described in the
subsection “Language”) may be used to measure initiation of
concepts, task persistence, and ability to think flexibly.
Patients with frontal lobe or diffuse brain injuries often have
difficulty with relatively open-ended tests that permit them to decide
how to perform the task, all the while receiving minimal instruction or
feedback. Tests such as the Wisconsin Card Sorting Test (WCST;
Heaton et al. 1993) and the Delis-Kaplan Executive Function System
(D-KEFS) Sorting Test (Delis et al. 2001) require several abilities,
including concept formation, hypothesis testing, problem solving,
flexibility of thinking, and working memory. For example, the WCST
requires the patient to deduce the principles by which to sort a deck
of cards (i.e., to generate an understanding of the pattern/category),
but without warning the patient, the examiner changes the correct
principle as the test proceeds. Therefore, the patient must figure out
independently that a shift in principles has occurred and change his
or her behavior accordingly (i.e., to avoid perseverating on the prior
pattern/category). As noted in the subsection “Attention and
Processing Speed,” Part B of the TMT is also commonly used to
assess a patient’s ability to think flexibly. Tests of planning and
foresight, such as the Tower of London (e.g., Shallice 1982), require
the person to move disks from stack to stack to match the
examiner’s configuration of disks but following certain rules (e.g., no
larger disk placed on top of a smaller disk, move only disk at a time).
Most performance-based tests of executive function are limited,
however, as they do not tap the integrated, multidimensional,
relativistic, priority-based decision making that is often demanded in
real-world situations (Goldberg and Podell 2000). Thus, some
patients reported to have executive dysfunction in their everyday
lives may perform well on tests because the examiner provides the
structure, organization, and monitoring necessary for an individual’s
optimal performance (Kaplan 1988). This has led to the development
of tests that try to enhance ecological validity by using real-world
scenarios and problems, such as the Behavioral Assessment of the
Dysexecutive Syndrome (Wilson et al. 1996), and standardized
rating scales of executive function as manifested in everyday life,
such as the Behavior Rating Inventory of Executive Function (Roth
et al. 2005) and the Frontal Systems Behavior Scale (Grace and
Malloy 2002).
Executive dysfunction has been reported in patients with a wide
variety of neurological and neuropsychiatric disorders, and executive
dysfunction contributes to difficulties maintaining socially appropriate
conduct, as well as successful academic and occupational
functioning. The presence of executive dysfunction can be helpful in
differential diagnosis in some situations, such as differentiating mild
Alzheimer’s disease from frontotemporal dementia; the latter is
generally associated with more prominent impairment. It should be
noted, however, that whereas executive function has historically
been most closely associated with the frontal lobes, there is a
plethora of evidence indicating involvement of wide neural networks,
including both cortical (frontal, parietal, and temporal lobes) and
subcortical (e.g., basal ganglia, cerebellum) regions. Indeed, patients
with focal lesions in nonfrontal brain regions may also present with
executive dysfunction, and thus poor performance on measures of
executive function does not necessarily imply frontal lobe damage.
Performance Validity Tests

As noted in the section “Interpretation: Principles and Cautions,”
inclusion of stand-alone and/or embedded measures of test-taking
effort, also called performance validity tests (PVTs), has become a
standard of practice in neuropsychological evaluations, especially
when issues such as litigation and disability claims are involved
(Bush et al. 2005). The basic premise of most PVTs is that they are
designed to appear cognitively challenging, but in actuality, PVTs
pose little difficulty for healthy individuals as well as the vast majority
of patients with clinical conditions such as TBI, depression, or mild
dementia.
Stand-alone PVTs most commonly involve a memory testing
format such as the Test of Memory Malingering (Tombaugh 1997),
the Word Memory Test (Green 2003), and the Rey 15-Item Test
(Goldberg and Miller 1986). Embedded performance validity
measures have been identified for numerous tests, such as reliable
digit span using the WAIS-IV Digit Span subtest, allowing the
examiner to gauge effort without adding additional time to the test
session. A combination of stand-alone and embedded PVTs is
generally preferred.
Intellectual Functioning
Intellectual functioning, often expressed as the intelligence
quotient (IQ), provides a context in which neuropsychological results
may be interpreted. The most commonly used measure of
intellectual ability in adults is the WAIS-IV (Wechsler 2008). It is
composed of tests of crystallized intelligence (e.g., academic-based
knowledge that is characteristically stable) as assessed through the
Verbal Comprehension Index (VCI) and Perceptual Reasoning Index
(PRI), as well as tests of fluid intelligence (e.g., constructs that can
vary across time, day, and situation), as measured by the WMI and
the PSI. The individual tests within each index were designed to
assess relatively distinct areas of cognition, such as mental
arithmetic, nonverbal abstract reasoning, and visuospatial
organization, and thus are differentially sensitive to identifying
dysfunction within various areas of the brain.
Specific information regarding the WAIS-IV indices, including the
subtests that compose them, can be found in the WAIS-IV manual
(Wechsler 2008). Each index of the WAIS-IV is composed of subtest
scores (e.g., the PRI contains the Block Design, Matrix Reasoning,
and Visual Puzzles subtests), and each of these subtest scores
contributes to the overall index score. Significant differences among
the subtest scores within an index (i.e., differences greater than 1.5
standard deviations) may result in IQ scores and/or ability levels that
may not accurately represent overall ability. For example, a patient
with a visuospatial deficit may have difficulty performing only the
Block Design test, which is averaged with the other PRI subtests,
and may produce a PRI score that does not reflect his or her true
overall perceptual reasoning abilities. Therefore, neuropsychologists
give consideration to both the index score and the individual subtest
scores.
The overall index scores, as well as the subtests that make up
each index, provide a wealth of information regarding cognitive and
intellectual strengths and weaknesses, in addition to potential
neuroanatomical implications of dysfunction. For example,
discrepancies between overall VCI and PRI scores can indicate
whether an individual has a particular proficiency for verbal or
perceptual reasoning abilities (i.e., greater left or right hemisphere
functioning, respectively).
It is important to note that many intellectual assessments, such as
the WAIS-IV, require intact auditory and verbal functioning.
Nonverbal measures of intellectual functioning are available for
those with primary difficulties in these areas (e.g., Test of Nonverbal
Intelligence; Brown et al. 2010).
Emotional Status and Personality

Formal assessment of emotional status is usually included in
neuropsychological batteries, as mood can impact an individual’s
actual and/or perceived cognitive abilities. In addition to information
obtained via the clinical interview, patients are asked to complete
standardized self-report mood rating scales. For example, the Beck
Depression Inventory (Beck et al. 1996) is a commonly used self-
report measure of depressive symptoms experienced during the past
2 weeks. A quantitative value is assigned to each response (i.e., 0–
4) for each item, which is summed to produce a total score. A total
score range of 0–13 indicates minimal symptoms; 14–19, mild
symptoms; 20–28, moderate symptoms; and over 29, severe
symptoms.
Personality assessment is often included in the
neuropsychological evaluation to further characterize the patient’s
psychological, behavioral, emotional, and social functioning.
Commonly used self-report measures in adults include the
Minnesota Multiphasic Personality Inventory, 2nd Edition (MMPI-2;
Butcher et al. 1989), and the Personality Assessment Inventory
(Morey 1991). Both of these measures include validity scales,
allowing the clinician to gauge the veracity of the patient’s responses
(i.e., exaggeration, minimization, inconsistency across items of
similar content), as well as a numerous clinical scales and subscales
reflecting various aspects of functioning. Examination of both
individual scales and the pattern of elevations among the scales
(higher scores reflecting greater endorsement of a problem area)
contribute to clinical interpretation. Many variations in patterns of
elevations exist (referred to as code types), and their interpretation
may differ depending on the population assessed. For example,
elevations on the MMPI-2 Hs (Hypochondriasis), D (Depression),
and Sc (Schizophrenia) scales are common because many
neuropsychiatric disorders are associated with symptoms reflected
within these scales (LaChapelle and Alfano 2005). Information
regarding these scales and their interpretations is available in the
MMPI-2 manual (Butcher et al. 1989).
Administration of these self-report measures is simple, and most
can be completed within 10 minutes. Personality assessments are
often lengthier, as is the case with the MMPI-2, which takes
approximately 60–90 minutes to complete. Nonetheless, such
measures can provide important insights into the patient’s
functioning and thereby contribute to differential diagnosis and
treatment planning.
Special Assessment Tools
Computerized Test Batteries

The use of computerized neuropsychological test batteries has
been gradually increasing, although considerably more in research
than in clinical contexts. There are numerous computerized test
batteries available, which vary widely with respect to the specific
domains of functioning assessed and measures employed, how the
measures are implemented (e.g., instructions, stimuli, response
requirements), and their psychometric properties (e.g., Cook et al.
2009). Advantages of computerized testing include test data
obtained under highly standardized conditions, ease of acquiring
precise data on accuracy and speed of responses, and minimal time
expenditure by the examiner. On the other hand, limitations exist that
render computerized testing problematic for regular clinical use. In
particular, failure to acquire important information about the way an
individual approaches a cognitive task or why performance is
impaired (e.g., motivation, fatigue, frustration tolerance, use of
strategy to complete a task), which is only possible if the examiner
observes test performance, can impact the validity of the test results
and thus limit interpretability. Furthermore, although people of all
ages are increasingly exposed to computers, research indicates that
computer-related anxiety and a negative attitude toward computers
can affect test performance on computerized neuropsychological
measures (Browndyke et al. 2002; Fazeli et al. 2013).
Decisional Capacity
Neuropsychiatrists and physicians are at times faced with patients
whose capacity to independently make personal decisions (e.g.,
legal, financial, medical) is called into question. Because
neuropsychologists have extensive training in standardized
assessment and interpretation, they can contribute objective data to
the determination of decisional capacity. Such evaluations typically
include neuropsychological measures used in standard evaluations,
but it is recognized that the relationship between individual
neuropsychological test scores and decision making is modest at
best (Wood and O’Bryan 2011). Thus, neuropsychological
evaluations conducted to help inform competency also usually
employ one or more additional measures of functional abilities.
Questionnaire measures pertaining to basic (e.g., hygiene,
feeding) and instrumental (e.g., managing medications and finances,
driving, cooking, cleaning) activities of daily living, completed by the
patient and ideally also by a knowledgeable informant, can be
informative. There are also semistructured interviews that facilitate
acquiring information that is more specific to the nature of the
suspected compromised decision-making ability. One example is the
Aid to Capacity Evaluation (Etchells et al. 1999), which can help
determine the extent to which a patient understands the relevant
information and the potential consequences with regard to a specific
medical treatment decision. The use of performance-based
measures of functional abilities is also recommended for capacity
evaluations. For example, the Texas Functional Living Scale (Cullum
et al. 2001) has tasks in which the examinee is asked to make
change, remember to take medications, tell time, look up and input a
telephone number, and use a calendar.
Conclusion
With advances in neuroimaging and other neurodiagnostics, there
has been a shift in the focus of neuropsychological assessment from
the diagnosis of possible brain damage to a better understanding of
specific brain-behavior relations and the psychosocial consequences
of brain damage. Patients are referred for neuropsychological
assessment for a variety of reasons. In some instances, the patient
will have a known brain disorder (e.g., cerebrovascular disorder,
developmental disorder, traumatic brain injury, Alzheimer’s disease
or related dementing disorder, Parkinson’s disease, multiple
sclerosis, Huntington’s disease, tumor, seizures, and psychiatric
disorder associated with brain dysfunction). Other times, the referred
individual may have a known risk factor for brain disorder; concerns
related to potential changes in cognition or behavior might be the
result of such a disorder. Furthermore, brain disorder or dysfunction
may be suspected when a person’s behavior or personality changes
without an identifiable cause. An explanation is sought because
behavior patterns and personality are relatively stable characteristics
of adults, and these changes require an explanation.
Neuropsychology is a specialty practice focused on the
assessment of brain function and brain-behavior relationships. It can
be useful in defining the nature and severity of cognitive difficulties,
as well as providing information about a patient’s personality
characteristics, social behavior, emotional status, and adaptation to
their conditions. The potential for independent living and productive
activity can also be inferred from these data. Information garnered in
the assessment provides a foundation for treatment planning,
vocational training, competency determination, and counseling for
both patients and their families. Clinical neuropsychologists serve as
invaluable clinical experts who integrate information from a person’s
history, behavioral observations, and test data to provide a snapshot
of current cognitive functioning, help identify factors contributing to
dysfunction, and guide treatment and recommendations; they are an
integral and unique contributor to the patient’s clinical team.
References
American Educational Research Association, American Psychological Association,
National Council on Measurement in Education, et al: The Standards for
Educational and Psychological Testing. Washington, DC, American Educational
Research Association, 2014
Barth JT, Pliskin N, Axelrod B, et al; NAN Policy and Planning Committee:
Introduction to the NAN 2001 Definition of a Clinical Neuropsychologist. Arch
Clin Neuropsychol 18(5):551–555, 2003 14591449
Bauer RM: The flexible battery approach to neuropsychological assessment, in
Clinician’s Guide to Neuropsychological Assessment. Edited by Vanderploeg
RD. Mahwah, NJ, Erlbaum, 2000, pp 419–448
Beck AT, Steer RA, Brown GK: Beck Depression Inventory–II (BDI-II). San
Antonio, TX, Psychological Corporation, 1996
Benedict RHB: Brief Visuospatial Memory Test—Revised. Odessa, FL,
Psychological Assessment Resources, 1997
Benton AL, Hamsher K, Rey HJ, et al: Multilingual Aphasia Examination. Iowa City,
IA, AJA Associates, 1994
Bieliauskas LA, Matthews CG: American board of clinical neuropsychology:
policies and procedures. Clin Neuropsychol 1(1):21–28, 1987
Brown L, Sherbenou RJ, Johnsen SK: Test of Nonverbal Intelligence—Fourth
Edition (TONI-4). Austin, TX, Pro-Ed, 2010
Browndyke JN, Albert AL, Malone W, et al: Computer-related anxiety: examining
the impact of technology-specific affect on the performance of a computerized
neuropsychological assessment measure. Appl Neuropsychol 9(4):210–218,
2002 12584075
Bush SS, Ruff RM, Tröster AI, et al: Symptom validity assessment: practice issues
and medical necessity NAN policy & planning committee. Arch Clin
Neuropsychol 20(4):419–426, 2005 15896556
Butcher JN, Dahlstrom WG, Graham JR, et al: The Minnesota Multiphasic
Personality Inventory–2 (MMPI-2): Manual for Administration and Scoring.
Minneapolis, University of Minneapolis Press, 1989
Butterfield LC, Cimino CR, Oelke LE, et al: The independent influence of apathy
and depression on cognitive functioning in Parkinson’s disease.
Neuropsychology 24(6):721–730, 2010 20853956
Conners CK: Conners’ Continuous Performance Test–II. North Tonawanda, NY,
Mental-Health Systems, 2004
Cook TH, Kay GG, Larrabee G: Computer-based cognitive testing, in
Neuropsychological Assessment of Neuropsychiatric and Neuromedical
Disorders. Edited by Grant I, Adams KM. Oxford, UK, Oxford University Press,
2009, pp 784–800
Cullum CM, Saine K, Chan LD, et al: Performance-based instrument to assess
functional capacity in dementia: The Texas Functional Living Scale.
Neuropsychiatry Neuropsychol Behav Neurol 14(2):103–108, 2001 11417663
Delis DC, Kramer JH, Kaplan E, et al: California Verbal Learning Test. San
Delis DC, Kaplan E, Kramer JH: Delis-Kaplan Executive Function System. San
Etchells E, Darzins P, Silberfeld M, et al: Assessment of patient capacity to
consent to treatment. J Gen Intern Med 14(1):27–34, 1999 9893088
Farah MJ: Disorder of visual-spatial perception and cognition, in Clinical
Neuropsychology. Edited by Heilman KM, Valenstein E. Oxford, UK, Oxford
University Press, 2003, pp 146–160
Fazeli PL, Ross LA, Vance DE, Ball K: The relationship between computer
experience and computerized cognitive test performance among older adults. J
Gerontol B Psychol Sci Soc Sci 68(3):337–346, 2013 22929395
Flashman LA: Disorders of awareness in neuropsychiatric syndromes: an update.
Curr Psychiatry Rep 4(5):346–353, 2002 12230963
Goldberg E, Podell K: Adaptive decision making, ecological validity, and the frontal
lobes. J Clin Exp Neuropsychol 22(1):56–68, 2000 10649545
Goldberg JO, Miller HR: Performance of psychiatric inpatients and intellectually
deficient individuals on a task that assesses the validity of memory complaints.
J Clin Psychol 42(5):792–795, 1986 3760213
Golden C: Stroop Color and Word Test: A Manual for Clinical and Experimental
Uses. Chicago, IL, Stoelting, 1978
Goodglass H, Kaplan E, Barresi B: Boston Diagnostic Aphasia Examination.
Austin, TX, Pro-Ed, 2001
Grace J, Malloy PF: Frontal Systems Behavior Scale (FrSBe). Lutz, FL,
Green P: Green’s Word Memory Test for Windows: User’s Manual. Edmonton, AB,
Canada, Green’s Publishing, 2003
Gronwall DM: Paced auditory serial-addition task: a measure of recovery from
concussion. Percept Mot Skills 44(2):367–373, 1977 866038
Haaland KY, Harrington DL, Knight RT: Spatial deficits in ideomotor limb apraxia: a
kinematic analysis of aiming movements. Brain 122 (Pt 6):1169–1182, 1999
10356068
Hannay HJ: Proceedings of the Houston Conference on specialty education and
training in clinical neuropsychology, September 3–7, 1997, University of
Houston Hilton and Conference Center. Arch Clin Neuropsychol 13(2):157–
158, 1998
Heaton RK, Chelune GJ, Talley JL, et al: Wisconsin Card Sorting Test (WCST)
Manual, Revised and Expanded. Odessa, FL, Psychological Assessment
Resources, 1993
Jorge RE, Acion L, Moser D, et al: Escitalopram and enhancement of cognitive
recovery following stroke. Arch Gen Psychiatry 67(2):187–196, 2010 20124118
Kaplan E: A process approach to neuropsychological assessment, in Clinical
Neuropsychology and Brain Function: Research, Measurement, and Practice.
Edited by Dennis M, Boll TJ, Bryant BK, et al. Washington, DC, American
Psychological Association, 1988, pp 129–167
Kaplan E, Goodglass H, Weintraub S: The Boston Naming Test, 2nd Edition.
Philadelphia, PA, Lea & Febiger, 2001
LaChapelle DL, Alfano DP: Revised neurobehavioral scales of the MMPI:
sensitivity and specificity in traumatic brain injury. Appl Neuropsychol
12(3):143–150, 2005 16131341
Lee RS, Hermens DF, Porter MA, Redoblado-Hodge MA: A meta-analysis of
cognitive deficits in first-episode Major Depressive Disorder. J Affect Disord
140(2):113–124, 2012 22088608
Lezak MD, Howieson DB, Bigler ED, Tranel D: Neuropsychological Assessment.
Oxford, UK, Oxford University Press, 2012
Mann-Wrobel MC, Carreno JT, Dickinson D: Meta-analysis of neuropsychological
functioning in euthymic bipolar disorder: an update and investigation of
moderator variables. Bipolar Disord 13(4):334–342, 2011 21843273
Meyers JE, Meyers KR: Rey Complex Figure Test and Recognition Trial:
Professional Manual. Lutz, FL, Psychological Assessment Resources, 1995
Moberg PJ, Kniele K: Evaluation of competency: ethical considerations for
neuropsychologists. Appl Neuropsychol 13(2):101–114, 2006 17009883
Morey LC: Personality Assessment Inventory. Lutz, FL, Psychological Assessment
Resources, 1991
Perfect TJ, Maylor EA: Models of Cognitive Aging. Oxford, UK, Oxford University
Press, 2000
Reitan RM, Wolfson D: The Halstead-Reitan Neuropsychological Test Battery.
Tucson, AZ, Neuropsychology Press, 1985
Roth RM, Isquith PK, Gioia GA: Behavior Rating Inventory of Executive Function—
Adult Version (BRIEF-A). Lutz, FL, Psychological Assessment Resources,
2005
Schretlen DJ, Testa SM, Winicki JM, et al: Frequency and bases of abnormal
performance by healthy adults on neuropsychological testing. J Int
Neuropsychol Soc 14(3):436–445, 2008 18419842
Shallice T: Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci
298(1089):199–209 1982 6125971
Strauss EE, Sherman S, Spreen O: A Compendium of Neuropsychological Tests:
Administration, Norms, and Commentary. Oxford, UK, Oxford University Press,
2006
Stuss DT, Alexander MP: Executive functions and the frontal lobes: a conceptual
view. Psychol Res 63(3-4):289–298, 2000 11004882
Tiffin J, Asher EJ: The Purdue pegboard: norms and studies of reliability and
validity. 32(3):234–247 1948 18867059
Tombaugh T: Test of Memory Malingering. Toronto, ON, Canada, Multi-Health
Systems, 1997
Wechsler D: Wechsler Adult Intelligence Scale—Fourth Edition (WAIS-IV). New
York, Psychological Corporation, 2008
Wechsler D: Test of Premorbid Functioning. San Antonio, TX, Psychological
Corporation, 2009
Wilkinson GS, Robertson GJ: Wide Range Achievement Test 4 (WRAT4). Lutz, FL,
Wilson BA, Alderman N, Burgess P, et al: Behavioural Assessment of the
Dysexecutive Syndrome (BADS). Suffolk, UK, Thames Valley Test Company,
1996
Wood S, O’Bryan M: Assessment of civil capacities: an evaluative framework and
practical recommendations, in Civil Capacities in Clinical Neuropsychology:
Research Findings and Practical Applications. Edited by Demakis GJ. New
York, Oxford University Press, 2011, pp 185–205
Yousef G, Ryan WJ, Lambert T, et al: A preliminary report: a new scale to identify
the pseudodementia syndrome. Int J Geriatr Psychiatry 13(6):389–399, 1998
9658274
CHAPTER 4
Neuroimaging in
Neuropsychiatry
Shiv S. Patel, M.D.
The marvels of engineering and physics have provided powerful

approaches to elucidating the brain-based sources of emotion and
behavior. Subspecialists in behavioral neurology and
neuropsychiatry assess and treat patients with cognitive, emotional,
and/or behavioral disturbances due to brain dysfunction. The advent
of multiple methods to image the brain has contributed significantly
to the knowledge base of this subspecialty. During the past century,
neuroimaging technology advanced from providing a primitive skull
X-ray to furnishing highly detailed pictures of brain structure and
function. Cutting-edge neuroimaging can contribute not only to the
diagnosis but also to prognosis, prediction of treatment response,
and development of new treatments (Filippi et al. 2012; Osuch and
Williamson 2006).
Clinical Neuroimaging
There are two categories of neuroimaging currently used in
clinical neuropsychiatry (Aguirre 2014; Carter and Coles 2012; Malhi
and Lagopoulos 2008): structural neuroimaging and functional
neuroimaging. Structural neuroimaging technologies are used to
evaluate brain tissue integrity and to identify abnormalities
associated with many pathological processes; computed tomography
(CT) and magnetic resonance imaging (MRI) are the most commonly
used structural neuroimaging technologies in clinical
neuropsychiatry. Functional neuroimaging provides images that
(indirectly) reflect brain activity, the most common of which do so by
measuring blood flow, glucose, and oxygen utilization; single-photon
emission computed tomography (SPECT) and positron emission
tomography (PET) are the most commonly used functional
neuroimaging technologies in clinical neuropsychiatry. Clinical
applications for other functional imaging techniques, such as
functional MRI, xenon-enhanced CT, and magnetoencephalography,
are still quite limited.
Structural Neuroimaging
Diagnostic neuroimaging has advanced considerably over the last
decade and has facilitated concurrent advancement of our
understanding of brain-behavior relationships. It is recognized now
that even subtle lesions can give rise to disturbances of cognition,
emotion, and behavior through the disruption of the neural circuits
and networks subserving these neuropsychiatric functions (Bonelli
and Cummings 2007; Filley 2010, 2011; Haber and Rauch 2010). A
lesion anywhere within a circuit (Figure 4–1), including the tracts that
connect nodes within that circuit or the networks in which that circuit
participates, has the potential to cause neuropsychiatric
impairments.
FIGURE 4–1. Circuits.
See Plate 15 to view this figure in color.
There are three areas within the prefrontal cortex (PFC) that govern important
aspects of behavior via reciprocal connections with subcortical structures, thus
forming cortico-subcortical circuits. The dorsolateral PFC circuit (pink) mediates
executive functions such as organization, planning, and allocation of attention. The
orbitofrontal PFC circuit (blue) mediates socially appropriate behavior, impulse
control, and empathy. The anterior cingulate PFC circuit (green) contributes to
motivation by balancing the inhibitory input of the supplemental motor areas with
its own stimulus that supports wakefulness and arousal. Evidence supports the
participation of the cerebellum, although its functions still need further study. The
anterior cingulate PFC also participates in emotional and memory-related functions
as part of the circuit of Papez (gold). nuc=nucleus.
A study of psychiatric patients without dementia found that

treatment was changed in 15% of patients as a result of imaging
examinations (Erhart et al. 2005). A study of psychiatric inpatients
(general university hospital) with dementia reported that more than
one-third of the structural imaging examinations (i.e., CT, MRI)
resulted in a change in diagnosis (Tanev et al. 2012). Neuroimaging
should be considered whenever the brain might have sustained
injury because the information obtained may assist with differential
diagnosis, alter a treatment plan, and/or be of prognostic value
(Table 4–1). There are many situations in which injury to the brain is
known to have occurred either as a result of an event (e.g., stroke,
traumatic brain injury [TBI]) or as a result of an exposure (i.e.,
intentional, accidental, occupational) to a toxin or poison (including
significant alcohol misuse). Neuroimaging may also provide insight
into cases with atypical clinical presentations (Table 4–1).
TABLE 4–1. Indications for neuroimaging

Historical information/clinical signs or symptoms
New-onset mental illness after age 50
Manifestation of psychiatric symptoms at atypical age for diagnosis
Atypical evolution of psychiatric symptoms
Abrupt personality change
Initial psychotic break
Focal neurological signs
Dementia or cognitive decline
Catatonia
Diagnosis or medical condition
Traumatic brain injury
Alcohol misuse with psychiatric symptoms
Seizure disorder with psychiatric symptoms
Movement disorder with psychiatric symptoms
Autoimmune disorder
Eating disorder
Poison or toxin exposure
Delirium
Computed Tomography
The first clinical CT examination was performed in the 1970s, and
up to 9 days were required to collect and sort the data. Modern CT
employs multiple detectors that can scan and generate images in a
matter of seconds. Like a conventional radiograph, CT uses an x-ray
tube as a source of photons (Grignon et al. 2012; Thomas et al.
2010). As the patient moves through the central tunnel of the CT
scanner, rotating beams of photons pass through the patient’s head.
These photons move through varied tissues with different densities
that attenuate the beam accordingly. The photon beams are then
registered on a set of rotating detectors located opposite the beam
source. Complex algorithms are applied to the acquired data sets to
generate images for interpretation. The interpreting physician can
change the window and level of the images to bring out different
structures and pathology (Figure 4–2). Bone will appear white
(almost complete absorption of the X-rays or high attenuation)
because it has a very high density. Air will appear black (very low
rate of attenuation). Brain will appear gray (intermediate density).
The displayed shades of gray vary in accordance with the tissue
density, which is dependent upon the tissue composition. For
example, lipid has a lower relative density compared with other
tissue components; accordingly, white matter, which has much more
lipid (from myelin) than gray matter, appears darker than gray matter.
FIGURE 4–2. Computed tomography (CT) cases. See Plate 16 to view this
figure in color.
Intensity (brightness) in CT images is a function of tissue density. Dense tissues
such as bone and blood will appear white, indicating an almost complete
absorption of the X-rays (high attenuation). Brain tissues have intermediate
densities and so are shades of gray. CT provides excellent visualization of some
conditions, such as hemorrhage, and is the preferred imaging method for acute
head injury. CT is also useful when magnetic resonance imaging (MRI) is
contraindicated. (A) Middle-aged male with hyperdense subarachnoid
hemorrhage. (B) Middle-aged male with hyperdense subdural hematoma. (Case
contributed by David M. Keadle, M.D.) (C) Elderly male with isodense subdural
hematoma. (D) Bifrontal encephalomalacia in young adult male with retained
shrapnel (MRI contraindicated) and metallic artifact after exposure to improvised
explosive device. (E) Early-middle-aged male with significant generalized atrophy.
(F) Middle-aged male with old right frontal infarct, white matter ischemia, and
lacunar infarct (not well visualized on this slice). (G) and (H) Late-middle-aged
male with dilated ventricles/hydrocephalus. (I) Late-middle-aged male (CT
angiogram, coronal) with anterior communicating artery aneurysm and dilated
ventricles. (Case contributed by Daniel C. Barr, M.D.)
A routine noncontrast brain CT scan is acquired and formatted to

generate 2.5- to 5.0-mm slice thickness. The slice thickness of a CT
image is an important variable in clinical scanning. Thinner slices
allow visualization of smaller lesions. However, the thinnest sections
have less contrast (i.e., the signal intensity difference between gray
and white matter is less) because the signal-to-noise ratio is lower.
Thicker sections (or slices) have greater contrast, but smaller lesions
may be missed. There is also a greater incidence of artifacts due to
increased volume averaging (i.e., averaging of two adjacent, but very
different, parts of the brain within a single CT slice). This is
particularly true in tissues that approximate the margin of the
calvarium. Imaging of the brain stem and the posterior fossa can be
complicated by beam-hardening artifact as a result of the dense
surrounding bone. Noncontrast head CT examinations are obtained
and displayed in two-dimensional images in the axial plane;
however, coronal or sagittal reformatted images can be quickly
constructed. Three-dimensional reconstructions can also be
accomplished.
Magnetic Resonance Imaging
In 1946, the phenomenon of nuclear magnetic resonance was
discovered. The discovery led to the development of a powerful
technique for studying matter by using radio waves along with a
static magnetic field (measured in teslas [T]). The first MRI of a living
patient was taken in the 1970s. By the 1980s, commercial MRI
scanners were becoming more common. Clinical MRI is based on
manipulating the small magnetic field around the nucleus of the
hydrogen atom (proton), a major component of water in soft tissue
(Currie et al. 2013; Moser et al. 2009). The magnetic field of the MRI
scanner slightly magnetizes a small fraction of the hydrogen atoms
in the body and changes their alignment. To create an image, the
patient is placed in the center of the MRI scanner’s powerful
magnetic field. Currently, most magnets in clinical use employ a
static field strength of 1.2 T, 1.5 T, or 3.0 T. A series of precisely
calculated radio frequency (RF) pulses are then applied at variable
intervals. The hydrogen nuclei absorb this RF energy, causing them
to lose their alignment with the strong magnetic field temporarily. The
hydrogen nuclei gradually relax back into magnetic alignment and
release the absorbed energy in a characteristic temporal pattern,
depending on the nature of the tissue containing the hydrogen
atoms. This electromagnetic energy is detected by receiver coils and
is converted into an electrical signal that is sent to a computer. The
scanner’s computer converts these signals into a spatial map. The
final output is a matrix that specifies a three-dimensional image
composed of many small blocks or voxels. The voxel size is variable
but is roughly about 1 mm on each side for brain. Creation of an MR
image also requires the application of small magnetic field gradients
across the patient. This allows the scanner to detect which part of
the body is emitting what signal. The magnetic field gradients
needed to acquire the image are created by coils of wire embedded
in the magnet. These are driven with large-current audio amplifiers
similar to those used for musical concerts. The current in these coils
must be switched on and off rapidly. This causes the coils to vibrate
and creates loud noises during the scan, which may occasionally
distress the unprepared patient, although patients are always given
ear plugs, which greatly dampen the noise (Moser et al. 2009).
Some patients feel uncomfortable or frankly claustrophobic while
lying inside these huge enclosing magnets (Figure 4–3). Open-
design magnets are now available that help the patient feel less
confined (Bangard et al. 2007; Enders et al. 2013).
FIGURE 4–3. Neuroimaging equipment.
Several aspects of neuroimaging equipment can be challenging for some patients
to tolerate. The patient’s head is commonly restrained to minimize movement, and
the patient must remain still once placed into the rather narrow bore of the
scanner. MRI=magnetic resonance imaging; PET=positron emission tomography.
The combination of RF and magnetic field pulses used by the

computer to create the image is called the pulse sequence. Pulse
sequences have been developed that result in images sensitive to
different aspects of the hydrogen atom’s behavior in a high magnetic
field. Thus, each image type contains unique information about the
tissue (Currie et al. 2013; Moser et al. 2009). A pulse sequence is
repeated many times to form an image. All clinical MRI brain studies
will include spin echo or fast spin echo acquisitions as key
components (Figure 4–4). These pulse sequences emphasize
different tissue properties by varying two factors. One factor is the
time between applying each repetition of the sequence, referred to
as the repetition time or time to recovery (TR). The other is the time
at which the receiver coil collects signal after the RF pulses have
been given. This period is called the echo time or time until the echo
(TE). Images collected using a short TR and short TE are most
heavily influenced by the T1 relaxation times of the tissues and so
are called T1 weighted (T1W). T1W images are considered best for
displaying anatomy because there are clear boundaries between the
gray matter of the brain (medium gray), the white matter of the brain
(very light gray), and cerebrospinal fluid (CSF) (black) (Figure 4–4).
Images collected using a long TR and a long TE are most heavily
influenced by the T2 relaxation times of tissues and, therefore, are
called T2 weighted (T2W). Although boundaries between the gray
matter of the brain (medium gray), the white matter of the brain (dark
gray), and CSF (white) are more blurred than on T1W images, T2W
images are best for displaying pathology (white, similar in intensity to
CSF) (Figure 4–4). A highly useful variant on the T2W scan, called a
fluid-attenuated inversion recovery (FLAIR) image, allows the
intense signal from CSF to be nullified (CSF appears dark). This
makes pathology near CSF-filled spaces much easier to see
(Figures 4–4 and 4–5). FLAIR improves identification of subtle
lesions and makes it useful for neuropsychiatric imaging.
FIGURE 4–4. Computed tomography (CT) versus magnetic resonance
imaging (MRI).
MRI provides better visualization of anatomy and usually of pathology than CT, as
illustrated by a clinical case of a late-middle-aged female with a history of two mild
traumatic brain injuries (TBIs). The only abnormality noted on the CT is mild
hypoattenuation in the periventricular white matter. Gliotic foci that are likely
residual from the TBIs are clearly visualized on T2W and fluid-attenuated inversion
recovery (FLAIR) MRI (yellow circles) but not on T1W or diffusion-weighted
imaging (DWI) MRI. Magnetic resonance angiography (MRA) indicates that the
vasculature is patent.
FIGURE 4–5. Magnetic resonance imaging (MRI) cases.
(A)–(C) Young adult male with multiple demyelinating lesions of the cortical and
subcortical white matter and corpus callosum that did not enhance on contrast
imaging. (Case contributed by Tammy Smith, Pharm.D.) (D) and (E) Middle-aged
male with significant encephalomalacia (arrow) and gliosis (arrowhead) of both
frontal lobes and the right temporal lobe (not pictured) from an assault a decade
prior. Patient now has anosmia and significant orbitofrontal function deficits. Note
that these two types of pathology are more easily distinguishable on (E) fluid-
attenuated inversion recovery (FLAIR) MRI than (D) T2W MRI. (F) Adult male with
encephalomalacia (arrow) and gliosis (arrowhead) in the midline frontal cortex due
to being hit on the occiput decades earlier. (G) FLAIR and (H) T1W postcontrast of
young adult male with 13.5-mm lesion in the medial right cerebellum, without
edema, hemorrhage, mass effect, or enhancement on contrast. Differential
includes low-grade astrocytoma or early oligodendroglioma. (I) Early-middle-aged
male with multiple areas of increased signal in the cortical white matter on FLAIR
MRI, consistent with diffuse axonal injury from multiple exposures to explosions.
The gradient echo sequence is also commonly used. This

technique is very sensitive to anything in the tissue causing magnetic
field inhomogeneity, such as blood (or its breakdown products) or
calcium. These images are sometimes called susceptibility weighted
because differences in magnetic susceptibility between tissues
cause localized magnetic field inhomogeneity and signal loss. As a
result, gradient echo images have artifacts at the interfaces between
tissues with very different magnetic susceptibility, such as bone and
brain. The artifacts at the skull base are sometimes severe. Another
method that is clinically useful is diffusion-weighted imaging (DWI).
DWI is sensitive to the speed of water diffusion and provides
visualization of ischemic stroke in the critical first few hours after
onset (Grignon et al. 2012; Lerner et al. 2014). DWI is also
informative in other conditions, including metabolic encephalopathies
(e.g., hypoglycemic, hyperammonemic, osmotic), infection,
neurodegenerative conditions, and TBI (Figure 4–4) (Bathla and
Hegde 2013; Keogh and Henson 2012; Le and Gean 2009).
Diffusion tensor imaging, a more complex version of DWI, is
presently used primarily for clinical research (Grignon et al. 2012;
Lerner et al. 2014).
Contrast-Enhanced Imaging
Contrast agents travel in the vascular system and normally do not
cross into the brain parenchyma, because they cannot pass through
the blood-brain barrier (BBB). The BBB is formed by tight junctions in
the capillaries that serve as a structural barrier, and they function like
a plasma membrane. In some disease processes, the BBB becomes
permeable. As a result, contrast agents can diffuse into brain tissue.
Pathologic processes in which the BBB is disrupted include
autoimmune diseases, infections, and tumors. Contrast
enhancement can also be useful in the case of vascular
abnormalities (such as arteriovenous malformations and
aneurysms), although the contrast agent remains intravascular.
Computed Tomography Contrast Agents

The contrast agents used for brain CT contain iodine (iodinated)
and appear white on the CT scan. Without a companion noncontrast
CT scan, preexisting dense areas (calcified or hemorrhagic) might
be mistaken for contrast-enhanced lesions. In difficult cases, a
double dose of contrast agent may be used to improve detection of
lesions with minimal BBB impairment. Currently, most institutions
utilize iso-osmolar or low-osmolality agents (Weissleder et al. 2011).
Allergic-type reactions may develop with iodinated contrast agents,
so it is important to inform the radiologist prior to scanning about any
history of previous allergic-type reactions to contrast dyes and any
history of diabetes, renal insufficiency, sickle cell disease, or other
debilitating or serious medical conditions. Metformin can cause lactic
acidosis in patients with impaired renal function, so it is withheld in
at-risk patients following use of iodinated dye. The metformin can be
restarted after 48 hours with clinical and/or laboratory evidence of
normal renal function.
Magnetic Resonance Imaging Contrast Agents

To manufacture an MRI contrast agent, a paramagnetic metal ion
is attached to a very strong ligand that prevents any interaction with
surrounding tissue and allows the complex to be excreted intact by
the kidneys (Kanal et al. 2014). All seven currently approved contrast
agents for brain imaging utilize gadolinium, a metal ion that is highly
paramagnetic, with a natural magnetic field 657 times greater than
that of the hydrogen atom. Unlike the iodinated contrast agents used
in CT, the currently used clinical MRI contrast agents are not imaged
directly. Rather, the presence of the contrast agent changes the T1
and T2 properties of hydrogen atoms (protons) in nearby tissue
(Kanal et al. 2014). Accumulation within tissue is most easily seen
on a T1W scan, where it results in an increase in signal. Adverse
reactions/side effects are generally low with MRI contrast agents;
however, patients with renal compromise are at higher risk for
development of nephrogenic systemic fibrosis. It is again prudent to
inform the radiology team of any debilitating medical conditions,
particularly renal dysfunction or allergies, prior to referring the patient
for scanning (Kanal et al. 2014).
Practical Considerations Guiding Structural

Neuroimaging in Clinical Practice
Selecting the Neuroimaging Type
The clinical context determines the choice of imaging modality.
There are a few brain-based conditions best viewed with CT,
including calcification, acute hemorrhage, and skull fracture (Figure
4–2) (Thomas et al. 2010). Otherwise, MRI is the preferred modality
in clinical neuropsychiatry unless it is contraindicated, because
visualization of both neuroanatomy and pathology is much better
(Figures 4–4 and 4–5). In addition, MRI does not produce bone-
related artifacts (discussed above in subsection “Computed
Tomography”), so lesions near bone (i.e., those in brain stem,
posterior fossa, pituitary, hypothalamus) are generally well
visualized. When ordering the imaging procedure, the clinician
should be mindful to request a study with contrast enhancement if a
disease affecting the BBB or cerebrovascular architecture is
suspected.
Imaging Request
The clinician should provide very clear and complete clinical
information on the imaging request (not just “rule out pathology” or
“new-onset mental status changes”) because this is essential for
guiding selection of the best imaging methods and parameters.
Examples of information that is of value to the radiologist include the
following: “rule out diffuse axonal injury because patient was in a
high-speed motor vehicle accident”; “rule out basal ganglia lesion
because patient was exposed to carbon monoxide”; and “patient has
long history of alcohol dependence so evaluation of mammillary
bodies and anterior thalamus is important.” The radiologist and
technical staff also need information about the patient’s current
condition (e.g., delirious, psychotic, easily agitated, paranoid,
significant tremor) that might create difficulties with patient
management during the scan.
Patient Preparation
The clinician ordering an imaging examination should always
explain the procedure to the patient beforehand and be mindful to
mention the loud noises of the scanner (MRI), the tightly enclosing
imaging coil (MRI) (Figure 4–3), and the necessity for absolute
immobility during the test (MRI and CT). If it is likely that the patient
may become agitated or be unable to remain still for the length of the
examination, light sedation may be required. The clinician ordering
the imaging is usually responsible for prescribing any required
sedatives.
Safety Considerations for Structural Neuroimaging in

Clinical Practice
Computed Tomography
Routine brain CT scans deliver a low dose of radiation (less than
5 rads), and their acquisition is not contraindicated in healthy
pregnant patients (American College of Radiology and Society for
Pediatric Radiology 2014; Brunner et al. 2013).
Magnetic Resonance Imaging

At the time of this writing, there are no unequivocally
demonstrated, permanent, hazardous effects from short-term
exposure to magnetic fields and RF pulses generated in clinical MRI
scanners (Coskun 2011; Expert Panel on MR Safety et al. 2013).
Although there is no evidence of injury to the developing fetus
associated with such exposures, most experts recommend caution
when considering MRI of a pregnant woman. When possible,
informed written consent for clinical MRI studies should be obtained
from the pregnant patient, especially if the patient is in her first
trimester of pregnancy.
Volunteers scanned using systems with higher field strength have
reported effects, including vertigo and nausea. With very intense
gradients, it is possible to stimulate peripheral nerves directly, but
this is not a concern at clinical field strengths.
There are specific contraindications to the use of MRI. The
magnetic field can damage electrical, mechanical, or magnetic
devices implanted in or attached to the patient. Pacemakers and
defibrillators can be damaged by programming changes, possibly
inducing arrhythmias. Currents can develop within the wires, leading
to thermal burns, fibrillation, or movement of the wires or the device
itself. Cochlear implants, dental implants, magnetic stoma plugs,
bone-growth stimulators, and implanted medication-infusion pumps
can all be demagnetized or injure the patient by their movement
during exposure to the scanner’s magnetic field. In addition, metallic
implants, shrapnel (see Figure 4–2D), bullets, or metal shavings
within the eye (e.g., from welding) can conduct a current and/or
move, causing injury. Medication patches with metal foil backing are
at risk for both heating and altered pharmacodynamics. Any metal
has the potential to distort the magnetic resonance image locally and
may decrease diagnostic accuracy. Ferromagnetic objects near the
magnet—such as oxygen tanks—can be drawn into the magnet at
high speed, injuring the patient or staff. Difficulties have also been
encountered when a patient requires physiological monitoring during
the procedure. Several manufacturers have developed MRI-
compatible respirators and monitors for blood pressure and heart
rate.
Functional Neuroimaging
Functional neuroimaging may contribute to the clarification of
differential diagnosis, prognosis, clinical management, and
development of new interventions (Filippi et al. 2012; Osuch and
Williamson 2006). A study of patients with cognitive disorders
admitted to a medical psychiatry unit in a general university hospital
found that almost three-quarters of the functional imaging
examinations (i.e., SPECT, PET) resulted in a change in diagnosis
(Tanev et al. 2012). The most common reasons for ordering
neuroimaging were to rule out stroke or tumor and for screening for
an underlying cause of dementia. A study in a small rural hospital of
psychiatric patients (inpatients and outpatients) referred for SPECT
imaging (history of TBI, stroke or seizures, atypical mental status
presentations) reported that 81% of scans were abnormal (Sheehan
and Thurber 2008). This resulted in a change in treatment and/or
diagnosis in 79% of cases, including 13% in which the new diagnosis
was a previously unrecognized TBI. A case series presented three
elderly individuals with recent exacerbation of idiopathic obsessive-
compulsive disorder that had resolved decades earlier, all of the
patients demonstrated structural and/or functional abnormalities in
the frontal lobes and basal ganglia on clinical neuroimaging (Salinas
et al. 2009).
Regional cerebral blood flow (rCBF) and regional cerebral
metabolic rate (rCMR) are the most broadly used clinical functional
neuroimaging measures. Both rCBF and rCMR are high in gray
matter areas (e.g., thalamus, basal ganglia, cortex) and lower in
white matter. Although indirect measures of brain activity, rCBF and
rCMR are tightly linked under most physiological and
pathophysiological conditions and provide very similar functional
information (Raichle 2003). Both PET and SPECT involve
intravenous injection of a radioactive compound (radiotracer) that
distributes in the brain and emits (indirectly, in the case of PET)
photons that are detected and used to form an image. The
radiotracer is a molecule with properties that determine its
distribution in the body and that contains a radioactive atom
(radionuclide). For example, fluorodeoxyglucose distributes in cells
in proportion to their glucose metabolic rate.
Single-Photon Emission Computed Tomography

As the SPECT radiotracer decays, it emits a photon. This is
detected by a gamma camera and used by the computer to
reconstruct a tomographic image, similar to the procedure for CT
described in the subsection “Computed Tomography.” Resolution is
heavily dependent on the age and sophistication of the equipment.
Older systems had limited detectors and produced lower-quality
images. Most modern SPECT cameras have a theoretical resolution
of about 6–7 mm. In practice, the patient’s shoulders physically
prevent the camera heads from being positioned close enough to the
patient’s head, which reduces clinical resolution to about 1–1.3 cm
(Van Heertum et al. 2004). The two SPECT tracers for rCBF
approved for clinical use in the United States are [99mTc]-HMPAO
(Ceretec; d,l-hexamethylpropylene-amine oxime) and [99mTc]-ECD
(Neurolite; ethyl cysteinate dimer). Uptake occurs during the first 1–2
minutes after injection. After that, the tracer is “fixed” in the brain.
These are lipophilic compounds that diffuse across the BBB and into
brain cells. They are converted into hydrophilic compounds that
cannot diffuse out of the cell. Abnormalities in intracellular esterase
or glutathione metabolism might lead to SPECT abnormalities,
independent of rCBF changes. Although several differences between
these two tracers have been described (Inoue et al. 2003), they are
very comparable in terms of their clinical utility. A SPECT tracer for
imaging the dopamine transporter (DaTscan; [123I]Ioflupane) has
also been approved for the evaluation of neurodegenerative
movement disorders (Bajaj et al. 2013).
Positron Emission Tomography

PET radiotracers emit positrons as they decay. These travel a
short distance in tissue (about a millimeter on average for fluorine-
18) before encountering an electron, and the two mutually annihilate.
The mass of the two particles is converted into pure energy in the
form of two high-energy photons. These travel away from each other
in a straight line at the speed of light (line of response). The majority
of these photon pairs pass through the body and strike detectors on
opposite sides of the scanner almost simultaneously. The PET
scanner recognizes when two photons have struck the ring
simultaneously (annihilation coincidence detection) and estimates
the site of origin of the photons as lying somewhere on a path
between the two involved detectors. The object to be imaged (the
head) is surrounded by several parallel rings containing thousands of
these detector pairs. By combining the results of millions of such
coincidence detection events, the scanner’s computer can generate
a high-resolution image of the distribution of the radiotracer in the
body, with areas of relatively high concentration appearing as “hot
spots” on the image. Whereas the theoretical limit for spatial
resolution is about 2.5 mm (Turner and Jones 2003), the resolution
of clinical PET is on the order of 4–5 mm. Several positron-emitting
radionuclides are available for incorporation into radiotracers. Most
clinical PET uses fluorine-18 in the form of 18-fluoro-2-deoxyglucose
([18F]-FDG). The radio tracer is taken up into cells similarly to
glucose and undergoes metabolism to fluorodeoxyglucose-6-
phosphate. It does not undergo further metabolism and is trapped
within these cells, which provides a measure of cerebral metabolic
activity (rCMR glucose) (Figure 4–6). Three PET tracers for beta-
amyloid imaging (amyloid PET) have been approved for clinical use
(i.e., NeuraCeq, [18F]florbetaben; Amyvid, [18F]florbetapir; Vizamyl,
[18F]flutemetamol) (Nasrallah and Wolk 2014).
FIGURE 4–6. An 18-fluoro-2-deoxyglucose positron emission tomography
([18F]-FDG, FDG-PET) case.
Late-middle-aged male with cognitive and mood disorders after a frontoparietal
cerebrovascular accident. Note that the affected area in the high right frontal and
parietal lobes near the vertex is more fully visualized on axial FDG-PET
(decreased metabolism indicated by lighter area on grayscale and dark blue-
purple on pseudo color scale) than on fluid-attenuated inversion recovery magnetic
resonance imaging (FLAIR MRI). Visualization on PET is improved by application
of a pseudo color scale and fusion with companion computed tomography. Three-
dimensional (3D) reconstructions can also improve visualization.
Practical Considerations Guiding Functional

Neuroimaging in Clinical Practice
Selecting the Neuroimaging Type
PET has the advantages of higher spatial resolution and true
attenuation correction (nearly eliminating attenuation artifacts).
SPECT has the advantages of being more widely available and less
expensive.
Imaging Request
As discussed previously for ordering structural neuroimaging, it is
essential to provide an accurate and complete history when ordering
a functional imaging examination (“rule out pathology” or “new-onset
mental status changes” are unacceptable). If a lesion is suspected in
a particular location, this should be noted. The imaging physician
and nuclear medicine team also need information on the patient’s
current mental status (e.g., delirious, psychotic, easily agitated,
paranoid). Having this information may eliminate difficulties with
patient management during radiotracer administration or scanning.
Patient Preparation
The clinician ordering the examination should always explain the
procedure to the patient and be mindful to mention the requirement
for absolute immobility during the approximately 30 minutes of
scanning. During imaging, the head is generally held still with
support from a cradle attached to the imaging table, sometimes with
additional support from light taping (see Figure 4–3). Nuclear
cameras are not as confining as magnetic resonance scanners and,
consequently, induce claustrophobic reactions much less frequently.
Nonetheless, the scanning table is hard and can be uncomfortable
for some patients. If the clinician ordering the examination suspects
that the patient may become agitated or be unable to remain still for
the length of the examination, then light sedation may be required.
Many medications alter cerebral activity and blood flow; therefore,
antianxiety and other sedative medications are best administered
after the tracer distribution in the brain has become fixed, which is
less than 10 minutes after injection for SPECT and 20–30 minutes
after injection for PET. A sedative may be critical to achieving a
successful scan in selected patients. The patient may be requested
to abstain from certain activities or foods prior to scanning.
Furthermore, he or she may be required to rest in a dark room
immediately prior to and during tracer uptake.
Safety Considerations for Functional Neuroimaging

in Clinical Practice
The only relative contraindication to a clinical nuclear medicine
examination (SPECT or PET) is pregnancy. Of significant note, the
radiotracer doses used in clinical nuclear medicine examinations are
too low to have any pharmacological or allergenic effects (other than
placebo). They disappear by radioactive decay, so renal and hepatic
functions are not relevant. The radiation dose is comparable to that
of a CT scan and is generally considered to be without long-term
consequences (see discussion under CT scanning, in subsection
“Safety Considerations for Structural Neuroimaging in Clinical
Practice”).
Use of Neuroimaging Results in Clinical Practice

The clinician ordering the neuroimaging exam should always
review the images and radiology report with the patient and/or family.
In some cases, prior consultation with the radiologist may be
informative. It is helpful for the clinician to have some desk reference
materials on brain anatomy and circuit function available during the
consultation. If the images and reports were brought by the patient
and/or family, the clinician should verify that, indeed, he or she is
reviewing the correct patient’s exams and reports. Common
questions from patients when discussing positive findings include the
following: What does this mean in terms of my symptoms? Will this
get worse? Will I become demented? How will this affect me in the
future? The clinician should allot sufficient time with patients and
their families when presenting neuroimaging results.
Neuroimaging exams are displayed according to imaging
department protocols and as needed for the detection of specific
pathology. Typically, noncontrast head CT examinations are
displayed in axial cross section and, in most centers, in “radiologic”
rather than “anatomic” view (i.e., the patient’s left is on the right side
of the image and vice versa). Advanced CT imaging techniques,
SPECT, PET, and MRI examinations are interpreted utilizing multiple
planes (axial, coronal, and sagittal). Most anatomical landmarks are
easily recognized on the axial plane, although coronal planes may
be preferred for identifying some structures (i.e., amygdala,
mammillary bodies).
Neurocognitive Disorders
Cognitive decline is a common clinical reason for requesting
neuroimaging (Bhogal et al. 2013; Nasrallah and Wolk 2014;
Valkanova and Ebmeier 2014). For neurocognitive disorders due to
Alzheimer’s disease (AD), neuroimaging findings vary with the stage
of illness (Figures 4–7 and 4–8). Early-stage atrophy (structural
neuroimaging) in the mesial temporal area, which contains the
hippocampus and associated cortices, may be predictive for
progression from mild cognitive impairment to AD. In later stages,
MRI demonstrates generalized atrophy. SPECT/PET (functional
neuroimaging) is more specific, with a classic pattern of bilateral,
symmetrical, decreased perfusion or metabolism in the medial
temporal and lateral temporoparietal areas.
FIGURE 4–7. Single-photon emission computed tomography (SPECT)
cases.
Functional neuroimaging can provide insight into the etiology of cognitive decline,
illustrated here with SPECT imaging of (A–D) blood flow and (E and F) dopamine
transporter (DAT) binding. (A and B) In neurocognitive disorder due to Alzheimer’s
disease, perfusion deficits are commonly symmetrical and focal in (A) early stage
with widespread progression in (B) late stage. (C) Abnormalities are more likely to
be asymmetrical and to involve occipital and subcortical areas in neurocognitive
disorder with Lewy bodies. (D) A characteristic finding early in neurocognitive
disorder due to Huntington’s disease is decreased perfusion in the basal ganglia,
particularly caudate. (E) In Parkinson’s disease, striatal DAT binding is reduced
(pseudo color scale) compared with (F) a healthy individual (grayscale). (DAT
cases contributed by Akiva Mintz, M.D., Ph.D., Wake Forest School of Medicine.)
FIGURE 4–8. Positron emission tomography (PET) cases.
Functional neuroimaging may provide insight into the etiology of cognitive decline,
illustrated here with axial PET imaging of glucose metabolism (18-fluoro-2-
deoxyglucose [18F]-FDG, FDG-PET) and of amyloid binding (amyloid PET). (A
and B) Early-middle-aged male with progressive deficits in activities of daily living
and inability to continue working because of cognitive decline. FDG-PET indicates
mildly decreased metabolic activity involving only bilateral parietotemporal
association cortices. (Case contributed by Djenaba Bradford-Kennedy, M.D.) Note
the normal uptake in other cortices, striatum, thalamus, and cerebellum. This
activity pattern is common in early-stage Alzheimer’s disease (AD). (C) Elderly
woman with multiple areas of high amyloid binding (orange-red) throughout cortex
on amyloid PET. This supports a diagnosis of AD. (D) In contrast, little amyloid
binding is present in this middle-aged male with temporal variant frontotemporal
dementia. (Amyloid PET cases contributed by Tiffany Chow, M.D.)
It is not uncommon, however, for abnormalities to be

asymmetrical or initially to involve only the temporal or parietal
cortex. The defects can be recognizable as neurodegenerative in
origin, although not necessarily specific to AD. Atypical presentations
are more common in early-onset AD. Uptake in the subcortical
structures, primary visual cortex, and primary sensorimotor cortex is
usually preserved even in late-stage disease. Amyloid PET imaging
is highly sensitive to AD, with positive cortical findings often present
prior to the onset of clinical symptoms (see Figure 4–8). However,
the positive predictive value is low.
Neuroimaging findings in neurocognitive disorder with Lewy
bodies (NCDLB) overlap those of AD (including positive amyloid PET
imaging), although the abnormalities are more likely to be
asymmetrical and to involve the occipital cortex and subcortical
areas (Figure 4–7C). Dopamine transporter SPECT imaging may
distinguish NCDLB from AD, because the loss of dopamine neurons
is usually significant in NCDLB and results in striking abnormalities in
the striatum. This appearance is also characteristic of neurocognitive
disorder due to Parkinson’s disease, but Parkinson’s disease is
usually negative for presence of amyloid (see Figure 4–7). The final
working diagnosis is based on the entire clinical evaluation.
Frontotemporal neurocognitive disorder is usually readily
distinguished from AD and NCDLB by the frontal and/or anterior
temporal localization (usually bilaterally) of atrophy (structural
imaging) and by reduced metabolic activity and perfusion (functional
imaging). In neurocognitive disorder due to Huntington’s disease,
SPECT/PET imaging demonstrates characteristic reduced perfusion
to basal ganglia, especially the head of the caudate, often early in
the course of the illness (see Figure 4–7). Nuclear imaging is rarely
used for diagnosis, which is based on genetic testing, but it may be
informative for assessing progression.
Vascular Neurocognitive Disorders

Vascular neurocognitive disorders are commonly diagnosed by
structural imaging based on the presence of punctate and/or
confluent white matter lesions and multiple areas of infarction
(Bhogal et al. 2013; Valkanova and Ebmeier 2014). In addition, the
pattern of SPECT/PET abnormalities is often distinctive in vascular
neurocognitive disorder because of multiple infarctions, with multiple
moderate-sized perfusion defects possessing well-defined
boundaries. Small-vessel disease is not associated with a specific
SPECT/PET pattern, although basal ganglia and frontal cortex
lesions have often been reported.
Epilepsies
SPECT/PET is used along with MRI and electroencephalography
in presurgical planning for patients with treatment-refractory epilepsy
(Pittau et al. 2014). Nuclear medicine exams are obtained either
during a seizure (ictal exam, rCBF increased in the focus) or in
absence of seizure activity (interictal exam, rCBF decreased in the
focus). Scans are compared for focus localization. SPECT is
preferred for ictal exams because of rapid radiotracer uptake, thus
allowing capture of seizure-related rCBF changes. In practice,
nuclear imaging is primarily required in patients with normal MRI and
nonlocalizing or equivocal electroencephalogram.

Neuroimaging can be of value in patients with neuropsychiatric
symptoms in later stages (subacute, chronic) following TBI (Raji et
al. 2014). MRI may localize larger areas of injury (see Figures 4–4
and 4–5), but diffuse axonal injury is not usually well visualized.
Functional imaging is often abnormal in symptomatic patients—even
when structural imaging is negative or does not explain manifesting
symptoms. It must always be borne in mind, however, that many
healthy individuals have some limited areas of mildly reduced
perfusion. Although they are not commonly used in clinical practice,
several longitudinal studies have indicated that a negative (normal)
brain SPECT in the acute phase predicts good long-term
neurological outcome (Jacobs et al. 1994, 1996).
Conclusion
The subspecialty of neuropsychiatry/behavioral neurology, like
other areas in medicine, has been deeply influenced by advancing
technology. Structural and functional neuroimaging modalities have
progressed to the point that they now can contribute to multiple
aspects of clinical care. Thought, memory, and emotion are believed
to occur by way of complicated circuits or networks (Figure 4–1) that
include interconnected cortical and subcortical (Figure 4–9) areas of
brain (Bonelli and Cummings 2007; Filley 2010, 2011; Haber and
Rauch 2010). Additional functional anatomy reference materials can
be found at www.mirecc.va.gov/visn6/Tools-Tips.asp. Optimal
utilization of the rich information that neuroimaging potentially
provides requires that clinicians not only be able to identify clinical
conditions that warrant neuroimaging investigation (e.g., TBI, stroke,
poison/toxin exposure) but also have a basic understanding of brain
anatomy and circuit function.
FIGURE 4–9. Brief guide to subcortical functional anatomy.
The approximate positions and configurations of the major subcortical structures
are color-coded onto simplified renditions of axial brain sections and a sagittal
rendition of the cerebrum and brain stem. The sagittal image is also a key to the
locations for the axial sections. Additional teaching cases and functional anatomy
reference materials can be found at www.mirecc.va.gov/visn6/Tools-Tips.asp.
References
Aguirre GK: Functional neuroimaging: technical, logical, and social perspectives.
Hastings Center Report Spec No S8-18, 2014
American College of Radiology, Society for Pediatric Radiology: ACR-SPR
Practice Parameter for Imaging Pregnant or Potentially Pregnant Adolescents
and Women With Ionizing Radiation. Reston, VA, American College of
Radiology, 2014. Available at:
https://www.acr.org/~/media/ACR/Documents/PGTS/guideines/Pregnant_Patie
nts.pdf?la=en. Accessed September 7, 2017.
Bajaj N, Hauser RA, Grachev ID: Clinical utility of dopamine transporter single
photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of
parkinsonian syndromes. J Neurol Neurosurg Psychiatry 84(11):1288–1295,
2013 23486993
Bangard C, Paszek J, Berg F, et al: MR imaging of claustrophobic patients in an
open 1.0T scanner: motion artifacts and patient acceptability compared with
closed bore magnets. Eur J Radiol 64(1):152–157, 2007 17374468
Bathla G, Hegde AN: MRI and CT appearances in metabolic encephalopathies
due to systemic diseases in adults. Clin Radiol 68(6):545–554, 2013 23142023
Bhogal P, Mahoney C, Graeme-Baker S, et al: The common dementias: a pictorial
review. Eur Radiol 23(12):3405–3417, 2013 24081643
Bonelli RM, Cummings JL: Frontal-subcortical circuitry and behavior. Dialogues
Clin Neurosci 9(2):141–151, 2007 17726913
Brunner CC, Stern SH, Minniti R, et al: CT head-scan dosimetry in an
anthropomorphic phantom and associated measurement of ACR accreditation-
phantom imaging metrics under clinically representative scan conditions. Med
Phys 40(8):081917, 2013 23927331
Carter E, Coles JP: Imaging in the diagnosis and prognosis of traumatic brain
injury. Expert Opin Med Diagn 6(6):541–554, 2012 23480836
Coskun O: Magnetic resonance imaging and safety aspects. Toxicol Ind Health
27(4):307–313, 2011 21112927
Currie S, Hoggard N, Craven IJ, et al: Understanding MRI: basic MR physics for
physicians. Postgrad Med J 89(1050):209–223, 2013 23223777
Enders J, Rief M, Zimmermann E, et al: High-field open versus short-bore
magnetic resonance imaging of the spine: a randomized controlled comparison
of image quality. PLoS One 8(12):e83427, 2013 24391767
Erhart SM, Young AS, Marder SR, Mintz J: Clinical utility of magnetic resonance
imaging radiographs for suspected organic syndromes in adult psychiatry. J
Clin Psychiatry 66(8):968–973, 2005 16086610
Expert Panel on MR Safety, Kanal E, Barkovich AJ, Bell C, et al: ACR guidance
document on MR safe practices: 2013. J Magn Reson Imaging 37(3):501–530,
2013 23345200
Filippi M, Agosta F, Barkhof F, et al.; EFNS Task Force: The use of neuroimaging
in the diagnosis of dementia. Eur J Neurol 19(12):e131–140, 1487–1501, 2012
Filley CM: White matter: organization and functional relevance. Neuropsychol Rev
20(2):158–173, 2010 20352350
Filley CM: White matter: beyond focal disconnection. Neurol Clin 29(1):81–97, viii,
2011
Grignon B, Mainard L, Delion M, et al: Recent advances in medical imaging:
anatomical and clinical applications. Surg Radiol Anat 34(8):675–686, 2012
22644780
Haber SN, Rauch SL: Neurocircuitry: a window into the networks underlying
neuropsychiatric disease. Neuropsychopharmacology 35(1):1–3, 2010
20010702
Inoue K, Nakagawa M, Goto R, et al: Regional differences between 99mTc-ECD
and 99mTc-HMPAO SPET in perfusion changes with age and gender in healthy
adults. Eur J Nucl Med Mol Imaging 30(11):1489–1497, 2003 14579088
Jacobs A, Put E, Ingels M, Bossuyt A: Prospective evaluation of technetium-99m-
HMPAO SPECT in mild and moderate traumatic brain injury. J Nucl Med
35(6):942–947, 1994 8195879
Jacobs A, Put E, Ingels M, Put T, et al: One-year follow-up of technetium-99m-
HMPAO SPECT in mild head injury. J Nucl Med 37(10):1605–1609, 1996
8862291
Kanal E, Maravilla K, Rowley HA: Gadolinium contrast agents for CNS imaging:
current concepts and clinical evidence. AJNR Am J Neuroradiol 35(12):2215–
2226, 2014 24852287
Keogh BP, Henson JW: Clinical manifestations and diagnostic imaging of brain
tumors. Hematol Oncol Clin North Am 26(4):733–755, 2012 22794281
Le TH, Gean AD: Neuroimaging of traumatic brain injury. Mt Sinai J Med
76(2):145–162, 2009 19306377
Lerner A, Mogensen MA, Kim PE, et al: Clinical applications of diffusion tensor
imaging. World Neurosurg 82(1-2):96–109, 2014 23916498
Malhi GS, Lagopoulos J: Making sense of neuroimaging in psychiatry. Acta
Psychiatr Scand 117(2):100–117, 2008 18028255
Moser E, Stadlbauer A, Windischberger C, et al: Magnetic resonance imaging
methodology. Eur J Nucl Med Mol Imaging 36 (suppl 1):S30–S41, 2009
19104805
Nasrallah IM, Wolk DA: Multimodality imaging of Alzheimer disease and other
neurodegenerative dementias. J Nucl Med 55(12):2003–2011, 2014 25413136
Osuch E, Williamson P: Brain imaging in psychiatry: from a technique of exclusion
to a technique for diagnosis. Acta Psychiatr Scand 114(2):73–74, 2006
16836594
Pittau F, Grouiller F, Spinelli L, et al: The role of functional neuroimaging in pre-
surgical epilepsy evaluation. Front Neurol March 24, 5(31), 2014 24715886
Raichle ME: Functional brain imaging and human brain function. J Neurosci
23(10):3959–3962, 2003 12764079
Raji CA, Tarzwell R, Pavel D, et al: Clinical utility of SPECT neuroimaging in the
diagnosis and treatment of traumatic brain injury: a systematic review. PLoS
One 9(3):e91088, 2014 24646878
Salinas C, Dávila G, Berthier ML, et al: Late-life reactivation of obsessive-
compulsive disorder associated with lesions in prefrontal-subcortical circuits. J
Sheehan W, Thurber S: Review of two years of experiences with SPECT among
psychiatric patients in a rural hospital setting. J Psychiatr Pract 14(5):318–323,
2008 18832964
Tanev K, Sablosky M, Vento J, O’Hanlon D: Structural and functional neuroimaging
methods in the diagnosis of dementias: a retrospective chart and brain imaging
review. Neurocase 18(3):224–234, 2012 21879994
Thomas RH, Burke CJ, Howlett D: Cranial computed tomography 1: technical
aspects for clinicians. Br J Hosp Med (Lond) 71(8):457–460, 2010 20852488
Turner R, Jones T: Techniques for imaging neuroscience. Br Med Bull 65:3–20,
2003
Valkanova V, Ebmeier KP: Neuroimaging in dementia. Maturitas 79(2):202–208,
2014 24685291
Van Heertum RL, Greenstein EA, Tikofsky RS: 2-deoxy-fluorglucose-positron
emission tomography imaging of the brain: current clinical applications with
emphasis on the dementias. Semin Nucl Med 34(4):300–312, 2004 15493007
Weissleder R, Wittenberg J, Harisinghani MG, et al: Contrast agents, in Primer of
Diagnostic Imaging, 5th Edition. St Louis, MO, CV Mosby, 2011, pp 680–689
CHAPTER 5
Diagnostic Neurophysiology in
Neuropsychiatry
Ali S. Gonul, M.D.
In recent years, the rapid development of diagnostic

neurophysiological testing, particularly in the form of structural and
functional neuroimaging technologies, has yielded a wealth of
information concerning the relationship between structural/functional
brain abnormality and psychopathology. Neurophysiological testing
of the brain generally adopts one of two forms. Some techniques,
such as electroencephalography, quantitative
electroencephalography, and magnetoencephalography, assess the
spontaneous rhythms of the resting or idling brain. Other
assessment techniques use evoked potentials (EPs) to actively
interrogate the brain’s sensory systems or event-related potentials
(ERPs) to similarly interrogate higher-order cognitive systems.
Polysomnography is also potentially important for differential
diagnosis in psychiatry, but a discussion of this technique lies
beyond the scope of this chapter.
All of these forms of diagnostic neurophysiological testing provide
information on the brain-behavior relationships in health and
disease. They are particularly useful in clinical practice when a
patient’s presentation involves a sudden unexplained change in
mental status, is markedly atypical in terms of age at onset, or lacks
sufficient symptom-based evidence to clarify differential diagnosis or
when the patient’s illness remains refractory to treatment. A number
of specific clinical situations in which diagnostic neurophysiology
may be useful are described further in this chapter. The interested
reader is referred to flowcharts of electroencephalography workup
for psychiatric presentations published elsewhere (Boutros et al.
2011, 2013).
Standard Electroencephalography
Standard, or conventional, electroencephalography is a study of
brain electrical activity as recorded by scalp electrodes in a standard
array (i.e., the International 10-20 System or variations of it) and
displayed as a time series voltage record (traditionally on paper but
today often on a computer screen). The hallmark of standard
electroencephalography is visual interpretation of the
electroencephalogram (EEG) by a qualified
electroencephalographer; the electroencephalographer visually
scans the record looking for abnormalities. The detection of unusual
features, the assessment of their degree of abnormality, and the
interpretation of their clinical relevance are all based solely on the
judgment of the examiner.
Standard electroencephalography is widely available, often
portable, and relatively inexpensive. The electroencephalographer
generally looks for two types of EEG abnormalities: 1) paroxysmal
activity (i.e., episodic and unpredictable abnormal neuronal
discharges) of an epileptiform type and 2) slowing of the normal
rhythms of the brain or slow activity (delta or theta activity)
superimposed on normal background activity. Both types of
abnormalities can be seen diffusely, which indicates a generalized
pathological process such as delirium, or focally, which indicates a
localized area of pathology, for example, a small stroke. Paroxysmal
activity is poorly detected by quantitative electroencephalography
and is best detected in a standard EEG (given the limitations of
currently available paroxysmal detection software) by the trained eye
of the experienced electroencephalographer.
Applications of Standard Electroencephalography

Table 5–1 lists the psychiatric indications for a standard EEG for
which significant literature support exists (Boutros et al. 2011). These
indications represent the most solid bases on which a clinical service
can now be established. It should be made clear that ordering
laboratory tests must be guided by the experience of the treating
clinician.
TABLE 5–1. Conditions for which neurophysiological testing may be

ordered
1. Atypical presentation, such as an unusual age at onset or sudden
unexplained change in mental status
2. Atypical symptoms, such as unilateral or stereotyped hallucinations
3. Unexplained delirium or acute confusional states (medical emergencies)
4. Cerebrovascular disease or stroke
5. Repeated unmotivated aggressive episodes
6. Dissociative symptoms
7. Panic attacks
8. Autistic symptoms
9. Medically unresponsive attention-deficit/hyperactivity disorder
10. Differential diagnosis of depression versus dementia
Evaluating Delirium
A common reason for ordering an EEG is “altered mental status”
(i.e., delirium), which is a medical emergency. Delirium, which is also
known as acute confusional state, encephalopathy, toxic metabolic
state, central nervous system toxicity, intensive care unit psychosis,
sundowning, and organic brain syndrome, among other names, has
a wide range of causes. However, all of these causes produce a
similar pattern of clinical signs and symptoms, reflecting impairment
of the patient’s consciousness and cognition (Hughes et al. 2012)
and changes in the EEG that are typical of delirium.
In acutely agitated delirious patients, the EEG is often helpful in
indicating whether the alteration in consciousness is due to 1) a
diffuse encephalopathic process, 2) a focal brain lesion, or 3)
continued epileptic activity without motor manifestations (ambulatory
nonconvulsive status epilepticus). Most often patients with delirium
have a toxic-metabolic encephalopathy. Delirium is particularly
common among the institutionalized elderly, in whom the prevalence
ranges as high as 44%, but delirium also occurs commonly in
younger patients with primary psychiatric diagnoses as a result of
recreational or medicinal drug use (Bandettini di Poggio et al. 2011).
Brief standard EEGs can be obtained from the majority of even the
most uncooperative patients in psychiatric emergency services. An
abbreviated standard EEG may be similarly useful in evaluating
patients presenting to a psychiatric emergency service with a
difficult-to-assess mental status.
Delirium may be the only outward manifestation of nonconvulsive
status epilepticus (Epstein et al. 2009). Additionally, morning delirium
as a postictal confusional state may be the only observable sign of
nocturnal seizures, of which the patient may be completely unaware
(Bazil 2010). Delirium may also follow otherwise uncomplicated
surgery, especially among the elderly (Brown and Purdon 2013), or it
may be a consequence of sleep deprivation. Delirium generally has
a rapid onset, a fluctuating course, and rapid improvement once the
underlying problem has been corrected. However, even well-treated
delirium is a poor prognostic sign associated with greatly increased
mortality in the ensuing year. If inadequately treated, delirium can
rapidly lead to deterioration and death. In general, with the
progression of the encephalopathy, there is diffuse slowing of the
background rhythms from alpha (7.5–12.4 Hz) to theta (3.5–7.4 Hz)
activity. Delta (<3.5 Hz) activity usually does not become prominent
until the patient approaches nonresponsiveness. This slowing is
helpful in differentiating delirium from dementia or psychosis if the
diagnosis is not clear. The major exception to the above rule is seen
during delirium tremens following withdrawal from alcohol. Excessive
fast activity (rather than slowing) dominates the EEG in patients with
alcohol withdrawal delirium. Patients in alcohol withdrawal who are
not delirious could have a normal EEG. For a review of the role of
EEG in diagnosing and managing delirium, with emphasis on the
elderly, the interested reader is referred to the review by Brenner
(1991).
Differentiating Between Dementia and

Depression
Electroencephalography may aid in the differential diagnosis of
dementia and depression. Because patients with advanced dementia
rarely have a normal EEG, a normal finding can play an important
role in diagnosing cases of pseudodementia (dementia symptoms
secondary to depression or psychosis). When dementia and
depression coexist, it becomes important to have some idea about
the relative contribution of each disorder to the overall clinical
presentation. Brenner et al. (1989) compared the EEGs of patients
with depression, dementia, pseudodementia, and dementia plus
depression with the EEGs of normally functioning age-matched
control subjects. It was found that the greater the abnormality in the
EEG, the less the likelihood that a patient would respond favorably to
antidepressants. This is particularly important because aging is
associated with a higher adverse effect profile with antidepressants.
Identifying Covert Seizures

Another common reason for ordering an EEG is to assess for the
presence of covert seizures (i.e., absence seizures, focal seizures
without convulsion). Abrupt onset of psychiatric symptoms, atypical
symptom presentation, or an unusual age at onset may trigger
clinical suspicion. Of particular concern in children are absence
seizures, episodic loss of contact with the environment without a true
loss of consciousness, which can mimic the inattentiveness of
attention-deficit/hyperactivity disorder. The cause of such seizures
often goes unrecognized by parents and teachers because of the
lack of convulsions or other obvious signs of seizures. Although most
cases resolve spontaneously around puberty, early diagnosis and
prompt treatment may reduce the often-serious psychosocial
developmental consequences for the patient.
Other nonconvulsive seizure disorders of childhood such as
Lennox-Gastaut syndrome may produce attentional impairment, as
well as symptoms of aggression, panic, autism, or hyperactivity.
Personality disorders and psychosis (Hancock and Cross 2013) and
moderate intellectual disability (Crumrine 2011) often develop over
time.
In both children and adults, focal seizures without convulsion
(formerly referred to as simple or complex partial seizures when
involving no or some alteration of consciousness, respectively) are
also of concern, and, here too, the lack of convulsions may lead to a
diagnosis of a primary psychiatric disorder. Unusual cognitive states
such as déjà vu (a feeling of familiarity in the face of something
unfamiliar) or jamais vu (a feeling of unfamiliarity in the face of
something familiar) are seen often as part of a pre-ictus state (i.e.,
an aura preceding a seizure), as are aberrant affective states such
as panic, fear, or depression. Classical pre-ictal automatisms such
as chewing or lip smacking may be overlooked as they merge into
ictal symptoms of disorganized or uninhibited behavior, including
(very rarely) violence.
The postictal period is characterized by amnesia for the episode
and a resolving delirium that again may resemble depression. In
addition to the symptoms themselves, the ictal or interictal
electroencephalographic discharges may produce an epileptic
encephalopathy and progressive worsening of the disorder (Avanzini
et al. 2013). This appears to be particularly likely in complex partial
seizures deriving from undiagnosed mesial temporal lobe epilepsy.
Of special concern is the marked tendency for such patients to
develop personality disorders as persisting interictal symptoms. A
striking religiosity with increased moral and philosophical concerns
often develops, coupled with a “viscosity of personality” manifesting
as slow, ponderous, circumstantial speech patterns. These signs
may mimic prodromal symptoms of schizophrenia. Additionally, frank
interictal psychotic states complete with hallucinations and paranoid
delusions are not uncommon, occurring in about 10% of patients
with complex partial seizures. To complicate matters further,
approximately one-third of patients with such seizures have a
concomitant major mental illness such as depression.
Occasionally, what appears to be an overt seizure disorder may
be revealed by EEG to be unrelated to epileptic activity. Psychogenic
nonepileptic seizures are encountered most frequently in the context
of conversion disorder. As with psychogenic blindness, deafness, or
anesthesia (see section “Evoked Potentials”), treatment involves
addressing the patient’s underlying psychological distress, and
symptom remission can be dramatically rapid and complete
(Fiszman et al. 2004).
Identifying Epileptiform Discharges in Psychiatric

Disorders
Isolated epileptiform discharges that are not reflective of epilepsy
are commonly encountered in panic, aggression, and autistic
spectrum disorders (Francis et al. 2013). Estimates of the
prevalence of abnormal EEGs in clinical populations range widely
from as low as 6.6% in patients with rage attacks and episodic
violent behavior to as high as 53% in patients diagnosed with
antisocial personality disorder. Convit et al. (1991) reported that
violence was significantly related to a hemispheric asymmetry in
EEG over the frontotemporal regions. In a retrospective study of the
EEGs of 372 male patients in a maximum-security psychiatric
hospital, researchers who were blind to the specific histories of the
individual patients reported that 20% of the EEGs were abnormal in
the most violent patients compared with 2.4% in the least violent
patients.
Whether the appearance of an abnormal EEG predicts a
favorable therapeutic response to anticonvulsant medications
remains an unanswered question despite being readily answerable
and of profound clinical significance. Monroe (1975) showed that
anticonvulsants can block electroencephalographic epileptiform
discharges and can lead to dramatic clinical improvement in
individuals exhibiting repeated and frequent aggressive behavior.
Similarly, a reduction of aggressive episodes was seen when
carbamazepine was added to the neuroleptic regime of eight highly
aggressive women with schizophrenia who also had EEG
abnormalities (Hakola and Laulumaa 1982). Neppe (1983) provided
further evidence that the addition of carbamazepine to the treatment
of patients with schizophrenia, who also exhibited temporal lobe
abnormalities on the EEG but who had no history of a seizure
disorder, can be clinically useful. In a broader context, other studies
suggest that anticonvulsant therapy may have a beneficial effect on
aggressive tendencies regardless of the presence or absence of
EEG abnormalities (Luchins 1984). There is growing evidence that in
such patients, antiepileptic medications may lead to clinical
improvement and occasionally improvement of the EEG results as
well (Adamaszek et al. 2011).
To more fully address the above question, a recent literature
search was performed (Boutros et al. 2014), focusing on conditions
in which isolated epileptiform discharges are reported to be more
prevalent than in other psychiatric conditions, namely, panic disorder,
autism spectrum disorder, and repeated violence and aggression.
The literature search of the studies was guided by three criteria: 1)
patients did not experience seizures; 2) patients had EEGs, and 3)
an antiepileptic drug was administered. The most important finding
was that the number of controlled studies was extremely small.
Overall, the majority of reports suggest that use of an antiseizure
medication can be associated with clinical improvement and at times
with improvement of EEG abnormalities. Additionally, the authors
found six controlled studies with similar results for other psychiatric
disorders in which the prevalence of isolated epileptiform discharges
is not expected or reported to be particularly increased, such as
learning disorders. Overall, to establish the use of anticonvulsants to
treat nonepileptic psychiatric patients requires implementing
additional controlled studies to better define indications, ensuring
adequate electroencephalography workup, determining the best
anticonvulsant medication to use, and ascertaining optimal durations
of treatment attempts. A trial of an anticonvulsant medication should
not be discouraged in psychiatric patients who are unresponsive to
standard treatment and also exhibit epileptiform discharges on their
EEGs, given available literature.
Studying the Neurophysiology of Borderline

Personality Disorder
Borderline personality disorder is highly stigmatizing and is
considered one of the most difficult psychiatric disorders to manage.
A number of case reports have described patients diagnosed with
borderline personality disorder who were subsequently found to have
isolated epileptiform discharges over one or both temporal regions
(e.g., Schmid et al. 1989). Snyder and Pitts (1984) showed that
patients with borderline personality disorder have a significantly
higher rate of both definitive and less definitive EEG abnormalities
when compared with a dysthymic disorder patient group.
Abnormalities (mainly slowing) were most frequently bilateral and of
frontal, temporal, or frontotemporal distribution. Patients with
borderline personality disorder exhibited much higher prevalence of
symptoms commonly seen with complex partial seizures or episodic
dyscontrol than did a control group of patients with unipolar
depression.
Other Applications of Standard

Electroencephalography
Other clinical situations where standard electroencephalography
may be helpful include patients with rapid-cycling bipolar disorder
who may exhibit isolated epileptiform discharges on standard EEG.
This may explain the reported efficacy of anticonvulsants for rapid-
cycling bipolar disorders. As is stressed in the “Conclusion” section,
the larger studies necessary to definitively address such questions
are not possible unless such patients are routinely referred for
electroencephalographic studies and, once referred, a proper
electroencephalography workup is performed.
The characteristics of what have been termed subictal mood
disorders include brief euphorias, mixed bipolar episodes, brief
severe depressive dips with impulsive suicide attempts, compulsive
symptoms, irritability and hostile outbursts, and marked premenstrual
symptom worsening (Himmelhoch 1987). Patients with subictal
mood disorders may also have paradoxical reactions to medications
used to treat unipolar or bipolar depressive disorders (e.g., lithium
and antidepressants)—with better response to antiseizure
medications. A wide range of pleomorphic psychiatric conditions,
including episodic dyscontrol (Wong et al. 1994) and dissociative
disorders (Mesulam 1981), respond well to antiseizure medications.
These disorders are characterized by evidence of central nervous
system disturbance or family history of epilepsy and by mental
changes typical of the interictal phase of temporal lobe epilepsy
(Blumer et al. 1988).
Limitations of Standard Electroencephalography

Standard electroencephalography is burdened by several
constraints that place limitations on the information that it can
provide. These constraints have been extensively discussed
elsewhere (Struve 1985) and include 1) limited resolution due to the
sparse electrode montages used in standard
electroencephalography, 2) limited coverage because vast areas of
the brain are inaccessible to measurement by any array of external
scalp electrodes, 3) signal blurring imposed by differing electrical
impedances of skin, skull, dura, and brain tissue lying between the
source of the discharge and the scalp electrodes, 4) time sampling
that may miss important EEG abnormalities that are paroxysmal or
“episodic” and may require prolonged recording time, and 5)
nonspecificity of results because the brain’s electrical activity
measured by standard electroencephalography can only respond to
stimuli or insult by becoming faster or slower in frequency or higher
or lower in voltage—or some combination of these two responses.
Thus, identical EEG aberrations can result from different causes.
A number of additional problems make detection of isolated
epileptiform discharges in nonepileptic psychiatric patients difficult
and likely an expensive process. Standard training in EEG
interpretation strongly emphasizes underinterpretation because a
diagnosis has the potential to be highly stigmatizing. On the EEGs of
psychiatric patients, abnormalities, when present, tend to be
infrequent, thus requiring full vigilance during visual analysis on the
part of the interpreter. This requirement, coupled with the fact that
many neurologists without special training in reading EEGs,
nevertheless, do interpret EEGs, adds to the necessity that standard
EEGs of psychiatric patients be interpreted by fully trained
psychiatric electroencephalographers.
Dealing with this issue may also require repeating the
electroencephalographic studies or obtaining prolonged
electroencephalographic recordings, monitoring for extended periods
(e.g., 1–3 days) in hopes of recording the electroencephalographic
signal when the patient is actually experiencing a panic attack, rage
episode, or other psychiatric symptom of concern. Another difficult
problem is the nature of the patient population. Psychiatric patients
may not be very cooperative with respect to the stillness required to
obtain good EEGs, or they may be prone to activation behaviors like
hyperventilating or staying up all night before the procedure (sleep
deprivation improves the detection of isolated epileptiform
discharges). They may have difficulty being able to relax and fall
asleep during the recording. Furthermore, psychiatric patients may
demonstrate inappropriate behaviors during the recording. These
factors necessitate that the electroencephalography laboratory be
placed in a space oriented to psychiatric patients with psychiatrically
trained clinicians who can help patients (particularly children) relax
and cooperate.
Quantitative Electroencephalography
Quantitative electroencephalography describes a set of
techniques used to enhance the standard, visually analyzed and
interpreted EEG. Whereas standard electroencephalography utilizes
sparse electrode arrays of a dozen or so channels, quantitative
electroencephalography systems commonly employ denser arrays of
30–120 channels, thereby increasing spatial resolution. After the
standard EEG has been read and visually interpreted by the
electroencephalographer, a variety of statistical tests may be
performed on the patient’s digitally acquired and quantified EEG
data. The topographic distribution of brain activity across the head is
analyzed. Frequency analysis may be used to decompose the brain
activity into its component delta (0–3.4 Hz), theta (3.5–7.4 Hz), alpha
(7.5–12.4 Hz), beta (12.5–32 Hz), and gamma (>32 Hz) frequency
bands. (For a recent review of these bands in neuropsychiatric
disorders, see Yener and Başar 2013.) Coherence analysis may be
used to assess the connectivity between brain areas.
The sensitivity of quantitative electroencephalography systems to
subtle differences in electroencephalographic frequency, amplitude,
and coherence is generally superior to the sensitivity of the
electroencephalographer’s visual analysis (e.g., Nuwer 1997; Parks
et al. 1991). The American Psychiatric Association Task Force on
Quantitative Electrophysiological Assessment (1991) has long
endorsed quantitative electroencephalography as being particularly
useful for detecting the slowing of brain activity (increased slow
waves) characteristic of delirium, dementia, intoxication, and other
syndromes involving gross central nervous system dysfunction. In
the sometimes-difficult differential diagnosis of depression versus
encephalopathy (i.e., dementia, delirium), a focal or generalized
slowing strongly suggests an organic disorder. (See Olbrich and
Arns 2013 for a review of electroencephalographic biomarkers in
major depression.) Similarly, the American Academy of Neurology
and American Clinical Neurophysiology Society, in their 1997 review
of quantitative electroencephalography (Nuwer 1997), noted its high
sensitivity and specificity for detecting focal slowing. The quantitative
EEG (QEEG) is such a sensitive test of ischemia-related cerebral
impairment that it can indicate quite abnormal results even when the
results of structural imaging such as computed tomography still
appear normal, as in the first few days following a stroke. Perhaps
more important in a psychiatric context is the ability of quantitative
electroencephalography to detect cortical dysfunction caused by
ischemia without infarction. Conversely, as mentioned in the section
“Standard Electroencephalography,” the eye of the experienced
electroencephalographer is generally superior at detecting and
interpreting the isolated paroxysmal abnormalities often seen in
seizure disorders.
More advanced quantitative electroencephalography systems
may additionally compare the patient’s brain activity with a large
database of findings from normal subjects to empirically assess the
degree of abnormality and to display the degree of abnormality and
its topographic distribution on a head map in terms of z scores.
Some systems even compare the patient’s brain activity with clinical
databases based on findings from subjects with known illnesses,
allowing the degree of similarity to be assessed. This last capability,
intended as an advanced diagnostic aid, is controversial and has
been reviewed in detail previously (Coburn et al. 2006). Although
quantitative electroencephalography systems are not intended to
“diagnose” the patient, they may call the electroencephalographer’s
attention to aspects of the patient’s brain activity that may have been
overlooked in the initial visual assessment, thereby aiding in the
diagnostic process.
Quantitative electroencephalographic techniques can also be
applied to EP and ERP data. Presently, this is a rich area of clinical
research, and considerable progress is being made toward
identifying clinically useful EP and ERP biomarkers for disorders
such as schizophrenia (Onitsuka et al. 2013) and dementia (Yener
and Başar 2013).
Magnetoencephalography
Magnetoencephalography is similar to electroencephalography,
but it measures a different aspect of neuronal activity. In order for
neurons to generate a signal measurable at a distance, three
characteristics are required 1) the neurons must be elongated so
they can form electrical dipoles with a voltage difference between
their negative and positive ends; 2) they must be of large diameter
so that ionic currents can flow along the lumen easily with minimal
internal resistance; and 3) they must be oriented in parallel forming a
palisade so that their tiny individual signals can summate to a larger
signal recordable at the scalp. The apical dendrites of pyramidal
neurons embody these characteristics and are the primary
contributors to both electroencephalography and
magnetoencephalography. Electroencephalography uses scalp
electrodes to record the electrical “return” currents flowing through
the tissues. As electrical current flows along the length of the
pyramidal cell’s apical dendrite, it also creates a magnetic field
oriented 90 degrees to the electrical field. The summed magnetic
field emerges from the head and can be recorded just above the
scalp using supercooled quantum interference devices (SQUIDs).
In a typical magnetoencephalography system, up to several
hundred SQUIDs are packed into a dewar containing liquid helium,
the concave base of which fits over the patient’s head. The various
features of an EEG, its frequency bands and topographic
distributions, are well represented in the magnetoencephalogram
(MEG). Magnetoencephalography is unaffected by the differing
electrical resistances of dura, skull, and scalp, which cause a
blurring of encephalographic signals, and thus is superior for
localizing the brain tissue generating the signals. This quality of
magnetoencephalography makes it particularly useful for localizing
epileptic foci, and magnetoencephalography finds wide employment
in neurosurgery centers dealing with seizure disorders and in
research laboratories. MEG data can be processed and analyzed in
the same way as EEG data, and magnetic equivalents of sensory
EPs and cognitive ERPs can be derived.
Magnetoencephalographic recording devices are large and
cumbersome and require supercooling by liquid helium. They are
also prone to a wide variety of magnetic artifacts, which require great
care to avoid. These drawbacks severely limit the use of
magnetoencephalography as a general (or portable) assessment
method, although applications to psychiatric disorders have been
suggested (Williams and Sachdev 2010) and
magnetoencephalography is progressively proving to be unique in
what it can reveal about the neuropsychopathology of psychiatric
disorders (Lajiness-O’Neill et al. 2014).
Two factors may help hasten the arrival of clinically useful
magnetoencephalography in psychiatry. First, the industry is acutely
aware of the limiting factor of the high cost of setting up and
maintaining magnetoencephalography systems, and efforts are
underway to lower its cost. Second, magnetoencephalography tends
to detect more isolated epileptiform discharges than
electroencephalography, thus decreasing the impact of the problem
of false negative electroencephalographic studies. Historically, this
has been a two-edged sword, because although
magnetoencephalography has the sensitivity to detect isolated
epileptiform discharges, it lacks the specificity to distinguish them
reliably from artifacts and thus requires interpretation by an
electroencephalographer. Once it becomes more established among
psychiatrists that the discovery of isolated epileptiform discharges in
nonepileptic psychiatric patients is of clinical significance,
psychiatrists may elect to obtain magnetoencephalographic studies
despite the cost and possible distance traveled to obtain the test.
Finally, as shown recently, magnetoencephalography was able to
detect abnormally increased focal coherence in a group of patients
with panic disorder. Increased focal coherence is a hallmark of focal
epilepsy (Elisevich et al. 2011) and may indicate a state of localized
cortical hyperexcitability in a subgroup of patients with panic disorder
(Boutros et al. 2013). Whether increased focal coherence in patients
with anxiety, mood, or other psychiatric disorders predicts a
favorable response to anticonvulsant therapy remains to be
investigated.
Evoked Potentials
In contrast to measuring the brain’s resting or idling rhythms with
standard electroencephalography, quantitative
electroencephalography, or magnetoencephalography, brain activity
may be investigated using EP. In this modification of the standard
electroencephalography, quantitative electroencephalography, or
magnetoencephalography, discrete stimuli (e.g., light flashes, tone
bursts) are repeatedly administered to the patient, and the brain’s
electrophysiological responses to the stimuli are recorded. The
recorded waveform in response to these stimuli is described
according to the stimulus modality eliciting it (i.e., auditory, visual,
somatosensory), the direction of the waveform (i.e., positive or
negative, P or N), and the time (in milliseconds [msec]) poststimulus
at which it develops. For example, the positive waveform over the
lateral temporal cortex that develops 50 msec after presentation of
an auditory stimulus is referred to as the auditory P50.
Compared with the spontaneous EEG background, the response
to each stimulus is tiny. However, the background EEG is random
with respect to the stimulus, whereas the sensory response is time
locked. When the brain’s response to 50–100 stimuli is recorded and
averaged, the background EEG will “average out” to a flat line,
leaving the response to the stimulus intact in the form of an EP. The
series of 3–5 waves (components) constituting the typical EP yield
valuable information concerning stages of information processing of
the stimulus.
In neuropsychiatry, EP testing is most commonly ordered in cases
where a somatoform disorder is suspected, particularly when
sensory symptoms of blindness, deafness, or anesthesia are
present, such as in conversion disorder. In cases of conversion
disorder, typical EP findings reflect intact sensory processing up to
and including primary sensory areas of the cerebral cortex, although
later “cognitive” components (see section “Event-Related Potentials”)
may be abnormal. EP testing can also reveal subtle injuries to the
ascending sensory systems, which may be invisible on standard
structural imaging (Jani et al. 1991) and which effectively rule out a
diagnosis of conversion disorder. EP testing can be valuable in
cases of putative learning disorders. Using a /da/ syllable as a
stimulus to elicit responses from brain stem nuclei may reveal
selective deficiencies in neural encoding of acoustic features
associated with the filter characteristics of speech and help to
distinguish learning disorders from auditory-processing disorders
(Johnson et al. 2005).
Event-Related Potentials
ERPs are similar to evoked potentials, but they assess higher-
order cognitive processes in addition to sensory processes. As with
EPs, ERPs are described by the stimulus domain in which they are
evoked (i.e., auditory, visual, somatosensory), the direction of the
ERP waveform (i.e., positive or negative, P or N), and the time
poststimulus at which the ERP develops. For example, a negative
waveform that occurs about 100 msec after an auditory stimulus is
referred to as the auditory N100 (or auditory N1). The auditory N100
is generally followed by a positive peak 200 msec poststimulus,
which is referred to as the auditory P200 (or auditory P2). Other
ERPs are described by their character or relationship to stimulus
response, and they include contingent negative variation, error-
related negativity, early left anterior negativity, and closure positive
shift.
Among the most commonly studied ERPs in neuropsychiatric
research is the P300 response to an auditory oddball. This ERP
paradigm is a very commonly used procedure that assesses auditory
attention and stimulus discrimination via the differential production of
a specific ERP component, the P300 (i.e., positive waveform evoked
300 msec after stimulus delivery, also known as the “P3”), in
response to two types of auditory tones. In the oddball paradigm, the
patient listens to a long series of tone pips consisting of common
low-pitched “boops” randomly intermixed with rare high-pitched
“beeps.” The patient is told to count or otherwise respond to the
targets (i.e., “beeps”) while ignoring the common, nontarget, tones
(i.e., “boops”). Owing to their differing probabilities, on any given trial
the patient expects to hear the common (nontarget) tone, and the
brain’s responses to those common tones are essentially identical to
a simple auditory EP. By contrast, the rare, high-pitched (target)
tones violate the patient’s expectations and trigger additional brain
activity, reflecting active identification of those tones as “targets.”
That additional cognitive processing is reflected by the appearance
of a P300 ERP.
The auditory oddball ERP paradigm is sometimes used to assess
the presence of a dementing disorder such as Alzheimer’s disease,
in which the amplitude of the P300 is reduced and its latency (i.e.,
onset after stimulus presentation) is delayed (i.e., markedly later
than 300 msec poststimulus). These P300 abnormalities can
facilitate differentiation of dementia from the pseudodementia of
depression, because the P300 in the latter condition is usually
normal. In unusual cases in which a delayed or diminished P300 is
found among depressed patients, it may be a sign of selective
serotonin reuptake inhibitor treatment resistance (Işintaş 2012) or
psychotic features (Karaaslan et al. 2003).
A delayed or diminished P300 in patients with schizophrenia
correlates with the number of subtle (or “soft”) neurological signs but
not with positive or negative symptoms (Lapsekili et al. 2011).
Among such patients, antipsychotic medication may reverse the
P300 delay and increase its amplitude (Coburn et al. 1998).
In conversion disorder, in which typically normal sensory EPs
show intact processing up through primary sensory cortex, the later
cognitive P300 component may show abnormalities, indicating that
the altered brain processes responsible for the symptoms occur at a
later stage (Lorenz et al. 1998). Differences have also been reported
between ERP components in patients with pseudoseizure-type and
neurotic-type conversion disorder (Köse et al. 1998). Patients of both
types, however, differed from healthy control subjects.
In addition to the auditory oddball, a variety of other ERP
paradigms have been developed to assess various aspects of
cognition, such as attention, memory, expectancy, and language
processing. These may provide valuable information in cases of
attention-deficit/hyperactivity disorder (Kenemans et al. 2005) and
learning disorders among children and cognitive disorders among
adults.
Conclusion
Presently, neurophysiological testing is used by neuropsychiatrists
to address two key questions: 1) Is this a neurological disorder
instead of a psychiatric disorder? 2) Is this a psychiatric disorder with
significant neurological dimensions that may influence treatment?
Both questions are important, and, as reviewed in this chapter, the
answers provided by neurophysiological testing influence diagnosis
and treatment.
Because neuroscience research reveals the workings of the
healthy brain as well as the structural and functional brain
abnormalities underlying psychiatric disorders, clinically relevant
neurophysiological tests are moving beyond consideration of
traditional neurology and are addressing the biological foundations of
the psychiatric disorders themselves. Although fraught with
controversy (Coburn et al. 2006), quantitative
electroencephalography has led the way in the area of
physiologically informed diagnosis not only by comparing the
electrical activity of a patient’s brain with that of healthy control
subjects in order to assess abnormality but also by comparing the
electrical activity of a patient’s brain with that of patients
experiencing known psychiatric disorders in order to assess
similarity. This quantitative approach lends itself well to evidence-
based medicine. Moving from diagnosis to treatment, there have
been many efforts to predict psychotherapeutic medication response
based on the patient’s brain activity; most of these efforts have been
handicapped by small sample sizes in addition to other limitations.
The ability to match specific medications to specific patients would
greatly aid effective treatment and would reduce patient suffering
and cost.
For both patient diagnosis and prediction of treatment response,
neurophysiological tests will move from the research laboratory to
the clinic at a pace determined by the availability of research-based
information. As stressed repeatedly throughout this chapter, the role
of quantitative research is central to the advancement of our
understanding of and our ability to help patients with
neuropsychiatric disorders.
References
Adamaszek M, Olbrich S, Gallinat J: The diagnostic value of clinical EEG in
detecting abnormal synchronicity in panic disorder. Clin EEG Neurosci
42(3):166–174, 2011 21870468
American Psychiatric Association Task Force on Quantitative Electrophysiological
Assessment: Quantitative electroencephalography: a report on the present
state of computerized EEG techniques. Am J Psychiatry 148(7):961–964, 1991
2053652
Avanzini G, Depaulis A, Tassinari A, de Curtis M: Do seizures and epileptic activity
worsen epilepsy and deteriorate cognitive function? Epilepsia 54 (suppl 8):14–
21, 2013 24571112
Bandettini di Poggio M, Anfosso S, Audenino D, Primavera A: Clarithromycin-
induced neurotoxicity in adults. J Clin Neurosci 18(3):313–318, 2011 21269833
Bazil CW: Effects of sleep on the postictal state. Epilepsy Behav 19(2):146–150,
2010 20709603
Blumer D, Heilbronn M, Himmelhoch J: Indications for carbamazepine in mental
illness: atypical psychiatric disorder or temporal lobe syndrome? Compr
Psychiatry 29(2):108–122, 1988 3370963
Boutros NN, Galderisi S, Pogarell O, Riggio S (eds): Standard
Electroencephalography in Clinical Psychiatry: A Practical Handbook.
Chichester, West Sussex, UK, Wiley-Blackwell, 2011
Boutros NN, Galloway MP, Ghosh S, et al: Abnormal coherence imaging in panic
disorder: a magnetoencephalography investigation. Neuroreport 24(9):487–
491, 2013 23612562
Boutros NN, Kirollos SB, Pogarell O, Gallinat J: Predictive value of isolated
epileptiform discharges for a favorable therapeutic response to antiepileptic
drugs in nonepileptic psychiatric patients. J Clin Neurophysiol 31(1):21–30,
2014 24492442
Brenner RP: Utility of EEG in delirium: past views and current practice. Int
Psychogeriatr 3(2):211–229, 1991 1811775
Brenner RP, Reynolds CF 3rd, Ulrich RF: EEG findings in depressive
pseudodementia and dementia with secondary depression. Electroencephalogr
Clin Neurophysiol 72(4):298–304, 1989 2467795
Brown EN, Purdon PL: The aging brain and anesthesia. Curr Opin Anaesthesiol
26(4):414–419, 2013 23820102
Coburn KL, Shillcutt SD, Tucker KA, et al: P300 delay and attenuation in
schizophrenia: reversal by neuroleptic medication. Biol Psychiatry 44(6):466–
474, 1998 9777178
Coburn KL, Lauterbach EC, Boutros NN, et al: The value of quantitative
electroencephalography in clinical psychiatry: a report by the Committee on
Research of the American Neuropsychiatric Association. J Neuropsychiatry
Clin Neurosci 18(4):460–500, 2006 17135374
Convit A, Czobor P, Volavka J: Lateralized abnormality in the EEG of persistently
violent psychiatric inpatients. Biol Psychiatry 30(4):363–370, 1991 1912127
Crumrine PK: Management of seizures in Lennox-Gastaut syndrome. Paediatr
Drugs 13(2):107–118, 2011 21351810
Elisevich K, Shukla N, Moran JE, et al: An assessment of MEG coherence imaging
in the study of temporal lobe epilepsy. Epilepsia 52(6):1110–1119, 2011
21366556
Epstein D, Diu E, Abeysekera T, et al: Review of non-convulsive status epilepticus
and an illustrative case history manifesting as delirium. Australas J Ageing
28(3):110–115, 2009 19845649
Fiszman A, Alves-Leon SV, Nunes RG, et al: Traumatic events and posttraumatic
stress disorder in patients with psychogenic nonepileptic seizures: a critical
review. Epilepsy Behav 5(6):818–825, 2004 15582828
Francis A, Msall M, Obringer E, Kelley K: Children with autism spectrum disorder
and epilepsy. Pediatr Ann 42(12):255–260, 2013 24295159
Hakola HP, Laulumaa VA: Carbamazepine in treatment of violent schizophrenics.
Lancet 1(8285):1358, 1982 6123658
Hancock EC, Cross JH: Treatment of Lennox-Gastaut syndrome. Cochrane
Database Syst Rev 2(2):CD003277, 2013 23450537
Himmelhoch J: Cerebral dysrhythmia, substance abuse, and the nature of
secondary affective illness. Psychiatr Ann 17(11):710–727, 1987
Hughes CG, Patel MB, Pandharipande PP: Pathophysiology of acute brain
dysfunction: what’s the cause of all this confusion? Curr Opin Crit Care
18(5):518–526, 2012 22941208
Işintaş M, Ak M, Erdem M, et al: Event-related potentials in major depressive
disorder: the relationship between P300 and treatment response [in Turkish].
Türk Psikiyatri Derg 23(1):33–39, 2012
Jani NN, Laureno R, Mark AS, Brewer CC: Deafness after bilateral midbrain
contusion: a correlation of magnetic resonance imaging with auditory brain
stem evoked responses. Neurosurgery 29(1):106–108, discussion 108–109,
1991 1870669
Johnson MH, Griffin R, Csibra G, et al: The emergence of the social brain network:
evidence from typical and atypical development. Dev Psychopathol 17(3):599–
619, 2005 16262984
Karaaslan F, Gonul AS, Oguz A, et al: P300 changes in major depressive
disorders with and without psychotic features. J Affect Disord 73(3):283–287,
2003 12547298
Kenemans JL, Bekker EM, Lijffijt M, et al: Attention deficit and impulsivity:
selecting, shifting, and stopping. Int J Psychophysiol 58(1):59–70, 2005
15950304
Köse S, Tunca Z, Cakmur R, et al: Event-related auditory potentials (P300) in
conversion disorders: correlations with rating scales for depression and anxiety
[in Turkish]. Türk Psikiyatri Derg 9(1):1–11, 1998
Lajiness-O’Neill R, Richard AE, Moran JE, et al: Neural synchrony examined with
magnetoencephalography (MEG) during eye gaze processing in autism
spectrum disorders: preliminary findings. J Neurodev Disord 6(1):15, 2014
24976870
Lapsekili N, Uzun O, Sütçigil L, et al: Relationship between P300 findings and
neurological soft signs in patients with first episode schizophrenia. Düşünen
Adam: The Journal of Psychiatry and Neurological Sciences 24(3):167–174,
2011
Lorenz J, Kunze K, Bromm B: Differentiation of conversive sensory loss and
malingering by P300 in a modified oddball task. Neuroreport 9(2):187–191,
1998 9507953
Luchins DJ: Carbamazepine in violent non-epileptic schizophrenics.
Psychopharmacol Bull 20(3):569–571, 1984 6473664
Mesulam MM: Dissociative states with abnormal temporal lobe EEG. Multiple
personality and the illusion of possession. Arch Neurol 38(3):176–181, 1981
7469851
Monroe RR. Anticonvulsants in the treatment of aggression. J Nerv Ment Dis
160(2):119–126, 1975 1117287
Neppe VM: Carbamazepine as adjunctive treatment in nonepileptic chronic
inpatients with EEG temporal lobe abnormalities. J Clin Psychiatry 44(9):326–
331, 1983 6355069
Nuwer M: Assessment of digital EEG, quantitative EEG, and EEG brain mapping:
report of the American Academy of Neurology and the American Clinical
Neurophysiology Society. Neurology 49(1):277–292, 1997 9222209
Olbrich S, Arns M: EEG biomarkers in major depressive disorder: discriminative
power and prediction of treatment response. Int Rev Psychiatry 25(5):604–618,
2013 24151805
Onitsuka T, Oribe N, Nakamura I, Kanba S: Review of neurophysiological findings
in patients with schizophrenia. Psychiatry Clin Neurosci 67(7):461–470, 2013
24102977
Parks RW, Zec RF, Kuhn M, et al: Electrocortical mapping, MRI, and
neuropsychological measures: evidence of Alzheimer’s disease in the
presence of vascular lesions. Arch Clin Neuropsychol 6(4):393–408, 1991
14589529
Schmid EM, Handleman MJ, Bidder TG: Seizure disorder misdiagnosed as
borderline syndrome. Am J Psychiatry 146(3):400–401, 1989 2919699
Snyder S, Pitts WM Jr: Electroencephalography of DSM-III borderline personality
disorder. Acta Psychiatr Scand 69(2):129–134, 1984 6702475
Struve F: Clinical electroencephalography as an assessment method in psychiatric
practice, in Handbook of Psychiatric Diagnostic Procedures, Vol 2. Edited by
Hall RCW, Beresford TP. New York, Spectrum Publications/Springer
Netherlands, 1985, pp 1–48
Williams MA, Sachdev PS: Magnetoencephalography in neuropsychiatry: ready for
application? Curr Opin Psychiatry 23(3):273–277, 2010 20216218
Wong MT, Lumsden J, Fenton GW, Fenwick PB: Electroencephalography,
computed tomography and violence ratings of male patients in a maximum-
security mental hospital. Acta Psychiatr Scand 90(2):97–101, 1994 7976465
Yener GG, Başar E: Brain oscillations as biomarkers in neuropsychiatric disorders:
following an interactive panel discussion and synopsis. Suppl Clin Neurophysiol
62:343–363, 2013 24053048
CHAPTER 6
Attention-Deficit/Hyperactivity
Disorder
Tina Gurnani, M.D.
Anil Chacko, Ph.D.
Attention-deficit/hyperactivity disorder (ADHD) is the most

frequently occurring and researched psychiatric disorder of
childhood and accounts for the majority of referrals to child and
adolescent psychiatry services. ADHD persists into adulthood in
approximately 40%–60% of cases and is frequently comorbid with
other conditions. In children, the most frequent comorbid conditions
are oppositional defiant disorder (ODD) and conduct disorder (CD);
in adults, mood and anxiety disorders are the most common,
although risk for other conditions such as substance use disorders is
also elevated.
Descriptive Psychopathology
ADHD is defined by a persistent pattern of inattention and/or
hyperactivity-impulsivity that is more frequent and severe than is
typically encountered in individuals at a comparable developmental
level (American Psychiatric Association 2013). There are nine
inattention items characteristic of the disorder, six of which are
required to meet the symptom threshold for children and early
adolescents; if the diagnosis is being made in adolescents ≥17 years
and adults, only five symptoms are required (a change from DSM-IV
[American Psychiatric Association 1994] to DSM-5 [American
Psychiatric Association 2013]). Similarly, there are nine hyperactivity-
impulsivity items, with the threshold also being six items for children
and five for adolescents ≥17 years and adults. Although ADHD can
be diagnosed across the life span, the disorder begins in childhood.
Consequently, at least some symptoms must be present before age
12 (another DSM-5 change; previously the cutoff was age 7).
However, it is sometimes difficult to establish childhood onset of
symptoms in adults, because of the complexities of retrospective
assessment, and to specify the manner in which symptoms present
in adults compared with children. Other requirements for the
diagnosis are that at least some symptoms causing impairment must
be present in more than one setting, and there must be impairment
in social, academic, or occupational functioning.
The nine inattention symptoms are 1) failing to pay attention to
detail or making frequent careless mistakes; 2) having difficulty
sustaining attention in tasks/work or play; 3) having difficulty focusing
when spoken to directly; 4) having difficulty following through on
instructions and failing to complete tasks (especially when boring); 5)
having difficulty staying organized; 6) avoiding tasks that require
sustained mental effort; 7) losing things needed for school/work or
activities; 8) being easily distracted; and 9) being forgetful in daily
activities. The nine hyperactivity/impulsivity symptoms are 1)
fidgeting or squirming frequently; 2) getting out of one’s seat (or
having the urge to) when it is inappropriate to do so; 3) running or
climbing (or being excessively restless) when it is inappropriate to do
so; 4) being unable to play quietly or relax; 5) being uncomfortable
sitting still; 6) talking excessively; 7) blurting out answers,
interrupting others, or completing sentences for others; 8) having
difficulty waiting one’s turn in line or in play; and 9) interrupting or
intruding on conversations, games, or activities.
DSM-5 identifies three clinical presentations, based on presenting
symptomatology: combined, predominantly inattentive, and
predominantly hyperactive/impulsive. Consistent with the decision to
describe these as “clinical presentations” rather than subtypes (as in
DSM-IV), a recent meta-analysis concluded that although the
hyperactive/impulsive and inattentive symptom clusters have high
concurrent, predictive, and discriminant validity, the three DSM-IV
subtypes have poor longitudinal stability (Willcutt et al. 2012).
However, regardless of the designated clinical presentation, at least
some symptoms from both the inattentive and hyperactive/impulsive
domains are present in the vast majority of cases.
Key associated features of ADHD include 1) learning problems,
academic underachievement, or poor occupational attainment; 2)
problems in affect regulation (i.e., having a “short fuse” or anger
management problems); 3) poor understanding or appreciation of
social cues; 4) impaired family and/or peer relationships; 5)
aggression; 6) low self-esteem; and 7) substance abuse.
Epidemiology
The prevalence of ADHD in preschool children is estimated to be
2%–8%. The rate increases to 4%–12% in elementary school–age
children, declines to about 6% in adolescence, and declines again to
4.5% in adults (Kessler et al. 2006). Approximately half of children
with ADHD continue to have the full diagnosis as adults, with about
two-thirds having at least subthreshold symptoms. Similar
prevalence rates are found internationally, both in industrialized and
developing countries, although the reported prevalence in the United
States is usually higher. In preschool- and school-age children, boys
have substantially higher rates of ADHD than girls. Although the
combined presentation accounts for the majority of cases in both
genders, the relative proportion of cases with inattentive presentation
is higher in girls than in boys and in older than in younger children.
Recent data have raised questions about whether the high
prevalence rates of ADHD reported in U.S. studies reflect an
increase in the actual prevalence of the disorder over the past two
decades or, instead, are attributable to methodological variance in
how the diagnosis is made. It is unknown whether the changes in
DSM-5 criteria to increase the age at onset and lower the number of
symptoms required in late adolescents and adults may affect
prevalence.
ADHD is a neurodevelopmental disorder, and the nature and
impact of symptoms change in subtle ways over the course of
development. In preschool-age children, the hyperactivity/impulsivity
symptoms and aggressive behavior are common. Inattention is often
not reported until the child enters school, when cognitive and
behavioral demands increase. Executive function deficits are more
often present in adolescents and adults but are sometimes seen in
children as well. Characteristic impairments in adolescents and
adults are difficulty working independently, poor academic
performance and educational attainment, unemployment or lower
occupational status, and lower earning potential. Hyperactivity-
impulsivity symptoms often decline with age, but they may persist in
subtle ways, often with highly impairing functional consequences,
including risk for motor vehicle violations and accidents, elevated
rates of sexually transmitted diseases, early pregnancy, substance
abuse, and delinquent behavior (Barkley et al. 2006). However,
these problems are most often seen in the context of comorbid
behavioral disorders (i.e., ODD and CD).
Comorbidity is the rule in both children and adults with ADHD.
Data from several epidemiological studies and a recent meta-
analysis (Willcutt 2012) indicate that ODD and CD are present in
40%–70% of children with ADHD, the co-occurrence of which tends
to be highly impairing. Lifetime rates of comorbid depression and
anxiety in children are also high (depression: 15%–35%; anxiety
disorders: 25%–50%) (Spencer et al. 2007b). For adults, the lifetime
rates are 11.5%–53.5% for depression and up to 59% for anxiety
disorders (Kooij et al. 2012). The degree of comorbidity of ADHD
and bipolar disorder has been controversial, with high variability in
the cited prevalence rates across studies. This variation may in part
reflect potential symptomatic overlap and lack of consistency in the
way bipolar disorder is diagnosed. Other frequently co-occurring
neuropsychiatric conditions include Tourette syndrome (TS) and
developmental learning disorders (LDs). Approximately 50%–60% of
individuals with TS also have ADHD, although a much smaller
percentage of individuals with ADHD also have TS. The rates of LDs
among youths with ADHD have been reported to range from 20% to
90%, with the lower figure reflecting actual LDs and the higher rates
indicative of more broadly defined academic underachievement.
Last, conditions characterized by impulsive behavior also present
with increased frequency in adults with ADHD. The National
Comorbidity Survey Replication found lifetime prevalence rates of
70% for impulse-control disorders and 36% for substance use
disorders (Kessler et al. 2006). There also appears to be increased
risk for narcissistic, borderline, and antisocial personality disorders,
as well as pathological gambling.
Neuropsychological Models
Various neuropsychological models of ADHD have been
advanced, although none can fully explain the disorder. The most
popular model has stressed the importance of executive dysfunction,
which is exemplified by deficits in inhibitory control, planning,
working memory, and shifting sets. This model has been supported
by evidence from studies of neuropsychological test performance
and neuroimaging of frontostriatal brain regions. However, there are
several important observations regarding ADHD that pose
challenges for this model, including inconsistent findings in studies
examining performance on specific neuropsychological tests of
executive function, evidence suggesting that no more than half of
ADHD subjects have executive function deficits, and observations
that the developmental course of ADHD extends beyond the course
of neurodevelopment of the frontal lobe. Consequently, an
alternative conceptualization of ADHD has emerged, in which frontal
lobe development is thought to contribute to improvement in
symptoms and recovery rather than to the etiology of the disorder
(Halperin and Schulz 2006).
A host of other models have been proposed, such as sluggish
cognitive processing, reaction time variability, faulty time perception,
low reward sensitivity, and delay aversion, to explain core deficits in
ADHD. The reward sensitivity model, based on the observation that
individuals with ADHD are very sensitive to reward (Sonuga-Barke
2005), might explain why youths with ADHD respond so well to
contingency-based behavioral therapies. Reward sensitivity has
been studied using mathematical prediction models of delay
discounting, in which smaller, immediate rewards are chosen
impulsively over greater rewards to be obtained later (Killeen 2015).
In contrast, the cognitive-energetic model (Sergeant 2005), which is
based on the observation that many individuals with ADHD have a
slow and variable response style, may be relevant for understanding
the predominantly inattentive presentation, which is frequently
associated with sluggish cognitive tempo.
Pathophysiology
Genetic Factors
Numerous studies have demonstrated the prominent role of
genetics in the etiology of ADHD (for review, see Hawi et al. 2015).
Pharmacological, neuroimaging, and animal studies have implicated
dopaminergic and noradrenergic (and to a lesser extent
serotonergic) neural mechanisms in the pathophysiology of ADHD,
leading to a large number of candidate gene studies. Several
candidate genes had initially emerged as contributory (e.g.,
dopamine receptor genes [D2, D4, D5], dopamine transporter [DAT]
gene, catechol O-methyl transferase [COMT] gene, monoamine
oxidase A [MAO-A] gene), with considerable early research focusing
on the importance of DAT. However, no single candidate gene has
consistently been found to account for a sufficiently high percentage
of the variance to indicate a causal relationship. In addition, recent
research has examined common single-nucleotide polymorphisms
(SNPs) and copy number variants (CNVs) using whole-genome
analyses. The genes identified in these studies are more often
implicated in broad regulatory functions involving neuron growth,
development, and neuroplasticity, which overlap with genes involved
in other neurodevelopmental and psychiatric disorders. Although
some markers show promise for further investigation, thus far none
have been shown to contribute statistically to ADHD heritability or
the developmental trajectory of the disorder.
Neurobiological Factors
The neurobiological underpinnings of ADHD have not been fully
elucidated. However, much is known about the neurobiology of
inhibitory control, and neuroimaging techniques have been
invaluable in the development of biological models that highlight the
critical intercommunication across various brain regions and neural
networks.
Morphological studies using magnetic resonance imaging (MRI) in
children and adolescents have found that overall cortical size and
the volume of several key cortical and subcortical brain regions (e.g.,
the dorsolateral prefrontal cortex [PFC], caudate, pallidum, corpus
callosum, cerebellum) are reduced in individuals with ADHD. A
meta-analysis of voxel-based morphometry studies in children and
adults with ADHD confirmed global reductions in gray matter
associated with ADHD, with the most prominent reductions found in
the lentiform and caudate nuclei (Nakao et al. 2011). Recent findings
indicate that differences in white matter volume persist into
adulthood in patients with childhood ADHD (Cortese et al. 2013).
However, the relative decrease in volume of caudate and putamen
does not seem to persist into adolescence, perhaps reflecting the
relative decrease in observed hyperactive/impulsive symptoms over
the developmental trajectory of ADHD.
Single-photon emission computed tomography (SPECT) and
positron emission tomography (PET) studies investigating receptor
density and binding properties have yielded conflicting results. Some
have reported increased density of striatal DAT in adults with ADHD
(e.g., Spencer et al. 2007a), which could account for the
hypothesized hypodopaminergic state and the beneficial effects of
stimulant treatment (which blocks DAT and increases synaptic
dopamine). However, other studies in noncomorbid, medication-
naive adults found no change or even lower DAT density (Volkow et
al. 2009). Of note, 1 year of stimulant treatment has been shown to
upregulate DAT in adults with ADHD (Wang et al. 2013), highlighting
the importance of prior medication status.
A large number of studies have used functional MRI (fMRI) to
examine regional brain activation while subjects are performing
cognitive tasks. The majority of fMRI studies have focused on the
role of the PFC in providing “top-down” regulation of attention,
inhibitory control, motivation, and emotion via connections with
subcortical and posterior structures. Specific abnormalities found in
ADHD include disrupted connections between the inferior PFC and
striatal, parietal, and cerebellar regions. A recent meta-analysis of
fMRI findings (Hart et al. 2013) demonstrated dysfunction in normal
inhibitory control pathways, including the right inferior PFC,
supplemental motor area, and anterior cingulate gyrus. Inattention
symptoms were related to dysfunction in the frontobasal ganglio-
parieto-cerebellar pathway.
Research has also examined the role of the “default mode
network” (DMN) in ADHD (e.g., Castellanos and Proal 2012). The
DMN consists of brain regions that are activated during task-
irrelevant mental processes, including but not restricted to “mind
wandering.” The DMN is active during rest and nondemanding
cognitive situations and is suppressed during the completion of
cognitively demanding tasks. Several studies have found abnormal
connectivity of DMN regions with PFC in children with ADHD.
Finally, a robust literature base has examined the neurobiological
basis of ADHD treatment response. A meta-analysis of fMRI studies
of psychostimulants in youths with ADHD (most using single-dose
challenge) found that medication normalized brain function in the
PFC and anterior cingulate (Rubia et al. 2014). Other studies
suggest that stimulant treatment enhances activity in regions within
the reward network (e.g., Rubia et al. 2009), consistent with the
observation that stimulants enhance motivation for tasks otherwise
considered boring.
Risk Factors
Several studies have found that exposure to alcohol, nicotine,
cocaine, and other drugs of abuse during gestation substantially
increases risk for ADHD. However, recent research suggests that
this risk may also be due to the higher prevalence of smoking,
substance abuse, and other risky behaviors practiced by adults with
ADHD (Skoglund et al. 2014). Similar confounds plague the reported
correlations between disordered home environment and ADHD.
While it is unlikely that parenting style has an etiological relationship,
parent-child interactions can contribute to maintenance of pathology.
In particular, maternal depression and use of ineffective parenting
strategies have been associated with poor treatment response in
several studies. Other risk factors are gestational diabetes and use
of caffeine and certain medications during pregnancy.
Despite persistent interest in the potential role of diet in ADHD,
few high-quality studies have shown that any particular diet, in the
absence of toxicity, allergy, or medical disorder (e.g., celiac disease),
is disproportionately associated with ADHD (Arnold et al. 2013). The
relationship between sleep and ADHD symptoms is better supported
but complex (Yoon et al. 2012). While it is known that sleep
disturbance can mimic and/or exacerbate ADHD, it is one of many
contributing risk factors. Exposure to lead and other neurotoxins
(e.g., polychlorinated biphenyls, mercury) has been shown to
increase the rate of ADHD. However, it seems unlikely that the high
prevalence rates would be explained by such exposure.
Assessment
Clinical Assessment
Assessment procedures in children rely heavily on information
obtained from parents/caretakers and teachers/school professionals
regarding the presence and severity of core symptoms across
settings, age at onset, duration of symptoms, and degree of
impairment. Broad-band rating scales, such as the Conners Parent
and Teacher Rating Scales, 3rd Edition (Conner 3), Achenbach Child
Behavior Checklist and Teacher Report Form, and Behavioral
Assessment Scales for Children, 2nd Edition (BASC-2), survey a
wide range of behaviors and are excellent for screening. Rating
scales that more specifically evaluate DSM-delineated ADHD
symptoms include the Swanson, Nolan, and Pelham (SNAP and
SNAP-IV) Parent and Teacher Rating Scales; ADHD Rating Scale–
IV (ADHD-RS-IV), parent and teacher versions; Vanderbilt ADHD
Diagnostic Rating Scales (parent and teacher); and Conners’ Parent
and Teacher Rating Scales.
There are now several validated rating scales and structured
interviews to assist in the diagnosis of ADHD in adults. Conners’
Adult ADHD Rating Scales (CAARS) and the Wender-Reimherr
Adult Attention Deficit Disorder Scale are self-report scales that
assess a wide range of developmentally relevant symptoms for
ADHD and associated behaviors. Other adult ADHD rating scales
utilize actual DSM items or developmentally appropriate (for adults)
adaptations of these items, including 1) the Barkley Current
Symptoms Scale, 2) the Adult ADHD Self-Report Scale Version 1.1
(ASRS v1.1) Symptom Checklist, and 3) the Adult ADHD
Investigator Symptom Rating Scale (AISRS), a symptom-based
interview. The Conners’ scale also has a subscale that maps onto
the DSM diagnosis. The Brown Attention-Deficit Disorder Scales
assess the presence, severity, and consequences of cognitive and
executive dysfunctions in a self-report format. Structured or
semistructured interviews for ADHD in adults include Conners’ Adult
ADHD Diagnostic Interview for DSM-IV (CAADID) and the Adult
ADHD Clinical Diagnostic Scale Version 1.2 (ACDS v1.2).
Neuropsychological Assessment
Neuropsychological testing is not required to diagnose ADHD.
However, neuropsychological and/or educational tests can be used
to augment the clinical assessment of ADHD symptoms such as
attention and inhibitory control, provide normed data required for the
diagnosis of mental retardation and specific learning disabilities,
assess school placement, justify the need for supplemental services,
or request accommodations such as extended time on exams.
Intellectual capacity and academic achievement are routinely
assessed. There are numerous neuropsychological tests to assess
executive functions, but most lack specificity.
Objective Measures
A variety of objective measures have been used to quantify ADHD
symptoms and augment the information obtained from clinical
interviews and rating scales. The continuous performance test (CPT)
is a computer-based test that measures sustained attention,
inhibitory control, and reaction time. Originally developed to assess
sustained attention in adults with brain damage, the CPT has been
used for decades to assess ADHD symptoms in youths and adults.
The Quotient ADHD System, which combines a head movement
infrared monitor with a novel variant of the continuous performance
task, has been cleared by the U.S. Food and Drug Administration
(FDA) to augment assessment of ADHD. The Neuropsychiatric EEG-
Based Assessment Aid (NEBA) has also been cleared by the FDA to
augment diagnostic assessment. This instrument measures the ratio
of theta to beta wave forms obtained during EEG, based on studies
of children with ADHD that have found a relative increase in theta
relative to beta activity.
Treatment
Treatment of ADHD by necessity targets the core symptoms of
inattention and hyperactivity/impulsivity, but it should also address
associated cognitive, social, and psychological impairments.
Consequently, multimodal treatments incorporating both
psychopharmacological and psychosocial modalities are often
indicated.
Psychoeducation regarding the etiology of the disorder, nature of
symptoms, and the many ways symptoms can affect individuals and
families is essential. In addition, families must be counseled on the
range of aids and/or structural accommodations that can be
accessed and assisted in obtaining them if necessary. When
treatment is being initiated, it is important to identify and track
mutually agreed-on target behaviors and to assess the trajectory of
both ADHD and comorbid symptoms within a developmental
framework.
The American Academy of Pediatrics practice guidelines
(Wolraich et al. 2011) recommend that preschoolers should be
treated initially with behavioral therapy, with psychostimulants as
second-line treatment. In children ages 6–11 years,
pharmacotherapy is first-line treatment, with behavioral therapy
recommended as adjunct treatment. Adolescents should be treated
with pharmacotherapy; adjunctive behavioral therapy is
recommended, but the evidence base is weaker. The American
Academy of Child and Adolescent Psychiatry guidelines (Pliszka and
AACAP Work Group on Quality Issues 2007) recommend
pharmacotherapy using an FDA-approved medication as first-line,
with adjunctive behavioral interventions if pharmacotherapy alone is
not fully effective.
Pharmacotherapy
Medication treatment in youths and adults with ADHD is
dominated by the psychostimulants. There are also several FDA-
approved nonstimulant medications, as well as other medications
that are used “off-label.”
Psychostimulants
Stimulants are considered to be the most effective medication
treatments for ADHD, with mean effect sizes for core ADHD
symptoms in children and adolescents generally ranging from 0.8 to
1.0, and sometimes higher. Stimulant treatment can also produce
improvement in several associated symptoms and functional
domains, including oppositionality, impulsive aggression, peer
interactions, family dynamics, and self-esteem. There are several
different formulations of stimulant medications, divided among the
two major classes, methylphenidate (MPH) and amphetamine
(AMP), including immediate- and extended-release formulations and
branded and generic products. The psychostimulants have a short
half-life; continuous delivery of stimulant medication is accomplished
via administration of immediate-release formulations multiple times
daily or via extended-release or double-pulse formulations designed
to replicate the pharmacokinetics of multiple daily dosing.
Most MPH formulations contain the racemic form of the
compound (d and l stereoisomers), but there are also immediate-
release and extended-release forms of d-MPH, which is the active
stereoisomer. There are many long-acting formulations of d,l-MPH,
with activity generally ranging from 8 to 12 hours. Several of these
(e.g., d,l-MPH-CD, d,l-MPH-LA, d-MPH-XR) are double-pulse
formulations, which mimic twice-daily administration of immediate-
release MPH. In contrast, OROS-MPH uses an osmotically
controlled delivery system, whereas another extended-release (XR)
formulation uses multilayered beads, to produce constant and
gradually increasing plasma levels over the course of the day. There
are also long-acting liquid, chewable, and transdermal MPH
formulations, as well as an orally disintegrating tablet. The AMP
class of stimulants includes dextroamphetamine (DEX), racemic
AMP (50% d- and 50% l-AMP), and mixed amphetamine salts
(MAS). The latter is a mixture of several amphetamine compounds,
75% of which is DEX. MAS-XR, a double-pulse version of MAS, is
the most frequently prescribed single medication for ADHD. A
prodrug formulation of DEX, lisdexamfetamine (LDX), is inactive until
it is metabolized in the blood and is released gradually, presumably
accounting for the long duration of action. Other new AMP
formulations include a long-acting liquid and an orally disintegrating
tablet (each having an ~3:1 ratio of d- to l-AMP).
Typical group mean stimulant doses are 1 mg/kg for d,l-MPH and
0.5 mg/kg for d-MPH and AMP. However, these weight-based doses
are only guidelines, and medication is usually titrated using a fixed
rather than a weight-based approach. There is a current preference
for using long-acting formulations first because of the increasing
recognition that ADHD symptoms last throughout the day. However,
because symptom management is often required for longer periods
than any of the extended-duration stimulant formulations remain
effective, particularly in adolescents and adults, extended-release
and immediate-release formulations are often used together.
Despite slight differences in mechanism of action, the different
stimulant classes and formulations are relatively comparable in
clinical efficacy and tolerability at the group level, provided they are
dosed equivalently. However, there are differences in the temporal
effects that generally follow mode of delivery, as well as individual
differences in response and/or tolerability. Determining which
stimulant class and formulation is best for the individual patient will
often depend on judgments regarding the nature of impairment,
duration of required coverage, and variability in individual response.
Thus, conducting sequential empirical trials of different classes or
formulations of stimulants may be required.
The most common adverse events associated with stimulants are
headache, abdominal pain, decreased appetite (with or without
weight loss), and initial insomnia. There are slight increases in pulse
and blood pressure, which are not very meaningful at the group level
but may be important in some individuals. Monitoring cardiovascular
indices is especially important in adults. Affective changes, including
blunted affect, irritability, and mood lability, can also be seen. Despite
initial concerns that motor or vocal tics can develop or be
exacerbated, most studies indicate that this is not usually the case.
Psychosis is a rare adverse event and most often occurs in the
context of an underlying mood or psychotic disorder.
Delayed weight and growth attainment on initiating treatment have
long been recognized, although the question of whether growth
delay persists has not been fully resolved. Findings from initial
studies indicated that slowing of growth occurs early in treatment but
that growth then stabilizes and catches up over time. However, the
Multimodal Treatment of Attention Deficit Hyperactivity (MTA) study
found that acute use of immediate-release stimulants (administered
three times daily, 7 days per week) produced a slowing of growth by
approximately 1 cm per year over the first 24 months of treatment,
compared with unmedicated subjects, and that growth did not “catch
up” by 36 months (Swanson et al. 2007). Fortunately, the amount of
growth suppression is not great, and such suppression is only seen
in patients who take medication consistently and at high doses.
Thus, growth trajectory is not a problem for the majority of youths
treated with stimulants.
Whether or not stimulant treatment is associated with elevated
cardiovascular risk has also been debated; consequently, several
large-scale database studies have examined cardiovascular risk in
children and adults treated with stimulants versus untreated control
subjects. Findings indicate that the risk for sudden death in patients
taking stimulants does not exceed the base rate in the general
population (0.6–6/100,000 per year), nor is there evidence of
increased rates of other potentially severe outcomes (Cooper et al.
2011; Habel et al. 2011). Nevertheless, there is an FDA warning for
cardiovascular risk (but not a black box warning). Current guidelines
state that it is not essential to obtain routine electrocardiograms prior
to initiating treatment. However, cardiac workup should be
considered in patients with arrhythmias, hypertension, structural
cardiac defects, or a family history of untoward cardiac events.
Finally, the potential for stimulant misuse, abuse, and diversion
represents an additional important safety consideration. Longitudinal
data indicate that 5%–9% of grade school and high school students
with ADHD report misusing their medications, while up to 35% of
college students report misuse (Wilens et al. 2008). Stimulant abuse
and dependence generally occur in the context of other addiction
disorders. However, diversion of medications to individuals not
diagnosed or treated by a physician is a substantial problem. Almost
all states in the United States have developed controlled substance
registries for physicians to access before prescribing to minimize
potential abuse of stimulants and other prescription medications.
Nonstimulants
Atomoxetine. Atomoxetine (ATX) was the first FDA-approved
nonstimulant medication for ADHD, and it is labeled for use in both
children and adults. ATX is a selective norepinephrine reuptake
inhibitor, which increases synaptic norepinephrine in multiple brain
regions and dopamine levels in the PFC. Because it does not affect
dopamine levels in the striatum and does not produce euphoria even
at high doses, ATX has low potential for abuse.
Numerous controlled trials have demonstrated that ATX is
effective in managing core symptoms of both inattention and
hyperactivity/impulsivity, although with somewhat lower effect sizes
than for stimulants. Treatment is also associated with improvements
in parental reports of child self-esteem, as well as social and family
function. ATX may be particularly useful in the treatment of ADHD
and several comorbid disorders, with the best data thus far in youths
with comorbid anxiety disorders. A review of all premarketing trials
found that response to ATX was bimodal, with most children being
either “much improved” or “nonresponders” (Newcorn et al. 2009).
Onset of response by 4 weeks was the only predictor of eventual
significant improvement. In a parallel group head-to-head
comparison study, response to OROS-MPH was greater than to
ATX, although both medications were superior to placebo, and about
one-third of patients showed preferential improvement with one
treatment or the other (Newcorn et al. 2008).
ATX is available in an immediate-release capsule with an
estimated duration of action of 10–12 hours. The medication can be
dosed once daily or twice daily. Although once-daily administration
may improve adherence, there may be more gastrointestinal side
effects and sedation initially. Nighttime dosing in the first 1–2 weeks
may minimize sedation effects, and taking the medication with food
can often minimize nausea and other unwanted gastrointestinal
effects. The starting dose for individuals weighing 70 kg or less is 0.5
mg/kg total daily, with a target dose of 1.2 mg/kg, and a maximum of
1.4 mg/kg total daily (although some clinical trials have found
benefits using doses up to 1.8 mg/kg). In children, adolescents, or
adults weighing more than 70 kg, ATX can be initiated at 40 mg total
daily, with a target dose of 80 mg, and a maximum of 100 mg total
daily.
ATX is metabolized via the cytochrome P450 (CYP) 2D6 system;
7% of individuals have a genetic polymorphism that makes them
poor metabolizers. In these individuals, the half-life of ATX is
approximately 19 hours (vs. 4.5 hours in extensive metabolizers),
and medication blood levels are much higher for any given dose.
Nevertheless, it is not necessary to determine CYP2D6 genotype
prior to treatment, as studies using blind titration in slow and
extensive metabolizers found that end-of-titration doses were nearly
equivalent.
The most commonly occurring adverse events include sedation,
nausea and vomiting, decreased appetite, weight loss, and an
increase in pulse and blood pressure (comparable to that with
stimulants). Irritability and increased aggression can also occur.
There are two FDA warnings in effect for ATX—for liver toxicity and
for suicidal ideation. Postmarketing surveillance identified two cases
(out of approximately two million exposures) of acute hepatotoxicity.
In both instances, the condition resolved with medication
discontinuation (Bangs et al. 2008a). Obtaining routine liver function
tests before initiating ATX treatment is not recommended because
pretreatment findings do not predict course. However, a thorough
workup is indicated in patients at risk or in those who develop
abdominal pain or jaundice in association with treatment. Likewise,
premarketing data from 12 short-term clinical trials showed a small
but statistically significant increased rate of suicidal ideation—
approximately 4 per 1,000 patients—leading to a black box warning
for suicidal ideation in the first few months of treatment (Bangs et al.
2008b). Conversely, Linden et al. (2016) report on a cohort study
that shows that there is not a higher risk for suicidal behavior for ATX
than for stimulants. However, it is important for clinicians and parents
to monitor patients frequently at the beginning of treatment.
α2-Adrenergic agonists. Originally developed as antihypertensives,
the α2-adrenergic agonists were used off-label (because of their
noradrenergic effects) in immediate-release form for the treatment of
ADHD and aggression. However, extended-release formulations of
clonidine and guanfacine have been developed and are now
approved by the FDA for children and adolescents with ADHD as
monotherapy or adjunctive to stimulants. Although clinical trials
indicate improvement in both inattention and hyperactive/impulsive
symptom domains, behavioral overarousal, aggression, and ODD
are frequent targets of treatment (Sallee et al. 2013). Other frequent
targets include motor or vocal tics and insomnia. Results from a
large seminal trial found that the combination of MPH and clonidine
was more effective than either drug alone in treating both ADHD
symptoms and tics (Tourette’s Syndrome Study Group 2002).
The behavioral effects of clonidine immediate release (CLON-IR)
last about 3–6 hours. Extended-release clonidine (CLON-XR) was
developed to address the limitations of frequent dosing with CLON-
IR. CLON-XR can be dosed once or twice daily, with total daily
dosages ranging from 0.1 to 0.4 mg. Recommended dose increases
are limited to 0.1 mg per day weekly. In a large multisite placebo-
controlled trial (Jain et al. 2011), CLON-XR significantly improved
ADHD symptoms, starting as early as week two of treatment with
both the 0.2 mg (i.e., 0.1 mg twice daily) and 0.4 mg (i.e., 0.2 mg
twice daily) total daily doses. Adverse events included mild to
moderate somnolence, as well as changes in heart rate, blood
pressure, and QTc interval. Sedation and vital sign changes tended
to occur early and resolve over the course of treatment. No
significant adverse events occurred related to changes in these
parameters, and QTc change from baseline was small. Because
there is the potential for rebound hypertension with clonidine, abrupt
discontinuation should be avoided.
The potential utility of guanfacine for youths with ADHD has
likewise been systematically evaluated in youths with ADHD alone
and in youths with ADHD plus tic disorders. Guanfacine is more
selective for α2-adrenergic receptors than clonidine; it has a longer
half-life and duration of action, and it may be less sedating. The
extended-release formulation of guanfacine (GXR) (doses of 1 mg, 2
mg, 3 mg, and 4 mg) was found to significantly decrease ADHD
symptoms in children, with increasing effects associated with higher
weight-adjusted doses (target dose ~0.08 mg/kg). Adverse effects
include sedation, decreased blood pressure, and QTc changes.
Sedation and blood pressure effects tend to resolve after about 2
weeks and are not significant and are not associated with
discontinuation of the medication. QTc changes were found to be
small and did not result in any adverse outcomes.
Off-Label Medications
Bupropion is a mixed noradrenergic-dopaminergic agent that is
chemically unrelated to other known antidepressants. Multicenter
studies in both children (Conners et al. 1996) and adults (Wilens et
al. 2005) with ADHD found that bupropion was effective, although
with a lower effect size than is typically seen for stimulants and also
for approved nonstimulants (in children). Bupropion may be
particularly useful in the treatment of ADHD with comorbid
depression or substance abuse.
Modafinil (FDA approved for the treatment of narcolepsy and shift
work sleep disorder and as an adjunct in obstructive sleep
apnea/hypopnea syndrome) is an atypical stimulant and wake-
promoting agent. An experimental formulation of modafinil was found
to yield significant improvement in ratings of ADHD symptoms both
at home and at school. However, the experimental medication was
not approved by the FDA because of concerns regarding possible
elevated risk for Stevens-Johnson syndrome.
Psychosocial Treatments
Numerous psychosocial therapies are available for youths and
adults with ADHD. Because the nature and consequences of
symptoms often differ as a function of age and developmental level,
different treatment approaches are used in preschoolers, school-age
children, adolescents, and adults. Interventions target key
impairments at home, school, or work, as well as interactions with
family and peers.
Evidence-based treatment guidelines are largely formulated from
4 literature reviews of research evidence among adults and 13
literature reviews and from 9 meta-analyses of the research
evidence among youths (Watson et al. 2015). Collectively, the data
suggest that psychosocial interventions for youths do not directly
affect ADHD symptoms (Sonuga-Barke et al. 2013). However, there
appear to be specific effects of certain psychosocial interventions—
namely, behavioral interventions—on improving child conduct
problems. Well-validated psychosocial interventions for youths
include behavioral parent training (BPT), classroom-based behavior
modification (CBM), and multimodal interventions (e.g., intensive
summer treatment programs that combine social skills training with
behavior modification). Skills-based interventions, such as
organizational skills training (OST), are gaining increased support for
use in youths with ADHD. Although quite popular, social skills
training and individual play therapy are well-researched but less well-
supported interventions for youths. Cognitive-behavioral therapy
(CBT) and metacognitive therapy (MCT) have been studied in adults
and youths with sufficient levels of self-awareness and capacity for
impulse control, with generally positive findings. There has been
recent interest in the use of mindfulness training, dialectical behavior
therapy, and other relaxation-based techniques, but these have been
less well supported by the literature.
Behavioral therapy (BT) is perhaps the best supported evidence-
based practice for treating ADHD and has been successfully utilized
in preschool- and school-age youths and adults, either alone or in
combination with other interventions. In children, BT approaches
advocate working with parents or teachers as the agents of change.
The focus of BT is on decreasing the frequency of problematic
behaviors while increasing the rate of desirable behaviors through
environmental manipulation and contingency management
techniques. Rewards or privileges are earned for meeting stipulated
desired or prosocial behaviors, and rewards are withheld or
punishments applied for rule violations. Older children, adolescents,
and adults benefit from BT with a cognitive component, such as CBT.
Although contingency management is often employed within a BT
framework, it may also be used alone. Target behaviors are clearly
defined, as are the gains to be achieved in meeting behavioral
expectations and the consequences of falling short. Participation of
the child in the treatment plan and input into the selection of rewards
help with engagement and maintenance of motivation. It is essential
that rewards reflect the individual values of the child and not be
onerous for the parent in terms of cost or personal values. Also,
rewards should be changed over the course of treatment, as the
child’s perception of the reward changes or the child grows too
familiar with it. The latter point is particularly important to recognize
because youths with ADHD tend to prefer novelty.
BPT is another well-supported approach for children, especially
for preschool children (Charach et al. 2013). BPT is administered in
group and/or individual sessions that combine psychoeducation with
instruction in behavioral treatment approaches. The crucial
component of BPT is to train parents in the competent use of
behavior management techniques that are appropriate for shaping a
child’s behaviors while minimizing conflict within the home. There are
now several commercially available BPT programs (e.g., Defiant
Children, Community Parent Education Program, Triple P—Positive
Parent Program, Parent Management Training, Parent-Child
Interaction Therapy, and The Incredible Years parenting program).
Although there are differences between some of the parameters of
these programs (e.g., group vs. individual, parent alone vs. parent
and child), the contents of many evidence-based BPT programs are
more similar than different. Importantly, the actual decision to use
one particular BPT program over another is often likely driven by
therapist and parent preferences, as well as practical issues (e.g.,
space constraints, insurance reimbursement rates, availability of
multiple providers to implement BPT, therapist training and
preference).
Behavior modification can be used to target school behavior and
function as well as home behavior and can be conducted in the
school setting. Classroom-based behavior modification assists
teachers in identifying target behaviors that require improvement
while shaping and reinforcing alternative behaviors. CBM is most
effective when there is communication between school and home
regarding the child’s attainment of daily goals. Such communication
is often facilitated through the development of a daily report card
system, in which reports of expectations and behaviors at school are
sent home for incorporation into the behavioral plan. The flexible
nature of BPT and CBM makes it possible to develop interventions
that are tailored to the problems and needs of the child and family, to
target specific tasks or settings, and to adapt the treatment to
changing needs and/or impairments as they arise.
Abikoff and colleagues (2013) have recently developed an OST
intervention for school-age youths with ADHD. This intervention
teaches children to use new tools and routines to record
assignments, organize school materials, effectively monitor the
amount of time involved in completing assignments, and break larger
tasks into smaller more manageable tasks. Parents and teachers are
taught to praise children for efforts at using the organizational skills.
This work has also been extended to older youths with ADHD as
well. As an example, Langberg and colleagues (2012) adapted an
organizational intervention for middle-school children with ADHD.
Results of randomized clinical trials of OST interventions suggest
that these interventions lead to significantly greater organization as
reported by parents and teachers, improved academic functioning,
better homework completion, and reduction in family conflict.
Interestingly, improvements in these outcomes appear to be
maintained over a 3- to 6-month follow-up period.
Cognitive therapy, CBT, and MCT approaches are particularly well
supported for adults (Safren et al. 2010; Solanto et al. 2010).
However, these interventions can only be implemented when there is
sufficient self-awareness and behavioral control. Cognitive therapy,
CBT, and MCT are based on the premise that certain undesirable
thoughts, perceptions, and behaviors are overlearned and that a
structured, symptom-focused intervention can help patients reframe
how they think about or manage behavior and implement self-
regulatory or other compensatory strategies. These interventions
help manage problems with task engagement, completion, and
organization and minimize secondary problems related to self-
esteem, demoralization, or anxiety.
Combined Treatments
There are several different evidence-based approaches to
combining treatment in individuals with ADHD. The MTA compared
14 months of randomized treatment with medication, psychosocial
treatment, combination treatment, and community standard
treatment in 579 children ages 7–10 years with combined subtype
ADHD (diagnosed using DSM-IV). The 14-month intent-to-treat
analyses indicated that for ADHD symptoms, treatments that
included medication performed better than other treatments (MTA
Cooperative Group 1999). This finding was replicated in a different,
two-site comparative medication-psychosocial trial using a similar
but slightly different design (Abikoff et al. 2004). For the non-ADHD
symptoms (i.e., oppositional/aggressive symptoms, parent-reported
internalizing problems, teacher-reported social skills issues, parent-
child relationship difficulties, reduced reading achievement) in the
MTA, there was a small difference in effect size favoring the
combined treatment over the community-treated comparison group
in several analyses. Longitudinal follow-up of the MTA sample has
yielded a complex pattern of results. The effect size favoring
randomization to medication treatment was reduced by
approximately 50% at 24 months posttreatment, 10 months after the
active study treatment ended. At the 3-year and 8-year
assessments, there was no longer a significant advantage for the
group originally randomly assigned to receive medication (Molina et
al. 2009).
Emerging Nonpharmacological Therapies

The recognition that ADHD is a neurodevelopmental disorder has
resulted in novel nonpharmacological interventions aimed at altering
its developmental trajectory. For example, a limited sample of
studies has suggested that physical exercise and nutritional
modifications (i.e., restricted diets, free fatty acid supplementation)
may improve ADHD symptoms and associated behavioral problems
(Arnold et al. 2013). While the overall percentage of children who
may benefit from these interventions is likely small, the interventions
may have greater benefit for certain children (Nigg and Holton 2014).
As such, these interventions may be considered after nonresponse,
or less-than-optimal response, to first-line pharmacological and
psychosocial interventions. Furthermore, several reviews (e.g.,
Tamm et al. 2013) have demonstrated that neurofeedback can
generate improvements on a range of outcome measures. However,
the improvement tends to be very small when blinded outcome
ratings are utilized (Sonuga-Barke et al. 2013). Similarly, while
cognitive training (i.e., brain exercises that target attention, working
memory, impulsivity) has received considerable interest for the
treatment of ADHD, recent reviews suggest minimal effects on a
variety of outcomes when blind ratings are obtained (Cortese et al.
2015).
Conclusion
ADHD is a highly prevalent neurodevelopmental disorder with a
strong neurobiological basis. However, despite the high degree of
heritability, variability in individual presentation, predisposing factors,
course, and treatment response is often seen. There are a variety of
evidence-based medication and psychosocial treatments. Of the
various approved medication treatments, stimulants are the most
supported and are generally more effective than nonstimulants,
although even with effective treatment, symptoms often persist over
time.
Nonstimulants are theoretically appealing because of their longer
duration of effects and their particular utility in ADHD patients with
comorbid conditions and those at increased risk for substance
abuse. However, because current nonstimulants are generally less
effective than stimulants for ADHD symptoms, at least in
uncomplicated cases, they are not customarily used first.
Psychosocial treatments have an important role for both children and
adults and can be used alone or together with medications.
Developmental considerations are important in deciding how to
prioritize treatments (e.g., primacy for behavior therapy in preschool
children) and how to best tailor treatment to individual patients’
needs—because different types of psychosocial treatments are
recommended for children and adults and medication options and
response are similar but not identical in children and adults. In
addition, eliciting parent preference and establishing treatment goals
may improve adherence and are important for shared decision
making in targeting ADHD symptoms and/or behavioral problems
resulting in functional impairments.
References
Abikoff H, Hechtman L, Klein RG, et al: Symptomatic improvement in children with
ADHD treated with long-term methylphenidate and multimodal psychosocial
treatment. J Am Acad Child Adolesc Psychiatry 43(7):802–811, 2004 15213581
Abikoff H, Gallagher R, Wells KC, et al: Remediating organizational functioning in
children with ADHD: immediate and long-term effects from a randomized
controlled trial. J Consult Clin Psychol 81(1):113–128, 2013 22889336
Disorders, 4th Edition. Washington, DC, American Psychiatric Association,
1994
Arnold LE, Hurt E, Lofthouse N: Attention-deficit/hyperactivity disorder: dietary and
nutritional treatments. Child Adolesc Psychiatr Clin N Am 22(3):381–402, 2013
23806311
Bangs ME, Jin L, Zhang S, et al: Hepatic events associated with atomoxetine
treatment for attention-deficit hyperactivity disorder. Drug Saf 31(4):345–354,
2008a 18366245
Bangs ME, Tauscher-Wisniewski S, Polzer J, et al: Meta-analysis of suicide-
related behavior events in patients treated with atomoxetine. J Am Acad Child
Adolesc Psychiatry 47(2):209–218, 2008b 18176331
Barkley RA, Fischer M, Smallish L, et al: Young adult outcome of hyperactive
children: adaptive functioning in major life activities. J Am Acad Child Adolesc
Psychiatry 45(2):192–202, 2006 16429090
Castellanos FX, Proal E: Large-scale brain systems in ADHD: beyond the
prefrontal-striatal model. Trends Cogn Sci 16(1):17–26, 2012 22169776
Charach A, Carson P, Fox S, et al: Interventions for preschool children at high risk
for ADHD: a comparative effectiveness review. Pediatrics 131(5):e1584–e1604,
2013 23545375
Conners CK, Casat CD, Gualtieri CT, et al: Bupropion hydrochloride in attention
deficit disorder with hyperactivit. J Am Acad Child Adolesc Psychiatry
35(10):1314–1321, 1996 8885585
Cooper WO, Habel LA, Sox CM, et al: ADHD drugs and serious cardiovascular
events in children and young adults. N Engl J Med 365(20):1896–1904, 2011
22043968
Cortese S, Imperati D, Zhou J, et al: White matter alterations at 33-year follow-up
in adults with childhood attention-deficit/hyperactivity disorder. Biol Psychiatry
74(8):591–598, 2013 23566821
Cortese S, Ferrin M, Brandeis D, et al; European ADHD Guidelines Group
(EAGG): Cognitive training for attention-deficit/hyperactivity disorder: meta-
analysis of clinical and neuropsychological outcomes from randomized
controlled trials. J Am Acad Child Adolesc Psychiatry 54(3):164–174, 2015
25721181
Habel LA, Cooper WO, Sox CM, et al: ADHD medications and risk of serious
cardiovascular events in young and middle-aged adults. JAMA 306(24):2673–
2683, 2011 22161946
Halperin JM, Schulz KP: Revisiting the role of the prefrontal cortex in the
pathophysiology of attention-deficit/hyperactivity disorder. Psychol Bull
132(4):560–581, 2006 16822167
Hart H, Radua J, Nakao T, et al: Meta-analysis of functional magnetic resonance
imaging studies of inhibition and attention in attention-deficit/hyperactivity
disorder: exploring task-specific, stimulant medication, and age effects. JAMA
Psychiatry 70(2):185–198, 2013 23247506
Hawi Z, Cummins TD, Tong J, et al: The molecular genetic architecture of attention
deficit hyperactivity disorder. Mol Psychiatry 20(3):289–297, 2015 25600112
Jain R, Segal S, Kollins SH, et al: Clonidine extended-release tablets for pediatric
patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc
Psychiatry 50(2):171–179, 2011 21241954
Kessler RC, Adler L, Barkley R, et al: The prevalence and correlates of adult
ADHD in the United States: results from the National Comorbidity Survey
Replication. Am J Psychiatry 163(4):716–723, 2006 16585449
Killeen PR: Models of ADHD: Five ways smaller sooner is better. J Neurosci
Methods 252:2–13, 2015 25597911
Kooij JJ, Huss M, Asherson P, et al: Distinguishing comorbidity and successful
management of adult ADHD. J Atten Disord 16(5)(suppl):3S–19S, 2012
22498754
Langberg JM, Epstein JN, Becker SP, et al: Evaluation of the Homework,
Organization, and Planning Skills (HOPS) Intervention for Middle School
Students with ADHD as Implemented by School Mental Health Providers.
School Psych Rev 41(3):342–364, 2012 25355991
Linden S, Bussing R, Kubilis P, et al: Risk of suicidal events With atomoxetine
compared to stimulant treatment: a cohort study.Pediatrics
137(5)::137(5):e20153199 2016 27244795
Molina BS, Hinshaw SP, Swanson JM, et al; The MTA Cooperative Group: The
MTA at 8 years: prospective follow-up of children treated for combined-type
ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 48(5):484–500,
2009 19318991
MTA Cooperative Group: A 14-month randomized clinical trial of treatment
strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative
Group. Multimodal Treatment Study of Children with ADHD. Arch Gen
Psychiatry 56(12):1073–1086, 1999 10591283
Nakao T, Radua J, Rubia K, et al: Gray matter volume abnormalities in ADHD:
voxel-based meta-analysis exploring the effects of age and stimulant
medication. Am J Psychiatry 168(11):1154–1163, 2011 21865529
Newcorn JH, Kratochvil CJ, Allen AJ, et al; Atomoxetine/Methylphenidate
Comparative Study Group: Atomoxetine and osmotically released
methylphenidate for the treatment of attention deficit hyperactivity disorder:
acute comparison and differential response. Am J Psychiatry 165(6):721–730,
2008 18281409
Newcorn JH, Sutton VK, Weiss MD, et al: Clinical responses to atomoxetine in
attention-deficit/hyperactivity disorder: the Integrated Data Exploratory Analysis
(IDEA) study. J Am Acad Child Adolesc Psychiatry 48(5):511–518, 2009
19318988
Nigg JT, Holton K: Restriction and elimination diets in ADHD treatment. Child
Adolesc Psychiatr Clin N Am 23(4):937–953, 2014 25220094
Pliszka S, AACAP Work Group on Quality Issues: Practice parameter for the
assessment and treatment of children and adolescents with attention-
deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 46(7):894–
921, 2007 17581453
Rubia K, Halari R, Cubillo A, et al: Methylphenidate normalises activation and
functional connectivity deficits in attention and motivation networks in
medication-naïve children with ADHD during a rewarded continuous
performance task. Neuropharmacology 57(7–8):640–652, 2009 19715709
Rubia K, Alegria AA, Cubillo AI, et al: Effects of stimulants on brain function in
attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.
Biol Psychiatry 76(8):616–628, 2014 24314347
Safren SA, Sprich S, Mimiaga MJ, et al: Cognitive behavioral therapy vs relaxation
with educational support for medication-treated adults with ADHD and
persistent symptoms: a randomized controlled trial. JAMA 304(8):875–880,
2010 20736471
Sallee F, Connor DF, Newcorn JH: A review of the rationale and clinical utilization
of α2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity
and related disorders. J Child Adolesc Psychopharmacol 3(5):308–319, 2007b
23782125
Sergeant JA: Modeling attention-deficit/hyperactivity disorder: a critical appraisal of
the cognitive-energetic model. Biol Psychiatry 57(11):1248–1255, 2005
15949995
Skoglund C, Chen Q, D’Onofrio BM, et al: Familial confounding of the association
between maternal smoking during pregnancy and ADHD in offspring. J Child
Psychol Psychiatry 55(1):61–68, 2014 25359172
Solanto MV, Marks DJ, Wasserstein J, et al: Efficacy of meta-cognitive therapy for
adult ADHD. Am J Psychiatry 167(8):958–968, 2010 20231319
Sonuga-Barke EJ: Causal models of attention-deficit/hyperactivity disorder: from
common simple deficits to multiple developmental pathways. Biol Psychiatry
57(11):1231–1238, 2005 15949993
Sonuga-Barke EJ, Brandeis D, Cortese S, et al; European ADHD Guidelines
Group: Nonpharmacological interventions for ADHD: systematic review and
meta-analyses of randomized controlled trials of dietary and psychological
treatments. Am J Psychiatry 170(3):275–289, 2013 23360949
Spencer TJ, Biederman J, Madras BK, et al: Further evidence of dopamine
transporter dysregulation in ADHD: a controlled PET imaging study using
altropane. Biol Psychiatry 62(9):1059–1061, 2007a 17511972
Spencer TJ, Biederman J, Mick E: Attention-deficit/hyperactivity disorder:
diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol
32(6):631–642, 2007b 17556405
Swanson JM, Elliott GR, Greenhill LL, et al: Effects of stimulant medication on
growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc
Psychiatry 46(8):1015–1027, 2007 17667480
Tamm L, Epstein JN, Peugh JL, et al: Preliminary data suggesting the efficacy of
attention training for school-aged children with ADHD. Dev Cogn Neurosci
4:16–28, 2013 23219490
Tourette’s Syndrome Study Group: Treatment of ADHD in children with tics: a
randomized controlled trial. Neurology 58(4):527–536, 2002 11865128
Volkow ND, Wang GJ, Kollins SH, et al: Evaluating dopamine reward pathway in
ADHD: clinical implications. JAMA 302(10):1084–1091, 2009 19738093
Wang GJ, Volkow ND, Wigal T, et al: Long-term stimulant treatment affects brain
dopamine transporter level in patients with attention deficit hyperactive
disorder. PLoS One 8(5):e63023, 2013 23696790
Watson SM, Richels C, Michalek AP, et al: Psychosocial treatments for ADHD: a
systematic appraisal of the evidence. J Atten Disord 19(1):3–10, 2015
22647286
Wilens S, Haight BR, Horrigan JP, et al: Bupropion XL in adults with attention-
deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol
Psychiatry 57(7):793–801, 2005 15820237
Wilens TE, Adler LA, Adams J, et al: Misuse and diversion of stimulants prescribed
for ADHD: a systematic review of the literature. J Am Acad Child Adolesc
Psychiatry 47(1):21–31, 2008 18174822
Willcutt EG: The prevalence of DSM-IV attention-deficit/hyperactivity disorder: a
meta-analytic review. Neurotherapeutics 9(3):490–499, 2012 22976615
Willcutt EG, Nigg JT, Pennington BF, et al: Validity of DSM-IV attention
deficit/hyperactivity disorder symptom dimensions and subtypes. J Abnorm
Psychol 121(4):991–1010, 2012 22612200
Wolraich M, Brown L, Brown RT, et al; Subcommittee on Attention-
Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and
Management: ADHD: clinical practice guideline for the diagnosis, evaluation,
and treatment of attention-deficit/hyperactivity disorder in children and
adolescents. Pediatrics 128(5):1007–1022, 2011 22003063
Yoon SY, Jain U, Shapiro C: Sleep in attention-deficit/hyperactivity disorder in
children and adults: past, present, and future. Sleep Med Rev 16(4):371–388,
2012 22033171
CHAPTER 7
Autism Spectrum Disorder

Throughout the Life Span
Autism spectrum disorder (ASD) is a lifelong

neurodevelopmental disorder defined by diagnostic criteria that
include deficits in social communication and social interaction and
restricted, repetitive patterns of behavior, interests, or activities
(American Psychiatric Association 2013). Autism is a disorder with
heterogeneity in phenotypes, including a spectrum of cognitive,
communication, and behavioral differences and differences in
etiology and outcomes. Initial signs and symptoms typically are
apparent in the early developmental period. However, social deficits
and behavioral patterns might not be recognized as symptoms of
ASD until a child or adult is unable to meet social, educational,
occupational, or other important life stage demands. Thus,
individuals may not receive an accurate diagnostic assessment until
they are well into adult years.
Background
The history of autism may be traced to the psychiatrist Dr. Leo
Kanner and his 1943 publication “Autistic Disturbance of Affective
Contact.” Dr. Kanner described 11 socially isolated children who
shared “an anxiously obsessive desire for the maintenance of
sameness” (Kanner 1943, p. 245). In his case studies, Dr. Kanner
shared the parents’ observations, as well as his own, in evaluating
the children. The following is his description of the 5-year-old boy
Donald (Kanner 1943, pp. 217–219):
Before he was two years old, he had “an unusual memory for faces and
names, knew the names of a great number of houses” in his hometown...“he
was not learning to ask questions or to answer questions unless they
pertained to rhymes.” It was observed that Donald was happiest when left
alone, almost never cried to go with his mother, did not seem to notice his
father’s home-comings.... Donald even failed to pay the slightest attention to
Santa Claus in full regalia.... He wandered about smiling, making
stereotyped movements with his fingers, crossing them about in the air....
Most of his actions were repetitious and carried out in exactly the same way
that they had been performed originally.
These children were differentiated from children with

schizophrenia by Kanner: “While the schizophrenic tries to solve his
problem by stepping out of a world of which he has been part and
with which he has been in touch, our children gradually compromise
by extending cautious feelers into a world in which they have been
total strangers from the beginning.” Dr. Kanner specifically noted
examples of “the astounding vocabulary of the speaking children, the
excellent memory for events of several years before, the
phenomenal rote memory for poems and names, and the precise
recollection of complex patterns and sequences” (Kanner 1943, p.
247).
In 1944, pediatrician Hans Asperger described four boys,
including 6-year-old Fritz, who
learnt to talk very early...[and] quickly learnt to express himself in
sentences and soon talked “like an adult.”...He was never able to become
integrated into a group of playing children.... Fritz did not know the meaning
of respect and was utterly indifferent to the authority of adults. He lacked
distance and talked without shyness even to strangers.... Although he
acquired language very early, it was impossible to teach him the polite form
of address.... Another strange phenomenon...was the occurrence of certain
stereotypic movements and habits. (Asperger 1991, pp. 39–40)
The children described by Asperger shared similarities with the

children described by Kanner but were different in that they showed
no cognitive impairments or language delays.
Despite these landmark publications, through the 1960s,
psychiatrists continued to view autism as a form of “childhood
schizophrenia.” Psychoanalysts theorized that emotionally distant
mothering caused autism (the “refrigerator mom” theory of autism).
The 1970s brought understanding that autism stemmed from
biological differences in brain development. Objective criteria for
diagnosing autism followed in the 1980s, indicating a clear
diagnostic separation from childhood schizophrenia, even if the
clinical presentations among individual children were somewhat
overlapping. The first operational definition appeared in the third
edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-III) (American Psychiatric Association 1980) and was strongly
influenced by Michael Rutter’s conceptualization of impaired social
development and communicative development, insistence on
sameness, and onset before 30 months of age (Rutter 1978).
In 1987, DSM-III-R included a checklist of diagnostic criteria for
autism (American Psychiatric Association 1987). The subsequent
revisions in DSM-IV (American Psychiatric Association 1994) in 1994
and the 10th revision of the International Classification of Diseases
(ICD-10) in 1992, in which autism was referred to as a pervasive
developmental disorder, emphasized the early onset of a triad of
features: impairments in social interaction, impairments in
communication, and restricted, repetitive, and stereotyped behavior,
interests, and activities. From 1994 to 2000, DSM-IV and DSM-IV-TR
(American Psychiatric Association 2000) expanded the definition of
autism to include a group of developmental disorders, including
Asperger’s disorder. The categories of pervasive developmental
disorders included autistic disorder, Rett’s disorder, childhood
disintegrative disorder, Asperger’s disorder, and pervasive
developmental disorder not otherwise specified.
The latest revision of DSM, DSM-5, published in May 2013,
subsumed the prior categories of pervasive developmental disorders
under the umbrella term autism spectrum disorder and reorganized
the triad of impairments into a dyad: 1) difficulties in social
communication and social interaction and 2) restricted and repetitive
behavior, interests, or activities (American Psychiatric Association
2013). The strict requirement for onset before 3 years of age was
changed to “onset in the early developmental period”; the occurrence
of potential sensory abnormalities was incorporated; and a severity
scale for impairments in each of the two core domains was included.
Diagnostic reporting now includes specifiers that may enhance
descriptive subtyping of the population, including specifiers for the
presence or absence of intellectual impairment, language
impairment, catatonia, and known medical, genetic, or environmental
factors. The new criteria allow for a history of symptoms that may not
be present currently, recognizing that through intervention or normal
development some children with autism no longer exhibit core
symptoms later in life. Atypical language development (historically
required to make a diagnosis of autism) was removed from the
criteria and is now classified as a co-occurring condition. The new
criteria give improved descriptions and organization of key features,
emphasize the dimensional nature of autism, provide one diagnostic
label with individualized specifiers, and allow for an assessment of
the individual’s need for support, which helps in provision of clinical
and educational services, as necessary. The reader is encouraged to
refer to DSM-5.
Prevalence
The median global prevalence of autism is 62/10,000 (Elsabbagh
et al. 2012). The global prevalence of autism has increased almost
30-fold since the first epidemiological studies were conducted in the
late 1960s and early 1970s. By the 2000s, prevalence estimates
from large surveys indicated that 1%–2% of all children had an ASD
(Lai et al. 2014). It is difficult to empirically study the underlying
reasons for the apparent prevalence changes in both new and
existing case detection. Select studies suggest that much of the
recent prevalence increase may be attributable to extrinsic factors
such as improved awareness and recognition (social factors);
changes in diagnostic practice, including use of broader diagnostic
criteria (medical practice standards); or service availability (health
care delivery system). Other researchers point out that
environmental factors must be considered to play a role because
these dramatic increases cannot be fully explained simply by the
changes in social and clinical awareness and diagnostic practice
(Hertz-Picciotto et al. 2006).
Recent survey results from 11 sites in the United States revealed
that 1 in 68 children had an ASD (Centers for Disease Control and
Prevention 2014). Overall ASD prevalence estimates varied among
sites, from 5.7 to 21.9 per 1,000 children age 8 years; ASD
prevalence estimates varied also by sex and racial/ethnic group.
Approximately 1 in 42 boys and 1 in 189 girls were identified as
having ASD. Non-Hispanic white children were approximately 30%
more likely to be identified with ASD than were non-Hispanic black
children and were almost 50% more likely to be identified with ASD
than were Hispanic children. The median age at earliest known ASD
diagnosis was 53 months and did not differ significantly by sex or
race/ethnicity.
Over the last decade, a growing number of children diagnosed
with ASD have average or above-average intellectual ability. This
proportion has increased consistently over time, from 32% in 2002 to
38% in 2006 to 46% in 2010. Concurrently, the proportion of children
with ASD and co-occurring intellectual disability has steadily
decreased from 47% in 2002 to 31% in 2010. This shift in distribution
of intellectual ability indicates that a large proportion of the observed
ASD prevalence increase can be attributed to children with average
or above-average intellectual ability (IQ >85) (Centers for Disease
Control and Prevention 2014).
Worldwide estimates are that approximately 45% of individuals
with autism have intellectual disability (Fonbonne 2011) and 32%
have regression (the loss of previously acquired skills; mean age at
onset 1.78 years) (Barger et al. 2013). ASD is diagnosed four times
more often in males than in females (American Psychiatric
Association 2013). In clinic samples, females tend to be more likely
to show accompanying intellectual impairment.
Etiology
ASDs are thought to result from complex interactions between
multiple genetic and environmental factors. ASDs are highly
heritable, with concordance rates of 60%–92% in monozygotic twins
and 0%–10% in dizygotic twins (Bailey et al. 1995). Although genetic
causes, such as chromosomal abnormalities and de novo copy
number variations, are implicated in 10%–20% of cases of ASD, no
single genetic etiology accounts for more than 1%–2% of cases
(Abrahams and Geschwind 2008). Syndromes frequently associated
with ASD, including fragile X syndrome and tuberous sclerosis, have
led to the conclusion that many different gene-environment
interactions may result in similar behavioral phenotypes.
Epidemiological studies have identified various risk factors for
developing ASD, but none has proven to be necessary or sufficient
alone for autism to develop; inflammation and immunological risk
factors are being studied as part of gene-environment interactions.
Electroencephalographic abnormalities and seizure disorders are
observed in 20%–25% of individuals with autism, suggesting that
similar neurobiological underpinnings are involved in autism and
epilepsy, with habitual overuse of circuits or localized neuronal
hyperexcitability (Hertz-Picciotto et al. 2006).
Advanced paternal or maternal reproductive age, or both, is a
consistently identified risk factor for ASD (Reichenberg et al. 2010).
Gestational factors that affect neurodevelopment, such as
complications during pregnancy, prematurity, low birth weight, and
exposure to chemicals, have been linked to increased risk of autism.
Prenatal exposure to rubella, thalidomide, and valproic acid are
environmental influences associated with development of ASD.
Conversely, folic acid supplements before conception and during
early pregnancy seem to be protective (Surén et al. 2013). There is
no evidence that the MMR (measles, mumps, and rubella) vaccine
(Madsen et al. 2002), thiomersal-containing vaccines (Parker et al.
2004), or repeated vaccination (DeStefano et al. 2013) causes
autism. While parents and some parental groups have voiced
concerns about the risk of vaccinations causing autism, these
studies have assiduously demonstrated a lack of causation.
Neurobiology
There are reports of changed brain growth trajectories in people
with ASD. In ASD, brain development may include a period of
overgrowth between ages 2 and 4 years, followed by normal or
decreased growth between 4 and 6 years of age; by adulthood the
brain volume is within normal range or decreased (Courchesne et al.
2011). Cortical and neuronal connectivity differences are being
studied; for the purpose of this review, we will not delve into the
minutiae of separate studies. There are no pathognomonic features
in children or adults with ASD on static or dynamic brain imaging or
from neuropathological studies performed at autopsy.
Clinical Presentation, Diagnosis, and Course

Individuals with ASD can present for clinical care at any point
during their development. Signs of autism are not reliably present at
birth but emerge through a process of diminishing, delayed, or
atypical development of social-communicative behaviors, starting
between the ages of 6 and 12 months. Symptoms are generally first
noted in the first 2 years of life. The age at onset and pattern of
onset of observed symptoms are important to make a proper
differential diagnosis. Some children with ASD experience a plateau
in their development or a regression with a gradual or relatively rapid
loss of social behaviors or language skills. The median age at
earliest confirmed ASD diagnosis has remained fairly constant, at
approximately 4.5 years (Centers for Disease Control and
Prevention 2014). Individuals with normal or high intellectual
capabilities are often diagnosed at older ages, as are females
(Begeer et al. 2013).
Common initial parental concerns include a child’s lack of
language or delay in language development or the possibility that the
child might be deaf. Delayed language development is often
accompanied by a lack of social interest or social responsiveness.
Early indicators are deficits or delays in the emergence of joint
attention (shared focus on an object) and pretend play, atypical
implicit perspective taking, deficits in reciprocal affective behavior,
decreased response to own name, decreased imitation, delayed
verbal and nonverbal communication, motor delay, unusually
repetitive behaviors, atypical visuomotor exploration, inflexibility in
disengaging visual attention, and extreme variation in temperament
(Lord et al. 2012).
Preschool children with autism often present with marked lack of
interest in others, absent or severely delayed speech and
communication, marked resistance to change, restricted interests,
and stereotyped movements. Distinguishing restricted and repetitive
behaviors diagnostic of ASD can be difficult to identify in young
children, who tend to naturally enjoy structure and predictability, and
must be based on the type, frequency, and intensity of the behavior
(e.g., a 3-year-old child who lines up colored blocks for hours and
becomes inconsolable when a parent or sibling tries to engage with
them by adding a block). In children with autism, social and
communication skills usually increase by school age. However,
problems dealing with change and transitions and various self-
stimulatory behaviors become more evident at this age. A small
proportion of individuals with ASD have behavioral deterioration
during adolescence.
In adults, symptoms of ASD often present with characteristics of
having difficulty in getting along with others, rigid adherence to
specific rules or habits, and narrow fields of interest or hobbies.
Frequently, the diagnosis has been overlooked because of attributing
behavioral characteristics to intellectual disability (diagnostic
overshadowing). In circumstances of normal and high intelligence,
ASD may be perceived (or tolerated) as personality quirks and
idiosyncratic behavior. For example, individuals may be comfortable
wearing only certain types of clothing, be sensitive to specific fabrics
or touch, insist on placement of objects in specific locations, or follow
specific routines. When these routines are disrupted, then prolonged
dysphoria, anger, or emotional or behavioral shutdown may occur.
Assessment
Specific practice recommendations have been published by the
American Academy of Neurology (Filipek et al. 2000), the American
Academy of Pediatrics (Johnson et al. 2007), and the American
Academy of Child and Adolescent Psychiatry (Volkmar et al. 2014).
These practice parameters recommend two levels of
screening/evaluation.
Level I screening involves routine developmental surveillance

by primary care physicians for young children. Routine early
screening at ages 18 and 24 months has been recommended by
the American Academy of Pediatrics (Johnson et al. 2007).
Level II evaluation involves a diagnostic assessment performed
by experienced clinicians. This involves obtaining a developmental
history from the parents; conducting a review of available records,
including medical, school, and interventions; and directly
observing and interacting with the child. Second-hand reporting is
not sufficient. Assessment of intellectual functioning, language,
and adaptive functioning is expected. Extensive evaluations may
include neuropsychological testing, tests of motor function,
evaluation of psychiatric and behavioral comorbidities, and
medical examination for physical anomalies, disorders of organ
system functioning, and genetic screening.
The current best practices standard diagnostic tool for gathering

information concerning symptoms of autism from parents is the
Autism Diagnostic Interview—Revised (ADI-R; Rutter 2003). The
current best practices standard diagnostic tool for an observational
and direct assessment of symptoms of autism is the Autism
Diagnostic Observation Schedule (ADOS; Lord et al. 2001), which
involves a semistructured interview specifically formatted in various
modules that are developmentally appropriate for persons from
infancy to adulthood and across a wide range of language and
functioning levels.
Medical assessment is needed to identify potential etiological and
comorbid factors, to determine the necessity for additional individual
and family assessment, and to guide treatment decisions. A careful
medical history, including prenatal, perinatal, postnatal, and early
childhood, is important to assess risk factors associated with ASD,
including maternal illness (e.g., gestational diabetes, infectious
illness, exposure to teratogens), low birth weight or prematurity, and
serious illness. Sleep disturbances and gastrointestinal symptoms
are important to inquire about, both as treatable causes of disruptive
behavior and as concomitant medical comorbidities. Family history
helps identify other family members with developmental, educational,
and social difficulties, as well as psychiatric disorders.
Direct physical and neurological examination should seek to
identify physical evidence of genetic syndromes highly associated
with ASD, such as fragile X syndrome or tuberous sclerosis;
abnormal neurological findings suggestive of central nervous system
insult; and/or sensory impairment such as hearing loss or visual
impairment. Growth parameters, including head circumference,
should be assessed. Referral for specific hearing or vision
assessment (more than bedside examination) is indicated if any
concerns are raised through the history or examination.
Blood testing for lead or other toxin exposure is appropriate if
environmental risk factors persist, especially if children persist in
mouthing objects. Chromosomal microarray is recommended as a
standard of care for all individuals diagnosed with ASD and or
developmental delay (Miller et al. 2010). Targeted genetic testing,
such as fragile X DNA or methyl–CpG-binding protein 2 gene
(MECP2) mutations in females with a clinical presentation consistent
with Rett’s disorder (acquired microcephaly, neurological regression,
and stereotypical hand movements), is recommended. Routine
magnetic resonance imaging and electroencephalography are not
recommended unless a person has clinically relevant symptoms
such as focal neurological signs, an examination suggestive of
tuberous sclerosis, or a history that is indicative of seizures (Johnson
et al. 2007).
Differential Diagnosis
ASD should be differentiated from other specific developmental
disorders (including language disorders), intellectual disability,
reactive attachment disorder, obsessive-compulsive disorder,
selective mutism, and childhood-onset schizophrenia. In adults, a
similar differential is in order, as well as concerns for obsessive-
compulsive disorder, fixed delusional syndrome, depression with
psychotic features, or personality disorder. An extended clinical
interview or observation, along with an independent reporter’s
observations, will clarify these differential differences in ability to
remain alert to current events, ways of interacting with known and
novel individuals and settings, and daily activities and energy.
In some forms of language disorder, there may be problems of
communication and subsequent social difficulties. Language disorder
is not usually associated with abnormal nonverbal communication or
with the presence of restricted, repetitive patterns of behavior,
interests, or activities. When an individual shows impairment in
social communication and social interaction without restricted and
repetitive behavior or interests, criteria for the new diagnosis in
DSM-5 of social (pragmatic) communication disorder may be met.
Intellectual disability without ASD may be difficult to differentiate in
very young children. Intellectual disability (across the life span) is the
appropriate diagnosis when the level of social-communicative skills
and other intellectual skills are without discrepancy.
Children with reactive attachment disorder may exhibit deficits in
attachment and therefore inappropriate social responsivity; these
improve substantially with adequate caretaking. Obsessive-
compulsive disorder has a later onset than ASD, is not typically
associated with social and communicative impairments, and is
characterized by repetitive patterns of behavior that are ego-
dystonic. Selective mutism can be differentiated from ASD through
careful interview with the parents/caretakers. Typically, in selective
mutism, early development is not disturbed and the child is verbal
with trusted individuals, social reciprocity is not impaired, and
restricted or repetitive patterns of behavior are not present.
Symptoms that characterize anxiety disorders, such as excessive
worry, the need for reassurance, the inability to relax, and feelings of
self-consciousness, are prevalent in ASD. ASD and anxiety disorder
can be differentiated by the prominent social and communicative
impairments seen in ASD but not in anxiety disorders and the
developed social insight of persons (children and adults) with anxiety
disorders, not seen in persons with ASD.
Schizophrenia of childhood onset usually develops after a period
of normal development. In schizophrenia, the prodromal state of
social impairments and atypical interests and beliefs could be
confused with the social deficits seen in ASD. Hallucinations and
delusions are not features of ASD. Thus, sometimes it takes
patience and perseverance to allow sufficient time to pass for the
diagnostic picture to become clear.
Comorbidity
ASD is frequently associated with a variety of disorders and
symptoms; estimates are that more than 70% of individuals with
autism have concurrent medical, developmental, or psychiatric
conditions. Childhood co-occurring conditions tend to persist into
adolescence (Simonoff et al. 2013). Some conditions, such as
epilepsy or depression, first develop in adolescence or adulthood.
The question about correlation or causation of comorbid conditions is
not easily answered. For example, there are two peak periods of
epilepsy emergence: early childhood and adolescence, affecting
20%–25% of people with ASD. Treatment of epileptic symptoms
does not repair autistic behaviors; behavioral interventions or
medications for autistic behavior do not affect seizure frequency or
severity. However, reduction of stressors and reduction in stress
responses will reduce seizure frequency and intensity, as well as
severity of autistic reactive behavior.
Children and adolescents with autism have an increased risk for
accidental death (e.g., drowning). It appears this is due in part to the
inability to generalize patterns of risk across situations. The
experience of parents and adult caregivers is therefore of feeling like
they are “catching up” to new situations continually.
The most common comorbid conditions within the ASD population
include intellectual disability, seizure disorder, hyperactivity, anxiety
disorders, and depressed mood (Leyfer et al. 2006). When
intellectual impairment or structural language disorder is present, it
should be noted under the relevant diagnostic specifiers. When
criteria are met for ASD and other concurrent diagnoses, such as
anxiety disorders, attention-deficit/hyperactivity disorder (ADHD),
and depressive disorders, all diagnoses should be listed. Other
common comorbidities include gastrointestinal symptoms (Buie et al.
2010), tics, aggression, and problems with sleep and appetite.
Specific learning difficulties, as well as developmental coordination
disorder, are common; usually, these are more evident in children.
Avoidant/restrictive food intake disorder is a frequent feature of ASD,
and extreme and narrow food preferences may persist throughout
life. Disconcerting as it may be, sudden change in food preference is
also common, with retention of a very narrow range of choice.
Among individuals who are nonverbal or have language deficits,
observable signs, such as changes in sleep or eating or increases in
challenging behavior, that persist for days to weeks should trigger an
evaluation for anxiety or depression (American Psychiatric
Association 2013).
Research
Studies demonstrating that early intensive interventions promoted
improved (even optimal) outcomes in ASD have spurred further
research to try to find the earliest possible identifiable markers and
symptoms for diagnosing autism so that treatment interventions
could begin earlier. Studies of siblings of probands identified at an
early age could potentially help to distinguish early behavioral and
neural predictors of emerging autism (Samadi et al. 2012). Examples
of potential predictors of a subsequent autism diagnosis are poor
attention to social scenes or human faces at age 6 months
(Chawarska et al. 2013), little infant-parent interaction at age 12
months (Wan et al. 2013), and reduced flexibility in control of visual
attention or orientation (disengagement) at ages 7 months (Elison et
al. 2012; Wolff et al. 2012) and 14 months (Singhi and Malhi 2001).
Abnormalities in brain response when infants view faces with
dynamic eye gaze at ages 6–10 months (measured by event-related
potential) predict an autism diagnosis at 36 months (Elsabbagh and
Johnson 2010). The developmental trajectory of white-matter-tract
organization from ages 6 to 24 months predicts diagnosis at 24
months (Wolff et al. 2012), although clinicians do not usually have
access to such investigative imaging. Some siblings who are at high
risk for autism yet who do not meet criteria for a diagnosis of autism
by age 3 years have residual signs of delay in development and
more autistic-like behavioral responses than siblings at low risk.
These clinical patterns highlight the need for continued early
developmental monitoring and developmentally appropriate early
interventions for at-risk siblings. Enhanced interpersonal interactive
training may help foster the normal developmental repertoire of
behavior to achieve adolescent and adult functioning without
noticeable impairments.
Support, Interventions, and Treatment

The multiple developmental and behavioral problems associated
with ASD necessitate multidisciplinary care, coordination of services,
and advocacy for individuals and their families. Individuals vary
significantly in their strengths and needs related to core ASD
symptoms and other areas of development that may be affected by
autism. Behavioral interventions are the most successful approaches
for treating core symptoms and improving functional outcomes in
individuals with ASD. The initial diagnosis of ASD in childhood
should be followed by validated behavioral treatments as soon as
possible. All states in the United States have publicly funded
services for children ages 0–3 years with developmental difficulties
and do not require a specific medical diagnosis for the child to begin
access. Sustained intervention is expected to be needed over the life
span, with enhanced monitoring during times of transition (e.g.,
transition from early childhood programs to public school
preschool/kindergarten, from elementary school to middle school,
and from adolescence to adulthood).
A common dilemma is knowing how much and what type of
intervention to seek to provide the best outcomes. Practitioners and
parents may access listings of systematically reviewed effective
interventions and educational strategies. Intervention decisions and
recommendations should include consideration of each individual’s
unique presentation, including specific strengths and needs,
individual and family values and preferences, and available family
and community resources. Two early intervention approaches that
exceed others based on quality of research and outcomes include
Lovaas’s Early Intensive Behavioral Intervention (Lovaas 1987) and
the Early Start Denver Model (Dawson et al. 2010).
Lovaas’s approach involves several years of intensive (35–40
hours per week) one-on-one intervention, carried out in the home by
trained paraprofessionals and closely supervised by a senior
therapist certified in the model. The Early Start Denver Model was
designed for toddlers and was tested on children from 18 to 30
months of age, has a manual and curriculum that follow typical
sequences in early childhood developmental areas, and is based on
developmental science. The Denver approach focuses on dyadic,
responsive, developmentally specified joint play and activity routines
between adult and child, in which individualized and specified
teaching opportunities are embedded in play. The trained adult’s
ability to stimulate and support the targeted skills in the child and
reward the child within the play, using the intrinsic reward value of
the activity itself, follows the principles of applied behavior analysis.
The Early Start Denver Model approach can be delivered by many
different persons, including parents after specific training. In a
randomized controlled trial, children who received up to 20 hours per
week of the Early Start Denver Model of one-on-one instruction in
their homes from a trained person, as well as five or more hours per
week of instruction from their parents (also trained), showed large
and significant gains in IQ, language, and adaptive behavior
compared with the control group, who received a community
intervention (Dawson et al. 2010).
Applied behavior analysis is especially useful when maladaptive
behaviors interfere with provision of a comprehensive intervention
program. A functional analysis of the maladaptive behavior is
performed, in which patterns of reinforcement are identified and then
various behavioral techniques are used to promote a desired
behavioral alternative. Applied behavior analysis has been found to
be effective for specific problem behaviors (Campbell 2003),
academic tasks (Koegel et al. 2009), adaptive living skills (LeBlanc
et al. 2003), social skills (Pierce and Schreibman 1997),
communication (Jones et al. 2007), and vocational skills (Lattimore
et al. 2006). Because most individuals with autism tend to learn in
isolation, a focus on generalization of learned skills is important
(Foxx 2008). This deficit in learning can be subtle or very wide-
ranging and is evident irrespective of general intelligence (based on
clinical observation).
Many individuals with ASD process information more readily and
reliably through visual processing rather than auditory processing.
This is consistent with a high sensitivity to auditory stimuli and high-
pitched or loud noises, the ability to sense very quiet noises that are
ignored by other people, and experience of the startle response to
rapid visual (light) stimuli. Behavioral approaches can use these
processing preferences to communicate desired activities (e.g., lists
of daily self-care steps, pictures of activity choices) and to alter the
environment to provide opportunities to decrease multisensory
stimulation (e.g., quiet rooms, rocking chairs, deep massage).
Medication
At present, there are no medications that effectively treat the core
symptoms of autism. However, medications are used commonly to
treat comorbid emotional and behavioral symptoms. There have
been multiple randomized controlled trials on the effects of
risperidone in children with ASD, the largest being the federally
funded study of 101 children by the Research Units on Pediatric
Psychopharmacology (McCracken et al. 2002; McDougle et al.
2005). Risperidone reduces irritability and hyperactivity and may
reduce repetitive behavior and stereotypy. The combination of
risperidone and parent home training was found to provide better
efficacy than risperidone or parent home training alone (Aman et al.
2009). The systematic review by Siegel and Beaulieu (2012),
specific to autism research, found that aripiprazole reduced
irritability, hyperactivity, and stereotypy in children with autistic
disorder. Typical neuroleptics have been effective at reducing
severe, refractory negative behaviors in children and adults.
Treatment of comorbid conditions such as ADHD require
concurrent treatment. Smaller doses of methylphenidate were found
to be better tolerated, and seemed to have a greater effect, in
children with ASD without intellectual impairment compared with
those with intellectual impairment (McCracken et al. 2002; McDougle
et al. 2005). Preliminary evidence of efficacy includes treatment with
naltrexone and atomoxetine for hyperactivity, risperidone for
repetitive behavior and stereotypy, and pentoxifylline in combination
with risperidone for irritability and social withdrawal (Siegel and
Beaulieu 2012). Atypical antipsychotics cause metabolic changes
and may induce metabolic syndrome; it is recommended that
providers monitor fasting glucose, lipid, and triglyceride levels.
Additional risk factors that should be discussed include the
movement symptoms of dystonia, akathisia, and tardive dyskinesia.
Risperidone may also cause prolactinemia and gynecomastia.
Selective serotonin reuptake inhibitors were found not to be
efficacious in treating repetitive behaviors, but clinically they have
proven helpful in diminishing anxiety (although this has not been
definitively studied).
There is widespread interest in, and use of, complementary and
alternative medicines by parents of children with ASD and by
individuals with ASD. The hormone melatonin works to synchronize
diurnal cortisol levels, helping to regularize sleep. The long-acting
formulation of melatonin may show efficacy for sleep maintenance in
individuals with autism (Akins et al. 2010). Oxytocin is viewed as a
potential therapeutic agent for facilitating social cognition in ASD,
based on preliminary trials (Hollander et al. 2007).
Conclusion
ASD is a widespread spectrum disorder that demonstrates the
importance of sensory system integration to interacting comfortably
and effectively with our environments. Integrating our sensory
perceptions with motor and emotional responses is part of normal
development and an adaptation that is needed for all humans to
function. When we recognize that difficulties in this process are
limiting an individual’s ability to function effectively, our motivation to
influence and nurture the natural plasticity of the nervous system
should be encouraged. Diagnostic criteria change over time to
enhance communication and reflect advancements in our
understanding of disorders such as autism. Pharmacotherapy should
be used as sparingly as is possible, as there are no targeted ASD-
specific treatments identified or available as of this writing. ASD
occurs across the spectrum of cognitive intelligence. Affecting
peoples’ social and communication abilities, ASD has a direct impact
on their efficacy interacting with other members of their species.
Respecting, valuing, and including people with ASD in the entire
community will provide important openings for their abilities and
strengths to be appreciated and their disabilities to be less of an
impediment to participation. The types and intensity of supports
needed to achieve optimal daily and lifelong functioning are
expected to change over the life span as different challenges and
expectations confront these individuals in their daily lives. It is
incumbent upon the astute clinician to bear this in mind when
preparing to reevaluate his or her diagnoses and treatment
approaches.
References
Abrahams BS, Geschwind DH: Advances in autism genetics: on the threshold of a
new neurobiology. Nat Rev Genet 9(5):341–355, 2008 18414403
Akins RS, Angkustsiri K, Hansen RL: Complementary and alternative medicine in
autism: an evidence-based approach to negotiating safe and efficacious
interventions with families. Neurotherapeutics 7(3):307–319, 2010 20643384
Aman MG, McDougle CJ, Scahill L, et al; Research Units on Pediatric
Psychopharmacology Autism Network: Medication and parent training in
children with pervasive developmental disorders and serious behavior
problems: results from a randomized clinical trial. J Am Acad Child Adolesc
Psychiatry 48(12):1143–1154, 2009 19858761
Disorders, 3rd Edition. Washington, DC, American Psychiatric Association,
1980
Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric
Association, 1987
1994
Disorders, 4th Edition, Revised. Washington, DC, American Psychiatric
Association, 2000
Asperger H: ’Autistic psychopathy’ in childhood, in Autism and Asperger
Syndrome. Edited by Frith U. New York, Cambridge University Press, 1991, pp
37–92
Bailey A, Le Couteur A, Gottesman I, et al: Autism as a strongly genetic disorder:
evidence from a British twin study. Psychol Med 25(1):63–77, 1995 7792363
Barger BD, Campbell JM, McDonough JD: Prevalence and onset of regression
within autism spectrum disorders: a meta-analytic review. J Autism Dev Disord
43(4):817–828, 2013 22855372
Begeer S, Mandell D, Wijnker-Holmes B, et al: Sex differences in the timing of
identification among children and adults with autism spectrum disorders. J
Autism Dev Disord 43(5):1151–1156, 2013 23001766
Buie T, Campbell DB, Fuchs GJ III, et al: Evaluation, diagnosis, and treatment of
gastrointestinal disorders in individuals with ASDs: a consensus report.
Pediatrics 125(Suppl 1):S1–S18, 2010 20048083
Campbell JM: Efficacy of behavioral interventions for reducing problem behavior in
persons with autism: a quantitative synthesis of single-subject research. Res
Dev Disabil 24(2):120–138, 2003 12623082
Centers for Disease Control and Prevention: Prevalence of autism spectrum
disorder among children aged 8 years—Autism and Developmental Disabilities
Monitoring Network, 11 Sites, United States, 2010, MMWR Surveillance
Summaries. March 28, 2014. Available at:
http://www.cdc.gov/mmwr/pdf/ss/ss6302.pdf. Accessed November 15, 2016.
Chawarska K, Macari S, Shic F: Decreased spontaneous attention to social
scenes in 6-month-old infants later diagnosed with autism spectrum disorders.
Biol Psychiatry 74(3):195–203, 2013 23313640
Courchesne E, Campbell K, Solso S: Brain growth across the life span in autism:
age-specific changes in anatomical pathology. Brain Res 1380:138–145, 2011
20920490
Dawson G, Rogers S, Munson J, et al: Randomized, controlled trial of an
intervention for toddlers with autism: the Early Start Denver Model. Pediatrics
125(1):e17–e23, 2010 19948568
DeStefano F, Price CS, Weintraub ES: Increasing exposure to antibody-stimulating
proteins and polysaccharides in vaccines is not associated with risk of autism.
J Pediatr 163(2):561–567, 2013 23545349
Elison JT, Sasson NJ, Turner-Brown LM, et al: Age trends in visual exploration of
social and nonsocial information in children with autism. Res Autism Spectr
Disord 6(2):842–851, 2012 22639682
Elsabbagh M, Johnson MH: Getting answers from babies about autism. Trends
Cogn Sci 14(2):81–87, 2010 20074996
Elsabbagh M, Divan G, Koh YJ, et al: Global prevalence of autism and other
pervasive developmental disorders. Autism Res 5(3):160–179, 2012 22495912
Filipek PA, Accardo PJ, Ashwal S, et al: Practice parameter: screening and
diagnosis of autism: report of the Quality Standards Subcommittee of the
American Academy of Neurology and the Child Neurology Society. Neurology
55(4):468–479, 2000 10953176
Fonbonne E: Epidemiology of pervasive developmental disorders, in Autism
Spectrum Disorders. Edited by Amaral D, Dawson G, Geschwind DH. New
Foxx RM: Applied behavior analysis treatment of autism: the state of the art. Child
Adolesc Psychiatr Clin N Am 17(4):821–834, 2008
Hertz-Picciotto I, Croen LA, Hansen R, et al: The CHARGE study: an
epidemiologic investigation of genetic and environmental factors contributing to
autism. Environ Health Perspect 114(7):1119–1125, 2006 16835068
Hollander E, Bartz J, Chaplin W, et al: Oxytocin increases retention of social
cognition in autism. Biol Psychiatry 61(4):498–503, 2007 16904652
Johnson CP, Myers SM; American Academy of Pediatrics Council on Children
With Disabilities: Identification and evaluation of children with autism spectrum
disorders. Pediatrics 120(5):1183–1215, 2007 17967920
Jones EA, Feeley KM, Takacs J: Teaching spontaneous responses to young
children with autism. J Appl Behav Anal 40(3):565–570, 2007 17970271
Kanner L: Autistic disturbances of affective contact. Nervous Child 2:217–250,
1943
Koegel RL, Vernon TW, Koegel LK: Improving social initiations in young children
with autism using reinforcers with embedded social interactions. J Autism Dev
Disord 39(9):1240–1251, 2009 19357942
Lai MC, Lombardo MV, Baron-Cohen S: Autism. Lancet 383(9920):896–910, 2014
24074734
Lattimore LP, Parsons MB, Reid DH: Enhancing job-site training of supported
workers with autism: a reemphasis on simulation. J Appl Behav Anal 39(1):91–
102, 2006 16602388
LeBlanc LA, Coates AM, Daneshvar S, et al: Using video modeling and
reinforcement to teach perspective-taking skills to children with autism. J Appl
Behav Anal 36(2):253–257, 2003 12858990
Leyfer OT, Folstein SE, Bacalman S, et al: Comorbid psychiatric disorders in
children with autism: interview development and rates of disorders. J Autism
Dev Disord 36(7):849–861, 2006 16845581
Lord C, Leventhal BL, Cook EH Jr: Quantifying the phenotype in autism spectrum
disorders. Am J Med Genet 105(1):36–38, 2001 11424991
Lord C, Petkova E, Hus V, et al: A multisite study of the clinical diagnosis of
different autism spectrum disorders. Arch Gen Psychiatry 69(3):306–313, 2012
22065253
Lovaas OI: Behavioral treatment and normal educational and intellectual
functioning in young autistic children. J Consult Clin Psychol 55(1):3–9, 1987
3571656
Madsen KM, Hviid A, Vestergaard M, et al: A population-based study of measles,
mumps, and rubella vaccination and autism. N Engl J Med 347(19):1477–1482,
2002 12421889
McCracken JT, McGough J, Shah B, et al: Risperidone in children with autism and
serious behavioral problems. N Engl J Med 147(5):314–321, 2002 12151468
McDougle CJ, Scahill L, Aman MG, et al: Risperidone for the core symptom
domains of autism: results from the study by the autism network of the
research units on pediatric psychopharmacology. Am J Psychiatry
162(6):1142–1148, 2005 15930063
Miller DT, Adam MP, Aradhya S, et al: Consensus statement: chromosomal
microarray is a first-tier clinical diagnostic test for individuals with
developmental disabilities or congenital anomalies. Am J Hum Genet
86(5):749–764, 2010 20466091
Parker SK, Schwartz B, Todd J, et al: Thimerosal-containing vaccines and autistic
spectrum disorder: a critical review of published original data. Pediatrics
114(3):793–804, 2004 15342856
Pierce K, Schreibman L: Multiple peer use of pivotal response training to increase
social behaviors of classmates with autism: results from trained and untrained
peers. J Appl Behav Anal 30(1):157–160, 1997 9103991
Reichenberg A, Gross R, Sandin S, et al: Advancing paternal and maternal age
are both important for autism risk. Am J Public Health 100(5):772–773; author
reply 773, 2010 20299637
Rutter M: Diagnosis and definition of childhood autism. J Autism Child Schizophr
8(2):139–161, 1978 670129
Rutter M: Introduction: autism—the challenges ahead. Novartis Found Symp
251:1–9; discussion 109–111, 281–197, 2003
Samadi SA, Mahmoodizadeh A, McConkey R: A national study of the prevalence
of autism among five-year-old children in Iran. Autism 16(1):5–14, 2012
21610190
Siegel M, Beaulieu AA: Psychotropic medications in children with autism spectrum
disorders: a systematic review and synthesis for evidence-based practice. J
Autism Dev Disord 42(8):1592–1605, 2012 22068820
Simonoff E, Jones CR, Baird G, et al: The persistence and stability of psychiatric
problems in adolescents with autism spectrum disorders. J Child Psychol
Psychiatry 54(2):186–194, 2013 22934711
Singhi P, Malhi P: Clinical and neurodevelopmental profile of young children with
autism. Indian Pediatr 38(4):384–390, 2001 11313510
Surén P, Roth C, Bresnahan M, et al: Association between maternal use of folic
acid supplements and risk of autism spectrum disorders in children. JAMA
309(6):570–577, 2013 23403681
Volkmar F, Siegel M, Woodbury-Smith M, et al; American Academy of Child and
Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI): Practice
parameter for the assessment and treatment of children and adolescents with
autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 53(2):237–257,
2014 24472258
Wan MW, Green J, Elsabbagh M, et al; BASIS Team: Quality of interaction
between at-risk infants and caregiver at 12–15 months is associated with 3-
year autism outcome. J Child Psychol Psychiatry 54(7):763–771, 2013
23227853
Wolff JJ, Gu H, Gerig G, et al; IBIS Network: Differences in white matter fiber tract
development present from 6 to 24 months in infants with autism. Am J
Psychiatry 169(6):589–600, 2012 22362397
CHAPTER 8
Delirium
Delirium has been recognized for thousands of years. The origins

of the word trace back to the Latin delirare, literally meaning to “go
off the furrow” (de “off, away from”+lira “earth thrown up between two
furrows”) and metaphorically referring to a state of deviation or
derangement. As early as 500 B.C., the terms phrenitis and delirium
were used to denote mental changes associated with fever, head
trauma, or poisoning. Hippocrates’ writings reference phrenitis and
lethargus to distinguish between what are now recognized as the two
major subtypes of delirium, hyperactive and hypoactive, respectively.
Formalized diagnostic criteria were eventually established and
published in DSM-III (American Psychiatric Association 1980).
The essential feature of delirium, inattention, has remained
consistent over the years; however, the secondary features have
changed as the conceptualization of delirium has evolved. At the
present time, the Diagnostic and Statistical Manual of Mental
Disorders (DSM) and International Classification of Diseases (ICD)
provide generally accepted criteria for the diagnosis of delirium.
Although the two systems are similar in their established diagnostic
criteria, DSM-5 (American Psychiatric Association 2013) tends to be
more inclusive than ICD-10 (World Health Organization 1992), which
can complicate the comparison of epidemiological data (Neufeld and
Thomas 2013). Criticism of these classification systems includes the
dichotomous nature of diagnosis, lack of minimum thresholds for
presence of symptoms, and lack of clarity regarding the duration of
symptoms (Davis et al. 2013). Table 8–1 compares these two
classification systems and organizes the diagnostic criteria into
primary features, secondary features, and exclusionary criteria.
TABLE 8–1. Comparison of DSM-5 and ICD-10 diagnostic criteria for
delirium
DSM-5 ICD-10
Core features Disturbance in attention and Clouding of consciousness
awareness
Develops over a short Disturbance of cognition,
period of time with impairment of both
(represents a change immediate recall and
from baseline) recent memory (but
relatively intact remote
memory) and
disorientation
Tends to fluctuate in Rapid onset and
severity over the course fluctuations of symptoms
of a day over the course of the
day
Secondary Disturbance in cognition Psychomotor disturbance
features
Evidence that the Disturbance of sleep or the
disturbance is a direct sleep-wake cycle
physiological Evidence of an underlying
consequence of another
cerebral or systemic
medical condition or
substance/toxin disease that can be
intoxication or presumed to be
withdrawal, or is due to responsible for the
multiple etiologies
manifestations
Exclusions Not better explained by Not induced by alcohol and
another preexisting or other psychoactive
evolving neurocognitive substances
disorder
Source. American Psychiatric Association 2013; World Health Organization
1992.
Epidemiology
Studies of delirium are confounded by its fluctuating course, which
is best captured through longitudinal studies and period-prevalence
measurements; the application of traditional cross-sectional study
methods therefore constitutes a major limitation of many studies of
delirium (Davis et al. 2013). Additionally, interpretation is complicated
by the evolution of diagnostic criteria and the myriad instruments
used in studies to identify delirium. Furthermore, early studies
evaluating the epidemiology of delirium failed to divide the population
into cohorts; instead, data were gathered from diverse inpatient
populations, yielding wide ranges in delirium prevalence. More
clinically and conceptually useful information has been obtained by
looking at subpopulations and appreciating the significance of
various statistical findings given the fluctuating nature of the
condition.
In outpatient communities, the point prevalence of delirium in
older adults is relatively low, at 1%–2%, but a higher prevalence is
found as age increases or with preexisting dementia (Davis et al.
2013; Hasegawa et al. 2013). Indeed, among older adults with
dementia living in the community, the total prevalence of delirium
neared 20% and the incidence was over 50% (Inouye et al. 2014).
The etiology of dementia appears to influence the prevalence of
delirium, as the prevalence among individuals with vascular
dementia or dementia with Lewy bodies was over 30%, which was
double that among individuals with Alzheimer’s dementia (Hasegawa
et al. 2013).
In hospitalized patients, the prevalence varies substantially by
clinical location and population. In the emergency department (ED),
10% of older adults have delirium, unless they are presenting from
nursing homes, in which case the prevalence nears 40% (Inouye et
al. 2014). Among general medicine inpatients of all ages, the
prevalence ranges from 18% to 35%, with a 15% incidence (Inouye
et al. 2014). The incidence increases to 30% when older adults
admitted to geriatric or general medicine units are evaluated (Inouye
et al. 2014). Nearly 15% of patients on a stroke unit experienced
delirium during a 1-week period, and among the hospitalized
poststroke population, the incidence ranges from 10% to 27%
(Inouye et al. 2014; Oldenbeuving et al. 2011). On an inpatient
palliative care unit, the prevalence of delirium was over 40% and the
incidence was 45%, resulting in nearly 90% of patients experiencing
delirium prior to death (Lawlor et al. 2000). In the post–acute care or
nursing home setting, the data pooled from several studies revealed
a prevalence of delirium around 15%, with an incidence of 20%
(Inouye et al. 2014).
Among surgical patients, the prevalence and incidence ranges
widely depending on age of the patient, type of surgery or procedure,
and the nature of the surgery (i.e., elective, nonelective, or
traumatic). Postoperative hospitalized orthopedic patients have a
nearly 20% prevalence of delirium, with an incidence ranging from
about 10% to 50% depending on the type of procedure, age of the
patient, and whether the surgery was elective or not (Inouye et al.
2014). Incidence of delirium ranges from 10% to 50% among other
postoperative hospitalized surgical patients (Inouye et al. 2014).
It is well established that delirium is common in the intensive care
unit (ICU). A unique study found that the 1-day point prevalence of
delirium in more than 100 adult ICUs across 11 countries was 33%
(Salluh et al. 2010). Among the adult ICU population, the prevalence
of delirium is as high as 50%, whereas the incidence can be as high
as 80%, with the prevalence and incidence among those intubated
and sedated at the higher ends of these values (Inouye et al. 2014).
The data on the frequency of delirium in children and adolescents
are extremely limited and are mostly limited to the pediatric ICU
setting. The overall prevalence in pediatric critical care is estimated
to be 20% (Traube et al. 2014). The psychiatric consultation-liaison
referrals for delirium from the pediatric ICU ranged from 17% to 66%
and constituted 10% of all inpatient child-adolescent referrals to
psychiatry (Hatherill and Flisher 2010).
Delirium is an exceptionally common neuropsychiatric condition.
Delirium is most common among older adults; those with preexisting
brain pathology, such as dementia; and individuals in the ICU.
Because of the circumstances of delirium’s onset and the nature of
its course, separating prevalence and incidence is of value, as the
true frequency might otherwise be overlooked.
Clinical Features and Presentation

Delirium is a disorder of attention, which is generally understood
to be an impaired or reduced ability to focus, sustain, or shift
attention. A frequent feature that characterizes delirium is
disorientation, also referred to as a disturbance in awareness. Sleep-
wake cycle disturbances are exceedingly common and occur in over
90% of delirious patients, whereas hallucinations or illusions are
identified in less than half of cases (Leonard et al. 2011). Other
common features include affective lability, motor abnormalities, and
visuospatial abnormalities, as well as impairment in memory,
language, and thought process (Leonard et al. 2011). Symptoms are
generally the same in children and adolescents; however, more rapid
acuity of onset, hallucinations, irritability, affective lability, and
agitation tend to be more common, whereas delusions, speech
disturbance, and memory deficits are less frequent (Hatherill and
Flisher 2010).
Delirium Subtypes
Delirium can be classified into subtypes based on motoric activity.
Three motor subtypes are generally recognized: hyperactive,
hypoactive, and mixed. Motor subtype influences detection,
outcome, and possibly etiology. Furthermore, increased dopamine
seems to be implicated in the pathophysiology of hyperactive
delirium, whereas decreased acetylcholine appears to be associated
with the hypoactive subtype (Meagher 2009b). Despite the
significant differences in motor features, the subtypes display similar
cognitive profiles along the domains of inattention, memory deficits,
and disorganized thinking (Leonard et al. 2011).
After much inconsistency in the motor subtyping, the Delirium
Motor Checklist (DMC; Meagher et al. 2009b) was developed to
capture the numerous elements that had been used to define motor
subtypes. Using the DMC and further studies to identify statistically
unique symptoms to each subtype, definitions of motor subtypes
were established (Figure 8–1; Meagher et al. 2008). Hyperactive
delirium often manifests as agitation, restlessness, wandering,
insomnia, and distractibility, whereas hypoactive delirium is
characterized by slowness of movements, decreased amount and
speed of speech, listlessness, hypersomnia, and withdrawal or
reduced alertness (Meagher 2009b). Additional symptoms of
delirium may include, irritability, combativeness, apathy, paranoia,
hallucinations, and delusions. Because of the obvious nature of
symptoms in hyperactive delirium, this subtype of delirium is more
readily identified than hypoactive delirium. The definition of the
mixed subtype varies based on source. The DSM-5 mixed subtype
description includes both those with rapidly fluctuating symptoms,
often oscillating from hyperactive to hypoactive symptoms, and those
with no motoric activity changes (Leonard et al. 2011). It is worth
noting that the hyperactive and mixed subtypes of delirium may be
associated with worse scores on symptom severity measures
because behavioral symptoms are more easily recognizable and
many severity measures are biased toward hyperactive behaviors,
yet there is evidence to support that hypoactive delirium is
associated with worse outcomes, including development of
decubitus ulcers and death (Meagher et al. 2011; Robinson et al.
2011).
FIGURE 8–1. Data-based definition of motor subtypes.
Source. Reprinted from Meagher D, Moran M, Raju B, et al: “A new data-based
motor subtype schema for delirium.” Journal of Neuropsychiatry and Clinical
Neurosciences 20(2):185–193, 2008. Copyright © 2008 American Psychiatric
Association. Used with permission.
Motor subtype frequency varies across populations. Each subtype
—hyperactive, hypoactive, and mixed—accounts for approximately
one-third of delirium cases among elderly medical inpatients;
however, in the ICU, only 1% of cases are hyperactive, with
hypoactive delirium being significantly more common (Meagher
2009b). Among elderly postoperative patients, hypoactive delirium
accounts for 70% of cases compared with hyperactive delirium,
which accounts for only 1% of cases (Robinson et al. 2011). Yet
presumably because of a strong selection bias in referrals, nearly
60% of psychiatry consultation-liaison patients with delirium manifest
the hyperactive subtype (Meagher 2009b).
Course of Delirium and Subsyndromal Delirium

Delirium has been described as having an acute onset followed
by rapid resolution, although this course is not supported by
longitudinal studies. Instead, the course of delirium is much more
varied, with some courses displaying a subacute onset with a
prodromal period and eventual gradual resolution of at least most
symptoms. Following a course of delirium in the hospital, symptoms
persist in nearly half of patients at the time of hospital discharge and
continue to persist in 33% and 21% of patients at 1 and 6 months
postdischarge, respectively (Cole 2010; Siddiqi et al. 2006). Patients
admitted to post–acute care with delirium may have especially
protracted symptoms, with more than one-half demonstrating
symptom persistence at 1 month and one-third at 6 months after an
acute episode (Anderson et al. 2012; Kiely et al. 2009). Among
patients who develop delirium in a long-term care setting, such as a
nursing home, over 90% of individuals manifest a prodrome or
lingering of delirium symptoms for up to several weeks surrounding
the delirious episode (Cole et al. 2012). Indeed, subacute onset and
gradual resolution of symptoms may actually be the norm.
Despite the existing dichotomous classification systems, delirium
is a spectrum disorder, with subsyndromal delirium (SSD) falling
between DSM-defined delirium and no symptoms of delirium
(Adamis et al. 2010). SSD has inattention as a central feature. It is
often identified as the presence of a subthreshold number of features
on the Confusion Assessment Method (CAM), the Delirium Rating
Scale—Revised–98 (DRS-R-98), or the Intensive Care Delirium
Screening Checklist (ICDSC) (Meagher et al. 2014). Although
frequently preceding or following a course of frank delirium, SSD
sometimes does not develop into a full-blown delirious episode. SSD
is common, shares risk factors with delirium, and has outcomes that
are intermediate between those with and without delirium (Cole et al.
2013).
Outcomes
Mortality
Delirium is strongly associated with multiple adverse outcomes.
Perhaps most notable is the increased risk of death during
hospitalization and in the following several months to years. Among
patients on a general medicine unit who develop delirium, in-hospital
mortality is about 30%, with the risk of death increased 1.5–5 times
during the following year and persisting elevated risk of death noted
for up to 2 years following hospitalization (Leslie and Inouye 2011;
Witlox et al. 2010).
Delirium in the ICU increases risk of in-hospital death
approximately threefold (Salluh et al. 2010). The risk of in-hospital
mortality among stroke patients with delirium was found to be
doubled (Oldenbeuving et al. 2011). Older patients with delirium who
presented to the ED had increased 30-day mortality (Kennedy et al.
2014). In the post–acute care setting, delirium at admission is
associated with a nearly threefold greater likelihood of mortality at 1
year (Kiely et al. 2009).
Morbidity
Complication rates, length of hospital stays, and rates of
institutionalization are also increased by the presence of delirium.
Medical inpatients with delirium experienced an increased length of
hospital stay and increased rate of institutionalization following
hospitalization (Siddiqi et al. 2006). Delirium in the ICU is associated
with increased length of ICU stay and increased total length of
hospitalization (Salluh et al. 2010). During hospitalization, nearly
25% of elderly patients with postoperative delirium experienced in-
hospital adverse outcomes such as pulling out lines or tubes, falling,
or developing pressure ulcers (Robinson et al. 2011). Elderly
patients with delirium admitted through the ED experienced longer
stays, were more likely to require ICU admission, were four times
more likely to be discharged to a new long-term-care facility, and
were twice as likely to be rehospitalized within 30 days as those
admitted through the ED without delirium (Kennedy et al. 2014).
Stroke patients who experienced delirium had increased days of
hospitalization and were two times more likely to experience
unfavorable outcomes (Oldenbeuving et al. 2011). Impairments in
activities of daily living (ADL) are present in more than 30% of
patients who experienced ICU delirium at 3 months after
hospitalization (Jackson et al. 2014). Furthermore, both increased
severity and longer duration of delirium episode are associated with
worse outcomes, including in-hospital functional decline, posthospital
cognitive decline, and greater 1-year mortality (Davis et al. 2013;
Inouye et al. 2014). Continued symptoms of delirium in post–acute
care settings were associated with the presence and increased
number of comorbid geriatric syndrome complications (Anderson et
al. 2012; Kiely et al. 2009).
Neuropsychiatric Morbidity
Only recently are the psychiatric sequelae of delirium being
recognized. Approximately 50% of patients can recall their delirious
episode, and many remain distressed by their memories several
months later (O’Malley et al. 2008). Psychiatric sequelae of ICU
delirium, specifically posttraumatic stress disorder (PTSD) and
depression, can be particularly long-lasting and functionally
impairing. Notably, in a prospective multicenter cohort study, PTSD
and depressive symptoms after ICU hospitalization were present in
7% and 30% of survivors of ICU delirium, respectively, up to 1 year
after the index episode of delirium (Jackson et al. 2014). It is
theorized that the fear associated with hallucinations and delusions
experienced during delirious states may result in PTSD.
There is an association between delirium and long-term cognitive
impairment, including dementia. It is theorized that delirium may
serve as a noxious event that aggravates or activates the
neurobiological disturbances that underlie dementia (Meagher
2009a). Among patients who experienced delirium, there is an
increased risk of incident dementia for at least 2 years following a
delirious episode when compared with matched control subjects
(Maclullich et al. 2013; Witlox et al. 2010). These findings are most
apparent in the ICU population, with over 50% of patients who
experienced delirium yielding global cognition scores similar to those
of patients with moderate traumatic brain injury or mild Alzheimer’s
dementia at 12 months after hospitalization (Pandharipande et al.
2013). In patients with preexisting Alzheimer’s dementia, risk of
cognitive decline and speed of cognitive decline are increased with
an episode of delirium (Hasegawa et al. 2013). The boundary
between persistent SSD and chronic cognitive impairment is unclear
and needs further study.
Financial Cost
The economic consequences of delirium are substantial. It is
estimated that delirium contributes $38–$152 billion annually in
health-related costs in the United States (2005 nominal dollars;
Neufeld and Thomas 2013). Increased delirium severity is
associated with greater in-hospital care costs (Inouye et al. 2014).
The 1-year postdischarge health care costs of delirium—inclusive of
inpatient, outpatient, nursing home, and home health care,
rehabilitation, and other services—range from $16,000 to $64,000
(2005 nominal dollars) per non–intensive care patient who
experienced delirium (Leslie and Inouye 2011). One factor
contributing to these costs is the functional impairment that results
from delirium, often necessitating an increased level of care upon
hospital discharge.
Risk Factors and Prevention
Risk Factors
Like many acute medical conditions, risk for development of
delirium can be conceptualized as a host vulnerability–insult severity
paradigm. In this vulnerability-insult model, the host’s cognitive
vulnerability influences the insult burden necessary to precipitate
delirium. This theory facilitates an understanding of the increased
propensity of older adults and those with underlying brain pathology
(e.g., dementia) to develop delirium in the setting of a seemingly
insignificant insult (e.g., urinary tract infection or initiation of a
medication), whereas others, presumably with more cognitive
reserve, require a more significant insult.
With this understanding of underlying vulnerability and insult
burden, risk factors can be identified and utilized to develop risk
stratification prediction rules for specific populations, eventually
allowing for targeted preventive interventions. In general, older age,
preexisting cognitive impairment such as dementia, and the severity
of preexisting cognitive impairment are associated with an increased
risk of delirium (Davis et al. 2013). Interestingly, not all dementias
confer the same risk; individuals with Lewy body dementia and
vascular dementia have significantly greater risk of developing
delirium than do those with Alzheimer’s dementia (Hasegawa et al.
2013). Polypharmacy, use of sedatives, visual impairment, severity
of physical illness, use of restraints, pain, malnutrition, and
dehydration are recognized risk factors, especially among older
medical inpatients (Neufeld and Thomas 2013). Among older
medical inpatients, exposure to anticholinergic medications is
associated with not only increased risk of delirium but also delirium
severity (Han et al. 2001).
In addition to the risk factors that are generally pertinent across
patients, specific settings confer unique risks. In the ICU, invasive
devices and use of benzodiazepines are independent risk factors for
development of delirium (Barr et al. 2013; Salluh et al. 2010). In
postoperative patients, severe cerebrovascular subcortical disease
and longer surgical procedures are associated with increased risk of
delirium (Cheong 2013). Among patients admitted to a stroke unit,
delirium was more likely with increased stroke severity, anterior
circulation large-vessel stroke, and right-sided hemispheric stroke
(Oldenbeuving et al. 2011). In the ER setting, older adults presenting
from a nursing home had a more than fourfold increased risk of
delirium compared with older adults presenting from home (Han et
al. 2009). Younger age, male gender, mental retardation, preexisting
emotional and behavioral problems, and caregiver anxiety or
absence have all been identified as risk factors for development of
delirium among children (Hatherill and Flisher 2010).
Studying risk factors in specific populations allows the
development of prediction rules that risk-stratify patients and enables
targeted interventions to prevent delirium. Older patients presenting
to the ED can be stratified into being at low, moderate, or high risk
for delirium on the basis of age, dementia, prior stroke or transient
ischemic attack, suspected infection, tachypnea, and ED diagnosis
of intracranial hemorrhage (Kennedy et al. 2014). Among medicine
inpatients, age, history of delirium, underlying malignancy, and
preexisting impairment in ADL yielded distinctive risk group
stratification (Cheong 2013). PRE-DELIRIC (PREdiction of
DELIRium in ICu patients) is a clinical tool for use within 24 hours of
being admitted to the ICU that risk-stratifies adults on the basis of
age, APACHE-II (Acute Physiology and Chronic Health Evaluation II)
score, admission group (medical, trauma, or neurology/neurosurgical
patients), coma status, infection, metabolic acidosis, use of
sedatives and morphine, urea concentration, and urgency of
admission (van den Boogaard et al. 2012). Prediction rules have
also been published for long-term-care and surgical populations.
Prevention
It is estimated that 30%–40% of delirious episodes can be
prevented (Neufeld and Thomas 2013). Primary prevention with
nonpharmacological approaches is the most effective strategy and is
most successful as a multifactorial intervention that addresses
modifiable risk factors, limits complications, and is tailored to the
specific population. Most delirium prevention initiatives include
proactive efforts to address hearing and vision impairment, ensure
adequate hydration and nutrition, reinforce orientation and
appropriate cognitive stimulation, and promote a healthy sleep-wake
pattern. Involvement of a pharmacist or geriatric specialist can be
beneficial in minimizing polypharmacy as well as removing and
avoiding deliriogenic medications. Avoidance of use of devices that
may have restraining properties and promotion of early mobilization,
often with physical therapy, are also beneficial. Recognizing the
significance of delirium, some experts advocate for a
“delirioprotective” environment that would include staff education
about the prevalence and general management of delirium, routine
delirium screening, a hospital-adopted delirium clinical pathway,
delirium education availability for patients and families, awareness of
the value and role of family/caregivers, and availability of expert
specialist care (Maclullich et al. 2013).
Evidence supporting the use of pharmacological interventions in
preventing delirium is mixed. Findings on the prophylactic use of
antipsychotics, including haloperidol, risperidone, and olanzapine, in
preventing postoperative delirium are limited and conflicting.
Although some studies show trends toward decreased incidence of
delirium, other studies indicate increased duration and severity of
delirium. Similarly, the prophylactic use of acetylcholinesterase
inhibitors yields variable results. Because of the nearly universal
symptom of altered sleep-wake cycle or sleep disturbance, targeting
the circadian rhythm has been considered a potential focus for
delirium prevention. Melatonin and the melatonin receptor agonist
ramelteon, as well as light therapy, have shown promising results in
decreasing the incidence of delirium in high-risk populations;
however, there are only very limited data (Fitzgerald et al. 2013).
Detection and Recognition
Detection
Studies show that delirium is unrecognized in approximately two-
thirds of cases (O’Regan et al. 2014; Siddiqi et al. 2006). Patients
with dementia or hypoactive delirium are more likely to have their
delirium unrecognized or misattributed to dementia or depression
(Teodorczuk et al. 2012). Among consults received by psychiatric
consultation services, nearly half of delirium diagnoses were
unrecognized by the referring team, with detection rates poorest in
patients who were older, had dementia, or had the hypoactive
subtype of delirium (O’Regan et al. 2014). Barriers to delirium
recognition likely exist at both the individual and organizational levels
and include failure to recognize the benefit of treating delirium and
the low priority given to the diagnosis (Teodorczuk et al. 2012).
Screening and Severity Instruments
Detection of delirium is best accomplished with the use of a
reliable and valid screening instrument (Neufeld and Thomas 2013).
Delirium screening in high-risk patients, including but not limited to
hospitalized older adults and ICU patients, is recommended
(Teodorczuk et al. 2012). Instruments, however, vary in their
intended purpose (e.g., screening, diagnostic, symptom severity),
threshold for detection, reliability, and validity among specific
populations (Adamis et al. 2010; Davis et al. 2013; Wong et al.
2010). For example, some instruments developed for use in the ICU
have been shown to be inadequate for use outside of the ICU setting
(Neufeld and Thomas 2013). Furthermore, awareness of instrument
bias is important because many screening instruments poorly detect
the hypoactive subtype of delirium.
No consensus exists regarding preferred delirium scales (Davis et
al. 2013). A comprehensive review of delirium scales indicated that
there were substantial psychometric and validation data to support
the use of the CAM, Delirium Rating Scale (DRS), DRS-R-98,
Memorial Delirium Assessment Scale (MDAS), and NEECHAM
Confusion Scale (Adamis et al. 2010). The Nursing Delirium
Screening Scale (NuDESC) has since been validated repeatedly. It
offers a rapid screening instrument designed for use by nurses that
takes less than a minute to complete (Wong et al. 2010). The
NEECHAM Confusion Scale is considered a screening tool and
allows for classification into categories, including “at risk” (Adamis et
al. 2010). The DRS, DRS-R-98, and MDAS were identified as being
good at measuring symptom severity (Adamis et al. 2010). The
DRS-R-98 is a 16-item clinician-rated scale comprising 3 diagnostic
and 13 severity items, whereas the MDAS contains 10 items that
include symptom and examination findings with ratings based on
severity (Adamis et al. 2010; Wong et al. 2010). The CAM, with its
accompanying algorithm, is the most widely utilized screening and
diagnostic instrument (Inouye et al. 2014). Although it is widely used
in studies, the CAM requires interviewer training and formal cognitive
testing, making it less clinically useful. The 3D-CAM, however,
operationalizes the CAM into a structured 3-minute diagnostic
assessment, creating an instrument that is more clinically convenient
(Inouye 2016).
There are several additional instruments used both clinically and
in research. Among these are screening tools such as the ICDSC
and the Delirium Observation Screening Scale, as well as severity
instruments such as the Delirium Index and CAM-S (Adamis et al.
2010; Inouye 2016). For the child and adolescent population, the
Pediatric Anesthesia Emergence Delirium Scale and the Cornell
Assessment of Pediatric Delirium are both designed for use in the
pediatric ICU (Hatherill and Flisher 2010; Traube et al. 2014).
Additionally, the CAM has been modified for use with children, while
the Family CAM provides a family assessment of delirium (Inouye
2016).
Pathophysiology and Neurobiology
Observations and Findings

The exact pathophysiology of delirium is unknown. In their
hallmark studies, Engel and Romano theorized that delirium was the
result of widespread cerebral metabolic insufficiency (Williams
2013). Although the specific pathophysiology is unknown, numerous
abnormalities are associated with delirium, including alterations in
electroencephalography, vascular integrity, neurotransmitter
systems, and biomarkers. These associations are not necessarily
causal; any etiological connections, however, remain theoretical.
Electroencephalographic changes during delirium were identified
decades ago. The typical electroencephalographic pattern
associated with delirium is global slowing with complete loss of
posterior background rhythm and intermittent rhythmic delta activity
(Neufeld and Thomas 2013). In addition to these electrical
disturbances, vascular disturbances have also been noted. Diffuse
cerebral hypoperfusion has been observed on imaging in the frontal,
parietal, and temporal lobes (Williams 2013). It is hypothesized that
this decrease in cerebral blood flow, sometimes by as much as 40%,
during an episode of delirium may result in cell damage and death,
thereby yielding the chronic cognitive impairments that persist after
an episode of delirium (Yokota et al. 2003). Several biomarkers and
neurotransmitter abnormalities are associated with delirium, but their
relationship to delirium remains unclear. In general, elevated
markers of inflammation and coagulation (e.g., tumor necrosis factor
α, interleukin [IL]–1RA, IL-6, IL-8, IL-10, C-reactive protein) and low
anti-inflammatory markers (e.g., insulin-like growth factor 1 [IGF-1])
are associated with increased risk and more severe course of
delirium (Maldonado 2013). Levels of cerebrospinal fluid S100B, a
marker of central nervous system damage, are increased in acutely
ill patients with delirium compared with levels seen in acutely ill
patients without delirium (Kamholz and Blazer 2013). Genetic factors
such as risk associated with the presence of the apolipoprotein E4
genotype continue to be investigated.
Neuroendoimmunological Hypothesis
It is hypothesized that the various precipitants of delirium act
through several different pathways, ultimately implicating a common
endpoint that clinically manifests as delirium. Current evidence
supports significant involvement of the cholinergic, melatonergic, and
hypothalamic-pituitary-adrenal axis (HPA) inflammatory systems in
the pathophysiology of delirium. These three systems interact and
influence each other in a maladaptive response that creates the
clinical signs and symptoms of delirium.
The core pathology of delirium centers on the cholinergic system.
There is a direct relationship between exposure to anticholinergic
agents and precipitation of delirium, with higher levels of
anticholinergic activity associated with increased delirium severity
(Han et al. 2001). Additional evidence supports the idea that
endogenous serum anticholinergic activity is increased in states of
delirium (Maldonado 2013; Williams 2013). Attention, the impairment
of which is the core symptom of delirium, is modulated in part by the
cholinergic system. Visual hallucinations, a common symptom of
delirium, are associated with cholinergic dysfunction in both the
frontal cortex and the ventral visual system (Meagher et al. 2010),
and the cholinergic system is intimately connected with the
dopaminergic system, allowing downstream influence on other
neurotransmitter systems, providing a plausible explanation for any
possible therapeutic role of antipsychotic medications.
Cholinergic activity and circadian mechanisms have a complex
relationship. Melatonin is critical in the maintenance of a healthy
circadian rhythm, and abnormalities can cause sleep disturbance, a
nearly ubiquitous symptom of delirium. Melatonin levels decrease
with age and dementia, both of which are significant risk factors for
delirium. Melatonin induces acetylcholine release at the nucleus
accumbens, and cholinergic projections from the brain stem to the
thalamus and midbrain have a significant role in the regulation of the
sleep-wake cycle (Fitzgerald et al. 2013). Melatonin secretion may
be disrupted by infections, inflammatory response, and medications.
There are also connections between the circadian system and
dopaminergic mechanisms, tryptophan, serotonin, γ-aminobutyric
acid (GABA)–ergic mechanisms, and the HPA axis, which may
contribute to the various perturbations in the dopamine, serotonin,
and GABA neurotransmitter systems observed during delirium
(Fitzgerald et al. 2013; Williams 2013).
Cortisol, which is released in response to physical and
psychological stress, aids in triggering an inflammatory cascade. A
linear relationship has been described between cortisol levels and
serum anticholinergic activity, suggesting that endogenous factors
such as stress states may contribute to serum anticholinergic activity
(Plaschke et al. 2010). Elevated cortisol may be the result of
infection, medical disease, or underlying psychological stressors.
Cortisol leads to a release of various chemokines and interleukins,
accounting for perturbations in levels of IL-6, IL-8, and IGF-1 in
delirium. It is suspected that cortisol elevation, even when within the
expected stress range, is likely of relevance to the development of
delirium, especially in vulnerable individuals (Pearson et al. 2010).
Clinical Evaluation and Management
Clinical Evaluation
Although screening instruments can be helpful in identifying
individuals at risk of or needing further evaluation for delirium, the
diagnosis of delirium is clinical and based on the diagnostic criteria
as listed in DSM-5 or ICD-10. Use of screening instruments alone or
as a verification of a bedside evaluation can lead to overdiagnosis or
underdiagnosis (O’Regan et al. 2014). The clinical examination
should focus on assessing attention as well as noting other cognitive
or perceptual disturbances. Methods for assessing attention vary,
because there is no generally accepted means. The most accurate
bedside assessments of attention may vary by population. One study
found that listing the months of the year backwards (MOTYB) was
the most accurate for assessment in older patients, whereas a
combination of spatial span forward (SSF) and either MOTYB or
reports of confusion was best in younger adults (O’Regan et al.
2014). Obtaining collateral information through chart review or
discussion with staff and family is essential for establishing the acuity
of symptoms, determining the existence of fluctuation in symptoms,
and obtaining information regarding additional symptoms that may
not be observed at the time of examination of the patient.
Known or suspected comorbid dementia can complicate the
evaluation for possible delirium. The core feature of delirium is
impairment in attention, regardless of the presence of dementia.
Inattention, disorientation, and noncognitive symptoms are more
severe in individuals with delirium superimposed on dementia than in
those with dementia alone (Meagher et al. 2010). When compared
with persons with delirium alone, individuals with delirium
superimposed on dementia manifest more psychomotor agitation,
disorganized thinking, and disorientation (Cole et al. 2002).
Identification of Etiologies
Once the diagnosis of delirium has been made, a thorough
medical evaluation is necessary to identify all potential causes of
delirium. Updated vital signs, physical examination, and basic
laboratory studies, including a complete blood count, comprehensive
metabolic panel, and urinalysis, are appropriate. Additional aspects
of the initial evaluation should be tailored to the specific risk factors
and exposures of the patient. The medication list review is
recommended, because medications, including many commonly
used medications possessing anticholinergic properties, frequently
contribute to the development of delirium (Han et al. 2001).
Specifically, avoidance of new prescriptions of benzodiazepines,
opioids, dihydropyridines, and histamine1 antagonists is
recommended in those at risk of delirium, and caution is
recommended with histamine2 antagonists, tricyclic antidepressants,
antiparkinsonian medications, steroids, nonsteroidal anti-
inflammatory drugs, and muscarinic agents (Clegg and Young 2011).
Involvement of a knowledgeable pharmacist can be very helpful.
For situations in which a plausible etiology is not identified after
initial investigation, additional evaluation is indicated. Additional
laboratory studies, including, among other possibilities, serum
medication levels, toxicology, cortisol, and thyroid-stimulating
hormone, as well as imaging of head, chest, or other areas pertinent
to the specific patient, should be considered. A more exhaustive
search may be indicated, especially if the course of delirium is
worsening, because worsening of the delirium suggests offending
etiologies have yet to be addressed. Continuous
electroencephalographic monitoring in older patients without an
identifiable cause is reasonable. Lumbar puncture may also be
appropriate. Involvement of other specialties may be indicated and
helpful. Table 8–2 describes a two-tiered approach for evaluation of
delirium etiologies in general medical inpatients.
TABLE 8–2. Evaluation for delirium etiologies
Primary assessment Vital signs
Interval physical examination
(including neurological exam)
Complete blood count
Comprehensive metabolic panel
Urinalysis with microscopy and
culture
Prescription drug levels
Other studies focusing on known or
suspected areas of pathology
Secondary assessment Thyroid function
Ammonia level
Vitamin B12
Cortisol level
Blood cultures
Urine drug screen
Arterial blood gas
Sputum culture
Posteroanterior and lateral chest
radiograph
Computed tomography of head
Electrocardiogram
Electroencephalogram
Magnetic resonance imaging of brain
Lumbar puncture
Management
There is no cure or definitive treatment for delirium. Management
is often categorized into nonpharmacological and pharmacological
interventions. A few professional organizations, such as the Society
of Critical Care Medicine (Barr et al. 2013), the American Geriatrics
Society (Samuel et al. 2015), and the American Psychiatric
Association (American Psychiatric Association 1999; Cook 2004),
have published guidelines regarding the management of delirium in
specific populations. As summarized and synthesized from these
guidelines here, the goals of management are focused on secondary
and tertiary prevention, such as reducing the duration and severity of
delirium and minimizing any adverse sequelae.
Nonpharmacological Interventions
Many of the approaches used in delirium prevention are also
useful as nonpharmacologic management interventions for
continued use after delirium has been diagnosed (see section “Risk
Factors and Prevention” earlier in this chapter). These
nonpharmacological interventions focus on reducing the impact of
predisposing factors and optimizing physiological conditions for the
brain. Additionally, they aim to treat the syndrome itself through
providing a stable and reassuring environment, avoiding
complications such as aspiration pneumonia and prolonged
immobility, providing rehabilitation, and promoting effective
communication with families (Maclullich et al. 2013). In the ICU
setting, early mobilization, daily sedation interruption and analgesia-
first sedation in mechanically ventilated patients, and promotion of
sleep cycle preservation with environmental changes are
recommended (Barr et al. 2013).
Pharmacological Interventions
Excluding alcohol withdrawal delirium, no medication is approved
for or recognized by experts for treatment of delirium, nor does any
medication have convincing evidence that supports its beneficial
effects in treating delirium. On the basis of the anticholinergic theory
of delirium, acetylcholinesterase inhibitors have been considered a
potential pharmacological intervention that might act as a treatment,
yet studies remain inconclusive. Although short-term use of low-dose
antipsychotics may result in decreased severity scores of delirium
symptoms in up to 75% of patients, it is unclear whether the
medication serves to manage the symptoms or to treat the
underlying syndrome (Meagher et al. 2013). Despite this lack of
evidence, antipsychotic medications remain the most commonly
used medications for managing symptoms of delirium.
In general, the use of these medications should be limited to
situations where psychotic symptoms of delirium are causing
clinically significant distress to the patient or severe agitation is
resulting in behaviors that endanger the patient or others.
Antipsychotics should be prescribed at the lowest effective dose and
for the shortest period of time necessary, with frequent reevaluation
of the need for the medication. Haloperidol, perhaps the
antipsychotic most commonly used for this indication, can be
administered through many routes but is associated with
extrapyramidal symptoms more than second-generation
antipsychotics. Risperidone, due in part to its minimal anticholinergic
activity, may be a preferred agent. All of the antipsychotics carry the
risk of cardiac dysrhythmia and extrapyramidal side effects, as well
as having an U.S. Food and Drug Administration black box warning
for increased risk of sudden death in elderly patients with dementia.
Furthermore, use of these medications can be viewed as a chemical
or medical restraint and may be associated with adverse
consequences, including excessive sedation leading to dehydration
and decubitus ulcers. Potential adverse effects need to be weighed
against potential benefit, and if used, the medication should be
limited to the lowest dose and for the shortest period of time
necessary.
Conclusion
Delirium is perhaps the oldest identified neuropsychiatric disorder.
While much remains to be understood, advances in neuropsychiatry
have furthered theories about the pathophysiology of delirium.
Delirium is the clinical manifestation of global cerebral disruptions,
likely in the cholinergic and melatonergic systems. There are several
adverse outcomes associated with delirium, including increased
mortality and morbidity.
Patient populations have specific and sometimes unique risk
factors that provide opportunities to mitigate the risk of developing
delirium. Prevention is currently the most successful intervention,
while management of existing delirium focuses on minimizing
complications. A clearer understanding of delirium, along with
advancements in its management, will emerge as the field of
neuropsychiatry evolves.
References
Adamis D, Sharma N, Whelan PJ, et al: Delirium scales: a review of current
evidence. Aging Ment Health 14(5):543–555, 2010 20480420
American Psychiatric Association: Practice guideline for the treatment of patients
with delirium. Am J Psychiatry 156 (5 suppl):1–20, 1999 10327941
Disorder, 3rd Edition. Washington, DC, American Psychiatric Association, 1980
Disorder, 5th Edition. Arlington, VA American Psychiatric Association, 2013
Anderson CP, Ngo LH, Marcantonio ER: Complications in postacute care are
associated with persistent delirium. J Am Geriatr Soc 60(6):1122–1127, 2012
22646692
Barr J, Fraser GL, Puntillo K, et al; American College of Critical Care Medicine:
Clinical practice guidelines for the management of pain, agitation, and delirium
in adult patients in the intensive care unit. Crit Care Med 41(1):263–306, 2013
23269131
Cheong JA: Diagnosis, risk factors, predisposing factors, and predictive models of
delirium. Am J Geriatr Psychiatry 21(10):931–934, 2013 24029013
Clegg A, Young JB: Which medications to avoid in people at risk of delirium: a
systematic review. Age Ageing 40(1):23–29, 2011 21068014
Cole MG: Persistent delirium in older hospital patients. Curr Opin Psychiatry
23(3):250–254, 2010 20224406
Cole MG, McCusker J, Dendukuri N, et al: Symptoms of delirium among elderly
medical inpatients with or without dementia. J Neuropsychiatry Clin Neurosci
14(2):167–175, 2002 11983791
Cole MG, McCusker J, Voyer P, et al: Symptoms of delirium occurring before and
after episodes of delirium in older long-term care residents. J Am Geriatr Soc
60(12):2302–2307, 2012 23194147
Cole MG, Ciampi A, Belzile E, et al: Subsyndromal delirium in older people: a
systematic review of frequency, risk factors, course and outcomes. Int J Geriatr
Psychiatry 28(8):771–780, 2013 23124811
Cook IA: Guideline Watch: Practice Guideline for the Treatment of Patients With
Delirium. Arlington, VA, American Psychiatric Association, 2004
Davis DH, Kreisel SH, Muniz Terrera G, et al: The epidemiology of delirium:
challenges and opportunities for population studies. Am J Geriatr Psychiatry
21(12):1173–1189, 2013 23907068
Fitzgerald JM, Adamis D, Trzepacz PT, et al: Delirium: a disturbance of circadian
integrity? Med Hypotheses 81(4):568–576, 2013 23916192
Han JH, Morandi A, Ely EW, et al: Delirium in the nursing home patients seen in
the emergency department. J Am Geriatr Soc 57(5):889–894, 2009 19484845
Han L, McCusker J, Cole M, et al: Use of medications with anticholinergic effect
predicts clinical severity of delirium symptoms in older medical inpatients. Arch
Intern Med 161(8):1099–1105, 2001 11322844
Hasegawa N, Hashimoto M, Yuuki S, et al: Prevalence of delirium among
outpatients with dementia. Int Psychogeriatr 25(11):1877–1883, 2013
23870331
Hatherill S, Flisher AJ: Delirium in children and adolescents: a systematic review of
the literature. J Psychosom Res 68(4):337–344, 2010 20307700
Inouye S: Delirium instruments. Hospital Elder Life Program, 2016. Available at:
https://www.hospitalelderlifeprogram.org/delirium-instruments/. Accessed
November 16, 2016.
Inouye SK, Westendorp RG, Saczynski JS: Delirium in elderly people. Lancet
383(9920):911–922, 2014 23992774
Jackson JC, Pandharipande PP, Girard TD, et al; Bringing to light the Risk Factors
And Incidence of Neuropsychological dysfunction in ICU survivors (BRAIN-
ICU) study investigators: Depression, PTSD, and functional disability in
survivors of critical illness in the BRAIN-ICU study: a longitudinal cohort study.
Lancet Respir Med 2(5):369–379, 2014 24815803
Kamholz B, Blazer DG: Progress in delirium. Am J Geriatr Psychiatry 21(12):1169–
1172, 2013 24206936
Kennedy M, Enander RA, Tadiri SP, et al: Delirium risk prediction, healthcare use
and mortality of elderly adults in the emergency department. J Am Geriatr Soc
62(3):462–469, 2014 24512171
Kiely DK, Marcantonio ER, Inouye SK, et al: Persistent delirium predicts greater
mortality. J Am Geriatr Soc 57(1):55–61, 2009 19170790
Lawlor PG, Gagnon B, Mancini IL, et al: Occurrence, causes, and outcome of
delirium in patients with advanced cancer: a prospective study. Arch Intern Med
160(6):786–794, 2000 10737278
Leonard M, Donnelly S, Conroy M, et al: Phenomenological and
neuropsychological profile across motor variants of delirium in a palliative-care
unit. J Neuropsychiatry Clin Neurosci 23(2):180–188, 2011 21677247
Leslie DL, Inouye SK: The importance of delirium: economic and societal costs. J
Am Geriatr Soc 59 (suppl 2):S241–S243, 2011 22091567
Maclullich AM, Anand A, Davis DH, et al: New horizons in the pathogenesis,
assessment and management of delirium. Age Ageing 42(6):667–674, 2013
24067500
Maldonado JR: Neuropathogenesis of delirium: review of current etiologic theories
and common pathways. Am J Geriatr Psychiatry 21(12):1190–1222, 2013
24206937
Meagher D: More attention, less confusion: time to lessen the burden of delirium.
Int Rev Psychiatry 21(1):1–3, 2009a 19219706
Meagher D: Motor subtypes of delirium: past, present and future. Int Rev
Psychiatry 21(1):59–73, 2009b 19219713
Meagher D, Moran M, Raju B, et al: A new data-based motor subtype schema for
delirium. J Neuropsychiatry Clin Neurosci 20(2):185–193, 2008 18451189
Meagher DJ, Leonard M, Donnelly S, et al: A comparison of neuropsychiatric and
cognitive profiles in delirium, dementia, comorbid delirium-dementia and
cognitively intact controls. J Neurol Neurosurg Psychiatry 81(8):876–881, 2010
20587481
Meagher DJ, Leonard M, Donnelly S, et al: A longitudinal study of motor subtypes
in delirium: relationship with other phenomenology, etiology, medication
exposure and prognosis. J Psychosom Res 71(6):395–403, 2011 22118382
Meagher DJ, McLoughlin L, Leonard M, et al: What do we really know about the
treatment of delirium with antipsychotics? Ten key issues for delirium
pharmacotherapy. Am J Geriatr Psychiatry 21(12):1223–1238, 2013 23567421
Meagher D, O’Regan N, Ryan D, et al: Frequency of delirium and subsyndromal
delirium in an adult acute hospital population. Br J Psychiatry 205(6):478–485,
2014 25359923
Neufeld KJ, Thomas C: Delirium: definition, epidemiology, and diagnosis. J Clin
Neurophysiol 30(5):438–442, 2013 24084176
Oldenbeuving AW, de Kort PL, Jansen BP, et al: Delirium in the acute phase after
stroke: incidence, risk factors, and outcome. Neurology 76(11):993–999, 2011
21307355
O’Malley G, Leonard M, Meagher D, et al: The delirium experience: a review. J
Psychosom Res 65(3):223–228, 2008 18707944
O’Regan NA, Ryan DJ, Boland E, et al: Attention! A good bedside test for
delirium? J Neurol Neurosurg Psychiatry 85(10):1122–1131, 2014 24569688
Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators:
Long-term cognitive impairment after critical illness. N Engl J Med
369(14):1306–1316, 2013 24088092
Pearson A, de Vries A, Middleton SD, et al: Cerebrospinal fluid cortisol levels are
higher in patients with delirium versus controls. BMC Res Notes 3:33, 2010
20181121
Plaschke K, Kopitz J, Mattern J, et al: Increased cortisol levels and anticholinergic
activity in cognitively unimpaired patients. J Neuropsychiatry Clin Neurosci
22(4):433–441, 2010 21037129
Robinson TN, Raeburn CD, Tran ZV, et al: Motor subtypes of postoperative
delirium in older adults. Arch Surg 146(3):295–300, 2011 21422360
Salluh JI, Soares M, Teles JM, et al; Delirium Epidemiology in Critical Care Study
Group: Delirium epidemiology in critical care (DECCA): an international study.
Crit Care 14(6):R210, 2010 21092264
Samuel M, Inouye SK, Robinson T, et al; American Geriatrics Society Expert Panel
on Postoperative Delirium in Older Adults: American Geriatrics Society
abstracted clinical practice guideline for postoperative delirium in older adults. J
Am Geriatr Soc 63(1):142–150, 2015 25495432
Siddiqi N, House AO, Holmes JD: Occurrence and outcome of delirium in medical
in-patients: a systematic literature review. Age Ageing 35(4):350–364, 2006
16648149
Teodorczuk A, Reynish E, Milisen K: Improving recognition of delirium in clinical
practice: a call for action. BMC Geriatr 12:55, 2012 22974329
Traube C, Silver G, Kearney J, et al: Cornell Assessment of Pediatric Delirium: a
valid, rapid, observational tool for screening delirium in the PICU*. Crit Care
Med 42(3):656–663, 2014 24145848
van den Boogaard M, Pickkers P, Slooter AJ, et al: Development and validation of
PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction
model for intensive care patients: observational multicentre study. BMJ
344:e420, 2012 22323509
Williams ST: Pathophysiology of encephalopathy and delirium. J Clin Neurophysiol
30(5):435–437, 2013 24084175
Witlox J, Eurelings LS, de Jonghe JF, et al: Delirium in elderly patients and the risk
of postdischarge mortality, institutionalization, and dementia: a meta-analysis.
JAMA 304(4):443–451, 2010 20664045
Wong CL, Holroyd-Leduc J, Simel DL, et al: Does this patient have delirium?:
value of bedside instruments. JAMA 304(7):779–786, 2010 20716741
World Health Organization: International Classification of Diseases, 10th Revision.
Geneva, Switzerland, World Health Organization, 1992
Yokota H, Ogawa S, Kurokawa A, et al: Regional cerebral blood flow in delirium
patients. Psychiatry Clin Neurosci 57(3):337–339, 2003 12753576
CHAPTER 9
Poisons and Toxins

It is well established that certain toxic substances have the

potential to disrupt homeostasis of the central nervous system
(CNS), resulting in cognitive dysfunction, memory disturbance, and
other neurological signs and symptoms. However, the initial
symptoms of neurotoxic injury may manifest themselves as subtle or
overt alteration in thoughts, moods, or behaviors, placing the
neuropsychiatrist in the unique position of diagnosing and treating
environmentally related disorders. Some neurotoxic agents may act
directly on components of the nervous system, whereas others
indirectly interfere with critical supportive functions on which the
nervous system is dependent. Over the past few years, the role of
the neuroinflammatory and neuroimmunological processes has
emerged as a unifying factor in the effects of neurotoxic substances
on the CNS (Kraft and Harry 2011; Vojdani 2014).
Over the past 20 years, a concerted search has been ongoing to
determine if an environmental factor is responsible for the increased
frequency of a number of neuropsychiatric disorders, particularly
those that have affected children born in the past 25 years. The
ever-increasing number of pharmaceutical agents complicates the
search, as well as the approximately 80,000–100,000 industrial and
agricultural chemicals introduced into the environment, most of
which have received little or no CNS toxicity testing. Currently, 1 in
50 children between the ages of 6 and 17 years has a diagnosis of
autism spectrum disorder according to the U.S. Department of
Health and Human Services and the Centers for Disease Control
and Prevention. In the past 20 years, there has been a 600%
increase in the incidence of autism, with only one-third of these
cases attributable to better awareness and diagnosis (Blumberg et
al. 2013). Some of the disorders are autoimmune in nature and
include the clinical entity known as autoimmune encephalitis, of
which the subset known as pediatric acute-onset neuropsychiatric
syndrome (PANS) has received the most publicity. A CNS insult by
an infectious agent, trauma, or exposure to an environmental factor
(Pollard et al. 2010) often precedes the onsets of several forms of
autoimmune encephalitis. In addition, there is evidence that the CNS
has become less likely to heal following various forms of trauma.
Soldiers returning from the Vietnam conflict that suffered brain
trauma have regained functioning to a larger extent than soldiers
returning from Iraq and Afghanistan. The latter individuals appeared
to be more likely to develop a neurodegenerative course following
trauma (Morley and Seneff 2014). Also notable is the steady and
disproportionate rise in the incidence of neurodegenerative diseases
despite an increase in life expectancy. As evidence in support of the
role of neuroinflammation and neuroimmunological abnormalities in
the pathogenesis of both neuropsychiatric illness and neurotoxicant
exposure converges, the search for an environmental factor has
grown in importance. Moreover, the recent discovery of a classical
central lymphatic system in the brain sheds new light on the etiology
of neuroinflammatory and neurodegenerative processes associated
with neuroimmunological dysfunction (Louveau et al. 2015). Thus far,
diverse environmental factors, such as metals and pesticides, and
multifaceted environmental toxins, such as air pollution, have been
implicated in neuroinflammation and autoimmunity leading to central
nervous system pathology (Pollard et al. 2010).
In this chapter, I focus on specific environmental toxicants relevant
to the practice of neuropsychiatry and highlight recent developments
in the rapidly evolving field of neurotoxicology. The discovery of the
gut microbiome and its role in shaping brain function and behavior
has led to an unparalleled paradigm shift in the conceptualization of
many psychiatric and neurological diseases. An example of a toxic
agent that disrupts the gut microbiome and is potentially responsible
for neuropsychiatric disease is presented. Information regarding
agents requiring emergent care, hospitalization, and life-saving
medical interventions; neurotoxic effects of medication; and
venomous exposures via bites and stings with known treatment
protocols are beyond the scope of this chapter. For the reader
interested in these specific topics, comprehensive textbooks are
available (Dart 2004; Dobbs 2009).
Routes, Sources, and Types of Exposure

Exposure to neurotoxic agents may occur through the respiratory
and olfactory tracts and through dermal and oral routes, via the
primary sources of air, water, food, and the environment. Water and
food supplies are the primary oral routes of exposure because many
neurotoxicants are contaminants. The most common source for
inhalation exposure is indoors, where the majority of our population
spends 90% of their time, whether at work, at school, or in other
enclosed buildings or spaces (Hope 2013).
Types of exposure that occur include acute, subacute, and
chronic. Acute exposure to a neurotoxic agent usually consists of a
single exposure less than 24 hours in duration. A subacute exposure
generally consists of a repeated exposure for a period of up to a
month. A chronic exposure often consists of a repeated exposure
lasting over a period of months to years. Following acute exposure,
toxicants can rapidly produce overt neuropsychiatric symptoms, with
the patient requiring emergent treatment and hospitalization and
either recovering or left with residual deficits. A temporal relationship
and causation can usually be established in acute exposure cases
and, at times, with subacute exposure. However, following chronic
exposure over a period of months to years, including prenatal
exposure, neuropsychiatric symptoms may be subtle, and although
determining a temporal relationship may be possible, causation is
less likely to be established.
Neuropsychiatry and Environmental Exposure:

An Intuitive Integration
The number of known neuropsychiatric symptoms is limited,
whereas existing chemicals, including poisons and toxins, that are
capable of producing symptoms number in the thousands. As a
result, many environmentally related illnesses share symptoms.
When a disease is diagnosed only by symptomatology, a rules-
based diagnostic method is not always possible because typically
the symptom can be ascribed to any number of distinctly different
disorders. Subtle changes, if any, in the results of diagnostic
imaging, inability to quantify or identify the substance due to a lack of
methodology, and, often, inconclusive clinical laboratory findings
make a precise diagnosis difficult or impossible. When a precise
diagnosis is not possible, diagnosis and treatment of a disorder must
be provided through a process known as the intuitive stage of
medicine. In this arena, a physician attempts to provide a reasonably
accurate diagnosis, often on the basis of a limited history, subtle
physical findings, nonstandardized laboratory testing, anecdotal case
reports, and pattern recognition. Treatment in the arena of intuitive
medicine is typically empirical and utilizes the clinician’s breadth and
depth of understanding with the ability to operate across disciplinary
boundaries. Later, as the knowledge of a medical disorder reaches
the precision stage, there follows an increase in research and
identification of standardized, validated tests and treatments based
on sound clinical trials. Aside from well-known major poisoning
syndromes, which are usually seen in an emergency setting and for
which there are established protocols, treatment approaches to the
neuropsychiatry of poisons and toxins often fall into the intuitive
stage of medicine (Dobbs and Rusyniak 2011).
Assessment of Neurotoxic Exposure

It is important that a physician consider environmental causation
for illness, given the thousands of industrial chemicals in our
environment. Integration of an exposure assessment as a first-line
screening tool is extremely helpful in the comprehensive assessment
of patients presenting with neurological, emotional, or psychiatric
symptoms. Attempting to identify a singular environmental agent
related to various symptoms has been likened to “looking for a
needle in a haystack.”
A more effective approach than looking for a specific exposure is
to search for any temporal change in the environment related to
symptom onset or exacerbation. It is helpful to organize the
exposure history by the possible source or setting. The three most
common sites of exposure are where patients spend the majority of
their day: work, home, and school. Questions grouped in these three
categories as shown in Table 9–1 can serve as a screening guide
prior to asking questions that are more specific. These questions are
easily integrated into an initial psychiatric or neuropsychiatric
interview and appear more natural when asked by the psychiatrist.
At the end of the interview, the physician or the patient may feel that
some or all areas require elaboration or that input from a family
member may be helpful. In that case, having the patient complete a
written form on their own time is most likely to elicit thoughtful
responses.
TABLE 9–1. Interview obtaining an environmental exposure history
Site Questions
Home How old is your home?
Do your symptoms get either worse or better at home? Do
you feel better when you are away from home for any
significant length of time?
Has your home had any recent or previous water damage?
Have you had roof or plumbing leaks? Any flooding?
Have you noticed any musty odors?
Is your home near any industrial facilities that give off
chemical odors? Is home near a hazardous waste site, a
chemical or power plant, a smelter? Do you smell chemical
odors in the air?
Does your drinking water come from a private well, city water
supply, or grocery store?
Are pesticides or herbicides used in your home or garden or
on pets?
Do you have a fireplace? Do you notice if you feel worse after
using your fireplace?
Have you had any problems with your air conditioning or
heating systems?
Work What kind of work do you do?
Do your symptoms get either worse or better at work?
Are you in contact with any chemicals?
Have you noticed others at work having health issues?
Describe your workplace air quality. Do you notice any odors
in your workplace?
Do you wear protective equipment at work?
Has your workplace undergone any environmental testing?
School Do your symptoms get either worse or better at school?
Has there been any environmental testing/evaluations for
mold or other substances, either airborne or surface,
conducted in the classrooms at the school?
Site Questions
Has there been any damage sustained in past or present
breaches of the outer building envelope, leakage into the
inner building, and the need for replacement of water-
damaged building materials?
Has there been any water damage secondary to HVAC
problems in the building?
Have there been any requests made by parents, teachers,
and staff regarding environmental or air-quality testing of
the building structures in classrooms at the school?
Is there any information pertaining to excess number of
students, teachers, and staff in the building who may have
reported illnesses associated with mold or chemically
related respiratory or other symptoms?
Mechanisms of Neurotoxicity
Some neurotoxic agents act by direct effects on the CNS or
indirectly by disrupting tissues and organs such as the
gastrointestinal, endocrine, and immune systems external to the
neural axis.
Oxidative Stress
Recently, studies have shown that the mechanisms of
neurotoxicity of numerous structurally unrelated environmental
agents appear to share a similar basis in that they increase oxidative
stress and mitochondrial dysfunction and neuroinflammation.
Oxidative stress is a condition in which an imbalance of cellular
oxidants and antioxidants leads to excess oxidants that damage or
modify biological macromolecules such as lipids, proteins, and DNA.
This excess results from increased oxidant production, decreased
oxidant elimination, defective antioxidant defenses, or a combination
thereof. The oxidants produced by the mitochondria are known as
reactive oxygen species and reactive nitrogen species, which
underlie oxidative damage (Cherry et al. 2014; Roberts et al. 2010).
The brain is particularly vulnerable to oxidative stress due to high
oxygen utilization; elevated amounts of peroxidizable
polyunsaturated fatty acids; and high content of trace minerals such
as iron, manganese, and copper with the ability to produce lipid
peroxidation and subsequently oxygen radicals. Excess oxidative
stress occurs in both neurotoxicant exposure and neuropsychiatric
illnesses such as major depressive disorder, bipolar disorder,
schizophrenia, and obsessive-compulsive disorder. Numerous
toxicants, such as metals, pesticides, or toxicant mixtures (e.g., air
pollution) all possess the ability to increase oxidative stress (Block
and Calderón-Garcidueñas 2009; Costa et al. 2014; Doi and
Uetsuka 2011; Farina et al. 2013).
Neuroinflammation
Neuroinflammation represents the coordinated cellular response
of an organism to nervous system damage. While the appropriate
regulation of this process facilitates recovery, uncontrolled
neuroinflammation can induce secondary injury. Activation of
microglia, the highly heterogeneous resident mononuclear
phagocytes of the brain that make up 10% of the total cell population
within the healthy CNS, is the likely early event in all forms of CNS
injury. More recently, a role for microglial activation and
neuroinflammation has been considered as an underlying unifying
factor of neurotoxicity from environmental exposures (Kraft and
Harry 2011). During the past several years, research has begun to
establish and define the role of neuroinflammation in the etiology of
psychiatric illness (Halaris and Leonard 2013; Najjar et al. 2013). It is
likely that the neuroinflammation produced secondary to exposure to
toxic agents may serve as the cause of neurological and
neuropsychiatric dysfunction. There is a growing body of literature on
the neurotoxicity of environmental agents that to date supports the
diversity and heterogeneity of the microglia and neuroimmune or
neuroinflammatory response (Vojdani 2014).
Dysbiosis
Another mechanism of neurotoxicity, albeit indirect, is dysbiosis.
Alteration by environmental agents or chemicals of the flora in our
intestinal tract produces a state of dysbiosis, reducing the number of
beneficial bacteria and increasing the number of pathogenic bacteria
in the gut. Salmonella and clostridium are highly resistant to
glyphosate, whereas enterococcus, bifidobacteria, and lactobacillus
are especially susceptible. Pathogens, through their activation of a
potent signaling molecule called zonulin, induce a breakdown of the
tight junctions in cells lining the gut, leading to “leaky gut” syndrome
(Fasano 2011). Beneficial bacteria can protect from celiac disease
through their enzymatic activities on gluten; this is the basis for
articles in the current literature recommending treatment plans based
on probiotics.
The deleterious effects of dysbiosis consist of pathogenic bacteria
attacking the intestinal mucosal membranes, the integrity of which is
essential in the defense and prevention of intestinal inflammation,
infections, and “leaky gut” syndrome (Galland 2014; Schippa and
Conte 2014). Strong evidence exists to support bidirectional
interactions between the gut microbiome and the CNS that involve
the endocrine and immune systems and neural pathways. Dysbiosis
is one of the primary mechanisms of neurotoxicity involving agents
such as the herbicide glyphosate, as well as aluminum and other
heavy metals (Samsel and Seneff 2015). It is important to
understand that the number of microorganisms or bacterial cells is
10 times greater than the number of human cells that make up our
bodies. The colon alone contains over 70% of the microbial flora
(Vyas and Ranganathan 2012). Invasion by pathogenic microbial
organisms through the intestinal mucosa can trigger a vigorous
autoimmune response to macromolecules entering the vasculature.
Subsequent release of high levels of inflammatory mediators into the
blood stream results in injury to the blood-brain barrier, increasing
permeability to macromolecules or toxic agents (Wang and Kasper
2014).
Induction of Autoimmunity
Another mechanism of neurotoxicity is the induction of
autoimmunity by neurotoxicants (Pollard et al. 2010). A number of
experimental studies and clinical reports have shown that
neurotoxicants can induce autoimmune reactivity and/or autoimmune
diseases in humans and in animal models. The mechanism of
toxicant-induced autoimmunity is the result of aberrant cell death—
release of usually hidden cellular components, allowing immune
surveillance to make them available to antigen-presenting cells.
Another immune reaction to xenobiotics is through covalent binding
of chemicals or haptens to human tissue proteins and formation of
neoantigens. Reactive organic compounds bind covalently; that is,
their electrophilic properties enable them to react with protein
nucleophilic groups such as thiol, amino, and hydroxyl groups on
proteins to form neoantigens (Pollard et al. 2010). Pesticides bind to
intracellular components, released because of apoptosis, and form
neoantigens, which when presented to the immune system begin the
process of autoimmunity.
Pesticides
Table 9–2 summarizes the neuropsychiatric manifestations of
exposure to selected pesticides. Sources and routes of exposure,
mechanisms of neurotoxicity, diagnostic procedures, and
detoxification methods, if available, are discussed below.
TABLE 9–2. Neuropsychiatric sequelae associated with exposure to
selected pesticides
Pesticide Neuropsychiatric symptoms

Phosphonoglycines (e.g., Anxiety, irritability, tremulousness,
glyphosate) parkinsonian features
Carbamates (e.g., carbaryl) Headache, nausea, giddiness,
blurred vision, weakness,
increased sweating, vomiting,
miosis, delayed neuropathy
Organophosphates (e.g., Mild: Weakness, headache,
chlorpyrifos) dizziness, nausea, salivation,
lacrimation, miosis, moderate
bronchial spasm
Moderate: Abrupt weakness, visual
disturbances, excessive
salivation, sweating, vomiting,
diarrhea, bradycardia, hypertonia,
tremor of hands and head,
impaired gait, miosis, chest pain,
cyanosis of mucous membranes
Severe: Abrupt tremor, generalized
convulsions, psychiatric
disturbance, intense cyanosis,
death from respiratory or cardiac
failure
Organochlorines (e.g., chlordane) Nervousness, tremor, ataxia, weight
loss, headache, disorientation,
confusion, auditory and visual
hallucinations, paranoia
Source. Adapted from Bleecker 1994; Bolla and Roca 1994.
Pesticides are unique among environmental chemicals; they are

deliberately placed in the environment to injure or kill animal, plant,
or microbial life. The well-known classes of pesticides are the
phosphonoglycines, such as glyphosate, organophosphates, and
carbamates. The organochlorine insecticides are not biodegradable
and accumulate in the environment; these agents are therefore no
longer used and are banned in the United States. In the past several
years, significant concerns regarding pesticides as a class of agents
have arisen. The greatest concern that has arisen with regard to the
toxicity of pesticides is the realization that the data from toxicology
studies that are submitted for approval to regulatory agencies are not
reflective of the results of toxicity seen following human exposure.
Throughout the world, pesticides are used in mixtures that are
termed formulations. The formulations contain adjuvants, which are
often proprietary and are called “inert agents” by the manufacturing
companies. However, only the declared active principal pesticide
undergoes toxicity testing. Following testing of all the classes of
pesticides currently on the market, the toxicity of the formulations,
including glyphosate, was found to be over a 100 times more toxic
than their active principles.
Glyphosate
Glyphosate, the active ingredient in Roundup, is the most widely
used pesticide around the world. Glyphosate-based herbicides were
initially patented as metal ion chelators. Glyphosate’s herbicidal
activity was discovered in the 1970s, and over the following 30 years
its use increased, becoming at present the most widely used
pesticide on the planet.
Glyphosate is commonly believed to be among the safest of
pesticides. The safety was based on glyphosate’s mechanism of
action, which is the disruption of the shikimate pathway utilized
selectively by plants but not human cells for the synthesis of the
essential amino acids tryptophan, phenylalanine, and tyrosine. As
the pathway is nonexistent in cells of vertebrates, it was generally
accepted that glyphosate is safe for mammals, including humans. As
a result, in addition to being used for crops, glyphosate is being used
in home gardens, in public parks (including city parks), on railway
lines, and on roadsides, as well as in a multitude of other
applications. Because of its relatively nontoxic standing with
regulatory agencies, glyphosate was approved for direct application
on the crop both before seeds were sown and before harvesting as a
desiccation aid. As a consequence, the acceptable daily intake and
the allowable residue have increased.
Glyphosate was found to disrupt the balance of gut bacteria in fish
by increasing the ratio of pathogenic bacteria to other commensal
microbes. Salmonella and clostridium are highly resistant to
glyphosate, whereas bifidobacteria and lactobacilli are especially
susceptible (Samsel and Seneff 2015). Fish exposed to glyphosate
develop characteristic mucosal changes and lesions in the digestive
tract similar to the findings in celiac disease. A similar state of
dysbiosis occurs in celiac disease, whose symptoms include
neuropsychiatric manifestations and whose incidence trends match
well with the increased usage of glyphosate on crops. The incidence
of celiac disease, as well as of gluten intolerance in general, has
risen dramatically over the last 20 years. Recent publications
presenting graphical data from the Centers for Disease Control and
Prevention (CDC) and U.S. Department of Agriculture (USDA)
identified the usage trend of glyphosate as correlating closely with
the increasing incidence of autism over the past 20 years (e.g.,
Samsel and Seneff 2015).
Although there is no established causation, data available from
the USDA and CDC indicate a temporal correlation of the increased
usage of glyphosate with an increase in anxiety, endocrine disorders,
and other degenerative disorders of the CNS. Again, with no
established causation, the most striking temporal relationship is that
of the increased usage trend of glyphosate with the increasing
incidence of deaths from dementia (Samsel and Seneff 2015).
Despite being notable and striking, the correlation does not establish
causation. The information, however, should raise awareness of
another potential mechanism by which a toxic agent can exert its
effects to produce neuropsychiatric symptomology and the need for
further studies in this area.
Organophosphate and Carbamate Compounds
In contrast to the organochlorine pesticides, which tend to
accumulate in the environment, the organophosphate and
carbamate pesticides degrade rapidly. The mechanisms of action of
organophosphate compared with carbamate compounds differ with
regard to the manner in which they produce inhibition of the enzyme
acetylcholinesterase, an essential enzyme necessary for normal
nervous system function. Inhibition occurs by binding with the serine
hydroxyl group at the active site of the enzyme (López-Granero et al.
2013). Excessive accumulation of acetylcholine at the synapse
hyperstimulates both muscarinic acetylcholine and nicotinic
cholinergic receptors and is responsible for many of the symptoms
that are produced by exposure to organophosphates and
carbamates.
The diagnosis of organophosphate toxicity is primarily by a history
of exposure to pesticides, as well as signs and symptoms of
excessive cholinergic activity. In addition, organophosphates usually
have a garlic-like odor, which may emanate from the patient or from
the container from which the poison was dispensed, and the
presence of this odor can help confirm the diagnosis. Red blood cell
cholinesterase is the preferred marker for organophosphate toxicity
because it is the same enzyme found in nervous tissue. Decreased
acetylcholinesterase activity, in conjunction with a history of
exposure, usually confirms the diagnosis. Short-term exposure may
decrease acetylcholinesterase activity to 50% of baseline, followed
by a return to normal activity after several weeks.
After exposure to organophosphates, the primary concern is
stabilization of vital signs, followed by decontamination.
Decontamination procedures include removing all contaminated
clothing and thoroughly washing all exposed skin surfaces. Atropine
is administered because it noncompetitively antagonizes both
muscarinic and nicotinic receptors, thereby blocking the effect of
excess acetylcholine. In addition to atropine, pralidoxime, an oxime
and acetylcholinesterase reactivator, is helpful.
Metals
The neuropsychiatric manifestations of exposure to selected
metals are shown in Table 9–3. Sources and routes of exposure,
updated mechanisms of neurotoxicity, diagnostic procedures, and
methods of detoxification, if available, are discussed below for the
selected metals.
TABLE 9–3. Neuropsychiatric sequelae associated with selected metal
exposure
Metal Neuropsychiatric symptoms

Alkyltin Depression, rage, loss of libido and motivation, sleep
(trimethyltin) disturbance, forgetfulness, personality
deterioration
Aluminum Personality change, fatigue, impaired memory and
attention and executive motor functions
Arsenic Impaired verbal memory, agitation, drowsiness,
confusion, emotional lability, stupor, delirium,
psychosis resembling paranoid schizophrenia
Lead
Inorganic
Children Lethargy; hyperactivity; impaired intellect, reaction
time, perceptual motor performance, memory,
reading, spelling, auditory processing, and
attention
Adults Depression; apathy; confusion; fatigue; tension;
restlessness; anger; decreases in visual
intelligence, general intelligence, memory,
psychomotor speed, rate of learning, attention,
and visuoconstruction
Organic Euphoria; psychosis; hallucinations; restlessness;
nightmares; delirium; impaired concentration,
memory, and abstract reasoning
Manganese Somnolence, asthenia, anorexia, impaired speech,
insomnia, hallucinations, excitement, aggression,
mania, dementia, frontal lobe dysfunction,
emotional lability, Parkinson-like symptoms,
impaired judgment and memory
Mercury
Inorganic Irritability; avoidance; shyness; depression; lassitude;
fatigue; agitation; decreases in visual memory,
reaction time, motor speech, and learning
Organic Incoordination, mood lability, dementia
(methylmercury)
Aluminum
Aluminum, the third most abundant element, constituting 5% of
the earth’s crust, is mined and refined for use in electrical wiring,
thermal insulation, paint, bricks, mufflers, and household and
industrial utensils. Routes of exposure to aluminum-containing
compounds are primarily ingestion and inhalation. Sources of
exposure include food, water, medicinals, vaccines, and cosmetics,
as well as industrial occupational settings. Aluminum has no known
physiological role.
Aluminum acts by causing dysregulation of other essential metals,
such as magnesium, calcium, and iron, and mimicking their
biological functions. As a result, aluminum can trigger biochemical,
structural, and functional alterations of essential cellular machinery
and enzymatic processes. Aluminum increases blood-brain barrier
permeability, induces autoimmunity, disrupts both presynaptic and
postsynaptic transmission at receptors and ion channels, and
corrupts neuronal-glial interactions (Shaw et al. 2014). Evidence
links aluminum exposure to human degenerative diseases such as
Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s
disease. Effects of aluminum on autoimmunity, oral tolerance,
hypersensitivity, and erythrocyte immune function are suggestive of
its immunotoxic activity (Shaw et al. 2014). Many of the features of
aluminum-induced neurotoxicity may arise in part from induction of
autoimmune reactions to neuronal antigens. A recent study indicates
that the herbicide glyphosate complexes with aluminum, allowing it
to cross the intestinal epithelium and blood-brain barrier more
readily, and that the complex has a synergistic effect in causing
neurotoxicity (Seneff et al. 2015).
Diagnosis is based on the presence of aluminum in a urine
screen. Preventative measures are more effective than treatment for
aluminum exposure. Chelation therapy utilizing
ethylenediaminetetraacetic acid (EDTA) and desferrioxamine
normalizes laboratory values, but it does not always result in
resolution of deficits.
Arsenic
Arsenic is used in the manufacture of fungicides, insecticides,
rodenticides, and wood preservatives, as well as in paints, pigments,
semiconductors, and “herbal” remedies. Most organic exposure in
humans is from water and water-based organisms such as shellfish,
fish, and seaweed. Contaminated groundwater is responsible for the
most significant exposures to inorganic forms of arsenic. On
absorption, arsenic is distributed to many organs, including brain and
nerve tissue. Biodistribution of arsenic is dependent on the duration
of the exposure (Genuis et al. 2012; Tolins et al. 2014) and the
chemical species.
Arsenic, which exists in multiple valence states, has been shown
to inactivate more than 200 enzymes, predominantly in pathways
involving cellular respiration. The neural mechanisms of dysfunction
after arsenic exposure include apoptosis of astrocytes; oxidative
stress; altered epigenetics; hippocampal dysfunction; disruption of
glucocorticoid and hypothalamus-pituitary-adrenal axis pathway
signaling; alterations in glutaminergic, cholinergic, and
monoaminergic signaling; and impaired neurogenesis (Sharma et al.
2014).
Toxicity is confirmed by demonstrating elevated concentrations of
arsenic in the body with urine testing for recent exposure and hair
testing for long-term exposure. Treatment after absorption may
require hemodialysis, chelation, or both.
Lead
Lead is the sixth most ubiquitous metal on our planet, and its use
by humans was extensive in early recorded history. Exposure occurs
through air, water, and food. The elimination of lead in gasoline has
dramatically reduced levels of lead in the air in the United States.
Even now, after its removal from gasoline and paints, lead continues
to be an environmental hazard, with varied sources of exposure in a
multitude of industries. Although lead can be absorbed through the
olfactory tract, lungs, skin, and digestive tract, the main route of
exposure is oral. Adults usually absorb about 15%–20% of intake;
children usually absorb about 45%.
Mechanism of neurotoxicity is primarily based on lead’s affinity for
sulfhydryl groups, which interferes with calcium-dependent protein
kinase C and disrupts many cellular events, such as cell growth
regulation, learning, and memory. The three major
neurotransmission systems that lead disrupts are the dopaminergic,
cholinergic, and glutaminergic systems (Sharma et al. 2014). The N-
methyl-D-aspartate receptor is a direct target for lead in the brain,
and lead’s action at these receptors interferes with glutaminergic
neurotransmission, inducing learning and memory deficits (Sanborn
et al. 2002). In the central nervous system, neuronal damage is
evident in the hippocampal CA1 and CA3 regions.
Toxicity is confirmed by demonstrating elevated concentration of
lead in blood, hair, and urine. The most common detoxification
available for lead poisoning is chelation therapy. The use of N-acetyl
cysteine has been shown to be helpful in reducing oxidative stress.
Manganese
Manganese is an essential trace element that is widely distributed
in the earth’s crust. Manganese is used in the production of dry-cell
batteries, metal alloys, fungicides, germicides, antiseptics, glass,
matches, fireworks, fertilizer, animal feeds, paints, varnish, welding
rods, and antiknock gasoline additives (Farina et al. 2011; Roels et
al. 2012). Exposure is usually by inhalation via welding fumes or the
oral route. Neurological symptoms have been attributed to
manganese fumes generated during welding. Intestinal absorption is
estimated at 3%. After its absorption through the intestinal wall,
manganese is carried through the blood stream bound to plasma
and crosses the blood-brain barrier with iron through a saturable
transport mechanism, primarily across the cerebral capillary-glial
network.
Manganese can form the powerful species Mn3+, which can
oxidize catecholamines, generating superoxide and hydroxyl
radicals. Oxidative stress results in depletion of protective enzymes
and substrates, such as reduced glutathione. As noted above,
manganese crosses the blood-brain barrier with iron. As a result, the
formation of 6-hydroxydopamine damages neuromelanin cells in the
substantia nigra and locus coeruleus, as well as cells in the caudate
nucleus, pallidum, putamen, and thalamus. A protein transporter of
manganese into astrocytes is responsible for the accumulation of
manganese in the brain. Caspase enzymes signaling programmed
cell death play a critical role in manganese-induced apoptotic cell
death and neurotoxicity (Farina et al. 2011).
Urinary manganese does indicate recent exposure. Chelation
therapy with calcium disodium EDTA may hasten elimination, but it
has limited success when administered in the presence of existing
neurological damage. Selenium is reported to protect neonates
against neurotoxicity from prenatal exposure to manganese (Yang et
al. 2014).
Mercury
The general population is exposed to mercury primarily by
inhalation and fish consumption. Mercury enters the atmosphere
from the smelting of the ore and the burning of coal. Levels in the
atmosphere range from 4 to 50 ng/m3. Levels in coastal and surface
waters average 6 ng/L and 50 ng/L, respectively. Mercury is utilized
in the manufacture of electric meters, batteries, industrial control
instruments, and fungicidal paints, in the production of chloralkali,
and a catalyst. Mercury in elemental form is a liquid and poorly
absorbed through the gastrointestinal tract; however, it vaporizes
easily. Elemental mercury vapor is well absorbed by inhalation, with
an affinity for the CNS. Organic mercury, particularly methylmercury,
is lipid soluble and is absorbed well through the gastrointestinal tract,
crosses the blood-brain barrier, and has substantial neurotoxic
effects (Farina et al. 2013).
Mercury has a high affinity for sulfhydryl groups, leading to
inhibition of numerous enzymes, including choline acetyltransferase.
Mercury also binds to membrane proteins, causing disruption of
transport processes, mitochondrial energy metabolism in skeletal
muscle, and apoptosis in the cerebellum. Methylmercury-mediated
oxidative stress plays an important role in the in vivo pathological
process of intoxication. During methylmercury-induced neurotoxicity,
degeneration of the granule cell layer in the cerebellum occurs, and
this leads to deficits in motor function. Methylmercury appears to act
preferentially on cerebellar granule cells through an increased
spontaneous release of glutamate, which, when coupled with
methylmercury’s ability to impair glutamate uptake by astrocytes,
would cause calcium-mediated cell death (Farina et al. 2011).
Presence of mercury in blood, urine, and hair testing helps
confirm the diagnosis. The use of penicillamine is helpful in the
treatment of poisoning with elemental and inorganic mercury, but it
has minimal benefit in patients with organic mercury intoxication.
Gases
The neuropsychiatric manifestations of exposure to selected
gases are shown in Table 9–4. Sources and routes of exposure,
mechanisms of neurotoxicity, diagnostic procedures, and treatment,
if available, for exposure to the selected gases are discussed below.
TABLE 9–4. Neuropsychiatric sequelae following exposure to selected
gases
Gas Neuropsychiatric symptoms

Carbon monoxide Impaired cognitive efficiency and flexibility and verbal
and visual memory; disorientation; irritability;
distractibility; masklike facies; dementia; amnesia
Ethylene oxide Polyneuropathy; diminished intelligence; impaired
verbal and visual memory and auditory and visual
attention
Formaldehyde Light-headedness; dizziness; impaired concentration
and memory; mood alteration
Hydrogen sulfide Headaches; dizziness; light-headedness;
nervousness; fatigue; sleep disturbances;
extremity weakness; spasms; convulsions;
delirium; impaired cognition, memory, and
psychomotor and perceptual abilities
Carbon Monoxide
Carbon monoxide (CO) poisoning continues to be a significant
cause of death throughout the world. Health concerns about CO
have increased greatly following results of studies in developing
countries showing a strong correlation between increasing CO levels
in air pollution and the incidence of neuropsychiatric and
neurological disorders. Also notable is the correlation between long-
term exposure of residents in those areas and the incidence of
dementia. In children, the most sensitive population, the greatest
concern is the strong correlation between CO levels in air pollution
and notable decreases in intelligence.
The most common sources of CO poisoning are the incomplete
combustion of carbon-based fuels and inadequate ventilation and
the operation of machinery using internal combustion engines.
Space heaters, oil or gas burners, tobacco smoke, blast furnaces,
and building fires are other sources of the gas. In the United States,
approximately 3,500 deaths occur each year because of CO
intoxication, and an even greater number of individuals experience
neurological damage because of subacute chronic exposure (Dart
2004).
CO combines with hemoglobin to form carboxyhemoglobin, a form
unable to carry oxygen, resulting in hypoxia in the central nervous
system. The affinity of hemoglobin for carbon monoxide is 200 times
greater than for oxygen and accounts for CO’s lethality. Factors
involved in determining the toxicity of CO include the concentration
in air, duration of exposure, respiratory minute volume, cardiac
output, hematocrit, and oxygen demand. Children are inherently
more sensitive than adults because of their faster metabolic rate. CO
increases intracranial pressure due to transudation across capillaries
of the brain.
Pathological changes in the brain observed in postmortem
examination include congestion, edema, petechial hemorrhage, focal
necrosis, and perivascular infarcts. The characteristic pathology of
CO toxicity is bilateral necrosis of the globus pallidus. The
hippocampus, cerebral cortex, cerebellum, and substantia nigra are
also vulnerable to CO toxicity (Block and Calderón-Garcidueñas
2009). The clinical features of CO poisoning roughly correlate with
the carboxyhemoglobin levels. Laboratory tests are usually not
helpful in establishing the diagnosis. Treatment involves control of
the airway, supportive breathing, high oxygen concentration therapy,
and cardiac monitoring. Supplemental oxygen is continued until
carboxyhemoglobin levels are significantly reduced.
Ethylene Oxide
Ethylene oxide (EtO) is an intermediary agent used in the
production of polyester fibers and rayon, photographic films,
antifreeze, bottles, and glycol ethers. Health care workers are
exposed through the use of EtO as a sterilizing agent for heat-
sensitive materials in central supply units. EtO is a highly reactive
gas and can produce a primary axonal neuropathy. At present, no
treatment is known for EtO poisoning. Symptoms improve when the
exposed individual is removed from the environment containing the
gas (Dart 2004).
Solvents
The neuropsychiatric manifestations of subacute chronic
exposure to selected gases are shown in Table 9–5. Sources and
routes of exposure, mechanisms of neurotoxicity, diagnostic
procedures, and methods of detoxification are discussed below for
the selected solvents.
TABLE 9–5. Neuropsychiatric sequelae following exposure to selected
solvents
Solvents Neuropsychiatric symptoms

Carbon disulfide Psychosis; depression; personality change; insomnia;
retarded speech; impaired hand-eye coordination,
motor speed, energy level, psychomotor
performance, reaction time, vigilance, visual-motor
functions, and construction
Methanol Visual toxicity with diminution of pupillary light reflex,
loss of visual acuity, and papilledema;
parkinsonian syndrome with reduced emotions,
hypophonia, masklike facies, tremor, rigidity, and
bradykinesia
Methyl chloride Somnolence; confusion; euphoria; personality
change; depression; emotional lability; impaired
psychomotor speed, vigilance, reaction time, and
hand-eye coordination
Trichloroethylene Headaches; dizziness; fatigue; diplopia; anxiety;
lability; insomnia; impaired concentration, manual
dexterity, reaction time, memory, and visuospatial
accuracy
Source. Bleecker 1994; Bolla and Roca 1994.
Hydrocarbon solvents have been used for many years as

therapeutic agents for anesthesia, in the chemical industry to
dissolve chemicals, as refrigerant agents, as typewriter correction
fluid, and as cleaning agents. Workers are exposed primarily through
inhalation and dermal exposure. Trichloroethylene, primarily used in
dry cleaning, is well known for causing peripheral neuropathy,
particularly of the trigeminal nerve. Methyl alcohol is used as a
gasoline additive, antifreeze, and feedstock for the synthesis of other
organic chemicals. N-hexane is an industrial solvent that can also be
found in gasoline. Abuse of solvents occurs commonly through
sniffing of glue or paint.
A history of exposure, cognitive impairment as shown on a
neuropsychological test battery, and the presence of clinical
symptoms are helpful in establishing the diagnosis of solvent toxicity
(Dobbs 2009). At present, few treatments exist for solvent-induced
neurotoxicity. Improvement is noted as symptoms decrease when
the patient is removed from the offending agent. Treatment primarily
involves minimizing future exposure. Monitoring of levels in the
workplace is helpful.
Toxins
Well-known syndromes of neurotoxicity have arisen from contact
of man with marine, microbial, plant, and animal species and have
led to episodes of poisoning in humans. The syndromes, symptoms,
procedures for care and stabilization, and antidotes are well known.
(For a complete review of the general toxicology of known marine,
microbial, fungal, plant, and animal toxins, see Dart 2004.)
Increased awareness of the dangers of mold and mycotoxins
followed the aftermath of hurricanes Katrina and Rita along the Gulf
Coast of the United States and the resultant fungal growth in
thousands of buildings, including homes, schools, and workplaces,
that sustained water damage (Chew et al. 2006; Rando et al. 2012).
Subsequently, physicians are increasingly encountering patients
made ill by exposure to water-damaged environments, mold, and
mycotoxins. Guidelines for recognition, diagnosis, management, and
treatment have been issued (Storey et al. 2004).
This section focuses on mycotoxins and serves to illustrate that
the practicing neuropsychiatrist is in a unique position to diagnose
conditions related to mycotoxin exposure, provide treatment using a
collaborative team approach, and initiate environmental interventions
on behalf of the patient.
Indoor fungal contamination has increased over the past 30 years.
Americans currently spend 90% of their time indoors. In the early
1970s, an oil embargo, with the resultant effect on energy
conservation, prompted a tightening of the design in construction of
buildings. The increased sealing off of the indoor environment from
the outdoor environment led to variations in fungal spore
concentrations indoors relative to the outside air and decreased the
ability for moisture exchange. As a result, minor water leaks from
poorly designed, operated, and/or maintained HVAC systems
resulted in indoor fungal growth. Mycotoxins appear in water-
damaged homes and buildings as intrusion of water into houses,
offices, and buildings leads to the growth of mold. Building materials,
including wood and wood products, insulation materials, carpet,
fabric and upholstery, drywall, and cellulose substrates (e.g., paper
and paper products, cardboard, ceiling tiles, wallpaper), are suitable
nutrient sources for fungal growth (Hope 2013). School buildings are
particularly vulnerable to indoor air problems, and increasing
numbers of students and teachers have sought evaluation for
symptoms. The CNS effects of exposure to mycotoxins in water-
damaged buildings from multiple species, each producing multiple
mycotoxins and consequently differing health effects of exposure,
are termed mixed mold mycotoxicosis. In addition to mycotoxins,
mold, mold spores, and spore fragments and bacteria and bacterial
endotoxins are found in water-damaged buildings. People with a
documented history of chronic mold exposure can display a range of
symptoms, including severe fatigue, malaise, and severe
neurocognitive impairment, which appear to be related to the length
of exposure (Morris et al. 2015). The most common groups of
neurotoxic mycotoxins found in indoor environments are the
trichothecenes, ochratoxins, and aflatoxins.
Trichothecene toxins are produced by a variety of different
species of fungi, such as Stachybotrys and Fusarium. Ochratoxins
are fungal metabolites produced by Aspergillus and Penicillium
species. Aflatoxins are produced by Aspergillus flavus and various
species of Penicillium, Rhizopus, Mucor, and Streptomyces. Chronic
exposure to mycotoxins may cause injury to the gastrointestinal tract
(Karunasena et al. 2010). For example, vomitoxin (or
deoxynivalenol) provokes intestinal inflammation in vivo (Pinton and
Oswald 2014). Ingestion of this toxin induces significant increases in
the levels of proinflammatory cytokines and chemokines. Bacterial
translocation as a result of mycotoxin-induced damage to the
intestinal endothelium, another source of lipopolysaccharides, is
known to provoke neurotoxicity and is the cause of chronic immune
activation. In addition to the adverse effects on the CNS in humans,
exposure to mycotoxins involves multiple organ systems, such as
the upper and lower respiratory tracts and the gastrointestinal,
urinary, and circulatory systems, as well as the peripheral nervous
system.
A significant body of literature exists regarding the
neuropsychiatric and neuropsychological effects of mixed-mold
exposure in the form of independent case series. Studies of more
than 1,600 patients experiencing ill effects from fungal exposure
were presented in 2003 at the 21st Annual International Symposium
on Man & His Environment in Health and Disease. Two of the case
series—comprising 48 and 150 mold-exposed patients, respectively
—found significant fatigue and weakness in 70% and 100% of
cases, respectively, and neurocognitive dysfunction, including
memory loss, irritability, anxiety, and depression, in more than 40%
of the patients in both series (Curtis et al. 2004). Classic
manifestations of neurotoxicity, including numbness and tingling,
ataxia, and tremor, were observed in a significant number of
patients. A study evaluated 119 mixed mold-exposed patients whose
subjective complaints included severe fatigue, depression,
decreased muscle strength, sleep disturbances, numbness and
tingling of extremities, tremors, and headaches. Objectively, more
than 80% of individuals had abnormal nerve conduction velocities
and the presence of neuronal antibodies (Brewer et al. 2013;
Campbell et al. 2003). Mycotoxins are cytotoxic and disrupt protein
synthesis and increase cellular oxidative stress, with resultant DNA
damage. Mycotoxins also have both immunosuppressive effects and
stimulant effects. In animal models, trichothecene toxins disrupt the
integrity of the blood-brain barrier and cause neuronal degeneration
in the cerebral cortex and neuronal cell apoptosis and inflammation
in the olfactory epithelium and olfactory bulb. Trichothecenes are
extremely neurotoxic and have been used as chemical warfare
agents. Much of the toxicity from trichothecene toxin is the result of
the inhibition of protein synthesis. Ochratoxin causes acute depletion
of striatal dopamine and its metabolites.
Patients with fungal exposure via inhaled spores usually carry a
source of continued exposure with them. Mold spores to which a
patient is exposed will often reside in an oily biofilm in the sinus
cavities and continue to produce mycotoxins even years after the
individual has been removed from the site of exposure (Brewer et al.
2013; Storey et al. 2004). Patients, over time, are reported to
develop Dennis-Robertson syndrome, a fungal sinusitis
endocrinopathy marked by anterior hypopituitarism following
exposure to mold. In a retrospective study of mold-exposed patients
with prominent fatigue and chronic rhinosinusitis, significant
deficiency of serum human growth hormone was confirmed by
insulin tolerance test in 80% (40 of 50) of those tested.
Adrenocorticotrophic hormone deficiency and primary or secondary
hypothyroidism were seen in 75% (59/79) and 81% (64/79) of
patients, respectively. Review of the literature indicates that the
mechanism of growth hormone deficiency following fungal exposure
involves glucan receptors in the lenticulostellate cells of the anterior
pituitary binding to fungal cell wall glucans, activating the innate
immune system, leading to destruction of lenticulostellate tissue in
the pituitary (Dennis et al. 2009; Storey et al. 2004). Treatment of
patients has included saline nasal irrigations, antifungal nasal
sprays, appropriate use of oral antibiotics, and hormone
replacement.
A neuropsychiatrist should evaluate patients with an
environmental assessment during the initial interview. It is important
to elicit a patient’s history of exposure to mold whether in the
workplace or at home. The initial presentation of the patient exposed
to fungal toxins often involves neuropsychiatric symptoms. For
symptomatic patients having a history of exposure to mold,
evaluation should include a neuropsychiatric examination that
includes a comprehensive genogram looking for autoimmune
disorders. Laboratory testing should include a complete blood count
with platelet and differential. A comprehensive metabolic panel that
includes electrolytes, blood glucose, liver and kidney function tests,
hemoglobin A1C, urinalysis, and a urinary mycotoxin analysis by
enzyme-linked immunosorbent assay (ELISA) testing should be
performed. Immunological testing should include an immunoglobulin
profile, an immunoglobulin G (IgG) subpanel panel, complement C3a
and C4a, human leukocyte antigen (HLA) testing for susceptibility,
and IgG fungal antibodies. Endocrine panels should include thyroid
function tests, estrogen and testosterone levels, and prolactin levels.
magnetic resonance imaging of the pituitary and brain is helpful in
determining neurological injury. Presence of mycotoxins in the urine
usually confirms the diagnosis. Quantitative testing for urinary
mycotoxins via ELISA is now available. Depending on results,
consultations are ordered in specialty areas of endocrinology,
otolaryngology, infectious disease, allergy and immunology, and
rheumatology. A complete endocrine workup and evaluation for
pituitary insufficiency is essential. An otolaryngologist should be
consulted for evaluation of the nasal cavities and sinuses.
The most important facet of treatment involves preventing any
further exposure of the patient to mold. The potent toxicity of these
agents warrants prudent prevention of exposure when levels of mold
species indoors exceed outdoor levels by any significant amount.
Conclusion
In an era marked by an unprecedented use of industrial and
agricultural chemicals, it is important that health practitioners
consider and explore toxicological factors when encountering
patients with mental health complaints. With the realization that
environmental agents may be responsible for the dramatic increase
in neuroinflammatory, autoimmune, and degenerative processes in
the brain, it is becoming increasingly important that physicians learn
to recognize the etiology, because the initial symptoms may be
subtle in nature and not fit the criteria for any specific illness.
There has been insufficient attention given to environmental
health and human exposure assessment in medical education, and
physicians are generally not equipped to assess and manage
chemical exposure. The process of diagnosis is often difficult
because demonstrating cause and effect between exposure and
illness is difficult. Chronic low-level exposures often lead to vague
and insidious symptoms in the early stages of toxicity. Moreover,
individual responses to specific toxins involve a myriad of factors,
including genetic vulnerability, psychological status, and individual
physiology; outcomes are frequently nonspecific; and the clinical
index of suspicion often remains low. As a result, diagnosis of
environmentally induced illness often requires using a different
approach involving a stage of medicine that is more intuitive than
precise.
It is important to incorporate an environmental assessment in the
neuropsychiatric evaluation of every patient. Categorizing by the
three most common sites of exposure—namely, work, home, and
school—is a simplified and structured approach for an initial
evaluation. In the treatment of environmentally related exposures, a
collaborative team effort with physicians in different specialty areas
in the treatment of patients is essential.
References
Bleecker M: Clinical presentation of selected neurotoxic compounds, in
Occupational Neurology and Clinical Neurotoxicology. Edited by Bleecker ML,
Hansen J. Baltimore, MD, Williams & Wilkins, 1994, pp 207–233
Block ML, Calderón-Garcidueñas L: Air pollution: mechanisms of
neuroinflammation and CNS disease. Trends Neurosci 32(9):506–516, 2009
19716187
Blumberg SJ, Bramlett MD, Kogan MD, et al: Changes in prevalence of parent-
reported autism spectrum disorder in school-aged U.S. children: 2007 to 2011–
2012. National Health Statistics Reports no 65. National Center for Health
Statistics, March 20, 2013. Available at:
http://www.cdc.gov/nchs/data/nhsr/nhsr065.pdf. Accessed November 17, 2016.
Bolla KI, Roca R: Neuropsychiatric sequelae of occupational exposure to
neurotoxins, in Occupational Neurology and Clinical Neurotoxicology. Edited by
Bleecker ML, Hansen J. Baltimore, MD, Williams & Wilkins, 1994, pp 133–159
Brewer JH, Thrasher JD, Hooper D: Chronic illness associated with mold and
mycotoxins: is naso-sinus fungal biofilm the culprit? Toxins (Basel) 6(1):66–80,
2013 24368325
Campbell AW, Thrasher JD, Madison RA, et al: Neural autoantibodies and
neurophysiologic abnormalities in patients exposed to molds in water-damaged
buildings. Arch Environ Health 58(8):464–474, 2003 15259425
Cherry JD, Olschowka JA, O’Banion MK: Neuroinflammation and M2 microglia: the
good, the bad, and the inflamed. J Neuroinflammation 11:98, 2014 24889886
Chew GL, Wilson J, Rabito FA, et al: Mold and endotoxin levels in the aftermath of
Hurricane Katrina: a pilot project of homes in New Orleans undergoing
renovation. Environ Health Perspect 114(12):1883–1889, 2006 17185280
Costa LG, Cole TB, Coburn J, et al: Neurotoxicants are in the air: convergence of
human, animal, and in vitro studies on the effects of air pollution on the brain.
BioMed Res Int 2014:736385, 2014 24524086
Curtis L, Lieberman A, Stark M, et al: Adverse health effects of indoor molds. J
Nutr Environ Med 14(3):261–274, 2004
Dart RC: Medical Toxicology. Philadelphia, PA, Lippincott, Williams & Wilkins, 2004
Dennis D, Robertson D, Curtis L, et al: Fungal exposure endocrinopathy in
sinusitis with growth hormone deficiency: Dennis-Robertson syndrome. Toxicol
Ind Health 25(9–10):669–680, 2009 19808744
Dobbs MR: Clinical Neurotoxicology: Syndromes, Substances, Environments.
Philadelphia, PA, Saunders/Elsevier, 2009
Dobbs MR, Rusyniak DE: Frontiers in Clinical Neurotoxicology. Preface. Neurol
Clin 29(3):xi–xii, 2011 21803208
Doi K, Uetsuka K: Mechanisms of mycotoxin-induced neurotoxicity through
oxidative stress-associated pathways. Int J Mol Sci 12(8):5213–5237, 2011
21954354
Farina M, Rocha JB, Aschner M: Mechanisms of methylmercury-induced
neurotoxicity: evidence from experimental studies. Life Sci 89(15–16):555–563,
2011 21683713
Farina M, Avila DS, da Rocha JB, et al: Metals, oxidative stress and
neurodegeneration: a focus on iron, manganese and mercury. Neurochem Int
62(5):575–594, 2013 23266600
Fasano A: Zonulin and its regulation of intestinal barrier function: the biological
door to inflammation, autoimmunity, and cancer. Physiol Rev 91(1):151–175,
2011 21248165
Galland L: The gut microbiome and the brain. J Med Food 17(12):1261–1272,
2014 25402818
Genuis SJ, Schwalfenberg G, Siy AK, et al: Toxic element contamination of natural
health products and pharmaceutical preparations. PLoS One 7(11):e49676,
2012 23185404
Halaris A, Leonard BE: Inflammation in Psychiatry. Basel, Switzerland, Karger,
2013
Hope J: A review of the mechanism of injury and treatment approaches for illness
resulting from exposure to water-damaged buildings, mold, and mycotoxins.
Scientific World Journal 2013:767482, 2013 23710148
Karunasena E, Larrañaga MD, Simoni JS, et al: Building-associated neurological
damage modeled in human cells: a mechanism of neurotoxic effects by
exposure to mycotoxins in the indoor environment. Mycopathologia
170(6):377–390, 2010 20549560
Kraft AD, Harry GJ: Features of microglia and neuroinflammation relevant to
environmental exposure and neurotoxicity. Int J Environ Res Public Health
8(7):2980–3018, 2011 21845170
López-Granero C, Cañadas F, Cardona D, et al: Chlorpyrifos-,
diisopropylphosphorofluoridate-, and parathion-induced behavioral and
oxidative stress effects: are they mediated by analogous mechanisms of
action? Toxicol Sci 131(1):206–216, 2013 22986948
Louveau A, Smirnov I, Keyes TJ, et al: Structural and functional features of central
nervous system lymphatic vessels. Nature 523(7560):337–341, 2015
26030524
Morley WA, Seneff S: Diminished brain resilience syndrome: a modern day
neurological pathology of increased susceptibility to mild brain trauma,
concussion, and downstream neurodegeneration. Surg Neurol Int 5:97, 2014
25024897
Morris G, Berk M, Walder K, et al: Central pathways causing fatigue in neuro-
inflammatory and autoimmune illnesses. BMC Med 13:28, 2015 25856766
Najjar S, Pearlman DM, Alper K, et al: Neuroinflammation and psychiatric illness. J
Neuroinflammation 10:43, 2013 23547920
Pinton P, Oswald IP: Effect of deoxynivalenol and other Type B trichothecenes on
the intestine: a review. Toxins (Basel) 6(5):1615–1643, 2014 24859243
Pollard KM, Hultman P, Kono DH: Toxicology of autoimmune diseases. Chem Res
Toxicol 23(3):455–466, 2010 20078109
Rando RJ, Lefante JJ, Freyder LM, et al: Respiratory health effects associated
with restoration work in post-Hurricane Katrina New Orleans. J Environ Public
Health 2012:462478, 2012 23365586
Roberts RA, Smith RA, Safe S, et al: Toxicological and pathophysiological roles of
reactive oxygen and nitrogen species. Toxicology 276(2):85–94, 2010
20643181
Roels HA, Bowler RM, Kim Y, et al: Manganese exposure and cognitive deficits: a
growing concern for manganese neurotoxicity. Neurotoxicology 33(4):872–880,
2012 22498092
Samsel A, Seneff S: Glyphosate, pathways to modern diseases, III: manganese,
neurological diseases, and associated pathologies. Surg Neurol Int 6:45, 2015
25883837
Sanborn MD, Abelsohn A, Campbell M, et al: Identifying and managing adverse
environmental health effects: 3. lead exposure. CMAJ 166(10):1287–1292,
2002 12041847
Schippa S, Conte MP: Dysbiotic events in gut microbiota: impact on human health.
Nutrients 6(12):5786–5805, 2014 25514560
Seneff S, Swanson N, Li C: Aluminum and glyphosate can synergistically induce
pineal gland pathology: connection to gut dysbiosis and neurological disease.
Agricultural Sciences 6:42–70, 2015
Sharma B, Singh S, Siddiqi NJ: Biomedical implications of heavy metals induced
imbalances in redox systems. BioMed Res Int 2014:640754, 2014 25184144
Shaw CA, Seneff S, Kette SD, et al: Aluminum-induced entropy in biological
systems: implications for neurological disease. J Toxicol 2014:491316, 2014
25349607
Storey E, Dangman KH, Schenck P, et al: Guidance for clinicians on the
recognition and management of health effects related to mold exposure and
moisture indoors. University of Connecticut Health Center, Division of
Occupational and Environmental Medicine, Center for Indoor Environments
and Health, September 30, 2004. Available at:
http://health.uconn.edu/occupational-environmental/wp-
content/uploads/sites/25/2015/12/mold_guide.pdf. Accessed November 17,
2016.
Tolins M, Ruchirawat M, Landrigan P: The developmental neurotoxicity of arsenic:
cognitive and behavioral consequences of early life exposure. Ann Glob Health
80(4):303–314, 2014 25459332
Vojdani A: A potential link between environmental triggers and autoimmunity.
Autoimmune Dis 2014:437231, 2014 24688790
Vyas U, Ranganathan N: Probiotics, prebiotics, and synbiotics: gut and beyond.
Gastroenterol Res Pract 2012:872716, 2012 23049548
Wang Y, Kasper LH: The role of microbiome in central nervous system disorders.
Brain Behav Immun 38:1–12, 2014 24370461
Yang X, Bao Y, Fu H, et al: Selenium protects neonates against neurotoxicity from
prenatal exposure to manganese. PLoS One 9(1):e86611, 2014 24466170
CHAPTER 10
Epilepsy and Seizures

David K. Chen, M.D.
For more than a century, clinicians have observed a strong link

between epilepsy and psychiatry as evidenced by frequent
psychopathologies, psychosocial disturbances, and cognitive deficits
among people with epilepsy. In many countries, until recently,
epilepsy was conceptualized as a mental health disorder.
Epilepsy can be associated not only with episodic behavioral
disorders ictally and during the peri-ictal period but also with chronic
behavioral disturbances interictally. Indeed, even when optimal
seizure control is achieved and cognitive impairment is absent,
epidemiological studies have shown greater vulnerability of people
with epilepsy toward psychosocial distress (Sillanpää et al. 1998). A
wide variety of etiologies affecting the central nervous system (CNS)
can involve very similar behavioral signs and symptoms (Table 10–
1).
TABLE 10–1. Primary signs and symptoms of central nervous system
disturbances
Cognitive
Affective dysregulation
Communication/language dysfunction
Intellectual impairment
Impaired judgment
Dysmnesia/inattention
Disorientation
Behavioral
Anxiety
Alteration in arousal
Mood (elevation, depression, apathy)
Motor (hyperkinetic, hypokinetic, or akinetic)
Personality traits/changes
Dyspraxia
Perceptions
Auditory
Gustatory
Kinesthetic pain/paresthesias/anesthesia
Olfactory
Visual
Source. Adapted from Tucker 2002, p. 674.
In this chapter, we first provide an overview of the evaluation and

management of epilepsy, focusing on the diverse neurobehavioral
manifestations of seizures as influenced by seizure origin and extent
of electrical propagation. In subsequent sections, we review the
evaluation and management of the more common neuropsychiatric
complications and comorbidities of the epilepsies and seizures.
Classification and Neurobehavioral
Manifestations of Seizures and Epilepsy
Electrical Seizure Versus Epilepsy

An electrical seizure is a transient occurrence of signs and/or
symptoms due to abnormal excessive or synchronous neuronal
activity in the brain. As implied in this definition, electrical seizure
describes a broad spectrum of clinical manifestations
(signs/symptoms) rather than a specific disease entity. Several
disease entities can cause electrical seizures, including epileptic
seizures, febrile seizures, and physiologic nonepileptic events, for
example, alcohol/sedative withdrawal states, significant electrolyte
disturbances, and oxygen deprivation from cardiac arrhythmia.
Epilepsy, more specifically, is defined as a family of disorders of
the brain characterized by an enduring predisposition to generate
unprovoked electrical seizures (i.e., without obvious systemic
disturbances known to trigger seizures). Historically, the diagnosis of
epilepsy is established after a patient has experienced two or more
unprovoked seizures, with the first two seizures being greater than
24 hours apart (Fisher et al. 2014). An International League Against
Epilepsy (ILAE) task force recommended broadening the definition of
epilepsy to address special circumstances when seizure propensity
is substantial, despite the patient having had only one unprovoked
seizure. The ILAE task force advised that epilepsy can be diagnosed
after a single unprovoked seizure, should the probability of further
seizures be similar to the general recurrence risk (~60%) after two
unprovoked seizures, occurring over the next 10 years (Fisher et al.
2014). Some clinical circumstances associated with heightened
probability of future seizures include the presence of remote brain
insults, such as a stroke, CNS infection, or trauma (Hesdorffer et al.
2009).
The term seizure, as noted in the ILAE consensus, refers to
sudden onset of symptoms that take hold of the patient, hence
preventing normal function in some ways. Electrical or epileptic
activity is frequently but not inherently invested in the word seizure,
as this term has been used to describe other nonepileptic
phenomena, such as psychogenic nonepileptic seizures (PNES) or
physiologic nonepileptic events (e.g., convulsive syncope). When
referring specifically to seizures of electrical origin, this term is
frequently modified by the preceding descriptive term “epileptic” or
“electrical.”
Classification of Seizures and Epilepsies

The terminology and concepts for organization of seizures and
epilepsies are constantly evolving, particularly consequent to recent
advances in neuroimaging, genomic technologies, and molecular
biology. Seizures are classified, by mode of seizure onset, as focal
or generalized seizures.
Focal seizures are conceptualized as seizures that originate from
epileptogenic networks (a system of neurons) that are limited to one
hemisphere. A focal epileptogenic network gives rise to seizures that
demonstrate fairly stereotyped clinical manifestations. The old
terminology added the descriptive term complex to denote seizures
involving impairment of consciousness or awareness, while the term
simple describes seizures without such impairment. However, the
extent of ictal sensorium can frequently be difficult to define
precisely. The new 2010 ILAE terminology recommends that focal
seizures should be described according to their clinical
manifestations (e.g., dyscognitive, focal motor), without trying to fit
them into “complex” or “simple” categories that sometimes cannot be
precisely distinguished (Berg et al. 2010).
Generalized epileptic seizures are conceptualized as seizures that
rapidly engage bilaterally distributed epileptogenic networks. Such
bilateral epileptogenic networks do not necessarily have to involve
the entire cerebral cortex in a “generalized” sense. In most
instances, limited bilateral cortical and subcortical structures are
involved in the inception of generalized seizures.
Under the 2010 ILAE classification, some epilepsies that involve
exclusively either focal or generalized seizures can be classified as
focal (localization-related) or generalized epilepsies, respectively.
However, the task force recognizes that many epilepsies can include
both seizure types and hence discourages the universal use of
overarching categories for classifying epilepsies across all cases.
The consideration of epilepsy etiologies is fundamental to the
understanding of this family of disorders. The new classification for
epilepsies also includes revisions of the descriptors of etiology (Berg
et al. 2010). Instead of the old terms “idiopathic,” “symptomatic,” and
“cryptogenic,” the following three new descriptors of etiology are
recommended:
1. The term genetic describes epilepsy as the direct result of

known/presumed genetic defect(s) of which seizures are the
primary sequelae.
2. The terms structural and metabolic refer to the presence of
distinct structural or metabolic conditions or diseases with
demonstrated propensity toward epileptogenesis.
3. The term unknown indicates that the underlying cause is not
yet identified.
Finally, the ILAE task force recognizes that the degree of

specificity to which the patients’ epilepsies are aligned within
particular “syndromes” (e.g., seizure types, electroencephalogram
[EEG] characteristics, age at onset) can portend significant
prognostic and therapeutic implications. Such syndromic diagnosis
would notably influence how patients are managed clinically or
investigated in research studies. Ordered from the most specific
(top) to the least specific (bottom), the syndromic categories are
listed in Table 10–2.
TABLE 10–2. Epilepsy syndromes and epilepsies, as characterized by the

International League Against Epilepsy Commission on Classification and
Terminology (2010) based on specificity of diagnosis
I. Electroclinical syndromes (arranged by age at seizure onset)

Neonatal period
Example: benign familial neonatal epilepsy
Infancy
Example: Dravet syndrome
Childhood
Example: Lennox-Gastaut syndrome
Adolescence–Adult
Example: juvenile myoclonic epilepsy
Less specific age relationship
Example: reflex epilepsies
II. Distinctive constellations
Example: mesial temporal lobe epilepsy with hippocampal sclerosis
III. Epilepsies attributed to and organized by structural-metabolic
causes
Examples: tumor, trauma, stroke
IV. Epilepsies of unknown cause
Note. Diagnoses ordered from the most specific (top) to the least specific
(bottom).
Source. Adapted from Berg et al. 2010.
Neurobehavioral Manifestations of Focal Epileptic

Seizures
The semiology of seizures results from activation of specific and
eloquent cortical areas by the ictal discharges and can help lateralize
and/or localize the seizure focus. Knowledge of cortical
representation as well as corresponding ictal symptomatology is
particularly important in the presurgical evaluation of epilepsy
surgery candidates. In addition, such recognition can help distinguish
neurobehavioral manifestations typical of epileptic seizures from
atypical presentations warranting alternative etiological
considerations.
Each of the seizure types is described briefly below, with
acknowledgment that clinical manifestations can vary across a wide
spectrum, ranging from the full constellation of symptoms occurring
in the sequence described to relatively fleeting or isolated subjective
symptoms during which consciousness is intact.
Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) represents the most common type
of focal epilepsy, accounting for approximately two-thirds (66%) of
focal epilepsies (Semah et al. 1998), implicating the inherent
vulnerability of the temporal lobe to epileptogenesis. In TLE, an
overwhelming majority (~90%) of seizures arise from the mesial
temporal region, frequently involving the hippocampus or
perihippocampal structures (Schramm et al. 2001). A focal epileptic
seizure emanating from these mesial temporal structures can
manifest at first with fairly isolated affective, psychic, visceral, or
special sensory symptoms such as fear, déjà vu, déjà entendu,
jamais vu, jamais entendu, epigastric rising, and gustatory/olfactory
perceptions, sometimes described as an aura. The most common
presentation of such focal seizures is epigastric rising, in which the
patient describes having fluttering sensations (“butterflies in
stomach”) starting at the lower abdomen and then spreading
upward. This epigastric sensation is frequently followed by
spontaneous, unprovoked perception of fear; bystanders may
observe expressions of distress in facial expression or verbalizations
(e.g., “Help me” or “Oh no”) as the correlates of these experiences.
When the electrical activity spreads beyond the mesial temporal
structures, the patient usually becomes amnestic and unconscious,
in conjunction with relative neurobehavioral arrest. Also commonly
occurring during this amnestic state are orogestural automatisms,
which can entail chewing/lip smacking movements of the mouth, as
well as semipurposeful fumbling or picking movements of the hands.
These automotor hand movements usually occur ipsilaterally to the
side of seizure onset. Meanwhile, the contralateral arm may assume
a tonically flexed posture or other forms of dystonic limb posturing.
Should the electrical activity continue to propagate outside of the
temporal lobe to involve widespread bilateral structures, then the
patient can demonstrate generalized convulsive activity, as
described below. Such convulsive activity is heralded by version, or
forced head turning, contralateral to the side of seizure onset.
Subsequently, the patient enters the tonic phase, whereupon all four
limbs demonstrate heightened tonicity. At times, the patient can
assume asymmetric tonic limb posturing, whereupon the elbow
contralateral to the side of seizure onset displays an extended
position, while the opposite arm flexes over the chest (i.e., figure-4
sign). Lateral temporal epileptic seizures are classically heralded by
simple auditory hallucinations, such as buzzing or ringing sounds (as
opposed to the predominant affective, psychic, and visceral
symptoms of mesial temporal seizures). At times, more complicated
auditory hallucinations, such as human voices or organized music,
can occur. Compared with mesial temporal seizures, lateral temporal
seizures usually manifest with earlier dystonic motor involvement
(rather than early oral automatisms), earlier widespread propagation
(secondary generalization), and briefer overall seizure duration
(Maillard et al. 2004).
Frontal Lobe Epilepsy

Frontal lobe epilepsy (FLE) represents approximately one-fourth
(24%) of all focal epilepsies, making FLE the second most common
type of focal epilepsy (Semah et al. 1998). Compared with other
epilepsies, seizures of frontal lobe origin frequently manifest several
unique features, including tendencies to have brief duration (<30
seconds), emerge out of sleep, present in clusters, and exhibit an
absence of or relatively mild postictal confusion. Because of the wide
expanse of the human frontal lobe, epileptic seizures from this region
have a wide variety of neurobehavioral manifestations, depending on
the particular cortical region involved.
When the epileptic seizure onset zone involves the primary motor
cortex, the patient will demonstrate contralateral focal motor
seizures, typically in the form of clonic jerking. These clonic
movements most frequently involve the hand and face, given the
comparatively large hand and facial representation on the motor
homunculus. One classic presentation is termed “Jacksonian
march,” when unilateral clonic jerking “marches” from the hand, arm,
shoulder, face, and then leg as the seizure discharge activity
spreads along the motor homunculus.
Seizures can arise from the supplementary motor area (SMA),
which resides mainly in the mesial, interhemispheric region of the
frontal lobe and anterior to the primary motor cortex. Tonic epileptic
seizures of SMA origin can sometimes manifest as the “fencing
posture,” in which the arm contralateral to the side of seizure onset is
raised and extended, while the ipsilateral arm is flexed at the elbow
and adducted toward the trunk. The head is usually turned to the
side of the extended arm.
Focal epileptic seizures emanating from the frontal operculum (the
cortex immediately above the Sylvian fissure anteriorly) are
characterized by features of excessive salivation and swallowing or
mastication mannerisms, as well as choking sensations (e.g., “lump
in throat”) that are related to ictal involvement of the laryngo-
pharyngeal muscles. Moreover, focal epileptic seizures that originate
from the dominant hemisphere operculum can be accompanied by
prominent expressive aphasia.
More floridly, focal epileptic seizures from several other regions of
the frontal lobe (i.e., ventromedial, dorsolateral, frontopolar, and
cingulate areas) can manifest as hyperkinetic seizures with complex
motoric features, where patients may jump around, thrash in bed,
rock back and forth, pound on objects, rotate around the body axis at
least 180 degrees, or make bicycling/stepping movements. These
motor manifestations are often accompanied by complex
vocalizations (e.g., screaming, yelling, shouting) during which the
patient can appear terrified. Sometimes, the patient may produce
understandable, cursing speech. Hyperkinetic FLE seizures
represent one of the rare exceptions where a patient, despite having
bilateral motor involvement, can still have preserved consciousness.
It is, therefore, not surprising that such frontal lobe epileptic seizures,
considering their bizarre nature coupled with an EEG recording that
is frequently obscured by copious movement artifacts, are
sometimes mistaken for PNES (Frontera 2014). One potentially
helpful distinguishing feature is that whereas the emotional overlay
of PNES will evolve and even enhance as the ictus progresses, the
affective components of hyperkinetic epileptic seizures are relatively
short-lived and restricted to the initial portion of the seizures. As
hyperkinetic epileptic seizures evolve and progress, these affective
components usually abate.
Parietal Lobe Epilepsy

Parietal lobe epilepsy (PLE) accounts for less than 5% of all focal
epilepsies (Semah et al. 1998). Focal epileptic seizures that arise in
and remain confined to the parietal lobe can present with
contralateral paresthetic sensory symptoms. Given that the face and
hand have the largest cortical representation on the sensory
homunculus (similar to the motor homunculus), focal PLE seizures
frequently involve paresthesias of the contralateral face and hand.
Because the parietal lobe largely consists of association cortex, it is
intricately interconnected with cerebral lobes. As such, rapid spread
of the ictal discharges to other regions leads to a wide variety of ictal
manifestations, including features that may resemble FLE or TLE.
Occipital Lobe Epilepsy

Occipital lobe epilepsy also accounts for less than 5% of all focal
epilepsies (Semah et al. 1998). Focal epileptic seizures emanating
from the primary visual cortex and visual association areas can
produce elementary visual hallucinations, such as static, flashing, or
moving lights, that take the form of basic geometric shapes. More
complex visual hallucinations of people, objects, or scenes can arise
from ictal activation of the temporo-occipital junction or basal
temporal cortex.
Neurobehavioral Manifestations of Generalized

Epileptic Seizures
Absence Epileptic Seizures
Absence epileptic seizures (historically referred to as petit mal
seizures) are characterized by paroxysmal impairment of
consciousness, during which the patient demonstrates staring and
behavioral arrest. However, unlike focal epilepsy with alteration of
consciousness, absence epileptic seizures demonstrate a briefer
ictal duration (2–30 seconds), abrupt onset (without warning
symptoms), and abrupt offset (without postictal confusion). Because
of these ictal characteristics and despite typically occurring up to
several times per day, patients are frequently unaware of their
absences. In fact, upon cessation of an absence seizure, some
patients may immediately resume preseizure activity or train of
thought—without apparent disruption. Autonomic symptoms can also
occur.
Tonic-Clonic Epileptic Seizures

The clinical manifestations of primarily generalized tonic-clonic
epileptic seizures (formerly referred to as grand mal seizures) are
characteristically similar to the tonic-clonic convulsions from focal
epilepsy that undergo widespread propagation to bilateral structures
(as noted earlier). With generalized activity, the diaphragmatic
muscles contract, producing a characteristic guttural utterance, or
“ictal cry.” The tonic phase of diffuse appendicular and axial stiffening
is followed sequentially by the clonic phase, characterized by
rhythmic, synchronous muscle contractions of the whole body,
including the face, trunk, and limbs. The seizure terminates upon
ending of the clonic phase. Consciousness is invariably impaired.
During the immediate period after a generalized convulsive
seizure occurs, the patient will temporarily demonstrate fairly deep
obtundation with accompanying deep, regular, sonorous breathing
sounds (stertorous breathing pattern).
Myoclonic, Clonic, Tonic, and Atonic Epileptic

Seizures
Myoclonic, clonic, tonic, and atonic epileptic seizures represent
additional subtypes of generalized epilepsy, and their specific
semiologies are described elsewhere (see Abou-Khalil and Misulis
2005).
Evaluation and Management of Epilepsy
Clinical Presentation
Careful and detailed evaluation of the patients’ historical seizure
presentation is among the most important elements of the diagnostic
process. Such evaluation is crucial because the diagnosis of
epilepsy is established “clinically,” meaning that a convincing
historical presentation alone may be sufficient to achieve the
diagnosis of epilepsy. Seizure workup procedures such as
electroencephalography or brain imaging provide supplementary
evidence that can be supportive but are not in themselves diagnostic
of epilepsy. In other words, the presence of epileptiform
electroencephalographic findings and/or potentially epileptogenic
substrates on imaging would not be sufficient to establish the
diagnosis of epilepsy without a convincing clinical presentation of
seizure, upon careful historical elucidation. Considering that patients
may often be amnestic regarding details of their own seizures, a
confident seizure assessment will frequently require investigation of
eyewitness accounts of the seizure manifestations.
Upon ascertaining the descriptions of seizures, an initial step in
the evaluation process should be to distinguish whether the
neurobehavioral manifestations of interest are typical of epileptic
seizures (as described earlier) or atypical of epileptic seizures such
that alternative etiologies might be possible. If the paroxysms of
interest are suggestive of epilepsy, then the next important step is to
classify the seizure type(s), as this distinction has important
implications regarding selection of antiepileptic drug (AED),
prognosis, and likelihood of underlying cerebral substrate. Key hints
for identifying seizure types can include: aura or “warning symptoms”
preceding the seizures, overt focality or asymmetry of the seizure
manifestation (especially if consistently evident), the extent of mental
status impairment, and the nature of the postictal phenomena.
Elicitation of etiology and risk factors can significantly influence
seizure classification and should include historical assessment of
febrile seizures, traumatic brain injury, strokes, brain tumor,
meningitis/encephalitis, prematurity, and birth-related injury.
Diagnostic Workups
Electroencephalography
For epilepsy workups, the main aim of a routine
electroencephalographic study is to survey for interictal epileptiform
abnormalities, which when present would indicate an underlying
propensity for seizure activity. With a clinical presentation that is
suspicious for epilepsy, the documentation of interictal epileptiform
discharges on the EEG reinforces this diagnostic impression. The
capturing of actual electrographic seizure in a routine
electroencephalographic study, while possible, occurs only rarely.
Meanwhile, the absence of interictal epileptiform abnormality does
not necessarily preclude the consideration of epilepsy, as many
epilepsies with deep epileptogenic foci (far from the cortical
convexity) can give rise to epileptiform discharges that escape scalp
electroencephalographic detection.
Moreover, the documentation of focal versus generalized
epileptiform discharges on the EEG can help distinguish epileptic
seizure types in most cases. For some cases, specific syndromic
classification of the epilepsy may be possible.
Brain Imaging
Considering that about 90% of incident cases of epilepsies in
adults are focal epilepsies, brain magnetic resonance imaging (MRI)
is indispensable in the investigation for these localized epileptogenic
substrates. Some of the more common and important epileptogenic
lesions visualized on MRI include hippocampal sclerosis, gliotic
scarring, malformations of cortical development, vascular
malformations (i.e., cavernous hemangioma and arteriovenous
malformation), and brain neoplasms. Similar to the role of the EEG,
the presence of such epileptogenic lesions on the brain MRI bolsters
the diagnostic impression of epilepsy (Fisher et al. 2014).
Management
Following a single unprovoked seizure, the risk of another is 34%
over the subsequent 5 years (Hauser et al. 1990). This risk
increases to as much as 60% should the workups uncover evidence
of enduring predisposition for seizures (i.e., culpable substrate on
brain MRI or epileptiform finding on EEG) or after the patient
sustains at least two unprovoked seizures occurring more than 24
hours apart (Hesdorffer et al. 2009). Initiation of AED therapy should
be based on a mutually agreed-upon decision between the patient
and clinician, rather than a rigid treatment algorithm. In general,
AEDs are started when the risk for seizure recurrence has reached
at least 60%.
The distinction of epileptic seizure types based on onset (focal vs.
generalized) has important implications regarding selection of AEDs,
which are categorized as either narrow spectrum or broad spectrum
(Table 10–3). Narrow-spectrum AEDs are considered effective for
focal epileptic seizures (with or without secondary generalization),
somewhat effective for primarily generalized tonic-clonic epileptic
seizures, and ineffective or possibly even detrimental for other
generalized epileptic seizures (e.g., absence epileptic seizures).
Broad-spectrum AEDs are considered effective for both focal
epileptic seizures (with or without secondary generalization) and all
types of primarily generalized epileptic seizures (Tortorice and
Rutecki 2014).
TABLE 10–3. Antiepileptic drug (AED) choices based on epilepsy type and
coverage spectrum
AED type
Narrow spectrum First-line: carbamazepine, oxcarbazepine, gabapentin
Second-line: phenytoin, pregabalin, lacosamide,
ezogabine,
primidone, phenobarbital
Third-line: vigabatrin, tiagabine
Broad spectrum First-line: lamotrigine, levetiracetam, valproate,
zonisamide
Second-line: topiramate
Third-line: benzodiazepines, felbamate, rufinamide
Source. Adapted from Tortorice and Rutecki 2014.
In addition to seizure types, the patients’ medical comorbidities

also influence the selection of AEDs. For example, gabapentin or
pregabalin can help with concurrent neuropathic pain, topiramate or
valproic acid can help prevent migraines, and lamotrigine or
carbamazepine can help stabilize comorbid mood disorder. Other
management considerations include risks of pharmacokinetic
interactions, whether the patient is a woman of childbearing
potential, and sequelae of long-term AED exposure.
Upon initiation of medication, monotherapy (use of a single AED)
should be pursued and the medication slowly titrated up to target
dosage. Adding a second AED (dual therapy) with a different
mechanism of action may be helpful when seizures do not abate.
Alternatively, substituting with a second AED as the lone agent
(monotherapy) may a more pragmatic strategy. Among patients with
newly diagnosed epilepsy, a study has shown that 60% of patients
achieve at least 1 year of seizure freedom with monotherapy of the
first or second AED trial in which therapeutic dosage is reached
(47% after the first AED, and another 13% after the second AED)
(Kwan and Brodie 2000). Should adequate trials of two monotherapy
attempts prove to be ineffective, then combination therapy (with two
or more AEDs) is more likely to lead to seizure improvement than a
third monotherapy attempt (Kwan and Brodie 2000). Moreover, there
is also some evidence that adverse effects from combination therapy
may be related to total drug load, rather than to the number of drugs
administered (Deckers et al. 1997). In other words, moderate doses
of two AEDs may in some cases be equally or better tolerated than
large doses of a single AED.
Among patients who did not either respond to or tolerate the initial
two monotherapy attempts, only 4% became seizure free for at least
1 year after starting a third AED or combination therapy (Kwan and
Brodie 2000). Therefore, pharmacoresistant epilepsy can be
identified fairly early on during the treatment course. For patients
with treatment-refractory epilepsy, resective epilepsy surgery may
offer a significantly higher response rate. Another consideration is
that “refractory epilepsy” may not, in fact, be epilepsy, as discussed
later in the chapter. Clinical features supportive of surgical candidacy
for epilepsy include the presence of a single and relatively well-
defined epileptogenic focus that does not overlap with eloquent
cortex, significant seizure burden that comparatively outweighs risks
of brain surgery, and stable medical as well as psychosocial
comorbidities.
Psychosocial Impacts of Epilepsy
Extent of the Problem

Compared with other chronic disorders, the psychosocial impact
of epilepsy on the patient differs in unique ways. The unpredictable
and behaviorally overt nature of most seizures is difficult to conceal,
especially when in public. Moreover, the poignant manifestations of
many seizures could easily be misinterpreted as misconduct of
“behavior,” hence associating culpability with the patient. During
early part of the 20th century, many people with epilepsy in the
United States were institutionalized either in psychiatric asylums or
in county jails (Kissiov et al. 2013). Many individuals in some
cultures continue to perceive of epilepsy as a form of insanity.
Beyond “enacted” stigma (i.e., external or societal stigma or
discrimination), some studies highlight struggles with social
adaptation due to “felt” stigma, patients’ own negative feelings
regarding the consequences of the disease on themselves. Children
with epilepsy suffer from social isolation and low self-esteem at
higher rates than children with learning disabilities (Austin 1996).
Adults with epilepsy—including those with less than one seizure per
year, on average—endorse concerns surrounding their financial
situation, employability, and marriage, suggesting that social
adjustment does not always parallel degree of seizure control (Gil-
Nagel and Garcia-Damberre 2001). The aforementioned evidence
supports the idea that impacts related to epilepsy can extend far
beyond the symptoms of the disease (i.e., seizures) themselves.
Social Interventions
Many epilepsy centers place great importance on ensuring that
not only the patients and their families but also others closely
interacting with the patient are well informed about epilepsy. At the
workplace, it can be helpful to have a coworker who is aware of the
nature of the seizures and who can explain the problem to other
workers, as well as assess the need for urgent medical intervention
should epileptic seizures occur. An ideal candidate would be an
individual who knows the patient well on a personal level, holds a
relevant position at the workplace, and is willing to learn about the
disease. For children attending school, proactive communication with
teachers and nursing staff should include the description of the
seizures, medications, effects on neuropsychological performance,
and detailed instruction for when seizures occur at school. One or
more responsible friends of the patient can be informed regarding
epilepsy, with the aim of dispelling fear and enhancing acceptance of
the disease. This education can be best accomplished when these
friends are encouraged to accompany the patient during a visit to the
epilepsy clinic (Gil-Nagel and Garcia-Damberre 2001) or through an
epilepsy support group.
Comorbid Psychiatric Syndromes
Mood Disorders
When people with epilepsy are being evaluated for affective
symptoms, it is necessary to determine the temporal association of
the mood disturbance(s) with the ictus, with respect to the ictal, peri-
ictal, or interictal relationship. Premonitory dysphoria, anxiety, and
irritability can occur hours before a seizure (prodrome) and may
either abort upon seizure occurrence or persist for hours or days
after the seizure. Postictal depressive episodes (without prodromal
mood disturbances) are also well documented and can last up to 2
weeks after the seizure. Ictal depressive symptoms are
characterized by the sudden onset of symptoms without precipitating
factors (corresponding to seizure onset) and can be known to
manifest as impulsive suicidality.
Interictal depression is the most common type of mood
disturbance in people with epilepsy. Patients with pharmacoresistant
epilepsy have a prevalence of depression up to 10 times greater
than that in the general population, and up to 5 times greater than
that in patients with well-controlled epilepsy (Hermann et al. 2000).
Notably, a case-control study of older adults found that in new-onset
cases of epilepsy (without prior known neurological insult), the
patients were 3.7 times more likely to have a preexisting diagnosis of
depression than were control subjects. This risk remains increased
after controlling for potential proconvulsant effects of some
antidepressant therapies (Hesdorffer et al. 2000). Moreover, the
most severe episodes of depression in this study occurred closer to
the index date among case patients when compared with control
subjects, suggesting that pathophysiology associated with
depression may influence seizure threshold. The depressive
symptoms of people with epilepsy frequently show atypical features
compared with the depressive symptoms of those without epilepsy,
including more neurovegetative than neurotic symptoms and a more
detached/distant affect than dysphoric affect. They also show
comparably more prominent paranoia and psychotic symptoms,
greater irritability and humorlessness, and a tendency to manifest a
chronic dysthymic state (Mendez et al. 1986). Suicide is of special
concern, because it is the cause of death in 10% of people with
epilepsy, compared with 1% in the general population (Jones et al.
2003).
Studies of the prevalence of bipolar affective disorders,
hypomania, and dysthymia in people with epilepsy remain sparse. A
conclusive link has yet to be established regarding whether
vulnerability to depression is enhanced as a result of epileptic
seizure classification (focal vs. generalized), lobar localization (e.g.,
TLE vs. FLE), or lateralization (left vs. right) of the epileptogenic
focus.
Treatment of Comorbid Mood Disorders

Ictal or peri-ictal mood disturbances are usually self-limited and
resolve without psychotropic treatment. Optimization of seizure
control through AED adjustments is therefore the primary approach
to treating these symptoms. The remainder of this section focuses
on the management of inter-ictal affective symptoms.
Once the diagnosis of affective disorder is established, it is
imperative to assess the severity of the symptoms, given the
increased risk of suicide in this population. Such risk is particularly
elevated in the presence of psychotic features (Barry et al. 2008).
Moreover, in 2008 the U.S. Food and Drug Administration produced
a warning that all classes of AEDs had been found to be associated
with increased risk of suicidal thoughts and behavior in people with
epilepsy. Health care professionals who prescribe AEDs, however,
should balance the risk for suicidality with the clinical need for the
drug to treat epilepsy.
The initial assessment of depression should include a thorough
search for a temporal relationship between AED adjustments and
onset or exacerbation of depressive symptoms. If an AED with
mood-stabilizing effects (i.e., carbamazepine, lamotrigine, valproic
acid) was recently discontinued, then re-institution of such an AED
should be considered. Alternatively, if initiation of an AED with
particularly notable depressogenic effects (i.e., levetiracetam,
topiramate, phenobarbital) correlated with relevant depressive
symptoms, then that AED should be replaced by one with mood-
stabilizing effects.
Some antidepressants have been shown to be proconvulsive to
varying degrees, although this effect usually occurs when at toxic
dose ranges. The incidence of seizures in healthy individuals is low.
In fact, for most cases, treating depression with antidepressants
often improves (rather than worsens) seizure control, in part because
of the reduction of psychological duress—a known provocative factor
in seizures (Favale et al. 1995). From the literature on
antidepressants, higher drug dosage, faster rate of dosage
escalation, and longer duration of treatment are all important factors
that positively correlate with seizure induction (Barry et al. 2008).
Among the antidepressants, amoxapine, clomipramine, and
bupropion have comparatively the highest risks for seizure induction.
The next group with comparatively moderate risk includes
amitriptyline, imipramine, and maprotiline. Selective serotonin
reuptake inhibitors (SSRIs) are generally considered the drugs of
choice for people with epilepsy, because of the SSRIs’ low base
rates for seizures, which are essentially indistinguishable from the
seizure incidence rates for SSRI use in the general population.
Among the SSRIs, citalopram and sertraline are more often used
because of their minimal interactions with AEDs, whereas fluoxetine
and fluvoxamine may lead to increases in AED levels (i.e., due to
enzyme-inhibiting effects). Antidepressant therapy should be
continued for 6 months after the patient has recovered from the first
depressive episode. However, for subsequent episodes,
antidepressants should be continued for at least 2 years after
recovery from the latest depressive episode (Kerr et al. 2011).
Psychotherapeutic approaches help people with epilepsy improve
their AED compliance, understand/accept their illness, correct
negative core beliefs, cope more effectively with stressful life events,
and develop an improved sense of agency as well as self-esteem.
Furthermore, preliminary studies utilizing behavioral intervention to
help people with epilepsy recognize seizure triggers and employ
relaxation techniques as a countermeasure against triggers have
shown significant improvement in seizure control and/or quality-of-
life measures (Ramaratnam et al. 2008).
Anxiety Disorders
The substantial overlapping of symptoms with epilepsy and
anxiety paroxysmal disorders (especially panic disorder) can
confound the evaluation of people with epilepsy presenting with
anxiety symptoms. For such patients, three clinical scenarios occur:
1) partial epileptic seizures that mimic symptoms of panic attacks; 2)
coexisting mixed diagnoses of epilepsy and panic disorder; and 3)
agoraphobia without panic attacks.
The aura of anxiety or fearfulness from some focal epileptic
seizures can markedly parallel panic attack symptoms. Key features
can be highlighted to facilitate differentiation. In panic disorder, the
affective components last from several minutes to, in some cases,
hours; the sequence of symptoms can vary between attacks, and
consciousness is preserved; and postattack confusion is usually
absent. The typical age at onset for panic attacks is between 20 and
30 years, often in association with a strong family history of panic
disorder (Scicutella 2001). By contrast, epileptic seizure duration is
usually not more than 2 minutes; ictal fear tends to be stereotyped
(reaching peak intensity fairly early, rather than a slower crescendo
over 10–20 minutes as in panic attacks); and focal epileptic seizures
with more widespread propagation will commonly involve impaired
consciousness and amnesia, as well as postictal confusion.
Furthermore, the incidence rate of epilepsy is bimodal, with a high
rate in early childhood, a low rate in young adult age, and a second
peak in individuals older than 65 years (Hauser et al. 1996). Overall,
estimates of anxiety disorders in outpatient and hospitalized people
with epilepsy are between 14% and 25%, which are much higher
levels than among those in the general population (Scicutella 2001).
Anticipatory anxiety over impending seizures, as opposed to panic
attacks, can also be similarly incapacitating. While symptoms may
not meet DSM-5 criteria for traditional anxiety disorders, people with
epilepsy can still be paralyzed from agoraphobia related to the
unpredictable nature of when, where, or how strong the next seizure
may be.
Treatment of Comorbid Anxiety Disorders

Comorbid anxiety disorders in people with epilepsy generally
respond to the same pharmacological and nonpharmacological
treatments used in those without epilepsy (Kerr et al. 2011). Clinical
experience indicates that the SSRIs should be among the first-line
pharmacological treatments for anxiety disorders in people with
epilepsy. High-potency benzodiazepines, such as clonazepam and
alprazolam, are useful in the acute treatment of anxiety disorders as
well as in the adjunctive treatment of seizures. However, patients
should be carefully selected to minimize the risk of addiction and
should be advised about the side effects of sedation, cognitive
impairment, and withdrawal-related seizures. Behavioral
interventions to help people with epilepsy employ relaxation
techniques as a countermeasure against negative states (fear) may
help disrupt this potential self-reinforcing cycle (Fenwick 1995).
Psychosis
Psychosis in epilepsy, similar to mood disturbances, can be
categorized on the basis of the temporal relationship to the ictus.
These categories of psychosis in relation to epilepsy include pre-
ictal, ictal, postictal, and interictal psychosis.
Psychic phenomena sometimes occur during epileptic seizures,
especially for those originating from limbic or lateral (neocortical)
temporal areas. Psychic symptoms can include visual or auditory
hallucinations, often combined with mood disturbances, such as
agitation or fear. Other experiential phenomena include
depersonalization, derealization, and autoscopy. Most epileptic
seizures last under 3 minutes and frequently manifest altered
consciousness (delirium). Therefore, the psychic symptoms evoked
during brief and isolated epileptic seizures rarely cause symptoms
that would be considered psychotic. In rare instances involving focal
or generalized nonconvulsive status epilepticus, longer sustaining
symptoms of delusions, hallucinations, panic, or apathy have been
described, sometimes with varying degrees of altered consciousness
(LaFrance et al. 2008). Electroencephalographic findings, in these
instances, are vital in clarifying the diagnosis.
Postictal psychosis (PIP) occurs in approximately 2%–7.8% of
people with epilepsy, with symptoms usually emerging after a 2.5- to
48-hour cognitively lucid interval following the last seizure (or more
commonly, a series of seizures). Sometimes, symptom onset may be
delayed up to 1 week from the last seizure. PIP frequently involves
delusions, hallucinations, and bizarre or disorganized behavior in
clear consciousness. Less typical of psychosis in the traditional
sense is the prominence of mood disturbances in PIP, including
depressed affect, manic symptoms, and irritable and aggressive
behaviors (Nadkarni et al. 2007). For the diagnostic criteria to be
met, psychotic symptoms should persist beyond 15 hours and can
last up to 3 months in duration. Caution should be taken to exclude
alternative explanations, such as AED toxicity, illicit substance
intoxication or withdrawal, nonconvulsive status epilepticus, and prior
chronic psychotic disorder (LaFrance et al. 2008). PIP is more likely
to occur in people with epilepsy who have focal epilepsy, bilateral
independent seizure foci, and a tendency to show clustering of
seizures as well as secondary generalization of seizures. Additional
risk factors include people with epilepsy who are older than 30 years
and have had a protracted course of epilepsy for more than 10
years. As the frequency of PIP increases, people with epilepsy
sustain higher risk for developing chronic interictal psychosis (CIP).
CIP occurs in 5% of people with epilepsy who are in the high-risk
group with a history of uncontrolled seizures. CIP presents during
seizure-free periods and does not demonstrate any direct correlation
with seizure activity. CIP resembles typical schizophrenia more
closely than PIP (Nadkarni et al. 2007). While persecutory delusions
and hallucinations are common, CIP differs from primary psychotic
disorders in showing less deterioration of premorbid personality,
fewer negative symptoms (such as flattening or restriction of affect),
less severe psychotic episodes, and more variable course of illness
(LaFrance et al. 2008).
An uncommon but noteworthy phenomenon affecting a subgroup
of patients with CIP is referred to as “forced normalization,” which
depicts an inverse relationship between the occurrence of psychotic
states and epileptic burden (Landoldt 1958). Thus, paradoxically,
improvement of seizures and electroencephalographic findings are
associated with worsening of behavioral disruption. Forced
normalization often occurs following effective intervention (i.e., with
AEDs or epilepsy surgery), so psychosis in some cases could be the
adverse effects of the intervention, with improvement on the EEG
reflecting an epiphenomenon.
Treatment of Comorbid Psychosis

For ictal psychosis, timely recognition of this condition is
paramount. Optimization of seizure control through AED adjustments
curtails and ultimately prevents this form of psychosis. Psychotic and
affective disturbances can be problematic in cases of PIP. Brief
antipsychotic and/or mood-stabilizing treatments are warranted in
such cases. For very short episodes of PIP (i.e., lasting a few days),
treatment can be tapered starting about 5 days after symptom
remission. For more sustained episodes of PIP (i.e., lasting more
than a few days), a period of 1–2 months of careful observation after
symptom remission is advised before antipsychotic treatment is
tapered (Nadkarni et al. 2007). Because frequent PIP substantially
increases the risk for developing CIP, preventing PIP recurrences
should be emphasized, and prevention can include patient and
family education to encourage AED adherence and recognize PIP
antecedents to expedite treatment when indicated. Formal
psychiatric evaluations and psychotherapy can help to clarify the
links between the psychosis, seizure experiences, and psychosocial
contributors.
Symptomatic treatment of CIP is similar to the treatment for
primary psychotic disorders and should be maintained long-term
following remission (Kerr et al. 2011). One main caution surrounds
the mild proconvulsive effect of antipsychotic medications; seizure
incidence with these medications has ranged from 0.5% to 1.2%
(Whitworth and Fleischhacker 1995). Proconvulsive risks are
elevated by rapid escalation of dose, high dosages, and combination
therapy with multiple antipsychotic drugs or other drugs that lower
the seizure threshold. Chlorpromazine and clozapine are most
associated with seizures and thus should be avoided in people with
epilepsy except in extraordinary circumstances. The overall risk-
benefit ratio should strongly favor the use of antipsychotic
medication for psychotic symptoms in people with epilepsy.
In the rare instances when seizure improvement is associated
with worsening of psychotic symptoms (forced normalization), a
reduction of AED dosage to allow for tolerable breakthrough seizures
can be helpful. Under these scenarios, patients, caretakers, and the
treatment team should closely collaborate in the decision making
regarding the management of AEDs and antipsychotic drugs (Kerr et
al. 2011).
Neurobehavioral Disturbances Associated With

Antiepileptic Drugs
AEDs have psychotropic properties in the form of negative as well
as positive effects on behavior and mood. The adverse behavioral
effects are the focus of this section, as functional or structural CNS
changes associated with epileptogenicity may augment the
susceptibility of people with epilepsy to AED-related neurobehavioral
disturbances (Ettinger 2006). Such susceptibility can be further
enhanced by the presence of pharmacoresistant epilepsy or
temporolimbic epilepsy, as well as a personal and/or family history of
psychiatric disturbances (Kerr et al. 2011). The adverse psychotropic
effects of psychotropic medications are discussed below.
Benzodiazepines are highly effective as acute treatment of
epileptic seizure exacerbation but are less efficacious for chronic
management, given their known predisposition to tachyphylaxis and
significant withdrawal effects. When benzodiazepines are abruptly
discontinued after chronic use, withdrawal symptoms can include
severe seizure exacerbation, delirium, and even psychosis (Hauser
et al. 1989). Despite having anxiolytic properties, benzodiazepines
can cause paradoxical disinhibition in some patients, as
demonstrated by aggressiveness, agitation, and hyperactivity.
Similar to benzodiazepines, a disinhibition syndrome can occur
with barbiturates even at low doses and especially in people with
epilepsy who are developmentally delayed. Moreover, barbiturates
have been linked to a higher rate of depressive symptoms, including
suicidal ideation. People with epilepsy who are taking barbiturates,
especially those with a personal or family history of depression,
should be carefully screened for potential depressive symptoms
(Ettinger 2006). Special caution should also be taken to avoid abrupt
withdrawal of these agents.
Treatment with levetiracetam has been associated with
depressive or anxiety symptoms in about 8%–16% of cases.
Adverse behavioral effects were greater among people with epilepsy
than those without epilepsy and among patients with preexisting
mood or anxiety disorders (Ettinger 2006). More common adverse
effects of topiramate are psychomotor slowing in conjunction with
memory impairment, trouble expressing words, and/or difficulty
organizing thoughts. In addition, several clinical studies have
documented topiramate’s association with acute depression and/or
anxiety upon initiation of this agent (Piedad et al. 2012). The adverse
psychotropic effects of topiramate may be diminished by slower
upward titration of the drug and minimization of other drugs prone to
neurobehavioral disturbances.
Psychogenic Nonepileptic Seizures
Overview
PNES represent paroxysms of altered movement, sensation,
cognition, or experience that, while resembling epileptic seizures, are
associated with underlying psychopathological processes rather than
epileptic neuronal discharges. PNES are most commonly
conceptualized as a form of somatoform conversion disorder in
which psychological conflicts are “converted” into physical
symptoms. There are two main “causes” of PNES: posttraumatic and
developmental (Kalogjera-Sackellares 1996). Posttraumatic PNES
develop in response to acute or chronic exposure to traumatic
experience(s), such as physical or psychological trauma and sexual
or physical abuse. Developmental PNES refers to coping difficulties
with tasks and milestones along the individual’s continuum of
psychosocial development. An underlying commonality of both is
that PNES may function as maladaptive coping strategies in the face
of stress—which may or may not be consciously recognized by the
patient. Volitionally feigned symptoms, as in the cases of malingering
or factitious disorders, are not PNES (i.e., not psychogenic) and are
rarely present in persons who are at risk for PNES.
PNES have an estimated prevalence of up to 33 per 100,000, a
rate that is comparable to that of other neurological disorders such
as multiple sclerosis and trigeminal neuralgia (Benbadis and Allen
Hauser 2000). Psychiatric comorbidities are common, with
prevalence rates of 62% for personality disorders, 49% for
posttraumatic stress disorder (PTSD), 47% for major depressive
disorder, and 47% for anxiety disorders (other than PTSD) (Bowman
and Markand 1996).
Video-EEG monitoring is the gold standard for the diagnosis of
PNES, which when present with a consistent history, witnessed
semiology, and absence of epileptiform activity provides a
documented diagnosis level of certainty (LaFrance et al. 2013a).
Likewise, the differentiation between psychogenic and physiological
seizures relies on careful evaluation of historical presentation, event
semiology (historically, as well as from video recording),
examination, and psychosocial comorbidities. Neuropsychological
testing is used in inpatient monitoring units; however, this testing
does not differentiate between epilepsy and PNES. Historical and
behavioral features that can help distinguish PNES from epileptic
seizures are listed in Table 10–4. Semiological groupings include
dialeptic, major and minor motor, sensory, and mixed (Szabó et al.
2012), and while semiology can be an important element in helping
differentiate epileptic from nonepileptic seizures, it is unclear if
semiology within PNES is useful in informing prognosis. During the
seizure evaluation process, an important clinical caveat is that no
single historical, semiological, or neuropsychological finding is
unconditionally or solely diagnostic of PNES. The diagnosis of PNES
should be determined on the basis of the overall aggregate of
evidence available.
TABLE 10–4. Historical and semiological features that can help distinguish
psychogenic nonepileptic seizures from epileptic seizures
Psychogenic
nonepileptic seizures Epileptic seizures
Distinguishing historical
features
Prolonged seizures or Common Rare
seizure clusters >30
minutes
Seizures in the presence of Common Unusual
doctors
Multiple unexplained Common Rare
physical symptoms, such
as unexplained “chronic
pain”
Multiple operations/invasive Common Rare
procedures
Seizure onset at <10 years Uncommon Common
of age
Distinguishing semiological
features
Slowly evolving seizure Common Rare
onset
Undulating motor activity Common Very rare
Closed eyelid during seizure Very common Rare
onset
Resistance to eyelid opening Common Very rare
Asynchronous limb Common Rare
movements
Side-to-side head shaking Common Rare
Severe tongue biting (side) Rare Common after GTC
Stertorous breathing Not present Common after GTC
postictally
Postictal nose rubbing Not present Occurs in TLE
Psychogenic
nonepileptic seizures Epileptic seizures
Ictal grasping (gripping of an Rare Occurs in FLE and
object with one hand or TLE
both hands)
Pupillary light reflex Usually retained Commonly absent
Note. FLE=frontal lobe epilepsy; GTC=generalized tonic-clonic epileptic seizures;
TLE=temporal lobe epilepsy.
Source. Adapted from Benbadis and LaFrance 2010.
A small subset (~10%) of patients with PNES will also have a

coexisting diagnosis of epilepsy (Benbadis et al. 2001). In mixed
cases, the PNES typically emerge at some point after the onset of
epilepsy, rather than vice versa or concurrently.
Management of Psychogenic Nonepileptic Seizures

Management of patients with PNES begins with comprehensive
evaluation (i.e., seizure history, formal psychiatric assessment,
video-EEG monitoring). The explanation of this diagnosis should be
communicated to the patient via a tactful, empathetic, but
unequivocal approach to patient, family, and providers (Shen et al.
1990). Merely sharing the diagnosis is not sufficient, however,
because other somatic and affective symptoms often develop if the
core issues are not addressed. PNES intervention should entail
addressing not only seizure frequency but also patient functionality
as well as overall health-related quality of life (LaFrance et al.
2013b).
Among psychotherapeutic approaches for patients with PNES, the
most substantial body of controlled data that exists pertains to
cognitive-behavioral therapy (CBT). To date, two randomized
controlled pilot trials of classic CBT (Goldstein et al. 2010) or CBT-
informed psychotherapy (LaFrance et al. 2014) for PNES have
shown clinically meaningful results. Manualized treatments (Reiter et
al. 2015) have been used for epileptic and nonepileptic seizures,
showing reduction in seizures and comorbidities.
Whereas efficacy data are less definitive for other modalities,
other psychotherapeutic approaches may provide beneficial
complementary roles. Psychoeducational approaches aim to
consolidate the patients’ understanding of PNES, hence promoting
more open-mindedness toward acceptance of this diagnosis. This
modality can serve as a “stepping stone” to more in-depth
psychotherapies, particularly for patients who are skeptical regarding
their diagnosis.
For patients with PNES alone who have been prescribed AEDs,
the first intervention should involve discussion with the patient
explaining that AEDs do not treat and are not warranted for PNES. If
a specific AED has no alternative indication (e.g., for mood
stabilization, alleviation of pain syndromes, migraine prophylaxis),
then AED taper is advisable. For patients who express hesitance to
discontinue their AEDs, the decision to taper the AED should not be
coerced and can be revisited during subsequent follow-up
discussions. Whenever clinically relevant, symptomatic treatment of
frequent PNES comorbidities, such as mood and anxiety disorders,
with psychotropic agents can be helpful. Addressing the comorbid
personality disorders is also essential. Current efficacy data are
nondefinitive regarding the use of psychopharmacological
interventions to treat somatoform disorders directly.
In cases of the 10% of patients with mixed PNES and epilepsy,
optimal management requires that the patient and caregivers learn
to identify, distinguish, and quantify the different seizure types, if
possible, in order to direct treatment targets. Reviewing the videos of
seizures captured on video-EEG with patients and caregivers may
help consolidate such diagnostic insights. Since AED toxicity can
exacerbate PNES, AEDs should be administered at the minimum
required dose to achieve satisfactory control of the patient’s epileptic
seizures. Clear communication between neurological, primary care,
and mental health treatment providers and a coordinated approach
to care are particularly imperative in the management of these
challenging cases, in which the patients face high risks for further
unnecessary investigations, interventions, and adverse iatrogenesis.
Conclusion
Epilepsy is a prevalent neurological disorder that represents a
disease model epitomizing the complex and fascinating elements of
brain-behavior relations. This review has described how varying
seizure types, depending on location of epileptic seizure origin within
the brain, can manifest a vast spectrum of behaviors. The
psychosocial impacts from seizures must also be emphasized.
Moreover, psychiatric symptoms not only accompany seizure activity
but also are frequently present interictally—even after optimal
seizure control has been achieved. As epilepsy and PNES affect
essentially all aspects of a patient’s life, interdisciplinary dialogue
and partnership are important in the treatment of this challenging
conditions.
References
Abou-Khalil B, Misulis KE: Atlas of EEG and Seizure Semiology. Philadelphia, PA,
Butterworth-Heinemann, 2005
Austin JK: A model of family adaptation to new-onset childhood epilepsy. J
Neurosci Nurs 28(2):82–92, 1996 8718755
Barry JJ, Ettinger AB, Friel P, et al; Advisory Group of the Epilepsy Foundation as
part of its Mood Disorder: Consensus statement: the evaluation and treatment
of people with epilepsy and affective disorders. Epilepsy Behav 13 (suppl
1):S1–S29, 2008 18502183
Benbadis SR, Allen Hauser W: An estimate of the prevalence of psychogenic non-
epileptic seizures. Seizure 9(4):280–281, 2000 10880289
Benbadis SR, LaFrance WC Jr: Clinical features and the role of video-EEG
monitoring, in Gates and Rowan’s Nonepileptic Seizures, 3rd Edition. Edited by
Schachter SC, LaFrance Jr WC. New York, Cambridge University Press, 2010,
pp 38–50
Benbadis SR, Agrawal V, Tatum WO IV: How many patients with psychogenic
nonepileptic seizures also have epilepsy? Neurology 57(5):915–917, 2001
11552032
Berg AT, Berkovic SF, Brodie MJ, et al: Revised terminology and concepts for
organization of seizures and epilepsies: report of the ILAE Commission on
Classification and Terminology, 2005–2009. Epilepsia 51(4):676–685, 2010
20196795
Bowman ES, Markand ON: Psychodynamics and psychiatric diagnoses of
pseudoseizure subjects. Am J Psychiatry 153(1):57–63, 1996 8540592
Deckers CL, Hekster YA, Keyser A, et al: Reappraisal of polytherapy in epilepsy: a
critical review of drug load and adverse effects. Epilepsia 38(5):570–575, 1997
9184603
Ettinger AB: Psychotropic effects of antiepileptic drugs. Neurology 67(11):1916–
1925, 2006 17159095
Favale E, Rubino V, Mainardi P, et al: Anticonvulsant effect of fluoxetine in
humans. Neurology 45(10):1926–1927, 1995 7477995
Fenwick P: The basis of behavioral treatments in seizure control. Epilepsia 36
(suppl 1):S46–S50, 1995 23057111
Fisher RS, Acevedo C, Arzimanoglou A, et al: ILAE official report: a practical
clinical definition of epilepsy. Epilepsia 55(4):475–482, 2014 24730690
Frontera AT Jr: Classification of seizures and epilepsy syndromes, in Department
of Veterans Affairs Epilepsy Manual. Edited by Husain AM, Tran TT. San
Francisco, CA, Epilepsy Centers of Excellence Department of Veterans Affairs,
2014, pp 2–19
Gil-Nagel A, Garcia-Damberre A: The social impact of epilepsy, in Psychiatric
Issues in Epilepsy: A Practical Guide to Diagnosis and Treatment. Edited by
Ettinger AB, Kanner AM. Philadelphia, PA, Lippincott Williams & Wilkins, 2001,
pp 289–295
Goldstein LH, Chalder T, Chigwedere C, et al: Cognitive-behavioral therapy for
psychogenic nonepileptic seizures: a pilot RCT. Neurology 74(24):1986–1994,
2010 20548043
Hauser P, Devinsky O, De Bellis M, et al: Benzodiazepine withdrawal delirium with
catatonic features: occurrence in patients with partial seizure disorders. Arch
Neurol 46(6):696–699, 1989 2730383
Hauser WA, Rich SS, Annegers JF, Anderson VE: Seizure recurrence after a 1st
unprovoked seizure: an extended follow-up. Neurology 40(8):1163–1170, 1990
2381523
Hauser WA, Annegers JF, Rocca WA: Descriptive epidemiology of epilepsy:
contributions of population-based studies from Rochester, Minnesota. Mayo
Clin Proc 71(6):576–586, 1996 8642887
Hermann BP, Seidenberg M, Bell B: Psychiatric comorbidity in chronic epilepsy:
identification, consequences, and treatment of major depression. Epilepsia 41
(suppl 2):S31–S41, 2000 10885738
Hesdorffer DC, Hauser WA, Annegers JF, et al: Major depression is a risk factor
for seizures in older adults. Ann Neurol 47(2):246–249, 2000 10665498
Hesdorffer DC, Benn EK, Cascino GD, et al: Is a first acute symptomatic seizure
epilepsy? Mortality and risk for recurrent seizure. Epilepsia 50(5):1102–1108,
2009 19374657
Jones JE, Hermann BP, Barry JJ, et al: Rates and risk factors for suicide, suicidal
ideation, and suicide attempts in chronic epilepsy. Epilepsy Behav 4 (suppl
3):S31–S38, 2003 14592638
Kalogjera-Sackellares D: Psychological disturbances in patients with
pseudoseizures, in Psychological Disturbances in Epilepsy. Edited by
Sackellares JC, Berent S. Boston, MA, Butterworth-Heinemann, 1996, pp 191–
217
Kerr MP, Mensah S, Besag F, et al; International League of Epilepsy (ILAE)
Commission on the Neuropsychiatric Aspects of Epilepsy: International
consensus clinical practice statements for the treatment of neuropsychiatric
conditions associated with epilepsy. Epilepsia 52(11):2133–2138, 2011
21955156
Kissiov D, Dewall T, Hermann B: The Ohio Hospital for Epileptics—the first
“epilepsy colony” in America. Epilepsia 54(9):1524–1534, 2013 24010576
Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med
342(5):314–319, 2000 10660394
LaFrance WC Jr, Kanner AM, Hermann B: Psychiatric comorbidities in epilepsy. Int
Rev Neurobiol 83:347–383, 2008 18929092
LaFrance WC Jr, Baker GA, Duncan R, et al: Minimum requirements for the
diagnosis of psychogenic nonepileptic seizures: a staged approach: a report
from the International League Against Epilepsy Nonepileptic Seizures Task
Force. Epilepsia 54(11):2005–2018, 2013a 24111933
LaFrance WC Jr, Reuber M, Goldstein LH: Management of psychogenic
nonepileptic seizures. Epilepsia 54 (suppl 1):53–67, 2013b 23458467
LaFrance WC Jr, Baird GL, Barry JJ, et al; NES Treatment Trial (NEST-T)
Consortium: Multicenter pilot treatment trial for psychogenic nonepileptic
seizures: a randomized clinical trial. JAMA Psychiatry 71(9):997–1005, 2014
24989152
Landoldt H: Serial electroencephalographic investigations during psychotic
episodes in epileptic patients and during schizophrenic attacks, in Lectures on
Epilepsy. Edited by Lorentz De Haas AM. Amsterdam, The Netherlands,
Elsevier Science Ltd, 1958, pp 91–133
Maillard L, Vignal JP, Gavaret M, et al: Semiologic and electrophysiologic
correlations in temporal lobe seizure subtypes. Epilepsia 45(12):1590–1599,
2004 15571517
Mendez MF, Cummings JL, Benson DF: Depression in epilepsy: significance and
phenomenology. Arch Neurol 43(8):766–770, 1986 3729756
Nadkarni S, Arnedo V, Devinsky O: Psychosis in epilepsy patients. Epilepsia 48
(suppl 9):17–19, 2007 18047594
Piedad J, Rickards H, Besag FM, et al: Beneficial and adverse psychotropic
effects of antiepileptic drugs in patients with epilepsy: a summary of
prevalence, underlying mechanisms and data limitations. CNS Drugs
26(4):319–335, 2012 22393904
Ramaratnam S, Baker GA, Goldstein LH: Psychological treatments for epilepsy.
Cochrane Database Syst Rev (3):CD002029, 2008 18646083
Reiter JM, Andrews D, Reiter C, LaFrance WC Jr: Taking Control of Your Seizures:
Workbook. New York, Oxford University Press, 2015
Schramm J, Kral T, Grunwald T, et al: Surgical treatment for neocortical temporal
lobe epilepsy: clinical and surgical aspects and seizure outcome. J Neurosurg
94(1):33–42, 2001 11147895
Scicutella A: Anxiety Disorders in Epilepsy, in Psychiatric Issues in Epilepsy: A
Practical Guide to Diagnosis and Treatment. Edited by Ettinger AB, Kanner
AM. Philadelphia, PA, Lippincott Williams & Wilkins, 2001, pp 495–109
Semah F, Picot MC, Adam C, et al: Is the underlying cause of epilepsy a major
prognostic factor for recurrence? Neurology 51(5):1256–1262, 1998 9818842
Shen W, Bowman ES, Markand ON: Presenting the diagnosis of pseudoseizure.
Neurology 40(5):756–759, 1990 2330101
Sillanpää M, Jalava M, Kaleva O, et al: Long-term prognosis of seizures with onset
in childhood. N Engl J Med 338(24):1715–1722, 1998 9624191
Szabó L, Siegler Z, Zubek L, et al: A detailed semiologic analysis of childhood
psychogenic nonepileptic seizures. Epilepsia 53(3):565–570, 2012 22332748
Tortorice K, Rutecki P: Principles of treatment, in Department of Veterans Affairs
Epilepsy Manual. Edited by Husain AM, Tran TT. San Francisco, CA, Epilepsy
Centers of Excellence Department of Veterans Affairs, 2014, pp 121–127
Tucker GJ: Neuropsychiatric aspects of seizure disorders, in The American
Psychiatric Publishing Textbook of Neuropsychiatry and Clinical
Neurosciences, 4th Edition. Edited by Yudofsky SC, Hales RE. Washington,
DC, American Psychiatric Publishing, 2002, pp 673–695
Whitworth AB, Fleischhacker WW: Adverse effects of antipsychotic drugs. Int Clin
Psychopharmacol 9 (suppl 5):21–27, 1995 7622830
CHAPTER 11
Cerebrovascular Disorders
Ricardo Jorge, M.D.
Cerebrovascular disease encompasses a wide range of

disorders, including transient cerebral ischemia, cerebral infarction,
and hemorrhagic phenomena caused by hypertension and other
more rare conditions such as vascular malformations and amyloid
angiopathy. In this chapter, we review the major neuropsychiatric
disorders associated with stroke, such as depression, anxiety, manic
syndromes, apathy, pathological affective display (PAD), and the
catastrophic reaction (Figure 11–1). We present the frequency,
phenomenology, clinical correlates, and treatment of these disorders,
and we also provide critical discussion about the conceptualization of
these disorders.
FIGURE 11–1. Prevalence of neuropsychiatric disorders in the poststroke
population.
Poststroke Depression
Diagnosis
Depressive disorders are a frequent neuropsychiatric complication
of stroke. Investigators in this field categorize these disorders within
a common and reliable framework established by the Diagnostic and
Statistical Manual of Mental Disorders (DSM) nomenclature. The
rationale behind this approach is based on the assumption that a
constellation of symptoms, which is defined a priori by means of the
different DSM criteria, identifies a condition with a particular
functional impact, a specific prognosis and clinical course, and an
identifiable neurobiological substrate.
DSM-5 (American Psychiatric Association 2013) includes
poststroke depression (PSD) under the category of depressive
disorder due to another medical condition. This diagnosis
encompasses several depressive subtypes: 1) with major
depressive–like episode (if the full criteria for a major depressive
episode are met); 2) with depressive features (prominent depressed
mood but full criteria for a major depressive episode are not met);
and 3) with mixed features (e.g., associated with significant
expansive or irritable mood, pressured speech, and formal thought
disorder). A DSM-based diagnosis of this kind can be elicited using a
semistructured interview such as the Structured Clinical Interview for
DSM-5 Disorders, Research Version (SCID-5-RV) or the Mini
International Neuropsychiatric Interview (M.I.N.I. 6.0) (First et al.
2015; Sheehan et al. 1998).
In addition, a diagnosis of PSD rests on the clinician’s confidence
regarding the causal relationship between a stroke and the
depressive episode. In this regard, clinicians should bear in mind
that PSD is a complex behavioral disorder influenced by factors that
precede the injury (e.g., genetic vulnerability, previous history of
mood disorders); factors related to the injury itself (e.g., type, extent,
and location of brain damage; neurochemical and metabolic
alterations); and factors that influence the recovery process (e.g.,
rehabilitation treatment, level of disability, social support). These
factors individually and collectively contribute to the onset and
duration of depressive disorders and may vary in their importance at
different times following stroke.
It is generally recognized that in the case of PSD, some
depressive symptoms (e.g., lack of energy, sleep disturbance,
cognitive inefficiency) may not be related to the mood disturbance
and are thus attributable to other biological alterations produced by
stroke. Since the diagnosis of PSD following DSM criteria involves
determining the type and number of symptoms experienced by a
particular subject, depressive symptoms may be considered
independently of etiological attribution (i.e., an inclusive approach).
An alternative approach is to consider only the symptoms that are
specific to a mood disturbance in the stroke population with respect
to a diagnosis of PSD (i.e., an exclusive approach), or nonspecific
symptoms may be replaced by other symptoms found to be
significantly associated with depression (i.e., a substitutive
approach) (Robinson 2006). We have compared the inclusive and
exclusive approaches in a group of stroke patients who were
assessed at different times over a 2-year follow-up period. In this
study, when compared with criteria using only specific symptoms, the
sensitivity of unmodified DSM-IV criteria was consistently 100%, with
a specificity that ranged from 95% to 98% (Robinson 2006).
Furthermore, it has been shown that in stroke patients, most of the
symptoms listed as criteria for major depressive disorder are
significantly more frequent among subjects who acknowledged the
presence of depressed mood (an anchor symptom for depressive
disorders) than in subjects who denied the presence of a pervasive
alteration of mood (Robinson 2006). Thus, one could reasonably
argue that modifying the DSM criteria because of a coexisting stroke
is unnecessary.
However, it is frequently difficult to interpret the complex
neuropsychiatric presentation of stroke patients using the somewhat
rigid constructs of contemporary psychiatric nomenclature. Faithful
adherence to DSM categories may confound the findings of genetic
and pathophysiologic studies and obscure the impact of potentially
efficacious therapeutic options for a particular subgroup of PSD
patients. Thus, the time is right for considering risks and benefits of
abandoning the DSM conceptual framework and establishing a more
clinically useful nosology.
During the past two decades, strong evidence has been provided
for incorporating recent findings in neuroscience into more clinically
meaningful psychiatric classification schemes. Thus, when
confronting a complex disorder like PSD, intermediate phenotypes
amenable to being examined in genetic studies, animal models of
disease, and novel neuroimaging paradigms might constitute a more
promising focus of research (Insel et al. 2010). This may allow a
specific cluster of symptoms associated with depressive disorders
(e.g., apathy, anxiety, fatigue) to be conceptualized as resulting from
disturbances in specific neural networks, and, consequently, the
cluster of symptoms may provide further insight into the
pathophysiology of PSD. This approach will increase the possibility
of identifying subgroups of patients who will benefit from more
specific treatment options.
Assessment Scales
There are several scales assessing the number and severity of
depressive symptoms that have been consistently used in PSD
studies. The Patient Health Questionnaire—9 (PHQ-9) is a useful
screening tool for depression that has been validated in stroke
patients. Williams et al. (2005) reported that a PHQ-9 score ≥10 has
91% sensitivity and 89% specificity to diagnose a major depressive
episode and 78% sensitivity and 96% specificity for any PSD
diagnosis regardless of age, gender, or ethnic background. Other
helpful scales that have been used in the stroke population include
the Geriatric Depression Scale (GDS), the Hamilton Depression
Rating Scale (HDRS), and the Center for Epidemiologic Studies
Depression Scale (CES-D) (Hamilton 1960; Yesavage et al. 1982–
1983).
Frequency
PSD is among the most frequent neuropsychiatric complications
of stroke, and approximately one-third of stroke survivors develop a
depressive disorder during the first year after a stroke. Heterogeneity
in the reported frequency of PSD is related to multiple causes, such
as the method used to diagnose depression (e.g., structured
interviews compared with cutoff scores on severity scales); the
setting in which the study was conducted (e.g., at the community
level, in acute care hospitals, in rehabilitation facilities); and the
timing of the assessments (e.g., acute, subacute, chronic stages of
stroke).
Evidence on the prevalence of PSD has been summarized in
recent meta-analytic studies. Ayerbe et al. (2013) examined a total of
43 studies including 20,293 stroke patients. Of these 43 studies, 12
used DSM criteria to diagnose depression, 13 studies evaluated
patients at more than one time point, and only 8 studies assessed
PSD more than 1 year after stroke. Overall, the prevalence of
depression was 29% (95% confidence interval [CI] 25–32) at any
time point, with a prevalence of 28% (95% CI 23–34) during the first
month after stroke, 31% (95% CI 24–39) during the period from 1 to
6 months, 33% (95% CI 23–43) during the second half of the first
year after stroke, and 25% (95% CI 19–32) at more than 1 year. The
cumulative incidence of PSD varied between 39% and 52% within 5
years of stroke. The rate of recovery from depression among
patients who were initially depressed ranged from 15% to 57% at 1-
year follow-up (Ayerbe et al. 2013).
Another meta-analysis performed by Hackett and colleagues
examined data from 61 studies, including 25,488 stroke patients.
Depression was ascertained using DSM criteria in 17 of these
studies, but only 5 studies used a structured clinical interview.
Depression was observed in 31% (95% CI 28–35) of stroke survivors
at any time up to the first 5 years after stroke, with a slightly higher
frequency during the first year, whereas the frequency of depression
at 5-year follow-up was 23% (95% CI 14–31) (Hackett et al. 2014).
Taken together, the results of these comprehensive meta-analyses
suggest that about a third of patients who had a stroke will have PSD
at different times during a 5-year follow-up period. These prevalence
rates are consistent with those independently reported in the
pioneering studies of Robinson and colleagues (Robinson 2006) and
provide convergent validity with respect to both their observations
and interpretations.
Risk Factors
The risk factors for developing PSD might be related to subjects’
characteristics preceding the stroke; factors pertaining to the stroke
itself such as the type, mechanism, and location of brain lesions;
factors related to the physical and functional consequences of brain
lesions; and, finally, factors influencing the recovery process (Figure
11–2). Unfortunately, prospective studies with PSD as an outcome
variable are relatively scarce. Furthermore, only a few of the
available prospective studies proposed a specific model including
multiple relevant variables, and none of these models was validated
in an independent population.
FIGURE 11–2. Risk factors for developing poststroke depression (PSD).
Note. CI=confidence interval.
Premorbid Factors
Demographic factors. De Ryck et al. (2014) conducted a
systematic review of 24 studies examining risk factors for PSD.
Gender was analyzed in 21 studies, of which the majority (13
studies) did not find an association between PSD and gender. A third
of these studies, however, identified female sex as a risk factor for
PSD, with only a single article reporting that male patients were
more vulnerable to developing depression (De Ryck et al. 2014).
Age was not associated with PSD in 16 of 20 studies. However, 3
studies reported older age as a significant risk factor for PSD, and 1
study observed that younger age (<68 years) was an independent
predictor of PSD within the first year after stroke. These findings
were replicated in a recent updated review of 23 studies including
18,374 stroke patients (Kutlubaev and Hackett 2014).
Genetic factors. Common genetic variations might confer
vulnerability or resilience to developing psychiatric illness when a
subject faces an unusual stressful challenge. A few candidate genes
have been examined as risk factors for PSD. The 5HTTLPR and the
STin2 VNTR polymorphisms of the serotonin transporter gene
(SERT) have been associated with PSD in stroke survivors (Kohen
et al. 2008). These preliminary findings should be replicated using
state-of-the-art genetic methodology and larger samples.
Psychiatric history. Consistent with a genetic vulnerability to
develop psychiatric illness and developmental variations in stress
responses, a personal history of depression and/or anxiety was
consistently identified as a risk factor for PSD. A family history of
depression was associated with PSD in the only two studies that
examined this association (De Ryck et al. 2014; Kutlubaev and
Hackett 2014). In addition, a history of alcohol misuse constitutes a
risk factor for males only.
Medical history. Major cardiovascular risk factors such as
hypertension and hypercholesterolemia seem unrelated to PSD.
However, patients with PSD might be more likely to have a history of
diabetes mellitus.
Factors Associated With Stroke Characteristics

The available evidence strongly suggests a significant association
between stroke severity and PSD. However, recent systematic
reviews argue against an association between PSD and the type or
mechanism of stroke (De Ryck et al. 2014; Johnson et al. 2006;
Kutlubaev and Hackett 2014).
Robinson’s (2006) seminal work in the neurobiology of PSD
suggested that left anterior hemispheric lesions are associated with
the onset of PSD, and this finding was replicated in several
independent studies. A meta-analysis of these early studies
suggested that the significant relationship between PSD and left
anterior hemispheric lesions is restricted to the acute and the
subacute stages of stroke, whereas other factors become more
relevant in the chronic phase.
More recently, conflicting reports on the association between PSD
and lesion location were published. The most recent and larger
meta-analyses and systematic reviews failed to find an association
between PSD and lesion location (Wei et al. 2015). Wei et al.
analyzed 43 studies involving 5,507 stroke patients and reported an
odds ratio of 0.99 (95% CI 0.88–1.11) for the association of stroke
location and depression risk. This lack of association is hardly
surprising given the heterogeneity in the way in which depression
was assessed, the diverse timing of the assessments, and the
different neuroimaging methods used to determine lesion location.
Other neuropathological factors that might influence the risk of
developing depression after stroke are the presence of preexistent
brain atrophy, greater infarct volume, and the distribution of ischemic
changes in the frontosubcortical network.
In conclusion, the explanatory power of lesion location remains a
controversial issue that requires further study using larger samples
of patients, meaningful PSD phenotypes, and advanced
neuroimaging techniques.
Poststroke Factors
Functional and cognitive impairment. The severity of poststroke
functional impairment is the factor most consistently associated with
PSD. The severity of disability was found to be significantly related to
PSD in 16 out of 18 studies (Hackett and Anderson 2005) and in 24
out of 30 studies reviewed by Johnson et al. (2006).
The relationship between PSD and cognitive impairment
(especially executive dysfunction) has been well established. Initial
studies have shown that stroke patients with major depression had
significantly lower Mini-Mental State Examination (MMSE) scores
than nondepressed patients with similar background characteristics
who were matched for both lesion location and lesion volume
(Robinson 2006). This finding was replicated in an independent
study of stroke patients with left hemisphere lesions who were
assessed during the first year after stroke (Spalletta et al. 2002).
However, the evidence suggesting that cognitive impairment may
predict the onset of PSD is more tenuous: only two of four
prospective studies that examined cognitive impairment as a
predictor of PSD demonstrated a significant association (Kutlubaev
and Hackett 2014). Nevertheless, it is highly likely that there is a
bidirectional relationship between functional and cognitive
impairment and PSD, with each condition modifying the course of
the other.
Social support. Although it is reasonable to assume that an
enriched social support network would decrease patients’
vulnerability to developing depression following a stroke, the
available evidence is conflicting, probably because of significant
heterogeneity in the definition and evaluation of this construct. For
instance, although perceived social support and number of social
ties are inversely correlated with the severity of PSD (Robinson
2006), living situation and marital status have not been consistently
associated with PSD (Johnson et al. 2006). A recent prospective
study found that lack of social support at admission was associated
with the onset of PSD at 3-month follow-up (Choi-Kwon et al. 2012).
Effect of Poststroke Depression on Stroke Outcomes

There is strong consensus that PSD has an adverse influence on
stroke outcomes at all follow-up intervals. An early influential study
compared a consecutive series of 33 depressed stroke patients with
30 nondepressed patients with similar background characteristics
and stroke severity who also received equivalent rehabilitation
treatment. At 2-year follow-up, the depressed patients had
significantly greater impairments of activities of daily living than did
nondepressed patients (Robinson 2006). A comprehensive review of
this topic demonstrated that PSD was associated with poor
functional outcomes in six out of eight studies with appropriate
methods (Kutlubaev and Hackett 2014).
PSD has also been consistently associated with increased
mortality. Morris et al. (1993) were the first to examine mortality rates
among a group of 103 patients assessed 10 years after their stroke.
After controlling for confounding variables such as age, stroke
severity, and coexistent medical conditions, patients with acute PSD
were approximately three times more likely to have died during the
follow-up period than patients who were nondepressed after the
acute stroke (Robinson 2006). Furthermore, the significant
association between PSD and mortality is supported by the results of
a large retrospective analysis of medical records from 151,119 U.S.
veterans hospitalized for ischemic stroke (Williams et al. 2004) and
the findings of the South London Stroke Register, a large prospective
study of a stroke cohort (Ayerbe et al. 2014).
Mechanism of Poststroke Depression

The mechanism of PSD has not been elucidated. Notwithstanding
general statements about the importance of biological and
psychosocial factors, there are no empirically supported models for
PSD. Most proposed mechanisms have paralleled the hypotheses
proposed to explain idiopathic mood disorders. Early hypotheses
implicated lesions impinging upon ascending monoaminergic
pathways and consequent neurochemical changes (Robinson 2006).
More recently, neuropathological and neuroimaging studies
suggest that cerebrovascular disease, both clinically expressed and
silent, produces progressive disruption of neural circuits connecting
areas of the prefrontal cortex, the basal ganglia, and the limbic areas
involved in mood regulation (Alexopoulos et al. 1997). Thus, PSD
can be attributed to cumulative damage in these circuits,
independently of the changes that may be observed in
monoaminergic neurotransmission.
There is also an increasing interest in studying neuroinflammatory
changes elicited by stroke as mediators of PSD symptoms. Cerebral
ischemia is associated with an increased production of
proinflammatory cytokines such as IL-1β, IL-6, IL-18, TNF-α, and
INF-γ, and these elevations could be associated with PSD. Animal
and human studies suggest that proinflammatory cytokines may alter
hypothalamus-pituitary-adrenal axis reactivity, decrease
neurogenesis and plasticity in hippocampal circuits, and reduce
serotonergic transmission (Feng et al. 2014).
The recent emphasis on neuroplasticity as a critical
neurobiological substrate for depressive disorders suggests that
synaptic alterations in the prefrontal cortex and hippocampus are
etiologically implicated in PSD. In support, brain-derived
neurotrophic factor levels, one of the regulators of these processes,
have been shown to be reduced in PSD (Yang et al. 2011).
Finally, depressive disorders have been recently associated with
changes in glutaminergic neurotransmission. Magnetic resonance
spectroscopy provides preliminary evidence of altered glutamate
levels in the anterior cingulate cortex of depressed stroke patients
(Glodzik-Sobanska et al. 2006). Future studies should attempt to
integrate these diverse findings into an explanatory model of PSD.
Treatment of Poststroke Depression

There are relatively few randomized controlled trials (RCTs) for
PSD. Findings are difficult to interpret given differences in the
assessment of PSD and the variability observed in primary
outcomes.
A recent meta-analysis of 16 RCTs (12 using antidepressants and
4 evaluating the efficacy of psychotherapy) that included 1,655
patients found a significant beneficial effect of antidepressant
medication, whereas psychotherapy was not more effective than a
control intervention (Hackett et al. 2008). Of note, this meta-analysis
excluded a major pharmacological trial of frequently used
antidepressants (Robinson 2006) while including a trial of a
medication with controversial antidepressant effects (i.e.,
aniracetam) and a trial of a combination of an antipsychotic drug with
a tricyclic agent. This meta-analysis also found that adverse events
were more frequent among those subjects who received placebo,
including central nervous system side effects (odds ratio [OR] 1.96;
95% CI 1.19–3.24), gastrointestinal side effects (OR 2.37; 95% CI
1.38–4.06), and other side effects (OR 1.51; 95% CI 0.91–2.34).
Overall, on the basis of the available data, tricyclic
antidepressants, such as nortriptyline, have been demonstrated to
be efficacious in treating PSD. However, their use might be limited
by their known cardiac toxicity (e.g., ventricular arrhythmia,
conduction block); side effects of sedation, constipation, and
orthostatic hypotension; and tendency to produce cognitive
impairment secondary to their anticholinergic effects. In the absence
of contraindications and provided that serum concentrations are
carefully monitored, nortriptyline doses should be slowly titrated to
achieve a therapeutic serum concentration between 50 and 150
ng/mL (Figure 11–3).
FIGURE 11–3. Treatment of poststroke depression (PSD).
Note. FDA=U.S. Food and Drug Administration; MT=motor threshold;
RCT=randomized controlled trial.
The evidence is less consistent with regard to the efficacy of

selective serotonin reuptake inhibitors (SSRIs), but given their more
benign safety profile, they are currently considered an option of first
choice. Gastrointestinal and sexual side effects are the most
frequent adverse events encountered with their use. SSRIs have
also been associated with an increased risk of falls, hemorrhagic
complications, hyponatremia, and significant bradycardia. Although
rare, these adverse consequences should be kept in mind when
treating an elderly population with multiple medical comorbidities.
Citalopram and sertraline have fewer side effects and drug
interactions than other SSRIs, and they are usually preferred as
initial treatment. The suggested initial citalopram dosage is 20
mg/day for patients age 65 years and younger and 10 mg/day for
those who are older. The use of fluoxetine and paroxetine is limited
by their relatively greater potential for adverse effects and drug-drug
interactions. The prolonged half-life of fluoxetine and its principal
metabolite norfluoxetine extends the duration of such complications.
Paroxetine also has significant anticholinergic effects that increase
the risk of inducing cognitive deficits (Figure 11–3).
The available evidence on the efficacy of psychostimulants is
limited to case reports and open-label trials. Methylphenidate may be
useful in inpatient settings or when promptness of response is
required. Stimulants are also used to augment partial responses to
SSRIs, especially in the presence of residual cognitive impairments
and/or fatigue. Cardiovascular side effects of these medications
should be carefully monitored in the stroke population. The efficacy
of norepinephrine reuptake inhibitors to treat PSD has been
examined in a small RCT of reboxetine given at a daily dose of 4 mg.
Depressive symptoms were significantly reduced in the active
treatment group compared with the placebo group. Response and
remission rates, however, were not analyzed.
There is preliminary evidence that noninvasive brain stimulation
techniques such as repetitive transcranial magnetic stimulation might
be effective among depressed stroke patients who do not respond to
a trial with antidepressants (Jorge et al. 2008). In addition,
electroconvulsive therapy (ECT) may be used as a last resort to treat
refractory PSD. ECT should be started at the lowest effective energy
levels, using pulsatile currents, increased spacing of treatments (2–5
days between treatments), and fewer treatments in an entire course
(i.e., four to six). Nondominant unilateral ECT is the preferred
technique (Figure 11–3).
Effects of Antidepressants on Stroke Recovery

Common antidepressants are pleiotropic substances that have
other effects than the ones related to mood regulation. They may
certainly influence neuroplasticity and inflammatory responses
elicited by stroke and, consequently, affect recovery. A systematic
review and meta-analysis of 52 RCTs including 4,059 patients
suggested that antidepressants improve rehabilitation outcomes
(Hackett et al. 2008). More recently, it has been shown that
fluoxetine enhances motor recovery following cerebral ischemia
(Chollet et al. 2011), and beneficial effects of antidepressants on
memory function (Jorge et al. 2010), disability (Mikami et al. 2011),
and mortality following stroke (Jorge et al. 2003) have also been
reported.
Prevention of Poststroke Depression

Given the fact that approximately a third of stroke survivors will
develop PSD and that its presence is associated with functional
impairment, poor quality of life, and increased morbidity and
mortality, there is a need to develop treatment strategies to prevent
PSD.
A recent meta-analysis summarized the findings of eight RCTs
assessing the efficacy of preventive interventions among 776 initially
nondepressed stroke patients. Pooled analyses revealed the
likelihood of developing PSD was reduced among subjects receiving
active pharmacologic treatment (OR 0.34; 95% CI 0.22–0.53),
especially after a 1-year treatment (OR 0.31; 95% CI 0.18–0.56) and
with the use of an SSRI (OR 0.37; 95% CI 0.22–0.61). The most
commonly reported side effects were nausea, diarrhea, fatigue, and
dizziness. There were no significant differences between the active
and placebo groups in the frequency of these symptoms. Only
tremor was significantly associated with sertraline in one of the
RCTs.
Psychotherapeutic intervention might also be useful for PSD
prevention. Robinson et al. (2008) examined the efficacy of
escitalopram and problem-solving therapy to prevent PSD among
176 nondepressed patients within 3 months following acute stroke.
Patients who received placebo for a year were four times more likely
to develop depression than those who received escitalopram and
two times more likely than people who received problem-solving
therapy.
Poststroke Mania
According to DSM-5 nomenclature, bipolar and related disorder
due to stroke are subdivided as 1) with manic- or hypomanic-like
episode; 2) with manic features; and 3) with mixed features. In
contrast to the high frequency of PSD, hypomania or full manic
syndromes (also termed poststroke mania [PSM]) are unusual
consequences of stroke.
Phenomenology of Poststroke Mania

Few studies have examined the phenomenology of bipolar and
related disorders due to stroke. We have previously reported that
brain injuries may produce a syndrome that is very similar to a manic
syndrome in the absence of brain injury. Furthermore, we described
a group of patients who, after a brain injury, alternated manic with
depressive phases. Half of these patients had recurrent episodes of
depression, whereas one-fourth had recurrent manic episodes. Most
of these patients had right hemisphere lesions, mostly involving
subcortical regions, such as the head of the caudate and the
thalamus. A fourth of patients had mixed episodes. Patients with a
bipolar phenotype had greater cognitive impairment than patients
with unipolar mania (Robinson 2006).
In a recent systematic review article, Santos et al. (2011) reported
elevated mood as the most common symptom of PSM, followed by
irritability, pressured speech, decreased need for sleep, and
agitation.
Risk Factors for Secondary Mania

Given the low frequency of PSM and that most patients with
lesions in the areas usually involved in secondary mania do not
develop an affective disorder, the question arises as to the additional
risk factors for this condition. Starkstein et al. (1987) found a higher
frequency of positive family history of mood disorders among
patients with secondary mania, suggesting that a genetic
predisposition may constitute a risk factor for this condition. In
addition, we compared groups of patients with or without secondary
mania matched for size, location, and cause of lesion. Patients with
secondary mania had more severe subcortical atrophy and a higher
frequency of family history of psychiatric disorders than patients
without secondary mania (Robinson 2006).
Lesion Location as a Risk Factor for Poststroke

Mania
Case series as well as case reports suggest that PSM is related
to lesions in paleocortical areas of the right hemisphere, such as the
basotemporal and orbitofrontal cortices. In a series of 17 patients
with secondary mania reported by Robinson’s group, most of the
patients had lesions involving cortical regions of the right hemisphere
(basotemporal or orbitofrontal) or subcortical lesions involving the
head of the caudate or the thalamus (Robinson 2006). In three
patients with subcortical lesions, a positron emission tomography
scan using fluorodeoxyglucose (18F) showed hypometabolism of the
right basotemporal lobe (Starkstein et al. 1990). A systematic review
of lesion location in secondary mania supported previous findings of
lesions involving the dorsomedial thalamus, the head of the caudate,
and paleocortical regions (Santos et al. 2011).
Mechanism of Poststroke Mania

The amygdala has major outputs to both the basotemporal and
the orbitofrontal cortices, and it receives afferents from temporopolar
and basolateral cortices. In turn, the basotemporal cortex receives
major afferents from the orbitofrontal cortex and association areas.
The anterior region of the orbitofrontal cortex exerts a tonic inhibitory
control over the amygdala by means of its connection through the
uncinated fasciculus with the basotemporal cortex. Therefore, the
basotemporal cortex may mediate connections between
psychomotor and volitional processes generated in frontal regions
and instinctive behaviors generated in the amygdala (Starkstein et
al. 1990).
Treatment of Poststroke Mania

Given the low numbers of patients with secondary mania, RCTs
are unfeasible. However, evidence from case reports suggests that
these patients respond to the mood stabilizers and atypical
antipsychotics commonly used to treat bipolar disorder (Robinson
2006).
Poststroke Anxiety
Anxiety is a frequent comorbid condition of “primary” depression,
and similar findings were reported for PSD. Nevertheless, anxiety
disorders were also reported to occur independently from depression
after stroke lesions.
Frequency of Poststroke Anxiety

In the Robinson group series (Robinson 2006), 27% of 288
patients with acute stroke had generalized anxiety disorder (GAD),
albeit most of them (74%) were also depressed. About half of these
patients had a 2-year follow-up, and the main finding was that 23%
of patients developed GAD after the acute stroke period. Leppävuori
et al. (2003) reported that 21% of a series of 277 outpatients with a
stroke lesion met DSM-IV criteria for GAD, and most of them (81%)
had comorbid depression. Anxiety persists well into the chronic
stage of stroke recovery. For instance, Lincoln et al. (2013) found
that 29% of patients showed anxiety 5 years after the stroke.
Risk Factors for Poststroke Anxiety

Aström (1996) found that absence of social contacts outside the
family and dependence of patients on others to perform their basic
activities of daily living (ADLs) were the main correlates with
poststroke GAD. Leppävuori et al. (2003) reported GAD to be
significantly associated with a personal history of epilepsy, comorbid
depression, and prestroke use of anxiolytic drugs. After stroke, GAD
was associated with the level of psychosocial function and personal
history of migraine.
Anxiety
Initial studies suggested that patients with mixed anxious
depression had a significantly higher frequency of cortical lesions
than patients with depression only, who had a significantly higher
frequency of subcortical lesions. There was also an association
between GAD and right hemisphere lesions (Robinson 2006). More
recently, Leppävuori et al. (2003) reported GAD to be associated
with lesions in the anterior circulation territory.
Treatment of Poststroke Anxiety

Robinson (2006) examined anxiety as a secondary outcome
measure of an RCT of nortriptyline for PSD. He found that patients
on active treatment showed significant improvements on the
Hamilton Anxiety Scale compared with the placebo-treated group.
Wang et al. (2005) randomly assigned 81 patients with poststroke
anxiety to receive paroxetine (20 mg/day), paroxetine and supportive
psychotherapy, or usual management. The main finding was that
both active arms showed greater improvement in anxiety compared
with the control group. Moreover, the group treated with paroxetine
and psychotherapy also showed a significant improvement in ADLs.
There were no dropouts in any of the three groups, and the main
side effects reported for paroxetine were nausea and dizziness
(Wang et al. 2005).
There are no controlled studies of psychotherapy for treating
poststroke anxiety. In conclusion, anxiety is a common finding in
both the acute and chronic poststroke periods. Patients with anxiety
commonly present with depression; anxiety is related to social
isolation, increased dependence in performing ADLs, and poor
psychosocial function. Nortriptyline and paroxetine demonstrated
good efficacy in RCTs; however, there are no studies on the
usefulness of psychotherapy.
Poststroke Psychosis
The phenomenon of psychosis after stroke has been designated
with a variety of terms, such as agitated delirium, acute atypical
psychosis, peduncular hallucinosis, release hallucinations, and acute
organic psychosis. Psychotic symptoms including delusions,
hallucinations, and thought disorder are unusual consequences of
stroke, occurring in less than 0.5% of patients with an acute stroke,
and tend to be of short duration (Kumral and Oztürk 2004). There is
a reported association between delusions and right hemisphere
strokes, especially in fronto-temporo-parietal cortices and subcortical
regions such as the basal ganglia, thalamus, and brain stem (Kumral
and Oztürk 2004).
Devine et al. (2014) examined the anatomical basis of delusions
in three patients who developed delusions after right hemisphere
lesions and nine stroke patients with similar lesions but no delusions.
Patients with delusions had involvement of the right inferior frontal
gyrus and underlying white matter, including the superior longitudinal
fasciculus and the corona radiata. All three patients with delusions
had a prestroke positive psychiatric history, compared with one in the
control group.
Peduncular hallucinosis is a term coined by Jean Lhermitte to
refer to vivid and colorful visual hallucinations with preserved insight
after lesions of the cerebellar peduncles. Lesion-producing
hallucinations were also reported to involve the rostral and pretectal
brain stem, substantia nigra, red nucleus, and the periaqueductal
gray (McKee et al. 1990). It has been suggested that peduncular
hallucinosis may result from a “release phenomenon” due to
disruption of the pathway connecting the ascending reticular
activating system and the intralaminar thalamic nuclei (McMurtray et
al. 2014). Finally, seizures have been frequently reported among
patients with secondary psychosis (Robinson 2006).
Poststroke Apathy
Apathy is a syndrome of diminished motivation. It is defined by the
development of reduced goal-directed thought, feeling, and behavior.
It is distinct from depression, which is defined classically by the
presence of persistent and excessive sadness most of the day
nearly every day for at least 2 or more weeks. In other words,
depression reflects an excess of emotion (sadness/dysphoria) rather
than a deficit of or the absence of emotion. It also is contrasted with
anhedonia, which—strictly defined—is the inability to experience
pleasure from activities that one usually finds enjoyable but not a
loss of goal-directed or reactive emotion more generally (as is the
case with apathy).
Frequency of Poststroke Apathy

Starkstein et al. (1993a) found apathy only in 11% of patients
within the acute stroke period, whereas another 11% had both
apathy and depression. A recent systematic review on poststroke
apathy (van Dalen et al. 2013) reported that about one-third of stroke
patients will develop apathy, regardless of selection bias. Brodaty et
al. (2013) examined the longitudinal course of apathy in the context
of a 5-year follow-up study and found a steady increase in rates of
apathy with time since stroke—from 27% at baseline to 39% 5 years
later.
Risk Factors for Poststroke Apathy

Starkstein et al. (1993a) found that patients with apathy were
significantly older and had significantly more severe impairments in
ADLs than those without apathy. Apathy was reported to be
associated with cognitive deficits, older age, depression, and
increased disability (van Dalen et al. 2013). Among patients admitted
to a stroke rehabilitation unit, those with apathy were more likely to
be discharged to a nursing home, and they had worse functional
recovery (Harris et al. 2014). Brodaty et al. (2013) reported that the
main predictors of apathy were poor cognitive status, low functional
level, and high medical comorbidity. A more recent study (Tang et al.
2014) reported a strong association between poststroke apathy and
health-related quality of life.

Apathy
We have previously reported that nondepressed patients with
apathy have lesions usually involving the basal ganglia and the
posterior limb of the internal capsule (Starkstein et al. 1993a). A
study by Matsuoka et al. (2014) showed a significant association
between poststroke reductions in the volume of the posterior
cingulate cortex and increasing apathy during a 6-month period. In
addition, a study including 185 poststroke patients (Tang et al. 2014)
reported a significant association between poststroke apathy and
pontine infarcts.
Mechanism of Poststroke Apathy

Apathy is a disorder of motivation that is part of a spectrum of
conditions, ranging from motor neglect to psychic akinesia and
akinetic mutism. Starkstein et al. (1993a) speculated that apathy
may be related to disrupted connections between the pallidum and
brain stem motor centers. The ansa lenticularis is one of the main
internal pallidal outputs, ending in the pedunculopontine nucleus
after coursing through the posterior limb of the internal capsule. This
pathway has a prominent role in goal-oriented behavior (Starkstein
et al. 1993a). More recently, poststroke apathy was considered to
result from faulty control of goal-directed behavior due to posterior
cingulate degeneration (Matsuoka et al. 2014).
Treatment of Poststroke Apathy

An RCT with the nootropic drug nefiracetam (Robinson et al.
2009) showed a significant improvement on the Apathy Scale
scores, and the drug was well tolerated, with few side effects. In this
study, apathy was a secondary outcome measure; RCTs with apathy
as a main outcome are still lacking.
In conclusion, apathy is a common sequela of stroke, and it
usually occurs with comorbid depression. The mechanism of apathy
after stroke remains unknown. Poststroke apathy is associated with
older age, more severe disability, and more severe cognitive deficits.
Future studies should examine the role of nootropics in the
management of poststroke apathy.
Catastrophic Reaction
Catastrophic reaction is a term coined by Kurt Goldstein
(Goldstein 1939) to describe “the inability of the organism to cope
when faced with physical or cognitive deficits.” Clinically, the
catastrophic reaction is manifested by anxiety, tears, aggressive
behavior, swearing, displacement, refusal, renouncement, and
compensatory boasting. The severity of this phenomenon can be
measured by the Catastrophic Reaction Scale (Starkstein et al.
1993b).
Starkstein et al. (1993b) reported the catastrophic reaction in 19%
of consecutive patients with an acute stroke. Patients with the
catastrophic reaction had a significantly greater personal history of
depression, and most of them had comorbid major depression. On
the other hand, there were no significant differences in the frequency
of the catastrophic reaction between patients with or without
aphasia, suggesting that this phenomenon should not be construed
as an emotional reaction to the presence of speech deficits. Carota
et al. (2001) reported 12 patients with catastrophic reaction identified
from a prospective cohort of 326 patients with first-ever stroke.
Catastrophic reaction was associated with nonfluent aphasia and
opercular lesions. One limitation of this study is that catastrophic
reaction was diagnosed based on an ad hoc and nonvalidated
procedure.
Starkstein et al. (1993b) noted a significant association between
the catastrophic reaction and lesions involving the basal ganglia.
Nevertheless, it is still unclear whether the catastrophic reaction is
mostly an emotional response of patients confronted with their
limitations in the context of a prestroke history of depression or
whether specific neurophysiological mechanisms are involved.
Pathological Affective Display

PAD is a common complication of stroke lesions; it is usually
divided into two syndromes: affective lability (or emotional lability)
and pathological laughing and crying. Affective lability is
characterized by sudden, easily provoked episodes of crying that,
although frequent, generally occur in situations where the provoking
stimuli are sentimentally meaningful and the episodes are neither
fully stereotyped nor without some amenability to voluntary control.
By contrast, pathological laughing and crying is a more severe form
of pathological emotional display characterized by uncontrollable,
stereotyped episodes of laughing and/or crying that are often
provoked by sentimentally trivial or sentimentally meaningless
stimuli. Other terms used for pathological laughing and crying
include emotional incontinence, pathologic emotions, involuntary
emotional expression disorder, and pseudobulbar affect. PAD should
not be dependent on stimulus, should cause significant distress, and
should not be accounted for by a drug or a neuropsychiatric disorder
(Cummings et al. 2006).
Assessment, Frequency, and Comorbidity of

Pathological Affective Display After Stroke
Robinson (2006) developed the Pathological Laughter and Crying
Scale (PLACS) to assess the presence and severity of PAD. PLACS
scores were found to have no significant correlations with the HDRS
scores, MMSE scores, or deficits in ADLs, which indicates that
PLACS measures a factor independent of depression, cognition, and
functioning.
The frequency of PAD in stroke patients was estimated to range
between 20% and 25% in the first 6 months after the stroke and to
decline to about 10%–15% at 12 months (Hackett et al. 2010).
Mechanism of Pathological Affective Display in

Stroke
PAD has been associated with bilateral corticobulbar motor tract
lesions as well as lesions to the frontal lobes, the basal ganglia, and
the brain stem (Robinson 2006). It has been suggested that PAD
results from disconnection within cortico-pontine-cerebellar pathways
(Parvizi et al. 2001). Tang et al. (2014) found that patients with PAD
after an acute stroke had significantly more severe microbleeds in
the anterior and paramedian territories of the thalamus compared
with patients without PAD; this suggests that microbleeds in specific
brain regions have a significant role in the mechanism of PAD.
Treatment of Pathological Affective Display After

Stroke
Robinson’s group carried out a 6-week RCT of nortriptyline (up to
100 mg/daily) versus placebo to treat PAD. They found the active
medication to be significantly better than placebo in decreasing
PLACS scores. Moreover, PLACS scores improved in depressed
and nondepressed patients, suggesting that treatment response was
not simply related to an improvement in depression (Robinson
2006). A Cochrane review from 2004 included seven drug trials
using fluoxetine, sertraline, citalopram, or nortriptyline versus
placebo. Overall, antidepressants elicited a 50% or more reduction in
the severity of PAD (Horrocks et al. 2004).
In conclusion, PAD is a common behavioral manifestation after
stroke. PAD is subdivided into emotional lability and pathological
laughing and crying; these may have different mechanisms. Several
RCTs using SSRIs and nortriptyline showed adequate efficacy in
treating PAD after stroke.
Conclusion
Cerebrovascular disease is associated with frequent alterations in
cognitive and behavioral control as well as in emotional regulation.
These alterations result in varied neuropsychiatric syndromes that
include depression, anxiety, apathy, emotional lability, pseudobulbar
affect, irritability, aggression, and psychosis. There is extensive
clinical overlap among these syndromes, and the field is slowly
moving from purely symptom-based definitions to a more
comprehensive conceptualization of these conditions through novel
pathophysiological models that are based on recent advances in
basic neuroscience and neuroimaging methods.
Although the negative impact that neuropsychiatric alterations
have upon the recovery of patients with cerebrovascular disease is
widely recognized, there is, surprisingly, scarce evidence on the
efficacy of the available therapeutic interventions, both
pharmacological and nonpharmacological. It is reasonable to expect
that progress in the elucidation of pathophysiological mechanisms
and the development of useful biomarkers of these processes will
allow the identification of new therapeutic targets and inspire the
design of new treatment options.
References
Alexopoulos GS, Meyers BS, Young RC, et al: “Vascular depression” hypothesis.
Arch Gen Psychiatry 54(10):915–922, 1997 9337771
Aström M: Generalized anxiety disorder in stroke patients: a 3-year longitudinal
study. Stroke 27(2):270–275, 1996 8571422
Ayerbe L, Ayis S, Wolfe CD, et al: Natural history, predictors and outcomes of
depression after stroke: systematic review and meta-analysis. Br J Psychiatry
202(1):14–21, 2013 23284148
Ayerbe L, Ayis S, Crichton S, et al: The long-term outcomes of depression up to 10
years after stroke; the South London Stroke Register. J Neurol Neurosurg
Psychiatry 85(5):514–521, 2014 24163430
Brodaty H, Liu Z, Withall A, et al: The longitudinal course of post-stroke apathy
over five years. J Neuropsychiatry Clin Neurosci 25(4):283–291, 2013
24247855
Carota A, Rossetti AO, Karapanayiotides T, et al: Catastrophic reaction in acute
stroke: a reflex behavior in aphasic patients. Neurology 57(10):1902–1905,
2001 11723287
Choi-Kwon S, Han K, Choi S, et al: Poststroke depression and emotional
incontinence: factors related to acute and subacute stages. Neurology
78(15):1130–1137, 2012 22459674
Chollet F, Tardy J, Albucher JF, et al: Fluoxetine for motor recovery after acute
ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet
Neurol 10(2):123–130, 2011 21216670
Cummings JL, Arciniegas DB, Brooks BR, et al: Defining and diagnosing
involuntary emotional expression disorder. CNS Spectr 11(6):1–7, 2006
16816786
De Ryck A, Brouns R, Geurden M, et al: Risk factors for poststroke depression:
identification of inconsistencies based on a systematic review. J Geriatr
Psychiatry Neurol 27(3):147–158, 2014 24713406
Devine MJ, Bentley P, Jones B, et al: The role of the right inferior frontal gyrus in
the pathogenesis of post-stroke psychosis. J Neurol 261(3):600–603, 2014
24449063
Feng C, Fang M, Liu XY: The neurobiological pathogenesis of poststroke
depression. Sci World J 2014:521349, 2014 24744682
First MB, Williams JBW, Karg RS: Structured Clinical Interview for DSM-5
Disorders, Research Version (SCID-5-RV). Arlington, VA, American Psychiatric
Association, 2015
Glodzik-Sobanska L, Slowik A, McHugh P, et al: Single voxel proton magnetic
resonance spectroscopy in post-stroke depression. Psychiatry Res 148(2–
3):111–120, 2006 17088051
Goldstein K: The Organism, a Holistic Approach to Biology Derived From
Pathological Data in Man. New York, American Book Company, 1939
Hackett ML, Anderson CS: Predictors of depression after stroke: a systematic
review of observational studies. Stroke 36(10):2296–2301, 2005 16179565
Hackett ML, Anderson CS, House A, et al: Interventions for treating depression
after stroke. Cochrane Database Syst Rev (4):CD003437, 2008 18843644
Hackett ML, Yang M, Anderson CS, et al: Pharmaceutical interventions for
emotionalism after stroke. Cochrane Database Syst Rev (2):CD003690, 2010
20166068
Hackett ML, Köhler S, O’Brien JT, et al: Neuropsychiatric outcomes of stroke.
Lancet Neurol 13(5):525–534, 2014 24685278
Hamilton M: A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–
62, 1960 14399272
Harris AL, Elder J, Schiff ND, et al: Post-stroke apathy and hypersomnia lead to
worse outcomes from acute rehabilitation. Transl Stroke Res 5(2):292–300,
2014 24323716
Horrocks JA, Hackett ML, Anderson CS, et al: Pharmaceutical interventions for
emotionalism after stroke. Stroke 35(11):2610–2611, 2004 15472084
Insel T, Cuthbert B, Garvey M, et al: Research domain criteria (RDoC): toward a
new classification framework for research on mental disorders. Am J Psychiatry
167(7):748–751, 2010 20595427
Johnson JL, Minarik PA, Nyström KV, et al: Poststroke depression incidence and
risk factors: an integrative literature review. J Neurosci Nurs 38(4)(suppl):316–
327, 2006 16989301
Jorge RE, Robinson RG, Arndt S, et al: Mortality and poststroke depression: a
placebo-controlled trial of antidepressants. Am J Psychiatry 160(10):1823–
1829, 2003 14514497
Jorge RE, Moser DJ, Acion L, et al: Treatment of vascular depression using
repetitive transcranial magnetic stimulation. Arch Gen Psychiatry 65(3):268–
276, 2008 18316673
Jorge RE, Acion L, Moser D, et al: Escitalopram and enhancement of cognitive
recovery following stroke. Arch Gen Psychiatry 67(2):187–196, 2010 20124118
Kohen R, Cain KC, Mitchell PH, et al: Association of serotonin transporter gene
polymorphisms with poststroke depression. Arch Gen Psychiatry 65(11):1296–
1302, 2008 18981341
Kumral E, Oztürk O: Delusional state following acute stroke. Neurology 62(1):110–
113, 2004 14718709
Kutlubaev MA, Hackett ML: Part II: predictors of depression after stroke and
impact of depression on stroke outcome: an updated systematic review of
observational studies. Int J Stroke 9(8):1026–1036, 2014 25156411
Leppävuori A, Pohjasvaara T, Vataja R, et al: Generalized anxiety disorders three
to four months after ischemic stroke. Cerebrovasc Dis 16(3):257–264, 2003
12865614
Lincoln NB, Brinkmann N, Cunningham S, et al: Anxiety and depression after
stroke: a 5-year follow-up. Disabil Rehabil 35(2):140–145, 2013 22725629
Matsuoka K, Yasuno F, Taguchi A, et al: Delayed atrophy in posterior cingulate
cortex and apathy after stroke. Int J Geriatr Psychiatry 30(6):566–572, 2014
25092799
McKee AC, Levine DN, Kowall NW, et al: Peduncular hallucinosis associated with
isolated infarction of the substantia nigra pars reticulata. Ann Neurol 27(5):500–
504, 1990 2360791
McMurtray A, Tseng B, Diaz N, et al: Acute psychosis associated with subcortical
stroke: comparison between basal ganglia and mid-brain lesions. Case Rep
Neurol Med 2014:428425, 2014 25309765
Mikami K, Jorge RE, Adams HP Jr, et al: Effect of antidepressants on the course
of disability following stroke. Am J Geriatr Psychiatry 19(12):1007–1015, 2011
21358384
Morris PL, Robinson RG, Andrzejewski P, et al: Association of depression with 10-
year poststroke mortality. Am J Psychiatry 150(1):124–129, 1993 8417554
Parvizi J, Anderson SW, Martin CO, et al: Pathological laughter and crying: a link
to the cerebellum. Brain 124(Pt 9):1708–1719, 2001 11522574
Robinson RG: The Clinical Neuropsychiatry of Stroke. New York, Cambridge
University Press, 2006
Robinson RG, Jorge RE, Moser DJ, et al: Escitalopram and problem-solving
therapy for prevention of poststroke depression: a randomized controlled trial.
JAMA 299(20):2391–2400, 2008 18505948
Robinson RG, Jorge RE, Clarence-Smith K, et al: Double-blind treatment of apathy
in patients with poststroke depression using nefiracetam. J Neuropsychiatry
Clin Neurosci 21(2):144–151, 2009 19622685
Santos CO, Caeiro L, Ferro JM, et al: Mania and stroke: a systematic review.
Cerebrovasc Dis 32(1):11–21, 2011 21576938
Sheehan DV, Lecrubier Y, Sheehan KH, et al: The Mini-International
Neuropsychiatric Interview (M.I.N.I.): the development and validation of a
structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin
Psychiatry 59 (suppl 20):22–33; quiz 34–57, 1998 9881538
Spalletta G, Guida G, De Angelis D, et al: Predictors of cognitive level and
depression severity are different in patients with left and right hemispheric
stroke within the first year of illness. J Neurol 249(11):1541–1551, 2002
12420095
Starkstein SE, Pearlson GD, Boston J, Robinson RG: Mania after brain injury: a
controlled study of causative factors. Arch Neurol 44(10):1069–1073, 1987
3632381
Starkstein SE, Mayberg HS, Berthier ML, et al: Mania after brain injury:
neuroradiological and metabolic findings. Ann Neurol 27(6):652–659, 1990
2360802
Starkstein SE, Fedoroff JP, Price TR, et al: Apathy following cerebrovascular
lesions. Stroke 24(11):1625–1630, 1993a 8236333
Starkstein SE, Fedoroff JP, Price TR, et al: Catastrophic reaction after
cerebrovascular lesions: frequency, correlates, and validation of a scale. J
Neuropsychiatry Clin Neurosci 5(2):189–194, 1993b 8508037
Tang WK, Lau CG, Mok V, et al: Apathy and health-related quality of life in stroke.
Arch Phys Med Rehabil 95(5):857–861, 2014 24184306
van Dalen JW, Moll van Charante EP, Nederkoorn PJ, et al: Poststroke apathy.
Stroke 44(3):851–860, 2013 23362076
Wang Z, He Y, Xiao C, et al: A clinical trial of paroxetine and psychotherapy in
patients with poststroke depression and anxiety. Chinese Mental Health
Journal (8):564–566, 2005
Wei N, Yong W, Li X, et al: Post-stroke depression and lesion location: a
systematic review. J Neurol 262(1):81–90, 2015 25308633
Williams JB, Gibbon M, First MB, et al: The Structured Clinical Interview for DSM-
III-R (SCID), II: multisite test-retest reliability. Arch Gen Psychiatry 49(8):630–
636, 1992 1637253
Williams LS, Ghose SS, Swindle RW: Depression and other mental health
diagnoses increase mortality risk after ischemic stroke. Am J Psychiatry
161(6):1090–1095, 2004 15169698
Williams LS, Brizendine EJ, Plue L, et al: Performance of the PHQ-9 as a
screening tool for depression after stroke. Stroke 36(3):635–638, 2005
15677576
Yang L, Zhang Z, Sun D, et al: Low serum BDNF may indicate the development of
PSD in patients with acute ischemic stroke. Int J Geriatr Psychiatry 26(5):495–
502, 2011 20845405
Yesavage JA, Brink TL, Rose TL, et al: Development and validation of a geriatric
depression screening scale: a preliminary report. J Psychiatr Res 17(1):37–49,
1982–1983 7183759
CHAPTER 12

Traumatic brain injury (TBI) is a complex category of clinical

conditions defined by a functionally significant alteration of brain
function and/or structure resulting from the application of external
physical force (including acceleration/deceleration and/or blast
forces). TBI occurs along a continuum of injury severity and can
produce a broad range of neuropsychiatric disturbances of variable
duration. The heterogeneity and complexity of both TBI and its
sequelae present challenges in clinical care, research, public policy,
and medicolegal proceedings.
Some persons with TBI (particularly those with very severe
injuries) experience lifelong, disabling cognitive, emotional,
behavioral, motor, and sensory impairments. Other persons with TBI
(particularly those with history of a single mild TBI) can expect to
return to baseline functioning within days to weeks postinjury (Carroll
et al. 2004, 2014; Cassidy et al. 2014). The effects of injury and the
course of recovery vary, with injury severity (mild, moderate, or
severe), comorbid or complicating neuropsychiatric conditions, and
psychosocial circumstances all potentially influencing outcomes.
Competent clinical practice requires that clinicians consider all of
these factors when evaluating persons with neuropsychiatric
disturbances after TBI in order to identify opportunities to diagnose
and treat common neuropsychiatric conditions, including those that
bear no meaningful causal relationship to TBI. In this chapter, we
aim to provide guidance toward those ends through a brief review of
the definitions of TBI and the essential neurophysiology and relevant
neuroanatomy of TBI and syntheses of evidence-based assessment
and treatment for individuals living with TBI-related neuropsychiatric
disturbances.
Defining TBI
Traumatic brain injury is defined as an event-related disruption in
brain function and/or structure as a consequence of external physical
forces (e.g., acceleration/deceleration, blast), resulting in the acute
disruption of cognitive and/or elementary neurological functions
(Department of Veterans Affairs and Department of Defense 2009;
Menon et al. 2010; Mild Traumatic Brain Injury Committee of the
Head Injury Interdisciplinary Special Interest Group of the American
Congress of Rehabilitation Medicine 1993; National Institute of
Neurological Disorders and Stroke Common Data Elements Team
2013). The term TBI should strictly be reserved for biomechanical
force-induced injuries; acquired brain injury (or ABI) may be used to
denote brain injury resulting from other etiologies, such as anoxia,
stroke, tumors, infection, or toxins. TBI may be classified as either
penetrating or nonpenetrating, based on whether or not the cranium
has been breached. Outcomes related to penetrating injuries are
largely influenced by the nature and extent of neuroanatomy
compromised by the penetrating object(s), and penetrating injuries
carry additional risk for complication, particularly infection.
Nonpenetrating injuries are far more common and are divided into
three categories based upon severity: mild, moderate, and severe.
Neuropsychiatric formulations surrounding prognosis and/or the
development of physical, cognitive, emotional, and/or behavioral
symptoms in the postacute recovery phase are informed by TBI
severity, thereby highlighting the importance of clinically establishing
severity of injury.
There are a number of approaches for assessing TBI severity.
The Glasgow Coma Scale (GCS) (Teasdale and Jennett 1974) was
originally developed as a means for gauging impaired consciousness
after any type of brain injury. It was subsequently repurposed as a
measure with which to gauge TBI severity in the early postinjury
period, with GCS scores 3–8 reflecting severe TBI, 9–12 moderate
TBI, and 13–15 mild TBI (Rimel et al. 1979). Subsequent efforts to
clarify injury severity incorporated the GCS but extended the relevant
phenomenology to include posttraumatic amnesia (PTA)—the period
of densely impaired new learning after injury (anterograde amnesia),
with or without impairments in the period immediately preceding
injury (retrograde amnesia); alterations of consciousness (being
“dazed and confused”); and other focal signs of brain injury (e.g.,
aphasia, hemiparesis, cortical blindness).
The most widely used definition of mild TBI was offered by the
American Congress of Rehabilitation Medicine (ACRM) in 1993 (Mild
Traumatic Brain Injury Committee of the Head Injury Interdisciplinary
Special Interest Group of the American Congress of Rehabilitation
Medicine 1993). The ACRM defined mild TBI as a mechanically
induced physiologic disruption of brain function manifested by any
one of the following: a loss of consciousness (LOC); a loss of
memory for events immediately preceding or following the injury (i.e.,
PTA); an alteration in mental state (feeling dazed, stunned,
confused, or disoriented) at the time of injury; and focal neurological
signs that may or may not be transient. To remain within the category
of mild TBI, any associated LOC must be briefer that 30 minutes in
duration, PTA must not exceed 24 hours, and the GCS score needs
to be 13 or better by 30 minutes following injury. If any one of these
criteria is exceeded, then the TBI is regarded as moderate or severe.
TABLE 12–1. Classification of TBI severity integrating the approaches used

by the Department of Veterans Affairs and Department of Defense (2009) and
the American Congress of Rehabilitation Medicine (Kay et al. 1993) and
extending them to include complicated mild TBI
Criteria
PTA AOC GCS (after 30
TBI severity LOC (hours) (days) (days) minutes) CT or MRI
Mild ≤0.5 ≤1 ≤1 13–15 Normal
Complicated ≤0.5 ≤1 ≤1 13–15 Abnormal
mild
Moderate >0.5 to <24 >1 >1 9–12 Normal or
to abnormal
<7
Severe ≥24 ≥7 >1 3–8 Normal or
abnormal
Note. AOC=alteration of consciousness; CT=computed tomography; GCS=
Glasgow Coma Scale; LOC=loss of consciousness; MRI=magnetic resonance
imaging; PTA=posttraumatic amnesia; TBI=traumatic brain injury.
Source. Adapted from Arciniegas DB: “Addressing neuropsychiatric disturbances
during rehabilitation after traumatic brain injury: current and future methods.”
Dialogues in Clinical Neuroscience 13(3):325–345, 2011. © Les Laboratoires,
Servier, Suresnes, France. Used with permission.
ACRM criteria are usefully augmented with the concept of

complicated mild TBI (Williams et al. 1990). Most cases involving
phenomenologically defined mild TBI will be without early (i.e., day of
injury) computed tomography (CT) and/or magnetic resonance
imaging (MRI) evidence of neurotrauma-induced intracranial
abnormalities (i.e., hematoma, hemorrhage, contusion, axonal injury,
edema). An injury that meets ACRM criteria for mild TBI but is
associated with intracranial abnormalities on conventional structural
neuroimaging (consistent with the effects of neurotrauma) is termed
a complicated mild TBI. Table 12–1 (Arciniegas 2013) offers criteria
for mild, moderate, and severe TBI, integrating the grading system of
the ACRM with that of the Department of Veterans Affairs and
Department of Defense (2009), and further augments these
approaches with the concept of complicated mild TBI.
Epidemiology
In 2010, approximately 2.5 million TBI-associated emergency
room visits or hospitalizations occurred in the United States. The
majority of such injuries—about 80%—were mild in severity.
However, more severe TBI resulted in more than 50,000 deaths.
Although rates of TBI-related visits to emergency rooms have
increased by about 70% over the past decade, hospitalization rates
have increased by only 11%, and death rates have decreased by 7%
(Faul et al. 2010). This change is likely due in part to increasing TBI
awareness among both patients and providers, particularly as it
relates to injuries from sports/recreation. In support of this are data
demonstrating that emergency room visits secondary to sports-
and/or recreation-related TBI sustained by children (under the age of
19) increased by 57% in the past decade—a figure that seems
unlikely to reflect an increase of TBI of this magnitude in this
population and instead is better explained by the heightened
awareness of TBI among parents and a proportionally lower
threshold for parents to seek evaluation and treatment for their
children in the immediate period after a sports- and/or recreation-
related concussion. Approximately 20% of U.S. service personnel
serving in recent military conflicts have sustained a TBI, with 76.75%
being mild TBI (Centers for Disease Control and Prevention et al.
2013). Nearly 3.2 million Americans are living with long-term
neuropsychiatric consequences from TBI (Zaloshnja et al. 2008),
with most of those with long-term disability having experienced a TBI
requiring hospitalization.
Falls are the most common cause of injury, accounting for nearly
40% of TBI, resulting in U.S. emergency room visits, hospitalizations,
or deaths between the years 2006 and 2010. Both the very young
and old are particularly at risk for such injuries; 55% of TBI sustained
by children less than a year up to 14 years and 81% of TBI in those
age 65 and older were the consequence of falls. The second leading
cause of TBI is unintentional blunt trauma, which accounts for
approximately 15% of injuries. Motor vehicle accidents are the
mechanism associated with nearly 14% of injuries, although motor
vehicle accidents are second in terms of TBI-related deaths,
accounting for 26% of fatalities. Assaults are the cause of nearly
10% of TBI and disproportionately affect young adults; 75% of
assault-related TBI occurred in young adults between the ages of 15
and 44 (Centers for Disease Control and Prevention 2016). While
sports-related TBI has received increasing attention both in the
medical literature and popular press, many individuals with such
injuries may not present for evaluation or emergency care, and thus
these injuries are likely underrepresented in the above figures.
Neuropathophysiology of TBI
TBI involves a combination of contact and inertial forces that
mechanically induce disruption of cellular and metabolic processes.
Although every TBI involves a unique set of forces acting upon a
unique brain, the frontal and temporal lobes are particularly
vulnerable to the deleterious effects of biomechanical trauma.
Shearing and straining forces impact white matter, especially at the
brain stem, cerebral parasagittal white matter, corpus callosum, and
gray-white junctions of the cerebral cortex (Bigler 2007; Lipton et al.
2009; Meythaler et al. 2001; Povlishock and Katz 2005). This
combination of neuroanatomical vulnerabilities explains the
frequency with which clinically significant early and late
posttraumatic disturbances in cognition, emotion, and behavior
follow TBI. Regional susceptibility to injury and related
neuropsychiatric consequences are reviewed by Arciniegas (2011a).
Biomechanically induced neuronal injury precipitates a complex
and potentially injurious cascade of metabolic events, including
dysregulation of calcium, magnesium, and potassium across injured
cell membranes; biomechanically triggered action potentials; release
of neurotransmitters and excitatory amino acids; calcium-regulated
protein activation and mitochondrial dysfunction; alterations of
cellular metabolism with free radical release and oxidative stress;
activation of proteolytic enzymes; and in more severe cases,
activation of programmed cell death (apoptosis). An ensuing “energy
crisis” has been described, wherein increased energy demands to
restore cellular homeostasis cause hyperglycolysis in the setting of
normal or reduced cerebral blood flow. The resulting state is one of
mismatch, with uncoupling between energy supply and energy
demand (Giza and Hovda 2014).
Biomechanically induced release of neurotransmitters involves a
number of systems including glutamate, acetylcholine, dopamine,
norepinephrine, serotonin, and γ-aminobutyric acid (GABA). This
results in an early excess of neurotransmitters after injury, a state
sometimes referred to as a “neurotransmitter storm.” This state
usually resolves within days to several weeks in cases of severe TBI.
Although neurotransmitter excess features in the early postinjury
period, injury to efferent projections may eventually result in
insufficient levels of various neurotransmitters. For example, early
cholinergic and catecholaminergic excess is often followed by
cortical cholinergic and/or catecholaminergic deficits that may
contribute to the chronic neuropsychiatric impairments frequently
encountered in the wake of TBI, with implications for
pharmacological management (Arciniegas 2011b; Bales et al. 2009;
McAllister 2009).
Evaluation of Persons With TBI
Evaluation of persons with TBI entails a thorough neuropsychiatric
examination based on the principles of assessment delineated in
Chapter 2 (“Neuropsychiatric Assessment”). Importantly, for those
with a history of TBI it is essential to remain mindful that this history
is only one aspect of a much larger developmental, medical,
neuropsychiatric, and psychosocial history and that these other
historical elements must be given due consideration during the
evaluation. Comprehensive assessment of persons with TBI
therefore necessitates identifying any and all potential contributions
to the individual’s presenting neuropsychiatric status, including
preinjury, injury (e.g., TBI severity, concomitant injuries), and
postinjury factors. Relevant preinjury factors may include age;
gender; neurogenetics; neurodevelopment; premorbid intellectual
function; medical, neurological, and psychiatric conditions; history of
previous trauma (physical and emotional); substance use conditions;
personality and coping styles; sociocultural background; and
economic status. Such factors are likely to contribute to vulnerability
or resilience during recovery from TBI. All postinjury factors, such as
the presence or absence of appropriate medical care, concomitant
physical injuries and/or medical complications, medications,
education and expectations regarding TBI recovery, presence or
absence of social support systems, postinjury coping styles,
psychological issues, disability and role changes, and medicolegal
entanglements, may influence the course of recovery and/or
emergence of various neuropsychiatric symptoms (Arciniegas and
Silver 2013). Silver (2012) has described a number of factors that
may influence symptom manifestation, including stereotype threat,
loss aversion, and feelings of anger and injustice that produce a
unique differential diagnosis when compensation and/or litigation
complicates clinical presentations. Importantly, these various factors
will co-occur and mutually influence one another. Hence, any given
neuropsychiatric presentation will inevitably be the consequence of a
complicated interplay between injury, preinjury, and postinjury
factors, as illustrated in Figure 12–1 (Arciniegas and Silver 2013).
FIGURE 12–1. Model of the interactions of preinjury factors, injury factors,

and postinjury factors in relation to posttraumatic neuropsychiatric
disturbances.
Source. Figure by David B. Arciniegas, M.D. © 2017. Used with permission of the
author.
Clinical Interview to Establish the Historic Injury

Event
Obtaining information regarding the acute injury event is essential.
Clinicians are encouraged to anchor their clinical interviews to
accepted TBI definitions, such as those described in the section
“Defining TBI.” Specific questions should be asked to determine
whether an alteration of consciousness, LOC, or PTA associated
with an injury event occurred. Of course, if an individual experienced
LOC or PTA, self-reporting of injury-related events and symptoms
must be regarded with skepticism (i.e., one cannot self-report on
occurrences for which one was unconscious or is amnestic). In such
circumstances, the interview about the injury event will rely on what
the individual has been told about the event by others at the scene
or by medical providers. For example, the evaluator might also ask,
“What is the last thing you remember before getting hit, and what is
the first thing you remember afterward?"
The ability to provide a detailed narrative of the injury event,
capturing the moments just prior to impact and immediately
afterward, represents a valuable data point in itself. While it may be
difficult to precisely determine the duration of LOC or PTA, such
inquiries will generally facilitate an initial determination as to whether
an injury event meets or exceeds criteria for mild TBI. As noted
above, patients may be unable to provide accurate details and may
even inadvertently provide inaccurate histories. For example, an
individual may presume that he or she was unconscious based upon
a gap in memory, when in reality he or she was awake and alert but
amnestic. For these reasons, it is generally useful to obtain collateral
information when available.
Collateral information (e.g., emergency room records, in which
LOC and GCS scores are often documented), like the clinical
interview itself, should be used to identify requisite criteria
surrounding diagnosis and injury severity. Explicit documentation
regarding more subtle alterations in consciousness is frequently
lacking in such records. Emergency room records have been
reported to miss approximately half of the cases of TBI (Powell et al.
2008). Hospital and/or rehabilitation records will sometimes include
specific PTA assessments, such as the Galveston Orientation and
Amnesia Test (GOAT; Levin et al. 1979) or the Orientation Log (O-
Log; Jackson et al. 1998); their presence in the medical record
facilitates determination of the duration of PTA. Often, injury events
are witnessed by friends or family (especially injury events occurring
in the context of sports/recreation) and sometimes even captured on
video. Such data may help to precisely determine the occurrence
and severity of a TBI event.
Although a clinical history anchored to requisite criteria for injury
severity may be sufficient for establishing the occurrence of an injury
event, use of psychometrically sound structured clinical instruments
may also be useful for this purpose. The Ohio State University TBI
Identification Method (OSU TBI-ID; Corrigan and Bogner 2007) is
designed to elicit self-reports or proxy reports of a TBI occurring over
a person’s lifetime. The Brain Injury Screening Questionnaire (BISQ)
is another structured self-report instrument designed to elicit lifetime
history of TBI (Dams-O’Connor et al. 2014).
TBI remains a clinical diagnosis, and, as such, the possibility of
inaccurately attributing symptoms to an injury event exists. Many
factors other than TBI may cause or contribute to event-related
disturbances of consciousness and/or sensory motor abilities (e.g.,
intoxication, cerebrovascular compromise, hypoxia-ischemia,
subdural or epidural hematomas without overt brain injury, seizure,
head and neck injury). Consideration of such factors prior to
attributing disruptions in consciousness and/or sensorimotor abilities
to TBI is recommended (Arciniegas 2013).
Symptoms and Course of Illness After TBI

A broad array of neuropsychiatric symptoms may follow TBI of all
severities. Common physical symptoms include headache, fatigue,
sleep disturbance, vertigo or dizziness, sensitivity to light and/or
sound, and anosmia. Cognitive disturbances potentially range from
level of arousal and attention through higher-order executive
functions and social intelligence. Problems with complex attention,
executive functioning, learning, memory, and speed of processing
are common. Emotional disturbances often include irritability,
depression, anxiety, affective lability, and decreased frustration
tolerance. Behavioral disturbances or personality changes may
involve aggression, disinhibition, impulsivity, and apathy.
Although every individual and TBI should be conceptualized as
being unique, there remain reasonably predictable aspects regarding
the course and resolution of symptoms that are predicated on the
well-established natural history of TBI (see Figure 12–2; Arciniegas
et al. 2013).
FIGURE 12–2. Stages of posttraumatic encephalopathy.

Source. Reprinted from Arciniegas DB, Frey KL, McAllister TW: “Cognitive
impairments,” in Management of Adults With Traumatic Brain Injury. Edited by
Arciniegas DB, Zasler ND, Vanderploeg RD, et al. Washington, DC, American
Psychiatric Publishing, 2013, p. 141. Copyright © 2013. Used with permission.
Arciniegas et al. (2013) recommend describing the immediate

neuropsychiatric consequences of TBI as an acute posttraumatic
encephalopathy. The term encephalopathy denotes the broad range
of neurotrauma-induced clinical signs and symptoms that may follow
an injury, with the modifier acute posttraumatic establishing a
temporal relationship whereby the encephalopathy onsets
immediately following the injury event. Recovery should also follow a
reasonably predictable course involving the following five stages of
posttraumatic encephalopathy: posttraumatic coma; posttraumatic
confusional state; posttraumatic amnesia; posttraumatic
dysexecutive syndrome; and recovery. Although these stages are
named in accordance with the most salient cognitive feature
associated with each, additional areas of impairment are often
present. Some mild injuries never involve coma, confusional state, or
amnesia, with recovery starting at the dysexecutive syndrome stage.
Figure 12–2 illustrates a number of additional important principles
relating to the natural history of TBI. Across all severities of TBI,
symptoms and impairment are most pronounced immediately
following injury (absent some contributing or emerging complication,
such as intracranial hemorrhage), with subsequent improvement
being the norm. Late-emerging symptoms and/or downward
trajectories are atypical of TBI, across all levels of severity, and such
manifestations suggest the presence of additional factors in need of
consideration. Recognizing atypical trajectories following mild TBI is
particularly important in light of the highly nonspecific nature of
common postconcussive symptoms. Research comparing persons
with mild TBI with individuals with orthopedic injury reveals that
postconcussive symptoms, pain, and mental health are similar
across all acute injuries, whether or not there is brain involvement.
Hence, it is vital that clinicians attend to not only the nature of
postinjury symptoms but also their temporal evolution and their
trajectories (Cassidy et al. 2014).
Figure 12–2 also illustrates an important point regarding the
modifiers used to describe TBI severity. The terms mild, moderate,
and severe refer to parameters surrounding the acute injury event
(e.g., duration of LOC, PTA). These terms are not intended to denote
outcomes; a severe TBI is not necessarily associated with severe
neuropsychiatric impairment in the late recovery phase. It is
generally the case that more severe injuries feature a much broader
spectrum of potential outcomes. Severe TBI features the broadest of
spectrums, all the way from death or devastating neuropsychiatric
impairment to remarkable recovery that approximates the individual’s
baseline status. Mild TBI, on the other hand, generally features a far
narrower spectrum of plausible outcomes relating to the direct
effects of neurotrauma (see section “Mild TBI”).
Physical, Neurological, and Mental Status

Examination
A general physical examination should be performed on all
patients, with attention to findings suggesting other physical injuries
that potentially cause or contribute to symptoms commonly
encountered subsequent to TBI (i.e., cervical injury causing
headaches, painful musculoskeletal injury interfering with sleep). The
most common cranial nerve abnormality after TBI is of the olfactory
nerve. The relative frequency of anosmia and hyposmia subsequent
to TBI makes this a potentially high-yield aspect of neurological
examination. Eye movement disturbances are also relatively
common in the setting of TBI; these disturbances may be a
consequence of intracranial and/or extracranial injuries. Similarly,
problems with balance may result from injury to the brain, visual or
vestibular systems, and/or extracranial structures (such as the
propioceptive system in the deep neck muscles). Damage to frontal
subcortical circuits may result in disturbances of volitional motor
inhibition, or paratonia. Primitive reflexes, including glabellar, snout,
suck, palmomental, and grasp, may also feature and again suggest
disturbances of frontal subcortical circuits (Arciniegas 2013).
The choice of any specific psychometrically sound instruments
utilized to assess mood and/or cognition may need to be titrated to
the individual’s functional status, which will be influenced by the
severity of TBI, temporal proximity to the injury event, and
concomitant injuries to other organ systems. Assessment of
cognition is usefully anchored to measures with associated age- and
education-based normative data. Careful consideration of preinjury
cognitive abilities as well as psychological functioning is necessary
to identify any acute or persisting changes from baseline.
Importantly, the identification of any changes must be followed by
consideration of functional relevance. While cognitive impairment
may contribute to functional limitations, the degree to which an
individual’s functional status is accounted for by cognitive deficits
remains highly variable (Royall et al. 2007).
Neuroimaging
Neuroimaging can play an important role in the evaluation of
acute TBI. CT is particularly useful and appropriate in the setting of
potential skull fracture or intracranial bleeding and may help to
identify trauma-induced intracranial pathology necessitating
neurosurgical intervention. As previously discussed, early structural
neuroimaging with either CT or MRI helps to distinguish between
complicated and uncomplicated mild TBI. Identifying complicated
mild TBI is important because the prognosis associated with such
injuries may be more akin to moderate TBI (Iverson et al. 2012;
Williams et al. 1990). Neuroimaging’s role during the subacute or
late postinjury period of recovery remains less well established.
However, standard MRI sequences (typically involving T1- and T2-
weighted, fluid-attenuated inversion recovery, gradient echo or
susceptibility-weighted imaging, and diffusion-weighted imaging)
may reveal injuries or abnormalities not apparent on CT
examination. The identification of such lesions may help the clinician
to understand atypical recoveries and inform treatment, particularly
when abnormalities correspond to neuroanatomy salient to the
physical, cognitive, emotional, or behavioral symptoms experienced.
An extensive body of literature describes the application of
various advanced neuroimaging techniques to the study of TBI.
Techniques span a variety of modalities, including those investigating
white matter integrity (diffusion tensor imaging), those characterizing
the neurochemical composition of tissues (magnetic resonance
spectroscopy), and functional neuroimaging modalities investigating
various metabolic parameters (e.g., single-photon emission
computed tomography, positron emission tomography, functional
MRI). While all of these advanced neuroimaging techniques
represent powerful research tools, they continue to play a relatively
modest role in the clinical evaluation of TBI at the single
subject/individual level, in that results do not appear to add any
additional information that impacts treatment beyond that
ascertained from clinical history and routine brain imaging
(Wintermark et al. 2015).
Problems persist with respect to differentiating between the broad
range of what constitutes “normal” for the human brain and
pathological findings. This is an area of ongoing controversy,
particularly as it pertains to mild TBI and atypical outcomes. There
are overlapping neuroimaging abnormalities, as identified via various
advanced imaging techniques, in many common neuropsychiatric
conditions; the specificity of such findings is typically insufficient to
determine etiology or to allow attribution of such findings to TBI. The
lack of population-based normative reference data for neuroimaging
studies of all kinds, as well as normative data linking neuroimaging
findings to functional status, further limits the interpretation of such
data. Given these limitations, cautious interpretation of advanced
neuroimaging results is encouraged, and all interpretations need to
be informed by the totality of pertinent circumstances spanning
preinjury, injury, and postinjury neuropsychiatric and psychosocial
factors (Wortzel et al. 2014).
Electrophysiological Assessment
Approximately 5%–30% of adults with TBI will develop
posttraumatic seizures, and electroencephalogram (EEG) evaluation
is appropriate in the setting of clinical suspicion for such. Importantly,
interictal EEG may be unremarkable in the setting of posttraumatic
seizures and is relatively insensitive to identifying epileptiform
abnormalities. Hence, treatment for posttraumatic seizures should be
predicated upon the clinical phenomenology of events and not
strictly guided by EEG results. The use of EEG is also well
established for the evaluation of nonconvulsive seizures, coma, and
brain death following severe TBI (Arciniegas 2013).
The role for quantitative EEG (QEEG) for clinical purposes with
respect to TBI is not well established. While research suggests that
QEEG may distinguish between TBI populations and healthy control
subjects at the group level, the abnormalities identified tend toward
the nonspecific and overlap considerably with findings associated
with other common neuropsychiatric conditions, including those that
frequently are comorbid with TBI (e.g., depression, anxiety,
substance use disorders). In addition, QEEG data neither establish
the diagnosis nor dictate clinical decision making (Arciniegas 2013).
Neuropsychological Examination
Neuropsychological testing involves rigorous examination to
determine the individual’s cognitive status, including areas of
impairment as well as intact abilities. Ideally, the process enables the
identification of both relative strengths and weaknesses, such that
the former may be capitalized on in efforts to circumvent or minimize
the impact of the latter. Neuropsychological examination typically
involves a combination of measures to explore different areas of
functioning (e.g., attention, visual and verbal memory, executive
functioning). Neuropsychological tests should be psychometrically
sound (valid and reliable assessment techniques) and normed so
that an individual’s performance can be compared to a
demographically similar cohort (e.g., age, education).
Neuropsychological assessments often include measures of
psychiatric symptoms (e.g., depression, anxiety) (Vanderploeg
2013).
Factors in addition to TBI that may impact neuropsychological test
results and require consideration include uncertainty surrounding
preinjury functioning and ability, preinjury and/or comorbid
neuropsychiatric conditions, and effort put forth by the patient.
Therefore, identifying deficits on neuropsychological testing may be
consistent with TBI, but the presence of such deficits in the subacute
or late period after a purported injury does not necessarily confirm
the prior occurrence of a TBI.
Conversely, the absence of deficits on neuropsychological testing
does not rule out the occurrence of a TBI, particularly in the case of
mild TBI, wherein neuropsychological test performance typically
returns to baseline levels within 3 months of the time of injury. The
most commonly observed neuropsychological deficits following TBI
fall in the areas of attention and concentration, new learning and
memory, information processing speed, and executive functioning.
Areas less well evaluated by neuropsychological testing include
performing tasks in “real-world” environments (with distractions) and
the ability to sustain cognitive activity over a prolonged time.
However, neuropsychological testing is a clinically valuable means
for assessing cognition and guiding appropriate interventions for
individuals with TBI (Vanderploeg 2013).
Mild TBI
Substantial persisting neuropsychiatric impairment relating to
neuronal injury often features in cases of moderate to severe TBI,
although remarkable recovery may also occur, as can the
development of other neuropsychiatric conditions causing or
contributing to symptoms. As injuries become more temporally
remote, injury severity should feature more prominently when
considering the relative contributions of neuronal injury and other
factors pertinent to persisting symptoms and impairment. This is
particularly true in the setting of a single uncomplicated mild TBI.
Given the frequency with which mild TBI is encountered, the
complexities in managing individuals with atypical recoveries, and
the controversies surrounding this subject, additional consideration
regarding mild TBI (and multiple mild TBI) is warranted.
Single, Uncomplicated Mild TBI

The natural history and prognosis for a single uncomplicated mild
TBI are well established in the medical literature, involving a very
favorable long-term prognosis in the vast majority of cases. The
systematic review of the WHO Collaborating Centre Task Force on
Mild Traumatic Brain Injury (Carroll et al. 2004) reported that
complete recovery within weeks or months of injury is the norm for
both children and adults. More recently, the work of this group has
been updated by the International Collaboration on Mild Traumatic
Brain Injury Prognosis through systematic and critical review of the
mild TBI literature for the years 2001–2012. The International
Collaboration on Mild Traumatic Brain Injury Prognosis offered
results generally in keeping with prior meta-analyses portending
complete and relatively rapid recovery as the typical outcome after
mild TBI (Carroll et al. 2014). Mild TBI was consistently associated
with cognitive deficits in the first 48 hours to 2 weeks following injury,
and recovery frequently occurred early (during the first month after
injury). There was limited evidence that complete recovery among
civilians (i.e., those experiencing TBI outside sports or military
contexts) may take as long as 6 months or a year for some, and
lacking was any quality evidence to support long-standing severe
neurocognitive impairment. Very notable were three investigations
(Ozen and Fernandes 2011; Suhr and Gunstad 2002, 2005) offering
evidence that patient expectations influence outcomes of mild TBI
(with expectations of recovery facilitating good outcomes),
emphasizing the importance of appropriate education regarding the
expectation for recovery.
While a full and fast recovery is typical of mild TBI, there is a
subset of individuals who experience persistent symptoms after such
injuries. Atypical recovery of this sort occurs in about 10% of cases,
and such outcomes are significantly influenced by noninjury-related
factors (McCrea et al. 2013). Findings described by Cassidy et al.
(2014) extend the body of evidence regarding the nonspecific nature
of symptoms following mild TBI:
The weight of this evidence suggests that postconcussion symptoms are

not specific to MTBI [mild TBI], and clinicians should be cautious about
attributing common postinjury symptoms to the MTBI. This calls into question
the validity of diagnosing PCS [postconcussion syndrome]. (pp. S134–S135)
Some authors have instead suggested the term “persisting

symptoms after concussion” to better reflect the numerous potential
etiologies behind such symptoms. Atypical recovery is a reality, and
some individuals will go on to experience persisting symptoms
subsequent to mild TBI. However, such complaints may not be a
consequence of neuronal injury per se but instead may derive from a
host of non–brain injury factors. Thus, alternative explanations must
be examined when there is a prolonged recovery from mild TBI. The
more atypical (i.e., numerous, persisting, and/or severe symptoms
yielding substantial functional impairment) a presentation becomes,
the more likely it is that other contributing or causative factors need
attention.
Multiple Mild TBI

The state of the science regarding repetitive, or simply multiple,
mild TBI is considerably less well developed. Belanger et al. (2010)
performed a meta-analysis of neuropsychological outcomes
following multiple concussions. Eight studies, collectively
encompassing 614 repetitive mild TBI cases and 926 control
subjects, were reviewed. There were no significant main effects of
repetitive mild TBI on neurocognitive functioning or other symptoms.
Secondary analyses demonstrated associations between multiple
mild TBI and performance on measures of delayed memory and
executive functioning. However, the identified effect sizes were small
and of questionable clinical import (i.e., not clearly related to
everyday function or dysfunction). There is evidence that repeated
concussions increase the risk of additional concussions and may
portend lengthier recovery from subsequent injuries (Guskiewicz et
al. 2003; Harmon et al. 2013). A number of factors are probably
relevant regarding the consequences of repeated concussive
injuries, including the total number of concussive exposures, the age
at the time of concussion, the duration of time over which they are
accumulated, the interval between exposures, the extent of recovery
achieved during those intervals, and other characteristics of the
individual. There remains no quality evidence establishing a causal
relationship between several concussions and chronic traumatic
encephalopathy. The consequences of multiple mild TBI remain an
area in need of more research. Steps (such as those delineated for
athletes in return-to-play protocols) to minimize TBI exposures and
ensure adequate recovery time between injury events remain
prudent (Harmon et al. 2013).
Management of Neuropsychiatric Sequelae

Treatment modalities include pharmacological, behavioral,
psychological, and social interventions. A combination of such
treatment modalities, ideally delivered in a multidisciplinary and
collaborative approach, is best to target the various issues causing
or sustaining symptoms and to optimize recovery and restore
function. Prior to initiating treatment, it is important to clarify the
precise nature of target symptoms, as well as the frequency and
severity of such. The usefulness of any treatment modalities
deployed should be regularly reassessed. General principles of
pharmacotherapy for patients with traumatic brain injury offered by
Arciniegas and Silver (2011) are featured in Table 12–2.
TABLE 12–2. General principles of pharmacotherapy for patients with
traumatic brain injuries
Start low, go slow Initiate treatment at doses lower than those used in
patients without brain injuries and raise doses
more slowly than in patients without brain injuries.
Adequate Although patients with brain injuries may be more
therapeutic trial sensitive to the side effects of many medications,
standard doses of such medications may be
needed to adequately treat the neuropsychiatric
problems of these patients.
Continuous The need for continued treatment should be
reassessment reassessed in an ongoing fashion, and dose
reduction or medication discontinuation should be
attempted after achieving remission of target
symptoms. Spontaneous recovery occurs, and in
such circumstances, continued pharmacotherapy
is unnecessary.
Monitor drug-drug Because patients with brain injuries are often
interactions sensitive to medication side effects and because
they may require treatment with several
medications, it is essential to be aware of and to
monitor these patients for possible drug-drug
interactions.
Augmentation A patient experiencing a partial response to treatment
with a single agent may benefit from augmentation
of that treatment with a second agent that has a
different mechanism of action. Augmentation of
partial responses is preferable to switching to an
agent with the same pharmacological profile as
that producing the partial response.
Symptom If target psychiatric symptoms worsen after initiation
intensification of pharmacotherapy, lower the dose of the
medication; if symptom intensification persists,
discontinue the medication entirely.
Source. Reprinted from Arciniegas DB, Silver JM: “Psychopharmacology,” in
Textbook of Traumatic Brain Injury, 2nd Edition. Edited by Silver JM, McAllister
TW, Yudofsky SC. Washington, DC, American Psychiatric Publishing, 2011, p.
558. Copyright © 2011. Used with permission.
Although a comprehensive review of all potential neuropsychiatric
sequelae of TBI and the available treatment options is beyond the
scope of this chapter, we do offer a brief synopsis of treatment
options for the more common neuropsychiatric complications.
Disorders of Mood
Depression is among the most frequent of the neuropsychiatric
sequelae of TBI. Mania, hypomania, and mixed mood states occur
with considerably less frequency but, nonetheless, remain serious
complications of TBI. The management of mood disorders (like most
psychiatric symptoms) subsequent to TBI is not unlike that which
targets idiopathic psychiatric disorders. Cognitive-behavioral therapy
may be useful in decreasing depressive symptoms and enhancing
problem-solving skills, self-esteem, and psychosocial functioning.
Peer support programming for patients and families may increase
knowledge and enhance coping.
In terms of psychopharmacology, selective serotonin reuptake
inhibitors (SSRIs) may prove helpful with depressive symptoms, and
SSRIs are usually first-line for this purpose. In addition to their
relative safety and ease of use, SSRIs offer the advantage of being
potentially helpful for a number of common comorbidities, such as
post-TBI anxiety and posttraumatic stress disorder, and may also
decrease the number and perceived severity of somatic and
cognitive symptoms. Among the available SSRIs, sertraline,
citalopram, and escitalopram are recommended as first-line options.
Methylphenidate may improve depression following TBI and may
prove particularly useful during the acute rehabilitation period or
when a rapid response is required. There is less evidence
surrounding the efficacy and tolerability of other antidepressants.
Bupropion’s propensity for lowering seizure threshold warrants
consideration in this population. The use of monoamine oxidase
inhibitors should be avoided when cognitive or behavioral
impairment threatens the patient’s ability to adhere to dietary
restrictions. Electroconvulsive therapy may be used to treat severe
and refractory depression following TBI.
There is limited guidance literature for pharmacological
management of bipolar spectrum disorders following TBI, but agents
routinely used to treat idiopathic mania and mixed mood states are
typically employed for this purpose. The potential for cognitive side
effects warrants consideration in the selection of a mood stabilizer;
lamotrigine tends to be preferable to valproate, carbamazepine, or
lithium in this regard. Lithium may prove to be intolerable at doses
necessary to achieve mood stabilization because of adverse
cognitive and/or motoric side effects. Atypical antipsychotics may be
of use in managing posttraumatic mania, hypomania, or mixed states
(Jorge and Arciniegas 2014).
Disorders of Affect
Emotional dyscontrol, including affective lability, irritability, and
pathological laughing and crying (also known as pseudobulbar
affect), is a common problem following TBI. The management of
posttraumatic affective lability and irritability should start with
nonpharmacological approaches. Counseling, education, and/or
psychotherapy to improve self-efficacy and self-regulation are
appropriate initial treatment modalities. When these approaches
prove ineffective, or symptoms are severe, medications may provide
additional benefit. The pharmacological management of
posttraumatic affective lability and irritability starts with SSRIs as
appropriate first-line choices. Although the evidence is more limited,
affective lability may also respond to treatment with tricyclics,
methylphenidate, amantadine, or antiepileptics such as valproate,
carbamazepine, or lamotrigine. These agents, as well as quetiapine,
aripiprazole, buspirone, and propranolol, may prove helpful in the
setting of posttraumatic irritability.
SSRIs are appropriately employed as first-line treatment for
pathological laughing and crying. When SSRIs are not effective or
tolerated, dextromethorphan-quinidine is an approved treatment
option for pathological laughing and crying following TBI, although
risk for drug-drug interactions because of quinidine warrants
consideration (Arciniegas and Wortzel 2014).
Aggression
Posttraumatic aggression potentially places patients, their
families, and care providers at risk for harm, threatens social support
networks, and compromises rehabilitation. Treatment of
posttraumatic aggression requires precise clarification regarding the
nature of aggressive behaviors, including (but not limited to) context,
frequency, severity, purposefulness, and instrumentality. Effective
management of posttraumatic aggression involves the combination
of psychosocial and pharmacological interventions delivered via a
multimodal, multidisciplinary, and collaborative approach. Behavioral
analysis and behavioral management are important strategies for
addressing aggression in the wake of TBI. Cognitive-behavioral
therapy may also be useful in the management of posttraumatic
aggression.
Pharmacological management of aggression requires
distinguishing between acute aggression and chronic aggression. In
the face of acute aggression, especially when the safety of the
patient and others is of concern, antipsychotics and benzodiazepines
are most commonly deployed. Atypical antipsychotics are preferable
to typical neuroleptics in efforts to minimize extrapyramidal side
effects. If benzodiazepines are also required, agents with shorter
half-lives and lacking active metabolites are preferable. Medications
used to achieve behavioral control in the face of acute aggression
should be discontinued as soon as possible.
The management of chronic aggression frequently necessitates
long-term pharmacotherapy. SSRIs are often used as a first-line
treatment for chronic posttraumatic aggression, and recent evidence
points to a potential role for amantadine as well. Although beta-
blockers enjoy the best evidence of efficacy, in clinical practice these
agents are typically reserved for individuals whose aggressive
symptoms do not respond to other medications. Alternative
treatment options include buspirone and anticonvulsants (valproate
or carbamazepine, in particular). Treatment with atypical
antipsychotics may be appropriate when the other options noted fail
to afford adequate control of aggressive behaviors (Arciniegas and
Wortzel 2014).
Apathy
Careful assessment is often required to distinguish apathy from
depression, with the former involving predominantly a reduction in
goal-directed behavior and cognition and reduced concomitant
emotions. The distinction is an important one because treatment
commonly deployed for depression (e.g., SSRIs) may exacerbate
apathy. There remains a paucity of research regarding treatment for
apathy among persons with TBI. However, psychostimulants,
including methylphenidate and dextroamphetamine, are
recommended for this purpose. Alternative options include
amantadine, selegiline, and acetylcholinesterase inhibitors
(Starkstein and Pahissa 2014).
Disorders of Sleep and Fatigue

Problems surrounding sleep and fatigue frequently occur in the
context of common comorbid conditions, such as depression,
anxiety, or pain. Hence, an appropriate initial step in the
management of problems with sleep or fatigue involves identifying
and treating comorbid conditions contributing to such difficulties.
Similarly, underlying medical illnesses or diagnosed sleep disorders,
such as obstructive sleep apnea, require identification and
appropriate management. Nonpharmacological management
strategies are an important, albeit often neglected, aspect of
treatment. Behavioral interventions and psychoeducation to optimize
sleep hygiene and to better manage daytime symptoms are
appropriate first-line interventions. Patients with brain injury may
need to make accommodations to minimize symptoms and optimize
performance. Minimizing work hours, scheduling work to coincide
with periods of optimal efficiency, and incorporating scheduled break
times are often useful strategies. Work environments may also be
optimized to minimize distractions and mitigate cognitive fatigue.
Blue light therapy is reported to be effective in alleviating fatigue and
daytime sleepiness after TBI (Ponsford and Sinclair 2014).
Pharmacotherapy for posttraumatic insomnia requires careful
consideration of side effects. Although benzodiazepines and
nonbenzodiazepine hypnotics are frequently used to treat insomnia
in the general population, patients with brain injury may be
particularly susceptible to adverse effects, including cognitive
impairment and reduced daytime alertness. Hence, long-term use of
such agents is not recommended for posttraumatic insomnia.
Trazodone is often used in this context and enjoys a relatively
benign side-effect profile. Other sedating antidepressants may also
be useful for this purpose, including mirtazapine and tricyclic
antidepressants. Atypical antipsychotics are sometimes used for
posttraumatic insomnia; quetiapine may prove particularly useful for
this purpose when there is co-occurring paranoia or agitation.
Melatonin and ramelteon (a melatonin agonist) represent additional
treatment options.
Pharmacotherapy for posttraumatic fatigue should be adjunctive
to the above-described nonpharmacological interventions.
Psychostimulants, such as methylphenidate and
dextroamphetamine, may prove helpful in terms of arousal, fatigue,
inattention, and hypersomnia after brain injury. Other dopaminergic
agents, such as carbidopa-levodopa, bromocriptine, or amantadine,
may also prove useful in this regard. Modafinil and armodafinil may
represent additional options for posttraumatic fatigue.
Headache
Headaches are a relatively common problem after TBI and a
significant source of distress. As is the case for headache more
generally, it is necessary to characterize the nature of posttraumatic
headaches, with tension, cervicogenic, and migraine headaches
being particularly common. Episodic tension or cervicogenic
headaches typically respond well to treatment with nonsteroidal anti-
inflammatories (NSAIDs). Acetaminophen and/or aspirin may also
prove useful. Opioid analgesics are sometimes used to manage
more severe tension headaches. Importantly, persistent use of
medications may lead to rebound headaches or chronic daily
headaches. Preventative treatment strategies may be appropriate
when tension or cervicogenic headaches occur more than three
times per week. Tricyclic antidepressants, NSAIDs, and
acetaminophen may reduce the frequency of headaches. Cognitive-
behavioral therapies (including relaxation training and biofeedback),
physical therapy, education, and/or spinal manipulation represent
useful additional approaches to the management of posttraumatic
tension and cervicogenic headaches.
The management of migraine headaches, which accounts for
nearly 50% of posttraumatic headaches, involves both abortive and
preventative treatments. Preventative options commonly include
beta-blockers, topiramate, amitriptyline, and valproate. Abortive
treatments, best deployed early upon headache onset, may include
NSAIDs, triptans, ergotamines, tramadol, or oxygen inhalation.
Rescue medications may be deployed to break an acute headache
and include similar options as well as ketorolac, valproate,
butorphanol, and opioids. Cognitive-behavioral interventions may
also prove useful to improve the identification and avoidance of
migraine triggers and optimize lifestyle modification (e.g.,
maintenance of sleep, exercise, and meal schedules) (Ruff et al.
2013).
Cognitive Impairment
The differential diagnosis for posttraumatic cognitive impairment is
a broad one. Physical, emotional, and behavioral conditions may
contribute to such problems, as can substances of abuse and
prescription medications. Neuropsychiatric evaluation and treatment
to identify and optimize such contributing factors is typically
appropriate prior to initiating therapy specifically targeting cognitive
impairment. First-line treatments for posttraumatic cognitive
impairment are nonpharmacological and include education, realistic
expectation setting, lifestyle and environmental modification, and
cognitive rehabilitation. An essential component of treatment
includes the development of adaptive and compensatory strategies
that limit the adverse consequences of cognitive impairment and
capitalize on intact cognitive resources to circumvent areas of
weakness. Cognitive prosthetic devices are typically readily
available; these may include smartphone technology equipped with
sophisticated daily planners, alarms, and global positioning devices
and more readily available strategies involving memory notebooks
and task lists (Arciniegas et al. 2013).
Cognitive rehabilitation involves a systematic program of
interventions intended to improve cognitive abilities and everyday
functioning. Interventions typically reestablish or reinforce previously
learned skills, seek to develop compensatory strategies, and
facilitate adaptation to irreversible cognitive deficits. Readers are
directed to the American Congress of Rehabilitation Medicine
(Cicerone et al. 2011) and the European Federation of Neurological
Societies (Cappa et al. 2005) for systematic review and analysis of
the cognitive rehabilitation literature and evidence-based
recommendations regarding cognitive rehabilitation. Comprehensive-
holistic neuropsychological rehabilitation is recommended during the
postacute rehabilitation phase for individuals with moderate to
severe TBI.
Pharmacotherapy for posttraumatic cognitive impairment spans
strategies involving uncompetitive N-methyl-D-aspartate (NMDA)
receptor antagonism, augmentation of cerebral catecholaminergic
function, augmentation of cerebral cholinergic function, and
combinations thereof. Treatment with uncompetitive NMDA receptor
antagonists, amantadine in particular, during the immediate
postinjury period may decrease the duration of unconsciousness and
improve arousal. For more enduring or chronic cognitive impairment,
the selection of treatment strategy is usually guided by the nature of
the persisting cognitive deficits. Problems involving declarative
memory may respond to strategies involving cholinergic
augmentation, such as donepezil or rivastigmine. Catecholaminergic
augmentation may facilitate improvement in arousal, processing
speed, attention, and executive function and may also offer benefits
in terms of posttraumatic depression and apathy. Options include
methylphenidate, dextroamphetamine, amantadine, bromocriptine,
and carbidopa-levodopa (Arciniegas et al. 2013). Preliminary
evidence suggests that controlled aerobic exercise may improve
cognition, and concussive symptoms more generally, while restoring
normal cerebral blood flow regulation (Leddy et al. 2013).
Conclusion
Neuropsychiatric presentations after TBI are as unique and
diverse as the individuals sustaining such injuries. Assessment thus
requires a broad-based skill set that facilitates the identification of
neuronal injury and its related deficits, as well as the identification of
the full gamut of comorbid conditions and psychosocial
circumstances that potentially contribute to symptoms and
impairment. Only by identifying the totality of factors driving
neuropsychiatric impairment may we offer interventions to mitigate
the diffuse circumstances contributing to the individual’s experience
in the wake of injury. Such an approach will afford substantial
improvement for the vast majority of persons with a history of TBI,
improving function and/or quality of life for patients and their families.
References
Arciniegas DB: Addressing neuropsychiatric disturbances during rehabilitation
after traumatic brain injury: current and future methods. Dialogues Clin
Neurosci 13(3):325–345, 2011a 22034400
Arciniegas DB: Cholinergic dysfunction and cognitive impairment after traumatic
brain injury, part 2: evidence from basic and clinical investigations. J Head
Trauma Rehabil 26(4):319–323, 2011b 21734513
Arciniegas DB: Medical evaluation, in Management of Adults With Traumatic Brain
Injury. Edited by Arciniegas DB, Zasler ND, Vanderploeg RD, et al.
Washington, DC, American Psychiatric Publishing, 2013, pp 535–572
Arciniegas DB, Silver JM: Psychopharmacology, in Textbook of Traumatic Brain
Injury, 2nd Edition. Edited by Silver JM, McAllister TW, Yudofsky SC.
Washington, DC, American Psychiatric Publishing, 2011, pp 553–570
Arciniegas DB, Silver JM: Pharmacotherapy of neuropsychiatric disturbances, in
Brain Injury Medicine: Principles and Practice. Edited by Zasler ND, Katz DI,
Zafonte RD. New York, Demos Medical Publishing, 2013, pp 1227–1244
Arciniegas DB, Wortzel HS: Emotional and behavioral dyscontrol after traumatic
brain injury. Psychiatr Clin North Am 37(1):31–53, 2014 24529422
Arciniegas DB, Frey KL, McAllister TW: Cognitive impairments, in Management of
Vanderploeg RD, et al. Washington, DC, American Psychiatric Publishing,
2013, pp 131–166
Bales JW, Wagner AK, Kline AE, et al: Persistent cognitive dysfunction after
traumatic brain injury: a dopamine hypothesis. Neurosci Biobehav Rev
33(7):981–1003, 2009 19580914
Belanger HG, Spiegel E, Vanderploeg RD: Neuropsychological performance
following a history of multiple self-reported concussions: a meta-analysis. J Int
Neuropsychol Soc 16(2):262–267, 2010 20003581
Bigler ED: Anterior and middle cranial fossa in traumatic brain injury: relevant
neuroanatomy and neuropathology in the study of neuropsychological
outcome. Neuropsychology 21(5):515–531, 2007 17784800
Cappa SF, Benke T, Clarke S, et al; Task Force on Cognitive Rehabilitation;
European Federation of Neurological Societies: EFNS guidelines on cognitive
rehabilitation: report of an EFNS task force. Eur J Neurol 12(9):665–680, 2005
16128867
Carroll LJ, Cassidy JD, Peloso PM, et al; WHO Collaborating Centre Task Force
on Mild Traumatic Brain Injury: Prognosis for mild traumatic brain injury: results
of the WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury. J
Rehabil Med 43(suppl):84–105, 2004 15083873
Carroll LJ, Cassidy JD, Cancelliere C, et al: Systematic review of the prognosis
after mild traumatic brain injury in adults: cognitive, psychiatric, and mortality
outcomes: results of the International Collaboration on Mild Traumatic Brain
Injury Prognosis. Arch Phys Med Rehabil 95(3 suppl):S152–S173, 2014
24581903
Cassidy JD, Cancelliere C, Carroll LJ, et al: Systematic review of self-reported
prognosis in adults after mild traumatic brain injury: results of the International
Collaboration on Mild Traumatic Brain Injury Prognosis. Arch Phys Med Rehabil
95(3 suppl):S132–S151, 2014 24581902
Centers for Disease Control and Prevention: Traumatic brain injury and
concussion. September 20, 2016. Available at:
http://www.cdc.gov/traumaticbraininjury/get_the_facts.html. Accessed March 1,
2017.
Centers for Disease Control and Prevention, Department of Defense, National
Institutes of Health, Department of Defense, Department of Veterans Affairs:
Report to congress on traumatic brain injury in the United States:
understanding the public health problem among current and former military
personnel. June 2013. Available at:
http://www.cdc.gov/traumaticbraininjury/pdf/Report_to_Congress_on_Traumatic
_Brain_Injury_2013-a.pdf. Accessed March 1, 2017.
Cicerone KD, Langenbahn DM, Braden C, et al: Evidence-based cognitive
rehabilitation: updated review of the literature from 2003 through 2008. Arch
Phys Med Rehabil 92(4):519–530, 2011 21440699
Corrigan JD, Bogner J: Initial reliability and validity of the Ohio State University TBI
Identification Method. J Head Trauma Rehabil 22(6):318–329, 2007 18025964
Dams-O’Connor K, Cantor JB, Brown M, et al: Screening for traumatic brain injury:
findings and public health implications. J Head Trauma Rehabil 29(6):479–489,
2014 25370440
Department of Veterans Affairs and Department of Defense: Clinical practice
guideline: management of concussion/mild traumatic brain injury. April 2009.
Available at: http://www.dcoe.mil/files/VA-DoD-Management-of-Concussion-
mild-Traumatic-Brain-Injury.pdf. Accessed March 1, 2017.
Faul M, Xu L, Wald MM, et al: Traumatic brain injury in the United States:
emergency department visits, hospitalizations, and deaths 2002–2006. March
2010. Available at: http://www.cdc.gov/traumaticbraininjury/pdf/blue_book.pdf.
Accessed March 1, 2017.
Giza CC, Hovda DA: The new neurometabolic cascade of concussion.
Neurosurgery 75 (suppl 4):S24–S33, 2014 28173540
Guskiewicz KM, McCrea M, Marshall SW, et al: Cumulative effects associated with
recurrent concussion in collegiate football players: the NCAA Concussion
Study. JAMA 290(19):2549–2555, 2003 14625331
Harmon KG, Drezner J, Gammons M, et al; American Medical Society for Sports
Medicine: American Medical Society for Sports Medicine position statement:
concussion in sport. Clin J Sport Med 23(1):1–18, 2013 23269325
Iverson GL, Lange RT, Wäljas M, et al: Outcome from complicated versus
uncomplicated mild traumatic brain injury. Rehabil Res Pract 2012:415740,
2012 22577556
Jackson WT, Novack TA, Dowler RN: Effective serial measurement of cognitive
orientation in rehabilitation: the Orientation Log. Arch Phys Med Rehabil
79(6):718–720, 1998 9630156
Jorge RE, Arciniegas DB: Mood disorders after TBI. Psychiatr Clin North Am
37(1):13–29, 2014 24529421
Kay T, Harrington DE, Adams RE, et al: Definition of mild traumatic brain injury:
report from the Mild Traumatic Brain Injury Committee of the Head Injury
Interdisciplinary Special Interest Group of the American Congress of
Rehabilitation Medicine. J Head Trauma Rehabil 8:86–87, 1993
Leddy JJ, Cox JL, Baker JG, et al: Exercise treatment for postconcussion
syndrome: a pilot study of changes in functional magnetic resonance imaging
activation, physiology, and symptoms. J Head Trauma Rehabil 28(4):241–249,
2013 23249769
Levin HS, O’Donnell VM, Grossman RG: The Galveston Orientation and Amnesia
Test: a practical scale to assess cognition after head injury. J Nerv Ment Dis
167(11):675–684, 1979 501342
Lipton ML, Gulko E, Zimmerman ME, et al: Diffusion-tensor imaging implicates
prefrontal axonal injury in executive function impairment following very mild
traumatic brain injury. Radiology 252(3):816–824, 2009 19567646
McAllister TW: Polymorphisms in genes modulating the dopamine system: do they
influence outcome and response to medication after traumatic brain injury? J
Head Trauma Rehabil 24(1):65–68, 2009 19158598
McCrea M, Guskiewicz K, Randolph C, et al: Incidence, clinical course, and
predictors of prolonged recovery time following sport-related concussion in high
school and college athletes. J Int Neuropsychol Soc 19(1):22–33, 2013
23058235
Menon DK, Schwab K, Wright DW, et al; Demographics and Clinical Assessment
Working Group of the International and Interagency Initiative toward Common
Data Elements for Research on Traumatic Brain Injury and Psychological
Health: Position statement: definition of traumatic brain injury. Arch Phys Med
Rehabil 91(11):1637–1640, 2010 21044706
Meythaler JM, Peduzzi JD, Eleftheriou E, et al: Current concepts: diffuse axonal
injury-associated traumatic brain injury. Arch Phys Med Rehabil 82(10):1461–
1471, 2001 11588754
Mild Traumatic Brain Injury Committee of the Head Injury Interdisciplinary Special
Interest Group of the American Congress of Rehabilitation Medicine: Definition
of mild traumatic brain injury. J Head Trauma Rehabil 8(3):86–87, 1993
National Institute of Neurological Disorders and Stroke Common Data Elements
Team: Traumatic brain injury common data elements. 2013. Available at:
https://www.commondataelements.ninds.nih.gov/tbi.aspx#tab=Data_Standards
. Accessed March 1, 2017.
Ozen LF, Fernandes MA: Effects of "diagnosis threat" on cognitive and affective
functioning. J Int Neuropsychol Soc 17(2):219–229, 2011 21138607
Ponsford JL, Sinclair KL: Sleep and fatigue following traumatic brain injury.
Psychiatr Clin North Am 37(1):77–89, 2014 24529424
Povlishock JT, Katz DI: Update of neuropathology and neurological recovery after
traumatic brain injury. J Head Trauma Rehabil 20(1):76–94, 2005 15668572
Powell JM, Ferraro JV, Dikmen SS, et al: Accuracy of mild traumatic brain injury
diagnosis. Arch Phys Med Rehabil 89(8):1550–1555, 2008 18597735
Rimel RW, Jane JA, Edlich RF: An injury severity scale for comprehensive
management of central nervous system trauma. JACEP 8(2):64–67, 1979
439545
Royall DR, Lauterbach EC, Kaufer D, et al; Committee on Research of the
American Neuropsychiatric Association: The cognitive correlates of functional
status: a review from the Committee on Research of the American
Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci 19(3):249–265,
2007 17827410
Ruff RL, Riechers RG, Walker MF, et al: Headache, in Management of Adults With
Traumatic Brain Injury. Edited by Arciniegas DB, Zasler ND, Vanderploeg RD,
et al. Washington, DC, American Psychiatric Publishing, 2013, pp 323–344
Silver JM: Effort, exaggeration and malingering after concussion. J Neurol
Starkstein SE, Pahissa J: Apathy following traumatic brain injury. Psychiatr Clin
North Am 37(1):103–112, 2014 24529426
Suhr JA, Gunstad J: “Diagnosis Threat”: the effect of negative expectations on
cognitive performance in head injury. J Clin Exp Neuropsychol 24(4):448–457,
2002 12187458
Suhr JA, Gunstad J: Further exploration of the effect of “diagnosis threat” on
cognitive performance in individuals with mild head injury. J Int Neuropsychol
Soc 11(1):23–29, 2005 15686605
Teasdale G, Jennett B: Assessment of coma and impaired consciousness: a
practical scale. Lancet 2(7872):81–84, 1974 4136544
Vanderploeg RD: Neuropsychological assessment, in Management of Adults With
Traumatic Brain Injury. Edited by Arciniegas DB, Zasler ND, Vanderploeg RD,
et al. Washington, DC, American Psychiatric Publishing, 2013, pp 323–343
Williams DH, Levin HS, Eisenberg HM: Mild head injury classification.
Neurosurgery 27(3):422–428, 1990 2234336
Wintermark M, Sanelli PC, Anzai Y, et al; American College of Radiology Head
Injury Institute: Imaging evidence and recommendations for traumatic brain
injury: advanced neuro- and neurovascular imaging techniques. AJNR Am J
Neuroradiol 36(2):E1–E11, 2015 25424870
Wortzel HS, Tsiouris AJ, Filippi CG: The potential for medicolegal abuse: diffusion
tensor imaging in traumatic brain injury. AJOB Neurosci 5(2):9–15, 2014
Zaloshnja E, Miller T, Langlois JA, et al: Prevalence of long-term disability from
traumatic brain injury in the civilian population of the United States, 2005. J
Head Trauma Rehabil 23(6):394–400, 2008 19033832
CHAPTER 13
Hypoxic-Ischemic Brain Injury

The medical management of patients with hypoxic-ischemic brain

injury has improved substantially over the last 25 years. Although
advances in prehospital care and critical care management of the
conditions causing hypoxic-ischemic brain injury (e.g., cardiac arrest,
carbon monoxide poisoning, respiratory failure) have improved
overall survival rates and long-term outcomes, these remain
conditions that present substantial clinical challenges and entail
substantial neuropsychiatric morbidity (Betterman and Patel 2014;
Elmer and Callaway 2017; Howard et al. 2011; Sadaka 2013).
Cognitive impairment, parkinsonism, seizures, and other
neurobehavioral sequelae are among the most common
consequences of hypoxic-ischemic brain injury, and their occurrence
is associated with postinjury disability and reduced quality of life for
affected persons and their families (Arciniegas 2010). In this chapter,
we review the neurophysiology of some of the different mechanisms
of hypoxic-ischemic brain injury, the neuropsychiatric sequelae of
hypoxic-ischemic brain injury, and diagnostic and treatment options.
Defining Hypoxic-Ischemic Brain Injury
Hypoxic-ischemic brain injury is an umbrella term that includes
injury to the brain resulting from hypoxia, ischemia, and cytotoxicity,
alone or in combination and across a broad range of severity (Busl
and Greer 2010). It is important to recognize that hypoxic-ischemic
brain injury is a clinical category with several subtypes: hypotonic (or
hypoxic) hypoxia; anemic (or hypemic) hypoxia; ischemic (or
stagnant) hypoxia; histotoxic hypoxia (Table 13–1). Hypotonic (or
hypoxic) hypoxia describes a state in which low partial pressure of
oxygen (Pa02) in the blood compromises oxygen delivery to tissues.
Anemic (or hypemic) hypoxia is a state in which low blood oxygen-
binding capacity compromises oxygen delivery to tissues. Ischemic
(or stagnant) hypoxia refers to a condition in which inadequate
delivery of blood compromises delivery of oxygen and other
essential factors for cell metabolism and may occur with normal or
low Pa02. Histotoxic hypoxia is the result of insufficient oxygen
extraction from blood into tissues.
TABLE 13–1. Types of hypoxia in relation to hypoxic-ischemic brain injury
Injury type Characteristics Contexts Examples
Hypotonic Low Pa02 Low O2 tension High-altitude location
(hypoxic) Normal blood in inspired air Near-suffocation in
hypoxia oxygen- enclosed space
binding Choking on foreign object
capacity
Tracheal collapse
Normal
perfusion
Normal end-
tissue oxygen
extraction
capacity
Diffusion Inhalation of water
impairment (near drowning)
Severe pulmonary edema
Alveolar ventilation- Pulmonary embolism
perfusion Chronic obstructive
mismatch pulmonary disease
Venous-to-arterial Vessel-to-vessel or
shunts intracardiac shunts
Anemic Normal Pa02 Reduced Bone marrow failure
(hypemic) hemoglobin or Hemorrhage
Reduced blood
hypoxia blood cells
oxygen-
binding
capacity
Normal Interference Methemoglobinemia
perfusion with the due to carbon
Normal end- binding of monoxide
tissue oxygen oxygen to poisoning, including
extraction hemoglobin cigarette smoking
capacity
Injury type Characteristics Contexts Examples
Ischemic Normal or Insufficient Severe hypotension
(stagnant) low Pa02 blood flow Focal ischemia
hypoxia Normal blood Normal Pa02
Global ischemia due to
oxygen- near-strangulation
binding
Low cardiac output
capacity
Reduced
perfusion
Normal end-
tissue oxygen
extraction
capacity
Low Pa02 Cardiopulmonary
arrest
Histotoxic Normal Pa02 Blockade of Cyanide poisoning
hypoxia Reduced blood mitochondrial
oxygen- metabolism
binding
capacity
Normal
perfusion
Reduced end-
tissue oxygen
extraction
capacity
Although the concept of hypoxic-ischemic brain injury and these

subtypes are well established in the basic neurosciences and in
many areas in clinical medicine, this condition is often referred to by
the historical terms anoxic brain injury, anoxic brain damage, or
anoxic encephalopathy, especially in neurorehabilitation settings. It is
important to note that these terms are misleading with regard to the
mechanism of injury and the severity of oxygen deprivation required
to produce it. As described in more detail below, pure hypoxia—even
when relatively prolonged and/or severe—produces functional
changes within neurons without necessarily inducing cell death,
provided the systemic circulation is adequately preserved.
Accordingly, pure hypoxia is better tolerated than is ischemia or
combined hypoxia-ischemia (Busl and Greer 2010; Greer 2006).
True anoxia (i.e., complete absence of oxygen in the blood) is a
relatively rare event in clinical contexts given the affinity of
hemoglobin for oxygen and the sigmoidal nature of the relationship
between oxygen saturation and the partial pressure of oxygen in the
blood-hemoglobin dissociation. Although complete cessation of
respiratory function eliminates introduction of new oxygen into the
circulatory system, oxygen remains available, albeit in rapidly
diminishing quantities, in the blood for extraction and use by brain
tissue for at least several minutes thereafter. Indeed, the point when
true anoxia occurs is one after which survival is unlikely.
Anoxic brain injury and related terms therefore are problematic in
that they unduly emphasize oxygen deprivation and overstate its
severity in relation to this type of brain injury while simultaneously
directing attention away from the more injurious process of ischemia
—and thereby generating confusion about this condition and its
implications when these terms are used in research, education,
and/or clinical practice. Accordingly, anoxic brain injury and related
terms are eschewed in this chapter, as in similar works (Busl and
Greer 2010; Greer 2006; Ropper et al. 2014), and the problem of
interest is referred to as hypoxic-ischemic brain injury.
Pathophysiology of Hypoxic-Ischemic Brain

Injury
The high metabolic demands of the brain render it susceptible to
injury from prolonged periods of hypoxia as well as relatively brief
periods of combined hypoxia and ischemia. Hypotonic (hypoxic)
hypoxia, anemic hypoxia, ischemic hypoxia, and histotoxic hypoxia
are all potentially injurious to the brain. Conditions that lower the
oxygen blood levels deprive the brain of oxygen; such deprivation
produces changes in cellular energetics and metabolism that may
render neurons (and, by extension, the circuits and networks in
which they participate) dysfunctional without necessarily inducing
cell death—provided that systemic circulation is preserved (Busl and
Greer 2010).
Conditions that concurrently reduce brain oxygenation and
perfusion also deprive it of glucose and all other nutrients and impair
the nutrient-waste exchange process required to support brain
metabolism. Interruption of these processes is immediately followed
by cellular energy failure, membrane depolarization, brain edema,
excess neurotransmitter release (particularly the excitatory amino
acid neurotransmitters), and neurotransmitter uptake inhibition.
These processes result in N-methyl-D-aspartate receptor–mediated
increases in intracellular calcium, production of oxygen-free radicals,
lipid peroxidation, and disturbances in autoregulation of cerebral
blood flow at the microscopic and macroscopic levels (Busl and
Greer 2010; Calvert and Zhang 2005; Greer 2006). The collective
effects of these processes render brain tissues dysfunctional and
incite processes that lead to cell death.
The pathophysiology of hypoxic-ischemic brain injury is
characteristic of the nonhemorrhagic forms of stroke and more like
this category of brain injury than it is like traumatic brain injury
(Arciniegas 2010; Smania et al. 2013). The principal difference
between hypoxic-ischemic brain injury and stroke is the use of the
latter term to denote injury resulting from focal or multifocal ischemia
(i.e., that occurring in one or a few specific vascular territories),
whereas the former denotes injurious exposure to global (i.e., whole
brain) hypoxia and/or hypoxia-ischemia.
Carbon monoxide poisoning (the prototypic histotoxic hypoxic
injury and most common example of this injury type in clinical
practice) may produce a pattern of brain injury comparable to that
associated with pure (hypotonic) hypoxia. If the severity and duration
of carbon monoxide poisoning engender systemic hypotension,
however, the effects become increasingly similar to those of
ischemic-hypoxic injury.
The pathophysiology of hypoxic-ischemic brain injury therefore is
influenced both by the severity and duration of the hypoxia and the
presence or absence of concurrent ischemia. The short- and long-
term effects of hypoxia or hypoxia-ischemia are modified further by a
host of additional factors including, but not limited to, patient age,
comorbid medical and neurological conditions, individual differences
in susceptibility to the effects of hypoxia and ischemia, and the
provision (or not) of acute and chronic medical and rehabilitative
interventions (Greer 2006). If sufficiently severe and/or prolonged,
both hypoxic and hypoxic-ischemic states produce neuronal death
and irreversible brain injury, although this endpoint is reached more
rapidly during ischemic hypoxia. As Busl and Greer (2010) note, 15
minutes of global ischemia (e.g., during cardiac arrest) damages up
to 95% of brain tissue (Busl and Greer 2010).
Neuroanatomy of Hypoxic-Ischemic Brain Injury

Although exposure to hypoxia and/or hypoxia-ischemia is global,
not all areas of the brain are equally vulnerable to the injurious
effects of such exposures. Structures with higher metabolic rates
have greater oxygen nutrient demands, making them vulnerable to
injury by hypoxia or ischemic hypoxia (Cervós-Navarro and Diemer
1991). Injury resulting from these processes tends to be most
pronounced in the following: upper brain stem and lower
diencephalon (i.e., ascending reticular activating system);
cerebellum; CA1 region of the hippocampus; medium-size neurons
of the striatum (particularly dorsal striatum); and neocortical layers 3,
5, and 6 (injury to which produces laminar cortical necrosis, referring
to the death of cells in these layers, or lamina, in the cortex)
(Anderson and Arciniegas 2010; Arbelaez et al. 1999; Busl and
Greer 2010; Chalela et al. 2001; Jang et al. 2014). Neurons in the
CA1 region of the hippocampus and the dorsal striatum are
adversely affected by short periods of ischemia, which renders them
dysfunctional rapidly and initiates a cascade of cellular responses
that lead to delayed neuronal death (Busl and Greer 2010; Greer
2006). By contrast, glial cells and vascular cells in these regions are
less susceptible to comparable degrees and durations of ischemic
hypoxia.
The gradient of vulnerability to hypoxic-ischemic injury based on
the anatomy of the vascular supply of the brain diminishes with
proximity to the medulla oblongata (Busl and Greer 2010). Tissues in
the border zones between cerebral vascular territories (also
described as “watershed areas”) are anatomically susceptible to
ischemia (Cervós-Navarro and Diemer 1991). The watershed areas
include an anterior border zone between the anterior cerebral artery
(ACA) and middle cerebral artery (MCA); a posterior border zone
between the MCA and posterior cerebral artery; and an internal
border zone between the superficial branches of the MCA and the
deep branches of the MCA or ACA. Prolonged periods of ischemia
produce wedge-shaped lesions at the border zones between the
cerebral artery territories that are appreciable macroscopically and
on cerebral neuroimaging (particularly magnetic resonance imaging
[MRI]); these lesions have their bases at the pial surface and their
apices near the lateral ventricles. The vasculature of the deep white
matter of the cerebral hemispheres comprises linear arterioles with
few anastomoses, making the deep white matter particularly
vulnerable to hypoxic ischemic injury. Tissues in which perfusion
relies on small perforating arteries (e.g., lenticulostriate arteries) also
are vulnerable to the effects of ischemic hypoxia; these tissues
include the pallidum, in particular, as well as the capsular white
matter (Okeda 2003).
Predictors of Outcome After Hypoxic-Ischemic
Brain Injury
Clinical guidelines for assessing prognosis, which are still widely
used, derive mainly from neurological evaluation observations that
are found to predict a low likelihood of meaningful neurological
recovery. Examples include the presence or absence of pupillary
responses, motor response to noxious stimuli, and diagnostic studies
including the absence of somatosensory evoked potentials and
elevated neuron-specific enolase levels. In the setting of hypoxic-
ischemic brain injury after cardiac arrest, the advent of treatment
with therapeutic cooling has improved survival and outcomes and
called into question the validity and timing for many of these clinical
markers (Greer et al. 2013; Scirica 2013; Stevens and Sutter 2013).
Studies performed in the hypothermia era suggest that serial
multimodal clinical and imaging assessments (including evoked
potential, electroencephalogram [EEG], and MRI) are likely to yield
more robust predictors of long-term recovery after hypoxic-ischemic
brain injury (Estraneo et al. 2013; Heinz and Rollnik 2015; Rothstein
2014).
Neurological and Neurobehavioral

Consequences of Hypoxic-Ischemic Brain Injury
The neurological and neuropsychiatric sequelae of hypoxic-
ischemic brain injury follow the patterns of metabolic and anatomic
susceptibility to hypoxia and ischemic hypoxia. Consequences of
hypoxic-ischemic brain injury commonly include seizures (event
related and recurrent), disturbances of sensorimotor function, and a
broad array of cognitive, emotional, and behavioral disturbances
(Anderson and Arciniegas 2010; Lu-Emerson and Khot 2010).
Seizures and Myoclonus

Seizures develop in as many as 35% of patients with hypoxic-
ischemic brain injury during the immediate postinjury period, usually
beginning within 24 hours of injury but occurring or recurring over the
first 2 weeks thereafter. Event-related seizures may be generalized,
reflecting the excitotoxic consequences of global hypoxia and/or
ischemic hypoxia. After the immediate postinjury period, most
posthypoxic seizures are of focal onset; some may secondarily
generalize. Seizures in patients in coma or with other disturbances of
consciousness can be difficult to recognize. As continuous EEG
monitoring has become more common, it is clear that subclinical
seizures or subtle clinical manifestations of either partial or
generalized seizures may be overlooked.
The occurrence of immediate postinjury seizure does not
necessarily portend the development of posthypoxic epilepsy and
does necessarily predict poor neurological or functional outcome.
However, the development of posthypoxic status epilepticus (SE) is
associated with almost invariably fatal outcome after hypoxic-
ischemic brain injury (Rossetti et al. 2010). Whether the high rates of
mortality associated with posthypoxic SE merely reflect the severity
of injury or are the aggravating effects of SE, or both, remains
uncertain. The frequency of late seizures—posthypoxic epilepsy—is
not well established, although common clinical experience suggests
that a substantial minority of persons with hypoxic-ischemic brain
injuries develop this problem.
Myoclonus following hypoxic-ischemic brain injury is a syndrome
characterized by multifocal high-velocity muscle contractions often
brought on by action or volitional movements. In some cases, the
myoclonic jerks are elicited by environmental stimuli such as loud
noises, touch, pain, or procedures including phlebotomy, intubation,
and intravenous line placement. An analogous phenomenon known
as negative myoclonus, in which there is an abrupt loss of muscle
tone sometimes associated with contraction in antagonist muscle
groups, can also be seen. When negative myoclonus occurs in the
upper extremities, it leads to dropping objects, and in the lower
extremities falls can result. Myoclonus following hypoxic-ischemic
brain injury can originate in either cortical or subcortical structures.
Typically, cortical myoclonus involves the limbs or face and is
brought on by intentional movements. Subcortical myoclonus is
thought to originate in the brain stem and is more often associated
with proximal limb and axial generalized contractions that are often
triggered by environmental stimuli (Lu-Emerson and Khot 2010).
Myoclonus after hypoxic-ischemic brain injury sometimes progresses
to posthypoxic myoclonic status, the prognostic implications of which
are similar to those associated with posthypoxic SE.
While the presence of seizures or myoclonus is not necessarily a
poor prognostic sign, SE and ongoing myoclonus are both
associated with higher morbidity and mortality. At present, however,
seizure prophylaxis has not been demonstrated to prevent the
development of posthypoxic seizures, myoclonus, SE, or myoclonic
status. Applying current guidelines for seizure prophylaxis after
traumatic brain injury (i.e., 1 week of prophylaxis postinjury, after
which anticonvulsants are provided only if seizures develop) (Chang
and Lowenstein 2003) therefore remains standard practice (Turnbull
et al. 2016). However, the development of seizures, myoclonus, SE,
or myoclonic status therefore should prompt aggressive treatment
with anticonvulsants. The treatment of posthypoxic seizures and/or
myoclonus follows that of other secondary epilepsies and myoclonus
and appears to be similarly effective as the treatment of these
conditions after other severe neurological injuries.
Movement Disorders
A variety of disorders of movement have been described following
hypoxic-ischemic brain injury, including parkinsonism, tremor,
dystonia, chorea, and athetosis (Lu-Emerson and Khot 2010).
Neuroimaging and postmortem studies consistently associate basal
ganglia, thalamic, midbrain, and cerebellar injury with these
abnormal motor phenomena. Posthypoxic parkinsonism is generally
symmetric and predominantly akinetic-rigid (i.e., not tremor
predominant) but may sometimes include resting or postural tremor
as well. The development of posthypoxic akinetic-rigid parkinsonism
is most closely associated with injury to the globus pallidus.
Posthypoxic dystonia is often asymmetric initially but over time may
progress to a more symmetric and generalized form; it is generally
taken as an indication of injury to the putamen (Venkatesan and
Frucht 2006).
These motor abnormalities may develop early after hypoxic-
ischemic brain injury, but more commonly, they become apparent
weeks to many months after injury. A variety of mechanisms for this
delayed onset have been proposed, including demyelination,
oxidative changes, synaptic reorganization, and inflammatory
changes (Lu-Emerson and Khot 2010; Venkatesan and Frucht
2006).
Treatment of dystonia and parkinsonian states following hypoxic-
ischemic brain injury is similar to that used in other settings.
Response to treatment can vary significantly, with some patients
showing dramatic response to medications. In general, however,
these conditions appear less responsive to pharmacologic treatment
and interventional therapies (i.e., deep brain stimulation) than
primary parkinsonism (i.e., Parkinson’s disease) and idiopathic
dystonia, perhaps reflecting hypoxic-ischemic-induced damage
and/or destruction of the neurons in these structures that ordinarily
are the targets of these pharmacotherapies (Lu-Emerson and Khot
2010; Venkatesan and Frucht 2006).
Characteristic Patterns of Weakness

As noted earlier, watershed areas are particularly vulnerable to
the effects of reduced perfusion. When the injury occurs in anterior
frontal white matter and involves the zone between the anterior and
middle cerebral artery territories, patients may present with bilateral
arm weakness (brachial diplegia) and relatively preserved lower
extremity function. This condition is commonly referred to in
neurological practices as the “man-in-the-barrel syndrome.”
Involvement of parieto-occipital structures in the watershed zone
between the vascular territories of the middle cerebral and posterior
cerebral arteries is associated with the development of cortical
blindness or, more rarely, Balint’s syndrome (i.e., optic ataxia,
oculomotor apraxia, and simultanagnosia).
Pharmacotherapeutic and rehabilitative interventions for these
problems and their complications (e.g., spasticity, contractures, gait
and mobility impairments) are modeled on those applied for similar
motor impairments due to other acquired brain injuries. The
effectiveness of these motor-specific rehabilitative interventions in
this population is not well established, but common clinical
experience and several rehabilitation outcome studies suggest that
these interventions may improve the functional status of persons
with hypoxic-ischemic brain injuries (Burke et al. 2005; Shah et al.
2004, 2007).
Disorders of Consciousness
Following initial resuscitation efforts, abnormalities of wakefulness
and awareness of self and environment are common (Table 13–2).
The duration of these disturbances varies with the degree and
duration of hypoxia and/or ischemic hypoxia. Patients typically
progress from coma through the states of diminished arousal and
awareness—i.e., the disorders of consciousness, including
vegetative state (VS, also known as the unresponsive wakefulness
syndrome) and minimally conscious state (MCS)—albeit to varying
endpoints (Giacino and Kalmar 2005; Giacino et al. 2002; van Erp et
al. 2015; Whyte et al. 2009).
TABLE 13–2. Defining features of the disorders of consciousness and brain
death
Brain stem
function Wakefulness Awareness
Minimally Present Present Present
conscious
state
Vegetative state Present Present Absent
Coma Present Absent Absent
Brain death Absent Absent Absent
Coma
Coma represents a spectrum of reduced arousal and awareness
and results from severe injury or depressed function of bilateral
cerebral hemispheres, bilateral thalami, or brain stem arousal
systems (Posner and Plum 2007). Typically, patients in coma have
their eyes closed and do not respond to external stimuli. They
demonstrate no purposeful motor activity, and their sleep-wake
cycles are abolished, but they may have occasional purposeless
movements and reflex motor activity. After hypoxic-ischemic brain
injury, coma may be very brief in duration or last days to weeks (or
longer). Emergence from coma after this type of injury typically
means transitioning into either the VS or MCS (Bodart et al. 2013;
Giacino and Kalmar 2005).
Vegetative State
Emergence from coma into the VS represents the recovery of
arousal mechanisms in the absence of any recovery within cerebral
networks subserving the content of consciousness. VS is
characterized by the presence of wakefulness (i.e., spontaneous eye
opening, sleep-wake cycles) but no evidence of awareness of the
environment or the self (i.e., no observable responses to verbal,
visual, or external physical stimuli or to internal sensations) (Giacino
and Kalmar 2005; Giacino et al. 2002). There is sufficient autonomic
function to permit survival with medical and nursing care and
preserved brain stem function.
Depending on the severity of the injury, some patients may
emerge from the VS to MCS higher levels of function. While there
are exceptions, the likelihood of emerging from VS markedly
decreases after 3 months in adults with hypoxic-ischemic brain
injury. When patients do not emerge from VS, terms like “persistent”
or “permanent” VS are sometimes employed to describe them. The
recommendation of the Aspen Neurobehavior Conference Working
Group was to limit the diagnosis to the indefinite term “vegetative
state” and include the cause of the injury (i.e., hypoxic-ischemic
brain injury versus traumatic brain injury or other) and the length of
time that the patient had been in VS (Giacino et al. 2002). The
descriptor “vegetative” is also controversial because of the
implication that patients in this condition are “vegetables,” and an
alternative term—unresponsive wakefulness syndrome—has been
proposed (Laureys et al. 2010).
Because VS is diagnosed on the basis of observable behavior,
there is a risk of mistaking other states for VS—in particular, the
locked-in syndrome (in which consciousness is preserved but motor
output is interrupted at the level of the pons), particularly when the
anatomy of this syndrome extends rostrally and interferes with eye
movements. Indeed, the clinical diagnosis when made without the
benefit of structured clinical examination using validated metrics
designed for this purpose and performed serially may be wrong as
much as 40% of the time (Schnakers et al. 2009). The potential
liability of relying entirely on behavioral criteria for VS is highlighted
by functional MRI and EEG studies demonstrating preserved
consciousness in a small subset of patients who would otherwise
have been described as in VS (Fernández-Espejo and Owen 2013;
Owen and Coleman 2007; Sitt et al. 2014). Although the subset of
patients retaining consciousness that is amenable to detection with
advanced imaging have been survivors of traumatic brain injury
rather than hypoxic-ischemic brain injury, these studies, nonetheless,
suggest the need to maintain vigilance for such exceptions and to
remain open to the application of such technologies that may
improve diagnostic confidence as such become feasible, valid, and
reliable at the individual patient (rather than group) level.
The inherent complexity of these low-level states also naturally
leads to the potential for substantial misunderstanding among many
clinicians, family members, and others who are uneducated about
these conditions. For example, media reports of patients emerging
from the VS months or years following injury make for sensational
news stories; however, their exceptional nature is often not
understood clearly and creates unrealistic expectations with respect
to the likelihood, course, and completeness of recovery from
prolonged VS (or MCS) (Estraneo et al. 2013, 2014). It is worth
bearing in mind as a clinician and communicating empathically but
clearly that most patients with hypoxic-ischemic brain injuries who
remain in VS and MCS for extended periods continue to experience
functionally important cognitive impairments, motor impairments, and
functional limitations if they emerge from these states (Estraneo et
al. 2014).
The diagnosis of VS has many other significant implications,
including medicolegal issues such as the consideration of life-
sustaining interventions and decisions regarding end-of-life care.
Given potential errors in diagnosis, the uncertainty of prognosis, and
the many medical, ethical, legal, and moral implications of these
cases, it is important that the diagnosis be made as precisely as
possible and that care be used in selecting terminology in the
process of communicating with family members, caregivers, and
other interested third parties.
Minimally Conscious State

MCS is defined by the presence of wakefulness with at least
minimal and intermittent capacity for awareness of self or interaction
with the environment (Giacino and Kalmar 2005; Giacino et al.
2002). These latter features distinguish MCS from VS. Diagnosing
the MCS requires careful serial examination and observation and
consideration of potential confounds including medication effects and
focal disturbances such as aphasia, apraxia, sensory deficits, and
elemental motor impairments. MCS must also be distinguished from
akinetic mutism and the locked-in syndrome, a distinction that is
complicated by the occasional overlap between MCS and these
states. While the construct of the VS is based on an absolute
criterion—the absence of any awareness of self and interaction with
the environment—the MCS represents a spectrum of function
ranging from minimal and inconsistent interaction to a much higher
level with more consistent functional interaction.
As patients progress through posthypoxic MCS toward higher
states of cognitive and functional abilities, their awareness of self
and environment increases, and they regain the capacity for at least
intermittent functional communication and functional object use.
Defining emergence from the MCS to higher-level functioning
remains difficult. The Aspen Neurobehavioral Conference Working
Group recommended that the upper boundary of the MCS be
contingent on the patient demonstrating a consistent ability for
functional interactive communication, the functional use of objects, or
both (Giacino et al. 2002).
The prognosis for patients who recover rapidly to MCS after
hypoxic-ischemic brain injury is more favorable than for those who
do so after a protracted period in VS. The importance of the
prognostic difference between the VS and the MCS cannot be
overstated. Distinguishing between the two states carries important
considerations not only for judging prognosis but also for decision
making regarding continued supportive care and nutritional support
and the management of associated conditions.
Treatment of Posthypoxic Disorders of
Consciousness
While treatment of patients with any of the disorders of
consciousness remains an understudied area, there are
interventions of potential benefit. The first steps in the care of these
patients are 1) recognizing and treating any comorbid medical or
neurologic problems; 2) limiting the use of medications with the
potential to negatively affect arousal and cognition; and 3) providing
adequate supportive care including hydration, oxygenation, and
nutrition. As patients are stabilized, efforts to help normalize their
sleep-wake cycles with active engagement and stimulation during
daytime hours and limitation of environmental stimulation during
nighttime hours are crucial (Anderson and Arciniegas 2010).
Because the U.S. Food and Drug Administration (FDA) has not
approved any medications for the treatment of disorders of
consciousness due to any cause, all pharmacotherapies for
posthypoxic disorders of consciousness must be regarded as off-
label. Although there is emerging evidence for the use of amantadine
(Giacino et al. 2012) and zolpidem (Whyte and Myers 2009; Whyte
et al. 2014) to treat these disorders after traumatic brain injury, the
evidence base for pharmacological treatment of posthypoxic
disorders of consciousness is limited, but it includes amantadine,
baclofen, bromocriptine, levodopa, pramipexole, methylphenidate,
lamotrigine, modafinil, tricyclic antidepressants, and zolpidem
(Ciurleo et al. 2013). Empiric treatment with these drugs may be
considered and undertaken with caution; in general, beginning with
low doses and carefully monitoring patients for efficacy and adverse
effects is recommended. Transcranial direct current stimulation
(Naro et al. 2016) and other neurostimulation interventions also may
emerge to play a role in the treatment of patients with posthypoxic
disorders of consciousness.
Cognitive Impairments Following Hypoxic-Ischemic
Brain Injury
The most extensively studied neuropsychiatric sequelae of
hypoxic-ischemic brain injury are cognitive impairments. In addition
to the disorders of arousal and awareness (i.e., the disorders of
consciousness discussed in the preceding sections of this chapter),
impairments of attention and processing speed, memory impairment,
and executive dysfunction are common short- and long-term
consequences of hypoxic-ischemic brain injury (Anderson and
Arciniegas 2010). Less commonly, aphasia (often motor, sensory, or
mixed transcortical in character), apraxia (particularly ideational or
conceptual apraxia), agnosias, visuospatial dysfunction, Balint’s
syndrome (optic ataxia, oculomotor apraxia, simultanagnosia),
and/or Anton’s syndrome (anosognosia for visual impairment)
occurs.
This broad array of posthypoxic cognitive impairments follows on
the vulnerability of many cognitively salient areas to the adverse
effects of global hypoxia and/or ischemia. In brief summary, these
include upper brain stem and thalamus (arousal and basic aspects of
attention); deep white matter of the cerebral hemispheres
(processing speed); CA1 region of the hippocampus (episodic
memory); basal ganglia, anterior watershed area, and frontal cortex
(executive function and executive control of attention, memory,
language, and other cognitive function); and cortical layers 3, 5, and
6 (potential widespread effects on cognition depending on the area
injured).
Cognitive recovery is both common and remarkably robust in
many cases, with the most robust recovery occurring within the first
3 months after injury, and much of that occurring within the first 45
days postinjury (Lim et al. 2004; Lundgren-Nilsson et al. 2005). The
level of recovery reached by the end of the first year is generally
quite stable (Harve et al. 2007). Nonetheless, more than half of
those recovering to that postinjury point in time do so fully—or at
least well enough that their residual cognitive impairments are not
obvious using the bedside cognitive assessments employed in most
clinical practices, and the majority are not limited by cognitive
impairments in their daily activities (van Alem et al. 2004). Among
those who experience clinically important cognitive impairments,
comorbidity with motor impairment is not infrequent (Anderson and
Arciniegas 2010). Predictors of long-term cognitive impairment
include the duration of impaired consciousness following the injury,
shorter times to defibrillation, access to advanced life support, and
the time to restoration of functional circulation.
Treatment of Cognitive Impairments After

Hypoxic-Ischemic Brain Injury
When interventions for posthypoxic cognitive impairments and
their functional consequences are required, nonpharmacologic and
pharmacotherapeutic approaches are generally modeled after those
provided to persons with posttraumatic cognitive impairments. The
effectiveness of these interventions for patients with hypoxic-
ischemic brain injury is not well established, but common clinical
experience suggests that they may be of benefit to some persons
with these kinds of injuries.
Nonpharmacologic interventions are used in an attempt to
improve functional performance in real-world settings. The goal of
these interventions is to develop compensatory strategies that
capitalize on remaining cognitive strengths, enhance self-regulation,
establish environmental and behavioral performance supports (and
reduce sources of distraction and interference), and thereby improve
everyday function (Cicerone et al. 2000, 2005, 2011). Examples
include the use of daily planners, reminder lists, assistive devices
(i.e., alarms, notebooks, communication boards and devices), and
routines to encourage independence. Formal cognitive rehabilitation
targeting specific cognitive impairments is typically provided by
neuropsychologists, occupational therapists, and speech-language
pathologists and can be helpful in developing a plan for therapy that
includes the development of compensatory strategies. These
interventions are typically employed in persons with hypoxic-
ischemic brain injury who have mild to moderate impairments and
sufficient functional independence and motivation to participate in
the process and make use of compensatory strategies. In most
cases, these interventions are most helpful when provided in the
subacute or postacute rehabilitation period, rather than in the acute
phase of care immediately following the injury.
Studies of pharmacologic interventions are typically limited to
case reports or small case series, and there is no FDA-approved
therapy for posthypoxic cognitive disturbances. Accordingly, the use
of medications for this purpose is considered off-label. The two
principal approaches are augmentation of catecholaminergic function
or cholinergic function (Anderson and Arciniegas 2010). When slow
processing speed and sustained attention are the predominant
cognitive impairments, agents that augment catecholaminergic
function (e.g., methylphenidate, amantadine, levodopa,
bromocriptine) may be useful. When episodic memory impairments
are the most salient and functionally limiting cognitive impairment,
cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine)
may be useful. In some cases, combinations of these agents may be
required and, in general, are well tolerated by most patients. Much
like the effects of pharmacotherapy on the motor complications of
hypoxic-ischemic brain injury, common clinical experience suggests
that these agents tend not to be as effective as when they are used
to treat posttraumatic cognitive impairments. Although individual
patient experiences will vary, providing realistic, and relatively
modest, treatment response expectations to patients and their
caregivers is prudent.
Emotional Disturbances After Hypoxic-Ischemic
Brain Injury
Emotional and other behavioral disturbances are common after
hypoxic-ischemic brain injury. However, the literature on this topic
focuses predominantly on survivors of out-of-hospital cardiac arrest
rather than hypoxic-ischemic brain injuries more specifically. The
observations offered in these studies need to incorporate
psychological, medical (especially cardiac), and other influences on
the development of postevent emotional and behavioral issues and
to avoid narrowly focused attribution of emotional and behavioral
disturbances in this population to hypoxic-ischemic brain injury
alone.
That said, survivors of out-of-hospital cardiac arrest report high
rates of persistent anxiety (up to 60%), depression (more than 40%),
and posttraumatic stress (nearly 30%). Comorbid cognitive
impairments and fatigue also are commonly reported long-term
outcomes in this population, and these symptoms in combination
with emotional and behavioral symptoms negatively affect long-term
quality of life for persons with hypoxic-ischemic brain injuries (Green
et al. 2015; Moulaert et al. 2010; Wilson et al. 2014). Caregivers of
survivors of out-of-hospital cardiac arrest also report high rates of
depression, anxiety, and posttraumatic stress, with insufficient social
and financial support (Green et al. 2015; Moulaert et al. 2010).
The treatment of the emotional and behavioral sequelae of
hypoxic-ischemic brain injury remains understudied. Treatment by
analogy to other conditions, especially the neuropsychiatric sequelae
of traumatic brain injury, is common practice. Whether there are
substantive differences between these groups with respect to
treatment response remains uncertain. Providing psychotherapy and
support group and therapeutic activities during rehabilitation after
hypoxic-ischemic brain injury improves quality of life and social
participation (Tazopoulou et al. 2016) and therefore is encouraged
pending additional research with which to clarify this
recommendation.
Delayed Posthypoxic Leukoencephalopathy

A rare but noteworthy consequence of hypoxic-ischemic brain
injury is delayed posthypoxic leukoencephalopathy, a severe
demyelinating syndrome that occurs a few days to a few weeks after
an early and complete (or near complete) initial recovery. This
delayed demyelinating syndrome is characterized by acute or
subacute onset of severe and progressive neuropsychiatric problems
such as delirium, psychosis, parkinsonism, akinetic mutism, and/or
quadriparesis, among others. Although this condition was first
described as a delayed sequela of carbon monoxide–induced
hypoxic-ischemic brain injury, it has been described subsequently in
association with nearly all causes of hypoxic-ischemic brain injury
(Arciniegas et al. 2004; Shprecher and Mehta 2010). The
pathophysiological mechanism(s) of delayed posthypoxic
leukoencephalopathy are established definitively. However,
combinations of toxic exposure (e.g., carbon monoxide, inhaled
heroin), genetic factors (e.g., pseudodeficiency of arylsulfatase A,
abnormalities of other genes regulating myelin turnover), and age-
associated vascular risk factors have been suggested as possible
contributors to this unusual demyelinating syndrome. Regardless of
mechanism, this syndrome is characterized neuropathologically by
diffuse bihemispheric demyelination that generally spares the
cerebellum and brain stem.
Neurological and neurobehavioral improvement over the first 3–12
months following onset of this syndrome is typical, but many
survivors experience persistent cognitive impairments (particularly
impairments of attention, processing speed, and/or executive
function), parkinsonism, and/or corticospinal tract signs. There are
case reports describing symptomatic and functional improvement of
the cognitive and parkinsonian sequelae of delayed posthypoxic
leukoencephalopathy during treatment with stimulants, amantadine,
or levodopa. The observation that these agents offer some benefit in
this context despite their lack of efficacy for the same sequelae of
hypoxic-ischemic brain injury itself may reflect differences in the
anatomy of these conditions. Hypoxic-ischemic brain injury entails
widespread neuronal injury and, in severe cases, death in
anatomically and metabolically vulnerable brain areas. Recovering
early from this injury suggests relative preservation of those tissues.
The development of delayed posthypoxic leukoencephalopathy
selectively affects white, rather than gray, matter, creating anatomic
targets for drug action that may be less available in those with similar
clinical problems due to hypoxic-ischemic brain injury alone.
Conclusion
Advances in prehospital care, emergency resuscitation
techniques, therapeutic cooling, critical care, and rehabilitative
techniques have improved survival rates for patients with hypoxic-
ischemic brain injury and, in some cases, cognitive and functional
outcomes. Unfortunately, a substantial proportion of survivors of
hypoxic-ischemic brain injury will experience early and late
neurological and neuropsychiatric disturbances. These may include
seizures, myoclonus, movement disorders, motor weakness, the
disorders of consciousness (coma, VS, and MCS), cognitive
impairments, and emotional and behavioral disturbances. While the
outcomes after hypoxic-ischemic brain injury are highly variable, a
clear understanding of regional vulnerability to hypoxia and ischemic
hypoxia reveals an anatomy of injury that predicts all of these
neurological and neuropsychiatric sequelae. As new approaches for
prevention of hypoxic-ischemic brain injury, acute resuscitation and
critical care management, pharmacotherapy, and rehabilitation
emerge, improved outcomes from hypoxic-ischemic brain injuries
seem likely to follow as well.
References
Anderson CA, Arciniegas DB: Cognitive sequelae of hypoxic-ischemic brain injury:
a review. NeuroRehabilitation 26(1):47–63, 2010 20130355
Arbelaez A, Castillo M, Mukherji SK: Diffusion-weighted MR imaging of global
cerebral anoxia. AJNR Am J Neuroradiol 20(6):999–1007, 1999 10445435
Arciniegas DB: Hypoxic-ischemic brain injury: addressing the disconnect between
pathophysiology and public policy. NeuroRehabilitation 26(1):1–4, 2010
20130350
Arciniegas DB, Frey KL, Anderson CA, et al: Amantadine for neurobehavioural
deficits following delayed post-hypoxic encephalopathy. Brain Inj 18(12):1309–
1318, 2004 15666573
Betterman K, Patel S: Neurologic complications of carbon monoxide intoxication.
Handb Clin Neurol 120:971–979, 2014 24365364
Bodart O, Laureys S, Gosseries O: Coma and disorders of consciousness:
scientific advances and practical considerations for clinicians. Semin Neurol
33(2):83–90, 2013 23888393
Burke DT, Shah MK, Dorvlo AS, et al: Rehabilitation outcomes of cardiac and non-
cardiac anoxic brain injury: a single institution experience. Brain Inj 19(9):675–
680, 2005 16195180
Busl KM, Greer DM: Hypoxic-ischemic brain injury: pathophysiology,
neuropathology and mechanisms. NeuroRehabilitation 26(1):5–13, 2010
20130351
Calvert JW, Zhang JH: Pathophysiology of an hypoxic-ischemic insult during the
perinatal period. Neurol Res 27(3):246–260, 2005 15845208
Cervós-Navarro J, Diemer NH: Selective vulnerability in brain hypoxia. Crit Rev
Neurobiol 6(3):149–182, 1991 1773451
Chalela JA, Wolf RL, Maldjian JA, et al: MRI identification of early white matter
injury in anoxic-ischemic encephalopathy. Neurology 56(4):481–485, 2001
11222791
Chang BS, Lowenstein DH; Quality Standards Subcommittee of the American
Academy of Neurology: Practice parameter: antiepileptic drug prophylaxis in
severe traumatic brain injury: report of the Quality Standards Subcommittee of
the American Academy of Neurology. Neurology 60(1):10–16, 2003 12525711
Cicerone KD, Dahlberg C, Kalmar K, et al: Evidence-based cognitive rehabilitation:
recommendations for clinical practice. Arch Phys Med Rehabil 81(12):1596–
1615, 2000 11128897
Cicerone KD, Dahlberg C, Malec JF, et al: Evidence-based cognitive rehabilitation:
updated review of the literature from 1998 through 2002. Arch Phys Med
Rehabil 86(8):1681–1692, 2005 16084827
Cicerone KD, Langenbahn DM, Braden C, et al: Evidence-based cognitive
rehabilitation: updated review of the literature from 2003 through 2008. Arch
Phys Med Rehabil 92(4):519–530, 2011 21440699
Ciurleo R, Bramanti P, Calabrò RS: Pharmacotherapy for disorders of
consciousness: are ‘awakening’ drugs really a possibility? Drugs 73(17):1849–
1862, 2013 24170667
Elmer J, Callaway CW: The brain after cardiac arrest. Semin Neurol 37(1):19–24,
2017 28147414
Estraneo A, Moretta P, Loreto V, et al: Predictors of recovery of responsiveness in
prolonged anoxic vegetative state. Neurology 80(5):464–470, 2013 23303855
Estraneo A, Moretta P, Loreto V, et al: Clinical and neuropsychological long-term
outcomes after late recovery of responsiveness: a case series. Arch Phys Med
Rehabil 95(4):711–716, 2014 24275063
Fernández-Espejo D, Owen AM: Detecting awareness after severe brain injury.
Nat Rev Neurosci 14(11):801–809, 2013 24088810
Giacino JT, Kalmar K: Diagnostic and prognostic guidelines for the vegetative and
minimally conscious states. Neuropsychol Rehabil 15(3–4):166–174, 2005
16350959
Giacino JT, Ashwal S, Childs N, et al: The minimally conscious state: definition and
diagnostic criteria. Neurology 58(3):349–353, 2002 11839831
Giacino JT, Whyte J, Bagiella E, et al: Placebo-controlled trial of amantadine for
severe traumatic brain injury. N Engl J Med 366(9):819–826, 2012 22375973
Green CR, Botha JA, Tiruvoipati R: Cognitive function, quality of life and mental
health in survivors of out-of-hospital cardiac arrest: a review. Anaesth Intensive
Care 43(5):568–576, 2015 26310406
Greer DM: Mechanisms of injury in hypoxic-ischemic encephalopathy: implications
to therapy. Semin Neurol 26(4):373–379, 2006 16969737
Greer DM, Yang J, Scripko PD, et al: Clinical examination for prognostication in
comatose cardiac arrest patients. Resuscitation 84(11):1546–1551, 2013
23954666
Harve H, Tiainen M, Poutiainen E, et al: The functional status and perceived
quality of life in long-term survivors of out-of-hospital cardiac arrest. Acta
Anaesthesiol Scand 51(2):206–209, 2007 17261148
Heinz UE, Rollnik JD: Outcome and prognosis of hypoxic brain damage patients
undergoing neurological early rehabilitation. BMC Res Notes 8:243, 2015
26081628
Howard RS, Holmes PA, Koutroumanidis MA: Hypoxic-ischaemic brain injury.
Pract Neurol 11(1):4–18, 2011 21239649
Jang SH, Kim SH, Lim HW, et al: Injury of the lower ascending reticular activating
system in patients with hypoxic-ischemic brain injury: diffusion tensor imaging
study. Neuroradiology 56(11):965–970, 2014 25119256
Laureys S, Celesia GG, Cohadon F, et al; European Task Force on Disorders of
Consciousness: Unresponsive wakefulness syndrome: a new name for the
vegetative state or apallic syndrome. BMC Med 8:68, 2010 21040571
Lim C, Alexander MP, LaFleche G, et al: The neurological and cognitive sequelae
of cardiac arrest. Neurology 63(10):1774–1778, 2004 15557489
Lu-Emerson C, Khot S: Neurological sequelae of hypoxic-ischemic brain injury.
NeuroRehabilitation 26(1):35–45, 2010 20130354
Lundgren-Nilsson A, Rosén H, Hofgren C, et al: The first year after successful
cardiac resuscitation: function, activity, participation and quality of life.
Resuscitation 66(3):285–289, 2005 16039033
Moulaert VR, Wachelder EM, Verbunt JA, et al: Determinants of quality of life in
survivors of cardiac arrest. J Rehabil Med 42(6):553–558, 2010 20549160
Naro A, Russo M, Leo A, et al: Cortical connectivity modulation induced by
cerebellar oscillatory transcranial direct current stimulation in patients with
chronic disorders of consciousness: a marker of covert cognition? Clin
Neurophysiol 127(3):1845–1854, 2016 26754875
Okeda R: Concept and pathogenesis of “hypoxic-ischemic encephalopathy.. Acta
Neurochir Suppl (Wien) 86:3–6, 2003 14753393
Owen AM, Coleman MR: Functional MRI in disorders of consciousness:
advantages and limitations. Curr Opin Neurol 20(6):632–637, 2007 17992081
Posner JB, Plum F: Plum and Posner’s Diagnosis of Stupor and Coma, 4th
Edition. New York, Oxford University Press, 2007
Ropper AH, Samuels MA, Klein JP, et al: Adams and Victor’s Principles of
Neurology, 10th Edition. New York, McGraw-Hill Education, 2014
Rossetti AO, Oddo M, Logroscino G, et al: Prognostication after cardiac arrest and
hypothermia: a prospective study. Ann Neurol 67(3):301–307, 2010 20373341
Rothstein TL: Therapeutic hypothermia does not diminish the vital and necessary
role of SSEP in predicting unfavorable outcome in anoxic-ischemic coma. Clin
Neurol Neurosurg 126:205–209, 2014 25224644
Sadaka F: Therapeutic hypothermia for brain injury from near hanging: review of
the literature. Ther Hypothermia Temp Manag 3(1):13–16, 2013 24837635
Schnakers C, Vanhaudenhuyse A, Giacino J, et al: Diagnostic accuracy of the
vegetative and minimally conscious state: clinical consensus versus
standardized neurobehavioral assessment. BMC Neurol 9:35, 2009 19622138
Scirica BM: Therapeutic hypothermia after cardiac arrest. Circulation 127(2):244–
250, 2013 23319812
Shah MK, Al-Adawi S, Dorvlo AS, et al: Functional outcomes following anoxic
brain injury: a comparison with traumatic brain injury. Brain Inj 18(2):111–117,
2004 14660224
Shah MK, Carayannopoulos AG, Burke DT, et al: A comparison of functional
outcomes in hypoxia and traumatic brain injury: a pilot study. J Neurol Sci
260(1–2):95–99, 2007 17537457
Shprecher D, Mehta L: The syndrome of delayed post-hypoxic
leukoencephalopathy. NeuroRehabilitation 26(1):65–72, 2010 20166270
Sitt JD, King JR, El Karoui I, et al: Large scale screening of neural signatures of
consciousness in patients in a vegetative or minimally conscious state. Brain
137(Pt 8):2258–2270, 2014 24919971
Smania N, Avesani R, Roncari L, et al: Factors predicting functional and cognitive
recovery following severe traumatic, anoxic, and cerebrovascular brain
damage. J Head Trauma Rehabil 28(2):131–140, 2013 22333677
Stevens RD, Sutter R: Prognosis in severe brain injury. Crit Care Med 41(4):1104–
1123, 2013 23528755
Tazopoulou E, Miljkovitch R, Truelle JL, et al: Rehabilitation following cerebral
anoxia: an assessment of 27 patients. Brain Inj 30(1):95–103, 2016 26735867
Turnbull D, Singatullina N, Reilly C: A Systematic Appraisal of Neurosurgical
Seizure Prophylaxis: Guidance for Critical Care Management. J Neurosurg
Anesthesiol 28(3):233–249, 2016 26192247
van Alem AP, de Vos R, Schmand B, et al: Cognitive impairment in survivors of
out-of-hospital cardiac arrest. Am Heart J 148(3):416–421, 2004 15389227
van Erp WS, Lavrijsen JC, Vos PE, et al: The vegetative state: prevalence,
misdiagnosis, and treatment limitations. J Am Med Dir Assoc 16(1):85.e9–
85.e14, 2015 25528282
Venkatesan A, Frucht S: Movement disorders after resuscitation from cardiac
arrest. Neurol Clin 24(1):123–132, 2006 16443134
Whyte J, Myers R: Incidence of clinically significant responses to zolpidem among
patients with disorders of consciousness: a preliminary placebo controlled trial.
Am J Phys Med Rehabil 88(5):410–418, 2009 19620954
Whyte J, Gosseries O, Chervoneva I, et al: Predictors of short-term outcome in
brain-injured patients with disorders of consciousness. Prog Brain Res 177:63–
72, 2009 19818895
Whyte J, Rajan R, Rosenbaum A, et al: Zolpidem and restoration of
consciousness. Am J Phys Med Rehabil 93(2):101–113, 2014 24434886
Wilson M, Staniforth A, Till R, et al: The psychosocial outcomes of anoxic brain
injury following cardiac arrest. Resuscitation 85(6):795–800, 2014 24560827
CHAPTER 14
Infectious Diseases of the

Central Nervous System
Infections of the central nervous system (CNS) are a

heterogeneous group of disorders in both etiology and effects on the
nervous system. Some pathogens inflict damage by direct invasion
of neurons, whereas others do so by immune activation. Some
pathogens have a predilection for a specific brain topography,
whereas others cause a brisk immune activation with subsequent
injury in the leptomeninges. Some infections are acute and leave the
patient with static or gradually improving neurological and psychiatric
deficits, whereas others are chronic and may have a progressive
neurological and psychiatric course. This heterogeneity in
pathogenesis and pathophysiology explains the variety of
neuropsychiatric effects seen in CNS infections. In this chapter, we
will review some of the common bacterial, viral, fungal, and protozoal
infections of the brain, focusing on the neuropsychiatric sequelae of
these infections.
Human Immunodeficiency Virus
Soon after the first reports of an acquired immunodeficiency
syndrome (AIDS) in 1981 and the discovery of the human
immunodeficiency virus (HIV) as the causative agent of AIDS in
1983, clinicians recognized the protean effects of HIV on the brain
both through opportunistic infections and an end-stage, dementing
illness initially termed AIDS dementia complex (ADC). Additionally,
patients infected with HIV were found to suffer from the full range of
diagnosable psychiatric pathology, with profound impact on
treatment adherence and quality of life. With the advent of
combination antiretroviral therapy (cART) in 1996, HIV has evolved
from a uniformly fatal condition to a chronic, manageable disease
with a nearly normal life expectancy in treatment-adherent patients.
While opportunistic infections of the CNS still ravage untreated
patients, for a large proportion of HIV-infected individuals, the
neuropsychiatric sequelae of the infection are driven mainly by the
complex interplay of HIV infection and its treatment with general
medical, neurologic, and psychiatric comorbidities.
HIV-Associated Neurocognitive Disorders

Pathogenesis
HIV infects the brain early after acute systemic infection. This
brain infectivity is thought to result in the range of cognitive
impairment seen with HIV infection even in the absence of
opportunistic infections. HIV productively infects cells expressing
both CD4+ and a chemokine co-receptor, either CCR5 or CXCR4. A
productive infection allows the virus to hijack the infected cell’s
reproductive machinery and produce new virions that can, in turn,
infect other susceptible cells. Blood monocytes, tissue macrophages,
brain microglia, and CD4+ T cells are the primary hematopoietic
targets of productive HIV infection. Although investigators have
searched for evidence of other potential cellular targets for HIV brain
infection such as oligodendrocytes, endothelial cells, neurons, and
astrocytes, only perivascular macrophages and microglia are
convincing sources of productive infection in the CNS. However,
infected astrocytes, which are not a source of productive infection,
are still damaged by this infection. This additional source of
astrocytic dysfunction also helps drive excitotoxic damage. These
infected astrocytes are no longer able to reduce local excitotoxicity,
thereby damaging local neurons. Additionally, these infected
astrocytes damage endothelial cells of the blood-brain barrier (BBB)
and induce apoptosis in noninfected astrocytes (Brew and Chan
2014).
HIV brain infection proceeds through a number of stages and is
the pathophysiologic basis for the range and types of cognitive
dysfunction arising from the infection. Within hours to days of acute
systemic infection, infected circulating monocytes and lymphocytes
cross the BBB, releasing progeny virus and viral particles as well as
a large number of cytokines and chemokines. These cytokines and
chemokines bind to glial receptors and activate pro-inflammatory
genes through a positive feedback mechanism, perpetuating
downstream cytotoxicity. Additionally, infected monocytes express
HIV proteins such as vpr, tat, nef, and gp120, inducing apoptotic and
other proinflammatory pathways in microglia and astrocytes
(Desplats et al. 2013). Productively infected microglia and
perivascular macrophages, in turn, secrete a variety of
proinflammatory, proexcitotoxic molecules such as chemokines,
cytokines, viral particles, and glutamate. This immune dysregulation
further induces astrocytic and microglial activation and dysfunction,
synaptodendritic disruption, and neuronal and astrocytic apoptosis.
In response to this excitotoxic, inflammatory assault, the brain
upregulates neuroprotective and regenerative proteins attempting to
repair damage, although neither the patient’s immune system nor
cART can eradicate the virus from the brain. Additionally, HIV
establishes a reservoir within both the CNS and the periphery with
infected monocytes trafficking in from the bone marrow and other
peripheral reservoirs.
If an HIV-infected patient remains untreated and infection
progresses to the profound systemic immunosuppression of AIDS
(CD4+ T cell count below 200 cells/mm3), the patient’s brain grows
susceptible to the ravages of a number of infectious and neoplastic
opportunistic processes. Additionally, BBB permeability increases
and an influx of virus further compromises brain function, thereby
increasing the risk of dementia associated with direct HIV infection.
Disease Nomenclature and Diagnostic Criteria

Over time, the nomenclature of the cognitive impairment ascribed
to HIV has changed. In the pre-cART era (before 1996), the
emphasis was on the terminal condition associated with the profound
immunosuppression of AIDS—ADC. ADC was described as a
relentlessly progressive subcortical dementia with disturbances in
attention, concentration, working memory, fine motor skills, and gait
as well as behavioral manifestations such as apathy, depression,
agitation, and disinhibition progressing to severe dementia with
cortical features at the end-stage and leading to death within 1 year
of diagnosis. Its pathological substrate, HIV encephalitis or
encephalopathy (HIVE), is characterized by cortical atrophy,
leukoencephalopathy, microglial nodules, and multinucleated giant
cells (Bissel and Wiley 2004).
In 1991, an American Academy of Neurology working group
refined the diagnostic nosology and defined two levels of cognitive
impairment resulting from the direct effects of HIV brain infection: the
less severe HIV minor cognitive motor disorder and the more
profound HIV-associated dementia (HAD). HAD, the new name for
ADC, was subdivided into three variants: HAD with motor symptoms;
HAD with behavioral or psychosocial symptoms; and HAD with both
motor and behavioral or psychosocial symptoms (American
Academy of Neurology 1991).
In 2007, these criteria were further refined to reflect new
demographic and pathophysiologic knowledge and to address a
number of shortcomings of the 1991 American Academy of
Neurology criteria. These criteria, the so-called Frascati criteria,
reflect the fact that since the advent of cART, the prevalence of HIV-
associated neurocognitive disorders (HAND) has not changed, but a
larger proportion of HIV-infected patients have milder, subtler
cognitive impairment. The Frascati criteria therefore define three
stages of HAND: 1) asymptomatic neurocognitive impairment (ANI),
2) mild neurocognitive disorder (MND), and 3) HAD. A diagnosis of
ANI requires an acquired impairment (>1 standard deviation [SD]) in
two or more cognitive domains on neuropsychological testing but
without impact on daily functioning. MND also requires an acquired
impairment (>1 SD) in two or more cognitive domains on
neuropsychological testing but with mild functional impairment such
as an impact on work efficiency. HAD is a condition of marked
functional impairment with an acquired deficit in at least two
cognitive domains, but typically in multiple domains, with at least two
domains severely impacted (>2 SD) as demonstrated on
neuropsychological testing (Antinori et al. 2007).
Unlike HAD patients in the pre-cART era (or current treatment-
naive patients), cART-treated patients who progress to HAD
demonstrate not only subcortical but also cortical patterns of
dysfunction on neuropsychological testing, specifically impairment in
learning and memory as well as executive function (Heaton et al.
2011). Patients are also developing more parkinsonian features as
they grow older and cognitive function deteriorates, raising the
possibility of an interaction between HIV brain infection and
neurodegenerative diseases (Valcour et al. 2008).
Further complicating the HAND nomenclature, HAD is a label that
does not distinguish between two types of HIV-infected individuals
with dementia, those with dementia due to untreated AIDS whose
virologic status is a clear and active treatment target (previously
ADC) and those with dementing brain injury from the direct effects of
HIV but with quiescent, virologically stable disease in whom the
treatment targets are quite different but inadequately defined.
Whereas the pathological substrate for the first HAD group is the
classic HIVE, it is less clear for the second group. Additionally,
neither ANI nor MND is associated with specific neuropathological
correlates. However, in a longitudinal study, ANI was found to
convey a twofold to sixfold increase in the risk for a symptomatic
stage of HAND (Grant et al. 2014).
No standardized psychometric battery has been employed in
either HAND research or patient care. The Frascati criteria do call for
assessing at least five of the following appropriately normed domains
in the evaluation of HAND: 1) attention-information processing, 2)
language, 3) abstraction-executive function, 4) complex perceptual
motor skills, 5) memory, including learning and recall, 6) simple
motor skills, and 7) sensory perceptual skills. Other causes of
dementia as well as psychiatric and substance-related confounders
must be excluded. Functional impact is typically assessed by self-
report, although a number of self-administered questionnaires do
exist (Antinori et al. 2007).
In the pre-cART era, neuropsychological testing was used to
identify the gross deficits of HAD, and improvement with early
antiretroviral therapy was often very significant. In the cART era, with
multitiered HAND criteria, including the subtle diagnoses of ANI and
MND, testing must be increasingly sensitive to small changes in
cognitive function. The most commonly used bedside tests in HIV
clinics include variations on the Mini-Mental State Exam (MMSE),
Montreal Cognitive Assessment, International HIV Dementia Scale,
HIV Dementia Scale, and z scores of several brief
neuropsychological tests used in the AIDS Clinical Trials Group.
These and a number of other tests may lack adequate sensitivity to
detect subtle changes and may not be appropriately normed for the
diverse social and cultural groups afflicted with HIV worldwide.
These insensitivities impact both the initial detection of HAND as well
as the gauging of treatment effects. Patients may serve as their own
control subjects, but the impact of practice effects must be
considered (Clifford and Ances 2013).
Differential Diagnosis: Opportunistic Infections

and Neoplasms
In addition to HAND, HIV-infected patients with cognitive decline,
delirium, and/or focal neurological symptoms must be evaluated for
CNS opportunistic processes. A number of infections, such as
syphilis and tuberculosis, are often comorbid with HIV infection but
can occur independently of HIV. These infectious processes will be
discussed in greater detail later in this chapter. Additionally, patients
infected with HIV may suffer from the same infections and
neoplasms as non-HIV patients: bacterial meningitis, primary brain
tumors, and brain metastases. However, certain opportunistic
infections and neoplasms are associated with the severe
immunodeficiency of AIDS: Toxoplasma gondii encephalitis,
Cryptococcus neoformans meningitis, progressive multifocal
leukoencephalopathy (PML) due to infection with the JC virus,
cytomegalovirus (CMV) encephalitis, and primary CNS lymphoma
associated with Epstein-Barr virus (EBV) infection.
Toxoplasma gondii. Toxoplasmosis infection is the most common
cause of CNS mass lesions in HIV-infected patients. Between 60%
and 80% of AIDS patients with CNS mass lesions suffer infection
with this obligate intracellular parasitic protozoan. Patients typically
present with fever, headache, confusion, and focal neurological
signs. On neurological examination, patients evidence focal
neurological signs, ataxia, psychomotor retardation, or
encephalopathy. Seizures occur in approximately 30% of patients.
Patients become infected with either toxoplasma oocysts from cat
feces or bradyzoites from undercooked meat. After ingestion, the
organism spreads through the lymphatic system to brain, muscle,
and retina.
In the United States, the serologic evidence of latent
toxoplasmosis infection in HIV-positive men is reported to be 16%
(Dannemann et al. 1991). Immunoglobulin G (IgG) serum antibodies
are detected in the vast majority of patients with CNS toxoplasmosis
lesions. However, the cerebrospinal fluid (CSF) is essentially normal
in 50% of HIV-infected patients; intrathecal antibodies and
polymerase chain reaction (PCR) analyses are not sensitive enough
to be helpful in ruling out infection but are very specific and thus
helpful for ruling in the infection.
The most common locations for toxoplasma brain abscesses are
at the gray-white junction as well as within the basal ganglia, the
deep white matter, and the thalamus; the abscesses typically appear
as contrast enhancing (ring-enhancing lesions) on both computed
tomography (CT) and magnetic resonance imaging (MRI). Primary
CNS lymphoma (PCNSL) is the main differential diagnosis. Single-
photon emission computed tomography (SPECT) and positron
emission tomography (PET) can help differentiate between
toxoplasmosis and PCNSL because toxoplasmosis, unlike PCNSL,
exhibits no increased SPECT uptake and exhibits decreased
metabolic activity on PET. Toxoplasmosis is also more likely to have
multiple lesions (two-thirds of cases), whereas PCNSL tends to
manifest as a single lesion. Of course, brain biopsy provides a
definitive diagnosis, but biopsy is typically reserved until the patient
has been treated empirically for toxoplasmosis for 2 weeks and there
has been no radiological improvement (Roos 2005).
Primary central nervous system lymphoma. PCNSL is a type of
nonsystemic, aggressive non-Hodgkin’s lymphoma limited to the
cranial-spinal axis. It represents one-third of lymphomas in HIV-
infected patients and is the most common brain malignancy in this
group. During the pre-cART era, 0.5%–7% of HIV-infected patients
succumbed to PCNSL, but the current incidence is half that number.
This disease occurs in advanced AIDS when the CD4+ T cell count
is below 100 cells/mm3 and usually below 50 cells/mm3. Unlike in
HIV-negative patients, PCNSL in HIV-infected patients contains EBV
genomic sequences. EBV+ B cells undergo monoclonal expansion,
and EBV-specific CD8+ T cells are lost.
Brain lesions are three times more likely to be supratentorial than
infratentorial. They may develop close to either the cerebral
convexities or the ventricles and may also arise within the corpus
callosum, the basal ganglia, or the thalamus. Like most mass
lesions, the clinical presentation depends on the location of the
lesions. Approximately half of patients have a nonfocal,
encephalopathic presentation; the other half experience focal
neurological signs. Seizures occur in 10%–40% of patients, and
increased intracranial pressure occurs in 15%–30% of patients.
Neuropsychological symptoms include apathy, psychosis, and a
rapidly progressive dementia. The infiltrative nature of this neoplasm
results in a clinical picture worse than the focal manifestations
predicted on neuroimaging.
Stereotactic biopsy yields a diagnosis in 85%–95% of patients,
but the sensitivity of the biopsy is decreased when corticosteroids
are administered prior to the biopsy. Typically, AIDS patients with
ring-enhancing lesions are treated empirically for toxoplasmosis for 2
weeks, and if lesion size is not reduced, a biopsy should be
performed. CSF studies typically reveal elevated protein, a
mononuclear pleocytosis, and occasionally low glucose. Cytology is
positive in only 10%–25% of patients, usually late in the disease
course. EBV PCR in CSF has a sensitivity of greater than 80% and a
specificity of 90%. A positive CSF EBV PCR may precede diagnosis
of PCNSL by months and can be detected in patients with
microscopic foci of the disease (Roos 2005).
Cryptococcus neoformans. Cryptococcal meningitis is the most
common systemic fungal infection in HIV-infected individuals and is
the third most common opportunistic infection of the CNS. Between
2% and11% of HIV-infected patients fall ill with cryptococcal
meningitis, and it typically develops in those with a CD4+ T cell
count below 100 cells/mm3. Infection with C. neoformans is the
result of inhalation of the yeastlike fungus found in the excreta of
pigeons and other birds.
The disease typically manifests as a subacute meningitis with stiff
neck, headache, nausea, vomiting, visual disturbance,
encephalopathy, signs and symptoms of increased intracranial
pressure, and, rarely, seizures and focal neurological signs. Lumbar
puncture typically reveals increased opening pressure, elevated
protein, a lymphocytic pleocytosis, and, sometimes, decreased
glucose. The cryptococcal capsular polysaccharide antigen titer
(“crypto antigen”) is elevated in more than 90% of patients. Brain
imaging may either be unremarkable or demonstrate a number of
pathological features such as cortical atrophy, dilated Virchow-Robin
spaces, cryptococcomas, ventricular enlargement, or cerebral
edema (Roos 2005).
Progressive multifocal leukoencephalopathy. JC virus, the
causative agent of PML, is a DNA polyomavirus living latently in the
kidney, lymphoid tissue, and brain in immunocompetent hosts. In
severely immunocompromised AIDS patients, typically with a CD4+
T cell count of less than 100 cells/mm3, JC-specific CD8+ T cells are
lost, and the JC virus invades and lyses oligodendrocytes, resulting
in multiple asymmetric foci of demyelination in different states of
evolution.
Lesions usually evolve in the frontal, parietal, and occipital white
matter and involve the white matter U-fibers. The cerebellum, brain
stem, and even gray matter can be affected in advanced cases.
Before cART, the incidence of PML in the HIV-infected population
was 2–10 per 1,000 person-years, dropping to 1 per 1,000 person-
years in the cART era. Whereas survival at 1 year was only 9%
before cART, it is now approximately 70% at 1 year and 50%–60% at
2 years. However, even survivors are left with the burden of their
neurological impairment (Pavlovic et al. 2015).
Patients present with symptoms that vary with location and extent
of brain involvement. Cognitive decline, including dementia, is a
common symptom, affecting between 30% and 60% of patients. Fifty
percent to 70% of patients experience weakness. Visual field deficits
and cortical blindness afflict 20%–50% of patients. Gait,
coordination, and speech may also be affected. Unlike most other
CNS opportunistic infections in HIV, PML due to AIDS is not typically
inflammatory.
On CT, PML demonstrates multiple areas of low attenuation in
affected cerebral white matter but with neither mass effect nor
contrast enhancement. On MRI, PML lesions are hypointense on T1-
weighted images and hyperintense on T2-weighted images, and
lesions neither enhance with gadolinium nor demonstrate mass
effect (Roos 2005). Lumbar puncture findings are nonspecific and
are consistent with either a noninflammatory profile or mild protein
and cell count elevation seen in advanced AIDS. The CSF JC virus
PCR is very sensitive and specific in patients with a clinical and
radiologic picture highly suspicious for PML. PML immune
reconstitution inflammatory syndrome, although rare, does manifest
as an inflammatory form with mass effect, edema, and contrast
enhancement (Roos 2005).
Cytomegalovirus. CMV is the most common viral infection in HIV-
infected patients, manifesting as either retinitis or gastrointestinal
disease. CNS infections are less common and may manifest as
encephalitis, ventriculoencephalitis, meningitis, polyradiculitis,
myeloradiculitis, or any combination of these forms. Because CMV is
associated with profound immunosuppression, its incidence has
decreased in the cART era.
CMV encephalitis typically manifests as an acute to subacute
dementia with superimposed delirium and occasional focal
neurological signs. CMV ventriculoencephalitis manifests as a
rapidly progressive delirium with cranial neuropathies, nystagmus,
ataxia. CMV brain disease is associated with more delirium, a more
rapid progression, and a lower CD4+ T cell count than typically seen
in HAD.
On CT, CMV brain infection results in low attenuation in the brain
parenchyma with ventricular enlargement and periventricular
enhancement. MRI findings vary with the part of the neuroaxis
infected with CMV. Encephalitis may cause hyperintensity on T2-
weighted images in cortical regions, whereas ventriculoencephalitis
may result in hyperintensity in subependymal regions and the
meninges. CMV polyradiculitis or myeloradiculitis may cause
hyperintensity in the spinal cord or lumbosacral rootlets. CMV rarely
manifests as a ring-enhancing lesion with mass effect and edema
(Roos 2005).
Demographic Changes From the Pre-cART Era

The demographics of HAND have changed from the pre-cART era
to the cART era. A number of studies have attempted to quantify the
change in HAND prevalence by stage of neurocognitive impairment
and stage of HIV-related immunosuppression. Heaton and
colleagues (2011) compared 857 subjects from 1988 to 1995 (pre-
cART era) with 937 subjects from 2000 to 2007 (cART era) and
found that cognitive impairment increased with successive HIV
disease states in both eras. Among asymptomatic HIV patients, 25%
had cognitive impairment pre-cART compared with 36% receiving
cART. Among mildly symptomatic HIV patients, 42% experienced
cognitive impairment pre-cART compared with 40% receiving cART.
Among those patients with AIDS-defining illnesses, 52%
experienced cognitive dysfunction pre-cART compared with 45% in
the cART era.
Low CD4+ T cell count nadir predicted the presence of HAND in
both eras. However, the patient’s current level of
immunosuppression, estimated duration of infection, and viral
suppression in the CSF were related to impairment in the pre-cART
era (Heaton et al. 2011). Another study estimated the prevalence of
HAND pre-cART to be 35% overall, with 16% ANI, 5% MND, and
14% HAD, and found HAND prevalence during the cART era to be
44% overall, with 32% ANI, 10% MND, and 2% HAD (McArthur et al.
2010).
Contributions of Comorbidities to Cognitive

Dysfunction
The CNS HIV Antiretroviral Therapy Effects Research
(CHARTER) study examined a diverse group of 1,555 HIV-infected
individuals, representative of patients at university-affiliated HIV
treatment centers in the United States, and used the Frascati criteria
to diagnose patients. Subjects’ comorbidities for neurocognitive
impairment were stratified into three levels: incidental (54.2%,
n=843), contributing (30.4%, n=473), and confounding (15.4%,
n=239). By definition, confounding co-morbidities were severe
enough to exclude the diagnosis of HAND. Common comorbidities,
with a comparison of the prevalence of those incidental to versus
those confounding a HAND diagnosis, included the following: low
reading level (15.3% vs. 49.2%); special education history (2.8% vs.
31.8%); other scholastic difficulties (5.2% vs. 51.9%); traumatic brain
injury (3.4% vs. 40.6%); epilepsy (0% vs. 4.6%); other seizure
history (1.8% vs. 23.4%); systemic medical illness (27.2% vs.
63.6%); history of CNS opportunistic infections (1.2% vs. 5.4%);
current major depressive disorder (13.5% vs. 15.5%); psychotic
disorder (2.5% vs. 16.7%); and current substance use disorder
(5.8% vs. 7.8%). Neurocognitive impairment was found in 52% of
subjects, with higher rates in groups with greater comorbidity burden
(40% incidental, 59% contributing, and 83% confounding). The
prevalence estimates for specific HAND diagnoses (excluding
severely confounded cases) were 33% for ANI, 12% for MND, and
only 2% for HAD. As in previous studies, a history of a low CD4+ T
cell count nadir was associated with greater risk of HAND, even in
patients who experienced immune system recovery with cART
(Heaton et al. 2010).
Cardiovascular risk factors also appear to impact cognitive
function in HIV-infected patients, potentially through their association
with system inflammation. Increases in carotid intima-media
thickness, for example, were associated with memory impairment
and performance speed. Hypertension and hyperlipidemia appear to
be better correlates with baseline neuropsychological testing
performance than HIV disease markers such as CD4+ T cell count
and viral load in men age 40 and over (Becker et al. 2009). Central
obesity, systemic inflammation, and diabetes mellitus in older HIV-
infected patients are also associated with worse neurocognitive
impairment (Sattler et al. 2015). Additionally, HIV increases the risk
of stroke, an event that may have long-lasting neuropsychiatric
sequelae.
Plasma and CSF Biomarkers

HAND may be preventable with early virologic control and
prevention of CD4+ T cell nadir below 200 cells/mm3. Because
CD4+ T cell count and plasma viral load do not correlate with the risk
of cognitive impairment for patients receiving cART, researchers
have sought plasma, CSF, and neuroimaging biomarkers for HAND.
Plasma biomarkers have included markers of activated monocytes
and macrophages (e.g., increased plasma-soluble CD14 linked to
impairment in attention and learning), and CSF biomarkers have
focused on markers of inflammation (e.g., increased CSF neopterin,
MCP-1), neuronal injury (e.g., increased neurofilament), CSF viral
escape (presence of virus in CSF despite systemic viral
suppression), and viral genomics (Clifford and Ances 2013).
Neuroimaging Biomarkers
Gadolinium-enhanced structural MRI of the brain is an important
part of the workup of cognitive impairment in HIV-infected patients,
most importantly to exclude secondary causes of dysfunction such
as opportunistic processes, cerebrovascular disease, and non-HIV-
related pathologies. MRI is preferred to head CT. Brain MRIs in
HAND patients vary considerably in the pathological changes they
display, ranging from mild cortical and white matter atrophy to
periventricular hyperintensities on a T2 fluid-attenuated inversion
recovery (FLAIR) sequence that do not enhance with gadolinium on
the T1 sequence. Volumetric studies have found atrophy throughout
the cerebral cortex, particularly in the anterior cingulate cortex,
lateral temporal lobe, primary motor and sensory cortices, and frontal
and parietal lobes. Furthermore, cognitive and motor impairment is
associated with reduced basal ganglia volumes and nigrostriatal and
frontostriatal circuit atrophy (Steinbrink et al. 2013).
Magnetic resonance spectroscopy studies consistently
demonstrate reductions in N-acetylaspartate, a signature of neuronal
injury, along with an increase in myoinositol and choline levels,
indicative of glial proliferation, especially in the frontal white matter
and basal ganglia. Diffusion tensor imaging has demonstrated
reduced white matter integrity of the corpus callosum and alterations
in the caudate nucleus. Cognitive impairment has also been
associated with a reduction in the integrity of cortical white matter,
the corpus callosum, and the corona radiate (Clifford and Ances
2013).
Blood-oxygen-level-dependent (BOLD) functional MRI (fMRI)
studies have demonstrated both increased and decreased activation
in various brain regions depending on the type of tasks subjects
were asked to perform. fMRI may even demonstrate dysfunction
before neuropsychological testing. Compared with control subjects,
patients with HIV demonstrated a greater magnitude of brain
activation in the lateral prefrontal cortex with normal performance
during fMRI and on a battery of neuropsychological tests. HIV-
infected patients also showed increased activated brain volume in
the lateral prefrontal cortex, independent of task difficulty (Clifford
and Ances 2013). Resting state functional connectivity MRI changes
in the salience and default networks in HIV-infected patients are
similar to those that occur in normal aging (Clifford and Ances 2013).
Fluorodeoxyglucose (18F) PET (FDG-PET) studies have also
demonstrated both cortical hypometabolism and basal ganglia
hypermetabolism (Davison et al. 2011). A PET study utilizing tracers
that bind to dopamine transporters (DATs) or D2 receptors observed
decreased DAT binding in the putamen and ventral striatum but no
difference in D2 receptor binding in HAND patients relative to control
subjects. Decreases in DAT binding were associated with increasing
HAND severity (Wang et al. 2004).
Even early HIV infection leaves a neuroimaging mark on the
brain. The brain volumes of 15 acutely HIV-infected individuals (<100
days after infection) were compared with 20 HIV-uninfected control
subjects, and the HIV-infected individuals were found to have
reduced brain parenchymal volume, expansion of the third ventricle,
and brain stem enlargement (Ragin et al. 2012). Arterial spin labeling
MRI revealed reduced resting cerebral blood flow in the lenticular
nuclei in subjects within a year of seroconversion compared with
impaired reduced resting cerebral blood flow in both lenticular nuclei
and visual cortex in those with more chronic infection (Ances et al.
2009).
Treatment
The only effective treatment for HAND remains cART. By 48
weeks after cART initiation, 41% of patients with mild to moderate
cognitive impairment experience clinically meaningful and sustained
cognitive improvement (Cysique et al. 2009). Yet even receiving
cART, a large percentage of HIV-infected patients continue to
experience cognitive impairment (Heaton et al. 2010). Because the
BBB does not allow all antiretroviral agents to penetrate the brain in
equal measure, HIV may evolve independently in the CNS. Despite
systemic suppression of viral replication, even low-level CNS viremia
may perpetuate a deleterious proinflammatory, proexcitotoxic, and
ultimately degenerative effect on the brain. Neuropathological
studies have supported this hypothesis, finding that despite plasma
viral suppression, high levels of microglial activation are found in the
basal ganglia and hippocampus (Anthony et al. 2005). In fact, while
50% of patients had no detectable HIV RNA in examined brain
regions, among those with evidence of HIV RNA, the lowest levels
were identified in the CSF and the highest in the caudate even in
patients on cART (Kumar et al. 2007).
By studying the CSF pharmacokinetics of the different
antiretroviral agents, a CNS penetration effectiveness ranking
system has been validated (Letendre et al. 2008). Investigators have
demonstrated that more penetrant cART does result in more
prolonged CSF viral suppression. Some studies have shown that
more penetrant cART does positively impact performance on
psychometric testing (Smurzynski et al. 2011). However, a more
recent study looking at the risk of HAD and common CNS
opportunistic infections with more penetrant cART found an
increased risk of HAD, but not of other opportunistic processes,
raising the possibility that more penetrant cART has a neurotoxic
effect (Caniglia et al. 2014).
In addition to cART, a number of other phamacotherapeutic
strategies have been studied for the treatment of HAND, focusing on
medications that mediate microglia, reduce cytotoxic elements,
modulate NMDA, or manipulate neurotransmitter levels, including
nimodipine, selegiline, minocycline, rivastigmine, and memantine,
among others. Although a small pilot study demonstrated improved
processing speed with rivastigmine, no adjunctive strategy has been
proven effective in improving cognitive function in a large, controlled
study (Clifford and Ances 2013).
HIV-Associated Psychiatric Symptoms and Disorders
Depression
Major depressive disorder (MDD) is among the most common
psychiatric disorders in HIV-infected patients, and it appears to be
more prevalent in the HIV-infected than in the uninfected population.
The actual percentage of HIV-infected individuals experiencing
depression varies by study and ranges from 30% to 61%, with a
higher prevalence among women and a possible incidence beyond
this range for those with advanced HIV disease, although not all
investigators have found an association between advancing HIV
disease and worsening depression (Rabkin et al. 1997). Dysthymia
may be present in up to one-fourth of HIV-infected patients (Cruess
et al. 2003). Premorbid depression is another significant risk factor
for depression during HIV infection (Gallego et al. 2011). Untreated
MDD is a risk factor for medication nonadherence and is associated
with progression of HIV disease; however, treated psychiatric
disease may improve cART adherence above and beyond
adherence rates for the HIV-infected population without psychiatric
diagnoses (Treisman and Angelino 2007).
Recognizing MDD in HIV-infected patients can be challenging for
a number of reasons. First, normal feelings of sadness, fear, and
anxiety are common after a new diagnosis of HIV infection and may
rise to the level of adjustment disorder in a significant proportion of
patients—18% in one university-based inner-city HIV clinic with a
large proportion of patients with comorbid substance abuse
(Treisman and Angelino 2007). Adjustment disorder must be
distinguished from MDD because treatment for the two disorders
differs. Patients with MDD may benefit from antidepressant
medications as well as psychotherapeutic interventions such as
cognitive-behavioral and interpersonal therapies. Patients with
adjustment disorder will benefit from supportive psychotherapy and
coaching strategies. Anhedonia and early morning awakening are
two symptoms more specific to MDD that may help to distinguish
MDD from adjustment disorder. Second, vegetative symptoms of
MDD such as decreased appetite, insomnia, and fatigue can mimic
common symptoms of HIV infection, comorbid substance abuse, or
an opportunistic infection. Third, symptoms related to cognitive
slowing and apathy commonly reported in MDD are also the
hallmarks of the symptomatic stages of HAND. Of course, the two
conditions may be comorbid, confounding the diagnosis of both
disorders. Finally, comorbid personality disorders may also
complicate the way in which depressive symptoms manifest and
increase the risk of missing the diagnosis of a mood disorder
(Cruess et al. 2003). Additionally, determining whether depression is
primary or secondary to HIV infection or the antiretroviral agents
used to treat HIV can be very challenging and requires a careful
history of both current and past affective symptoms and a thorough
consideration of other general medical and neurological influences
on symptomatology (Abers et al. 2014; Cruess et al. 2003).
Treatment of depression with psychotherapy and
pharmacotherapy improves outcomes and quality of life. A
systematic review of interventions for the treatment of depression in
HIV-infected patients found evidence for the efficacy of both
pharmacological treatment and psychological treatments, especially
the cognitive-behavioral approach (Sherr et al. 2011). A number of
studies have demonstrated the efficacy of a wide range of
phamacotherapeutic approaches with low-anticholinergic tricyclic
antidepressants (TCAs), selective serotonin reuptake inhibitors
(SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs),
mirtazapine, and bupropion. Treatment of depression in HIV-infected
subjects with psychostimulants has also been reported, with some
variability in efficacy for primary treatment of depression. Given the
potential for abuse and impact on weight, psychostimulants should
be used with caution and may be more appropriate as adjunctive
therapy for depression rather than as primary treatment.
Psychotropic agents may be used safely with cART, but clinicians
must pay special attention to the cytochrome P450 (CYP)
interactions between these agents and antiretroviral agents,
especially those psychotropics with significant affinity for CYP2D6
and CYP3A4 (Cruess et al. 2003).
Suicide is the most feared result of depression, and suicidal
ideation and suicide attempts are more common in HIV-infected
individuals than in the general population. The advent of cART has
resulted in a decline in suicides among HIV-infected individuals.
However, suicide is still three times higher in the HIV-infected
population than in the general population (Gallego et al. 2011).
Mania
Mania in HIV-infected patients may occur at any time during the
disease course in patients with preexisting bipolar disorder.
However, new-onset secondary mania in patients with AIDS may be
a manifestation of HAD (Mijch et al. 1999). Some researchers have
found that the clinical profile of HAD-related mania differs from
traditional mania seen in bipolar disorder because it is accompanied
by marked cognitive deficits and more irritability than euphoria and is
generally more severe in its manifestation and clinical course
(Gallego et al. 2011). The differential diagnosis of new-onset
secondary mania includes not only HAND but also CNS
opportunistic processes, especially those affecting the right frontal
lobe. Treatment of mania in HIV-infected individuals follows the same
principles as for non-HIV-infected patients: lithium, anticonvulsants,
and atypical neuroleptics may all be considered as rational treatment
choices as long as careful attention is paid to drug interactions and
the potentially increased sensitivity to side effects, including
extrapyramidal side effects, in HIV patients with cognitive or medical
comorbidities (Cruess et al. 2003). One small study also suggested
that antiretroviral agents with greater CNS penetration may prevent
secondary mania (Mijch et al. 1999).
Psychosis
Like mania, psychotic symptoms in HIV have many potential
causes. Patients may experience psychosis as a manifestation of
premorbid schizophrenia, bipolar disorder, or MDD. Psychosis may
be the result of drugs of abuse as well as antiretroviral agents and
other prescribed medications. Psychosis may also be an unusual
manifestation of HAD. The prevalence of psychotic disorders in HIV-
infected patients ranges from 0.2% to 15%. Treatment of psychosis
includes removing any offending agents and treating the underlying
psychiatric disease with special attention to drug interaction (Gallego
et al. 2011).
Anxiety
Anxiety disorder is more prevalent in HIV-infected individuals than
in the general population. Studies vary significantly in prevalence
estimates, from 4% to 40%, depending on how long anxiety
symptoms must be present to be considered. However, the rates of
panic disorder do not appear to be elevated when compared with
non-HIV-infected individuals (Gallego et al. 2011). A review of all
treatments for anxiety in HIV-infected individuals between 1980 and
2009 found that psychological interventions, in particular, cognitive-
behavioral therapy and cognitive-behavioral stress management
interventions, were more effective than pharmacological
interventions. However, the reviewed studies had a number of
methodological limitations, tended to include mostly male patients,
and used a wide range of instruments to define anxiety (Clucas et al.
2011).
Substance and Alcohol Use Disorders

Substance and alcohol use disorders are common in the HIV-
infected population, are often comorbid with other psychiatric illness,
and lead to disinhibition, poor judgment, impulsivity, risk-taking
behaviors, diminished adherence to HIV treatment, and poor
neurocognitive and overall health outcomes. Lifetime rates of alcohol
use disorder range from 22% to 64%, and lifetime rates of substance
use disorder range from 30% to 56%. The prevalence of any current
substance abuse, including alcohol abuse, ranges from 20% to 73%
(Gallego et al. 2011).
Alcohol and a number of illicit drugs can alter the
pharmacokinetics of antiretroviral agents. Alcohol alters gastric
emptying, changes cytochrome P450 metabolism of antiretroviral
agents, and causes cirrhosis of the liver, thereby reducing the liver’s
ability to metabolize medications, such as protease inhibitors and
nonnucleoside reverse transcriptase inhibitors, properly. For
example, abacavir, like alcohol, uses alcohol dehydrogenase in its
metabolic pathway. Thus, concurrent alcohol and abacavir use
prolongs the half-life of the medication. Alcohol also potentiates the
hepatotoxicity of nevirapine. However, alcohol dependence is not a
contraindication for cART. Although cocaine and
tetrahydrocannabinol (THC) do not appear to interact with
antiretrovial drugs, protease inhibitors appear to inhibit the
metabolism of a number of illicit drugs, such as
methylenedioxymethamphetamine (MDMA), gamma-
hydroxybutyrate (GHB), amphetamines, ketamine, lysergic acid
diethylamide (LSD), and phencyclidine (PCP), with reports of
overdoses due to this interaction with some of these drugs (Gallego
et al. 2011).
Antiretroviral Medication–Induced
Neuropsychiatric Effects
Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor
(NRTI), was the first medication used to treat HIV infection. NRTIs
are most notorious for their effects on nerves and muscles, but
psychiatric adverse events, including mania, hallucinations, and
psychosis, have been reported with AZT. Symptom onset has ranged
from days to months after AZT administration. Risk factors for
developing these adverse effects include a previous history of
psychiatric disease and the use of 1,200 mg/day of AZT, double the
currently recommended dose. Whereas some patients required
active treatment of psychiatric disease even once AZT was
discontinued, others experienced symptom resolution shortly after
the drug was stopped. More rare and severe symptoms, including
depression, suicidal ideation, and psychosis, have also been
reported (Abers et al. 2014). Because of today’s extensive
antiretroviral armamentarium, many alternatives to AZT therapy
exist.
Neuropsychiatric side effects have been reported with a number
of other NRTIs, including emtricitabine, abacavir, and tenofovir.
Abacavir has been associated with a number of neuropsychiatric
effects including depression, nightmares, hallucinations, mood
changes, mania, anxiety, psychosis, and suicidal ideation.
Emtricitabine-related effects include headache, paresthesias,
confusion, irritability, and insomnia. It is unclear if tenofovir itself has
neuropsychatric effects or whether effects are due to elavirenz
coadministration. A few reports have described emtricitabine-related
headache, paresthesias, confusion, irritability, and insomnia. Reports
of tenofovir-related neuropsychiatric effects were all for patients for
whom efavirenz was coadministered, and it is unclear if tenofovir
itself was the offending agent (Abers et al. 2014).
The nonnucleoside reverse transcriptase inhibitor efavirenz is one
of the most commonly used cART agents. Although other
nonnucleoside reverse transcriptase inhibitors such as etravirine and
rilpivirine may rarely cause neuropsychiatric side effects, more than
50% of patients taking efavirenz experience neuropsychiatric side
effects. Premorbid psychiatric disease but not substance abuse
appears to be a risk factor for the development of these adverse
effects (Abers et al. 2014). Symptoms typically appear within weeks
of drug initiation and include dizziness, lightheadedness, sleep
disturbances, vivid dreams, anxiety, and irritability. Although these
initial symptoms typically resolve without dose alteration in the
majority of patients, at least one study found that almost one-half of
patients taking efavirenz for more than a year suffered cognitive
impairment, especially executive dysfunction (Ciccarelli et al. 2011).
In contrast, other studies found that the severity of neuropsychiatric
effects diminished with time and did not impact quality of life, and the
rate of discontinuation due to neuropsychiatric effects was 2%–8%
(Abers et al. 2014). Even patients with a history of substance abuse
(with the exception of methadone because efavirenz reduces
methadone levels by 45%) appear to maintain adherence to
efavirenz. However, more severe symptoms such as depression,
suicidal ideation, and psychosis may develop rarely and should
prompt drug cessation (Apostolova et al. 2015).
Pharmacokinetic and pharmacogenetic variables may explain
efavirenz neurotoxicity. Efavirenz is more than 99.5% protein bound,
and the CYP2B6 clears 90% of the drug. Many single-nucleotide
polymorphisms of the CYP2B6 isoform affect efavirenz metabolism
and may even predict neuropsychiatric adverse effects. Prospective
trials to guide medication selection are lacking (Abers et al. 2014).
Syphilis
Syphilis is caused by the spirochete Treponema pallidum. This
infection is primarily spread via sexual contact, although it may also
be transmitted from mother to fetus either during pregnancy or at
birth. Prior to the 1940s, T. pallidum infection was far more common.
The discovery of penicillin resulted in a substantial decline in the
number of cases. Rates of syphilis infection have increased since
the start of the twenty-first century, often in combination with HIV
infection. The lack of large-scale population studies in the penicillin
era makes an accurate assessment of epidemiological trends difficult
(Ghanem 2010).
Presentation
Within 3–90 days after exposure to T. pallidum, patients with
primary syphilis present with painless manifestations at the point of
inoculation, including chancres, which are solitary and nonpruritic
ulcers, and local lymphadenopathy. The infection invades
systemically by hematogenous dissemination within a few days.
Serologic studies may be falsely negative in up to 10% of patients.
Secondary syphilis occurs months later with systemic
involvement, with headache, malaise, mild fever, lymphadenopathy,
maculopapular rash of the palms and soles, condylomata lata (pale
elevated papules at moist body orifices), patchy alopecia, oral
mucosal erosions, mild hepatosplenomegaly, and elevated liver
function tests, particularly alkaline phosphatase. There may be
occasional cardiovascular, bone, and renal complications.
Ophthalmologic involvement includes uveitis, iritis, retinitis, and optic
neuritis. Neurological manifestations during this phase of infection
include an acute lymphocytic meningitis (syphilitic meningitis), an
acute lymphocytic meningitis with cerebrovascular complications
(cerebrovascular syphilis), or just an asymptomatic CSF lymphocytic
pleocytosis. In secondary syphilis, treponemal studies will be
positive; nontreponemal studies such the rapid plasma reagin and
Venereal Disease Research Laboratory (VDRL) tests may be either
positive or negative. Negative treponemal studies will rule out the
diagnosis.
Latent syphilis may occur in asymptomatic patients with positive
laboratory studies. Tertiary neurosyphilis occurs months to years
after resolution of secondary syphilis. Manifestation includes
gummas, which are granulomatous lesions, as well as
cardiovascular syphilis, and otosyphilis (Chahine et al. 2011). Late
neurological manifestations of syphilis include tabes dorsalis,
parenchymous neurosyphilis (general paresis of the insane), and
gummatous syphilis. Gummas are typically found in skin lesions;
however, they may rarely occur within the CNS, particularly in
immunocompromised patients (Ghanem 2010).
Tabes dorsalis may occur and is the most common manifestation
of late neurosyphilis. Men are more commonly affected, and the
incubation period may range from 5 to 20 years. There is a triad of
symptoms, including lightning pain, dysuria, and ataxia, and a triad
of signs, including Argyll Robertson pupils, areflexia, and loss of
proprioceptive sense, that are characteristic (Simon 1985).
Diagnostic Biomarkers
Nontreponemal antibody tests for syphilis include rapid plasma
reagin (RPR) and VDRL. Nontreponemal tests correlate with disease
activity and can be used to monitor response to therapy. False
positive results can occur with intravenous drug use, pregnancy,
borreliosis infection, several types of pneumonia, malaria,
tuberculosis, and autoimmune disorders including lupus (Chahine et
al. 2011).
Treponemal antibody tests, including fluorescent treponemal
antibody absorption, T. pallidum particle agglutination assay,
microhemagglutination assay, and automated immunoassay
analysis, are highly specific. Treponemal antibodies remain in an
infected person’s blood for the remainder of his or her life.
Nontreponemal antibodies do not persist in treated patients after a
few years. With the combination of treponemal and nontreponemal
antibodies, it is possible to differentiate between active infection and
past infection. Bacteria may also be directly detected by dark-field
microscopy and molecular testing (Chahine et al. 2011).
Diagnostic Criteria
Surveillance definitions for neurosyphilis from the Centers for
Disease Control and Prevention (CDC) include presumptive and
confirmed neurosyphilis. Confirmed neurosyphilis is any syphilis
stage plus a reactive CSF-VDRL. Presumptive neurosyphilis occurs
during any stage of syphilis, with a nonreactive CSF-VDRL, CSF
pleocytosis or elevated protein, and clinical signs or symptoms
consistent with syphilis without an alternate diagnosis (Roos 2005).
Treatment
First-line treatment for syphilis without central nervous system
involvement is a single dose of intramuscular penicillin G benzathine.
Ceftriaxone and doxycycline have been used in patients allergic to
penicillin. In neurosyphilis, penicillin is given in large doses
intravenously for a minimum of 10 days (Ghanem 2010). For
treatment of meningovascular syphilis, long-term aspirin therapy is
recommended, as platelet activation may result from endothelial cell
proliferation (Landi et al. 1990).
Neurosyphilis With Neuropsychiatric Manifestations

Forms of Neurosyphilis
While neurologic involvement is often thought to be limited to a
tertiary, or late, complication of syphilitic infection, neurosyphilis can
occur at any stage in the disease process. After the initial inoculation
with syphilis, about 40% of patients will demonstrate evidence of
central nervous system infection; clearance of neurologic syphilis
occurs in 70% of those patients. The remaining 30% will have
asymptomatic neurosyphilis and are at risk for development of
symptomatic neurosyphilis (Marra 2015).
Both meningitis and meningovascular types of neurosyphilis occur
early after initial infection, developing within weeks to the first few
years after initial infection. Late forms of neurosyphilis include
syphilitic dementia and tabes dorsalis, which commonly occur years
to decades after the initial infection. Gummas may occur early with
involvement of the pia in syphilitic meningitis or may occur late in the
disease course in the brain parenchyma (Marra 2015).
Syphilitic Meningitis
Meningeal involvement may cause lymphocytic meningitis. This
typically occurs within the first 2 years of infection. Patients tend to
be afebrile and to present with headache, meningeal irritation, and
confusion. Hydrocephalus occurrence can lead to cranial nerve
palsies. Cranial nerves VII and VIII are often affected, which can
cause facial palsy, hearing loss, vertigo, and nystagmus (Chahine et
al. 2011; Simon 1985). Sensorineural hearing loss may be the only
manifestation of syphilis in immunocompromised patients (Chahine
et al. 2011). Imaging with CT or MRI reveals meningeal
enhancement (Russouw et al. 1997).
Meningovascular Neurosyphilis
Endarteritis from syphilitic invasion occurs within a few months to
12 years after initial infection. Vascular syphilis induces a clinical
prodrome weeks to months prior to the onset of an identified
vascular syndrome. This prodrome includes headache, vertigo,
insomnia, and psychiatric disturbances such as emotional lability and
personality change. The prodromal course of stroke-like syndromes
secondary to this form of neurosyphilis can be contrasted with
infarction from other etiologies, which typically manifest with acute
onset. Stroke-like manifestations occur, commonly with involvement
of the anterior circulation, particularly the middle cerebral artery
(Chahine et al. 2011; Simon 1985).
Angiographic findings are nonspecific and include concentric
narrowing of the large vessels, focal arterial narrowing, and dilatation
of smaller vessels. The supraclinoid portion of the internal carotid
artery is more likely to be involved. Plaques are typically longer and
smoother than those seen in atherosclerotic disease (Simon 1985).
Parenchymatous Neurosyphilis
Within 2–20 years, T. pallidum may invade the brain parenchyma.
Parenchymatous neurosyphilis has been described as “general
paresis of the insane” and “dementia paralytica.” Men are affected
four to seven times more commonly than women (Simon 1985).
Early symptoms include the onset of memory loss and cognitive
dysfunction, irritability, insomnia, and personality change. Over
years, depression, confusion, and disorientation ensue. Psychiatric
manifestations include depression, hallucinations, mania, psychosis,
and delusions of grandeur (Ghanem 2010; Simon 1985). Clinical
examination may reveal tremor of the face, tongue, and extremities,
as well as pupillary abnormalities, masked facies, and hyperreflexia.
Seizures may also occur. Dementia progresses to death in months to
years.
Imaging by CT or MRI shows frontal, parietal, and temporal
atrophy and T2-weighted hyperintensities (Russouw et al. 1997).
Pathologically, there is atrophy of the frontal and temporal lobes with
sparing of the motor, sensory, and occipital cortex with
ventriculomegaly. Spirochetes are found within the gray matter, as
well as within endothelial cells and microglial cells (Ghanem 2010).
Lyme Disease
Lyme disease begins following a bite from the Ixodes tick that
passes along the spirochete Borrelia burgdorferi. The term Lyme
disease was coined after a cluster of cases initially thought to be
juvenile rheumatoid arthritis occurred in the towns of Lyme and Old
Lyme, Connecticut (Borchers et al. 2015). Nearly all confirmed cases
have occurred in the Northern Hemisphere, including the United
States, Europe, and Russia. Within the United States, the majority of
cases are found in the Northeast, the mid-Atlantic region, and the
upper Midwest (Borchers et al. 2015).
Presentation
Lyme disease is typically divided into three stages. In the early
stage, at the site of the tick bite, a nonpruritic targetoid rash known
as erythema migrans develops and expands over days to weeks.
Skin lesions may have either localized pain or pruritis and be
associated with local lymphadenopathy. There may be constitutional
symptoms such as fever, malaise, and headache (Borchers et al.
2015; Halperin 2012). In the secondary or early disseminated stage,
B. burgdorferi disseminates over a few months. There may be
multiple erythema migrans lesions, neuroborreliosis, and carditis.
European patients may develop borrelial lymphocytoma, a skin
lesion (Borchers et al. 2015). The third or late disseminated stage is
associated with both acrodermatitis chronica atrophicans, a focal
area of atrophic skin usually involving an extremity, and neurologic
manifestations (Borchers et al. 2015).
Lyme Neuroborreliosis
The CNS is affected in 10%–15% of patients with Lyme disease
and may be either the chief or only manifestation of disease.
Neuroborreliosis can occur within days to months following infection,
with cases typically appearing in June, July, October, and November
(Borchers et al. 2015; Halperin 2012). In patients with neurologic
involvement, two-thirds develop lymphocytic meningitis.
Approximately half of patients develop cranial neuropathy,
particularly of the facial nerve. One third of patients may develop
painful radiculitis. Encephalomyelitis may occur, commonly with
involvement of the spinal cord at the level of a radiculopathy
(Halperin 2012). Bannworth syndrome may occur with a triad of
painful radiculitis, peripheral motor deficits, and concomitant
lymphocytic CSF inflammation (Hansen et al. 2013). Facial palsy
and meningitis are the most common manifestations of childhood
Lyme neuroborreliosis. Rarely, patients may present with symptoms
typical of pseudotumor cerebri (Borchers et al. 2015).
Chronic neuroborreliosis occurs with continuous active disease
process for more than 6 months’ duration with persistent and
pronounced CSF inflammation. These patients may present with
either chronic meningitis or progressive encephalomyelitis.
Manifestation includes headache, malaise, weight loss,
sensorineural hearing loss, progressive spastic-ataxic gait
disturbance, cognitive deficits, cranial nerve palsies, spastic bladder
paresis, extremity paresis, and lacunar strokes, particularly of the
posterior circulation (Borchers et al. 2015; Hansen et al. 2013). The
pathology of chronic neuroborreliosis appears to be secondary to
meningovascular involvement, leading to inflammation and
obliteration of the small penetrating arteries, causing ischemia
(Hansen et al. 2013). Distal axonal polyneuropathies with intermittent
paresthesias have also been described (Borchers et al. 2015).
Neuropsychiatric Manifestations
Patients with chronic neuroborreliosis have been found to have
slight cognitive dysfunction, memory impairment, sleep disturbances,
and mood changes (Borchers et al. 2015). There has been
controversy regarding whether neuropsychiatric dysfunction is
attributable to infection or to a state similar to that caused by toxic
metabolic encephalopathies. Chronic nonspecific symptoms may
occur such as fatigue, cognitive slowing and dysfunction, and
headache (Borchers et al. 2015; Halperin 2012; Hansen et al. 2013).
While the gold standard for diagnosis of borreliosis is isolation of
Borrelia by culture with subsequent PCR-based confirmation, culture
is expensive, requires special expertise, and takes 2–6 weeks for
results. Also, the sensitivity is 3%–17% for CSF samples; thus,
negative results do not exclude diagnosis. PCR from DNA may be
performed; however, this also has low sensitivity, with 15%–30%
sensitivity in the CSF. CSF may have increased protein or, more
rarely, lymphocytic pleocytosis (Borchers et al. 2015).
A two-tier approach is recommended for diagnosis. This involves
a sensitive enzyme immunoassay or, less commonly, an indirect
immunofluorescence assay, followed by immunoblotting of samples
that are positive or indeterminate (Borchers et al. 2015). While
serologic testing is helpful, difficulties with this approach exist. Some
patients, particularly those with only dermatologic manifestations, do
not develop antibodies. Immunoglobulin M (IgM) antibodies become
detectable 1–2 weeks after infection and IgG after 4–6 weeks. Within
the United States, the baseline positivity rate with two-tier testing has
been shown to be up to 8.4% of the general population. Antibodies
may be present for decades after infection, making it difficult to
distinguish acute versus past infections (Borchers et al. 2015;
Halperin 2012).
Diagnostic Criteria
While there are no standardized diagnostic criteria, the CDC has
established case definitions for Lyme disease for surveillance
purposes. The CDC’s case definition for neuroborreliosis includes
any of the following, alone or in combination: lymphocytic meningitis;
cranial neuritis, particularly facial palsy, which may be bilateral;
radiculoneuropathy; and encephalomyelitis. Encephalomyelitis must
be confirmed by B. burgdorferi–specific antibody production in the
CSF.
Treatment
Treatment with antibiotics accelerates the resolution of Lyme
disease and prevents disease expansion. Beta-lactam antibiotics,
particularly cephalosporins, as well as tetracyclines and, to a lesser
extent, macrolides have been shown to be effective. Controversy
exists regarding duration of treatment; often antibiotics are given for
several weeks (Borchers et al. 2015).
Prion Disease
Prion disease is caused by pathologically misfolded prion
proteins, which lead to neurodegeneration. This disease
encompasses sporadic Creutzfeldt-Jakob disease (sCJD), inherited
prion diseases, and acquired prion diseases including variant CJD
(vCJD), iatrogenic CJD, and kuru. Clinical heterogeneity occurs with
etiological disease type, prion strain, genotype at polymorphic codon
129 of the prion protein (PRNP) gene, and demographic factors
including age (Thompson et al. 2014). sCJD occurs when there is a
sporadic mutation for the first time in a patient. vCJD occurs when
there is consumption of bovine-spongiform-encephalopathy-
contaminated meat. Iatrogenic CJD occurs with transmission of
misfolded prion protein through blood transfusions, organ
transplants, or surgical instrumentation. Kuru was transmitted by
funerary cannibalism among members of the Fore tribe in Papua
New Guinea. Management of prion disease is with supportive care.
Presentation
CJD can manifest in different ways. Classic sCJD begins with the
onset of cognitive symptoms, including cognitive decline, amnesia,
language impairment, executive dysfunction, and disorientation.
There are several variants of sCJD. The Heidenhain variant
manifests with visual disturbances such as diplopia, blurred vision,
cortical blindness, and/or visual hallucinations. The Oppenheimer-
Brownell variant manifests with ataxia. The cognitive variant
manifests with the onset of dementia, memory impairment, language
impairment, executive dysfunction, and/or disorientation at illness
onset. The affective variant manifests with neuropsychiatric
symptoms such as depression, mood lability, and/or anxiety
(Appleby et al. 2009).
Behavioral dysfunction has been noted in all types of prion
disease. The most common psychotic feature is visual
hallucinations, which occur both with other visual symptoms such as
visual distortion and agnosia and as an isolated phenomenon.
Multimodal (visual, auditory, tactile, olfactory) hallucinations have
been described. A smaller number of patients were found to have
delusions. Behavioral disturbances tend to manifest with signs of
frontal lobe dysfunction, such as disinhibition and impulsivity, and
progress to include irritability and hostility. Depressive symptoms are
commonly noted. Rarely, obsessive thoughts, compulsive or
repetitive behaviors, and déjà vu have been noted. Psychiatric
symptoms may be more likely in younger sCJD patients as well as in
vCJD patients (Thompson et al. 2014).
In sCJD, CSF can have elevated 14-3-3 protein and tau levels.
Real-time quaking-induced conversion, a relatively new CSF test,
detects minute amounts of prion by amplifying prion protein using
recombinant prion protein as the substrate. An
electroencephalogram (EEG) can show periodic sharp wave
complexes. MRI can show diffusion restriction and T2 hyperintensity
of the cortex and basal ganglia. Lymphoid tissue may contain prion
protein; as such, tonsil biopsies have become an alternative to brain
biopsy (Maheshwari et al. 2015).
In vCJD, CSF analysis and EEG are not traditionally revealing.
However, there is an experimental blood-based direct detection
assay that works through immunodetection and has a sensitivity of
71%. The “pulvinar sign,” hyperintensity of the bilateral pulvinar
nuclei of the thalamus on T2-weighted FLAIR MRI sequences, may
be visualized; however, it is nonspecific and absent in up to 9% of
cases. Another new method of detection involves urine samples,
which can be subjected to protein misfolding cyclic amplification
analysis. This method has nearly 93% sensitivity and 100%
specificity. Brain biopsy remains the standard for diagnosis of vCJD
in living patients (Maheshwari et al. 2015).
Diagnostic Criteria
Per the World Health Organization diagnostic criteria, vCJD is
possible when there is a progressive psychiatric disorder lasting
more than 6 months, with at least four of the following: early
psychiatric symptoms, persistent pain and/or dysesthesia, ataxia,
chorea/dystonia/myoclonus, dementia, and EEG without periodic
sharp wave complexes. vCJD is probable when in addition to
meeting the above criteria, there is a bilateral pulvinar high signal on
T2 FLAIR MRI brain scan or progressive psychiatric disorder lasting
more than 6 months without other explanation and positive tonsil
biopsy. vCJD is definite with neuropathologic confirmation.
sCJD is possible with a progressive dementia of less than 2 years’
duration and at least two of the following: myoclonus, visual or
cerebellar disturbance, pyramidal or extrapyramidal dysfunction, and
akinetic mutism with atypical EEG or lack of EEG. Probable sCJD
occurs when the above criteria are met plus typical EEG findings of
generalized periodic sharp wave complexes at 1 Hz and/or positive
14-3-3 assay in the CSF of patients with disease duration of less
than 2 years. Definite sCJD is confirmed neuropathologically (Zerr et
al. 2009).
Whipple’s Disease
Whipple’s disease is an infection caused by the gram-positive
bacterium Tropheryma whipplei. Although this bacterium is soilborne
and ubiquitously present in the environment, it rarely causes
infection (Schneider et al. 2008). T. whipplei has been found in
wastewaters in rural communities and has been identified in stool,
dental plaque, saliva, and duodenal tissue of asymptomatic
individuals. George Hoyt Whipple first described the infection in
1907. Without treatment, the disease is uniformly fatal. Middle-aged
men are the most commonly affected. CNS involvement may occur
as part of classic Whipple’s disease, as CNS relapse in previously
treated Whipple’s disease, or as an isolated CNS infection (Compain
et al. 2013). Approximately 50% of patients with Whipple’s disease
have CNS infection, as shown by PCR analysis of CSF. About 10%–
40% of patients with Whipple’s disease will have neurologic
symptoms (Schneider et al. 2008).
Presentation
Clinical presentation of systemic infection with Whipple’s disease
often involves gastrointestinal symptoms, weight loss, joint problems,
fever, and lymphadenitis (Compain et al. 2013). Isolated CNS
involvement is rare and can mimic the symptoms of many other
conditions, which causes Whipple’s disease to be easily
misdiagnosed (Balasa et al. 2014). There are two primary neurologic
syndromes: multifarious neurological symptoms and signs combined
with multiple enhancing lesions on CT or MRI and focal neurological
symptoms secondary to a solitary mass lesion (Panegyres et al.
2006). Neurologic involvement may manifest either acutely or
subacutely (Balasa et al. 2014).
Because T. whipplei may infect a variety of CNS structures, the
disease may manifest with a variety of symptoms, including
hypersomnia, facial weakness, dysarthria, ataxia, paralysis of the
extremities, upper motor neuron signs, extrapyramidal signs,
seizures or status epilepticus, generalized or focal myoclonus,
ophthalmoplegia with or without supranuclear gaze palsy, choreiform
movements, and palatal myoclonus. Oculomasticatory myorhythmia,
which is defined by pendular vergence oscillations of the eyes and
synchronous rhythmic contractions of the masticatory muscles, is
pathognomonic for Whipple’s disease (Balasa et al. 2014; Compain
et al. 2013).
Patients with Whipple’s disease may develop confusion, delirium,
impairment of consciousness, and coma. There may be fluctuating
cognitive impairment with signs of cortical dysfunction with intact
consciousness. Progressive cognitive impairment may develop over
days and is often both cortically and subcortically based (Balasa et
al. 2014; Compain et al. 2013).
The CSF of Whipple’s disease patients may lack a pleocytosis but
will still have elevated protein (Compain et al. 2013). Some patients
may also develop CSF oligodonal bands, indicating intrathecal
antibody synthesis (Panegyres et al. 2006). T. whipplei PCR has
been shown to be positive in 92% of Whipple’s disease patients with
tested CSF (Compain et al. 2013).
MRI may be normal despite neurologic symptoms or may
demonstrate tumor-life solitary mass lesions, multifocal lesions, or
even leptomeningeal enhancement with predominant involvement of
the basilar telencephalon, thalamus, hypothalamus, quadrigeminal
plate, and periaqueductal gray matter (Compain et al. 2013). On
MRI, T2 hyperintensities may be present in the brain parenchyma
and spinal cord with transient contrast enhancement. Diffuse
periventricular white matter involvement, diffuse cortical atrophy, and
pachymeningitis have all been described. Less frequently, there may
be scattered T2 hyperintense lesions involving the gray-white
junction with or without vasogenic edema. Rarely, lesions may
become confluent and be associated with hemorrhage. Diffusion
restriction is not typically a characteristic of the disease (Compain et
al. 2013). Treated infection reveals residual cystic lesions on imaging
(Balasa et al. 2014).
Diagnostic Criteria
Diagnosis of neurologic infection by T. whipplei requires a positive
PCR, periodic-acid-Schiff positivity, or immunoreactivity for T.
whipplei antigens of the CSF macrophages or brain biopsy samples.
False positive results can occur with PCR due to the presence of T.
whipplei or another related bacterium in healthy carriers.
Methodological failures such as environmental contamination and
difficulties performing PCR on paraffin sections may occur.
Therefore, diagnosis of Whipple’s disease should not be made with
an isolated positive PCR result (Schneider et al. 2008).
Treatment
Treatment for Whipple’s disease includes antimicrobial therapy for
several years. Oral monotherapy including trimethoprim-
sulfamethoxazole, doxycycline, third-generation cephalosporins, or a
combination of antibiotics sometimes followed by parenteral
treatment with beta-lactams and aminoglycosides has been used
(Compain et al. 2013). An immune reconstitution syndrome may
occur in the early months of treatment. Patients may have long-
lasting fever that responds to corticosteroid treatment (Compain et
al. 2013; Schneider et al. 2008).
Other Neurologic Infections

Bacterial meningitis may cause persistent cognitive impairment of,
for example, executive function, short-term and working memory,
language, verbal learning, and visuoconstructive ability and
psychiatric disturbances such as depression. Viral meningitis may
produce long-lasting impairment, particularly of short-term and
working memory. Dysfunction secondary to viral infection is
described as less severe than that which occurs with bacterial
meningitis (Schmidt et al. 2006).
Subacute sclerosing panencephalitis is caused by measles virus
infection. It may initially cause forgetfulness, behavioral change,
diminished speech, ataxia, and subtle cognitive impairment. Over
time, myoclonus, seizures, paresis, dystonia, vision change, acute
encephalopathy, and psychiatric disturbances can occur. In later
stages, spastic paresis, myoclonus, autonomic disturbances,
vegetative state, and death can occur (Anlar 2013).
Rocky Mountain spotted fever is produced by Rickettsia rickettsii,
an obligately intracellular bacterium that is spread to humans via
ticks. Initial signs are typical of rickettsial tick-borne disease and
include fever, rash, and headache. Systemic infection can occur, with
neuropsychiatric manifestations of lethargy, amnesia, and bizarre
behavior (Dantas-Torres 2007).
Cerebral malaria occurs with neurologic infection by the protozoan
Plasmodium falciparum, which is spread through mosquito bites. The
hallmark of this syndrome is coma. Seizure, intracranial
hypertension, brain stem signs, cortical infarctions, and cerebral
venous or dural sinus thrombosis may occur. Survivors tend to have
chronic neurologic deficits including impairments in cognition, motor
function, and behavior (Idro et al. 2010).
Herpes Simplex Virus

Herpes simplex virus (HSV)-1 is the most common cause of acute
sporadic encephalitis and is transmitted from an infected person to
those who are susceptible from close personal contact. Up to 90% of
encephalitis cases in immunocompetent individuals are associated
with HSV-1. HSV-2 encephalitis is more often found with
immunocompromised people and newborns (Więdłocha et al. 2015).
HSV-1 typically invades limbic structures such as the inferior and
medial temporal lobes and orbital frontal cortex.
Neurocognitive Disorders
Cognitive deficits of HSV encephalitis are specific for verbal
memory, verbal semantic functions, and visuoperceptual functions
(Hokkanen et al. 1996). Cognitive dysfunction tends to be moderate
to severe in the first few weeks to months. Improvement can be seen
within the first year, especially in individuals with unilateral findings
and in those who received acyclovir early in their clinical course to
prevent spread. Prior to aggressive treatment with acyclovir,
manifestations of Klüver-Bucy syndrome sometimes occurred with
bilateral temporal lobe involvement. This presentation included an
inability to differentiate between visual and auditory stimuli (psychic
blindness), increased oral behavior, loss of normal anger and fear,
and heightened sexuality. When bilateral involvement is seen, upper-
quadrant visual field cuts, aphasia, and loss of ability to store or
recall information can be seen. Additional neuropsychiatric
symptoms include headaches, confusion, psychosis, somnolence,
seizures with olfactory, gustatory, or déjà vu hallucinations, as well
as disruptions in corticospinal tracts. In rare cases, the occipital
lobes or brain stem can be affected, in which case temporal lobe
involvement is not typically seen.
Pathogenesis. Initially, HSV enters the endings of sensory nerves
that innervate a particular site of infection and regresses into a
noninfectious latent state in the peripheral nervous system. HSV
intermittently reactivates and, during reactivation, may be spread to
other people through contact with the site of infection (Saylor et al.
2015). After primary infection, CNS transmission from the peripheral
nervous system occurs through retrograde axoplasmic flow of the
virus in the trigeminal nerve. This ganglion then becomes the
established site of latent infection, subsequently leading to
transmission to sensory fibers and, most commonly, the meninges
overlying the temporal lobes. Encephalitis develops after reactivation
and replication of the virus in the temporal cortex and limbic
structures (Roos 2005). Alternate transmission is also seen via
intranasal inoculation of virus with subsequent involvement of
orbitofrontal and temporal cortex.
Diagnostic criteria. HSV encephalitis is defined by CSF
lymphocytic pleocytosis; normal CSF glucose concentration; positive
CSF PCR for HSV DNA; serum:CSF HSV antibody ratio of less than
20:1; and periodic stereotyped sharp and slow wave complexes on
EEG at intervals of 2–3 seconds, maximally seen over temporal
lobes.
Demographics. HSV is the most common cause of necrotizing
encephalitis, with an incidence of 10%–15% per year. The virus
affects men and women equally, with mortality ranging from 50% to
70% (Magaz Mde et al. 2015). It is also a common pathogen that
infects immunocompromised individuals.
CSF and plasma biomarkers. CSF findings for those with HSV
encephalitis may include elevated opening pressure, lymphocytic
pleocytosis, typically >50 cells/mm3 normal glucose, and normal to
mildly elevated protein. HSV DNA can be detected in CSF through
PCR, although the PCR may be negative in the first few days of
infection. Thus, patients with a negative CSF HSV PCR with a typical
clinical picture should undergo repeat lumbar puncture for HSV PCR
analysis several days (typically at least 3 days) after the initial
lumbar puncture. Viral culture is rarely positive in associated
meningitis (Roos 2005). HSV antibodies are not positive for up to 12
days after onset of symptoms.
Neuroimaging biomarkers. Characteristic findings on brain MRI of
patients with HSV encephalitis include high signal intensity on T2-
weighted and FLAIR sequences in the medial and inferior temporal
lobes that can extend into the insula. If these characteristic changes
are not present, the patient is very unlikely to have HSV encephalitis.
Additional findings include vascular congestion on vessel imaging,
petechial hemorrhages, cortical destruction, and involvement of
cingulate gyrus.
Treatment. Empiric intravenous acyclovir should be initiated
immediately upon suspecting HSV encephalitis as a potential
causative agent of a patient’s symptoms. Early treatment is
associated with a better outcome, whereas treatment more than 2
days after infection onset is associated with a poor neurological
outcome (Hokkanen et al. 1996).
Psychiatric Disorders
In addition to cognitive deficits, HSV-infected individuals can also
exhibit mood or personality changes including euphoria, manic
behavior, aggressiveness, irritability, and depression. Hallucinations
tend to be more auditory in nature. Progression of disease can result
in catatonic stupor with mutism (Więdłocha et al. 2015).
Varicella Zoster Virus

Varicella zoster virus (VZV) in its primary form causes chickenpox
and in its secondary, reactivated form causes varicella (or herpes)
zoster. As encephalitis, VZV has a number of manifestations.
Neurocognitive disorders of VZV manifest in three distinct
patterns involving hemorrhagic infarctions secondary to large-vessel
vasculopathy, necrotic or demyelinating lesions from small-vessel
vasculopathy, or ventriculitis from periventricular necrosis. The
behavioral deficits include disorientation, confusion, and somnolence
in the acute stages, deteriorating into difficulty with both verbal and
visual reasoning, perseveration, reversals, speech problems,
attention, planning, and impulse control in later stages. Although
persistence of deficits is common, long-term impairments in memory,
processing speed, language, and executive function (sometimes
constituting a dementia) may occur, even after treatment.
Pathogenesis
Primary infection leads to latent VZV infection. The virus resides
in trigeminal and thoracic ganglia. Spread occurs via afferent fibers
by means of transaxonal transport. Reactivation as well as
replication occurs during immunocompromised states. Alternative
transport methods have also suggested hematogenous spread
through T cells and subsequent infection of nerves supplying blood
vessels. CNS spread is not as well understood but is hypothesized
to include retrograde trafficking from vesicles of the face to trigeminal
ganglion to cerebral arteries.
Diagnostic Criteria
VZV encephalitis is defined by characteristic CSF findings. These
include mononuclear pleocytosis, elevated protein concentration,
decreased glucose concentration, IgM antibodies, or a positive PCR
for VZV DNA.
Demographics
VZV-infected individuals are contagious 4 days prior to and up to
5 days after the typical zoster rash. VZV encephalitis occurs in up to
5% of patients with shingles and primarily in the immunosuppressed
population. Additionally, individuals older than age 50 are more
susceptible to VZV infection (Roos 2005).
CSF and Plasma Biomarkers

Detection of VZV in the CNS is seen in CSF through PCR as well
as in situ hybridization techniques. Antibodies are also often present
and may be a more sensitive indicator of VZV infection than PCR;
however, viral culture is rarely positive (Roos 2005).
Neuroimaging
Although many times absent, CT and MRI abnormalities can
assist in the correct diagnosis of VZV encephalitis. Both gray and
white matter are affected, and both deep and cortical structures can
be involved. Although most VZV encephalitis cases are associated
with vascular abnormalities on either CT angiography or magnetic
resonance angiography, digital subtraction angiography remains the
gold standard for viewing vasculopathic changes. Typical changes
include segmental constriction and occlusion with post-stenotic
dilatation. Small vessels can also be affected, many times involving
the subcortical regions.
Treatment
VZV remains susceptible to treatment with acyclovir, and in
severe cases, intravenous administration at high doses is required.
Valacyclovir, the prodrug of acyclovir, has also been used as an
alternative (Roos 2005).
St. Louis Encephalitis

St. Louis encephalitis (SLE) is an arthropod-borne flavivirus
infection transmitted via a mosquito vector. SLE clinical sequelae
include memory loss, fatigue, sleeplessness, headaches, seizures,
and motor deficits. Additionally, there is an association with
inappropriate antidiuretic hormone secretion.
The neurocognitive disorders of SLE typically manifest with fever
and headache but in more severe cases can progress to
disorientation, seizures, or paralysis. Encephalitic features consist of
slowed cognitive processing with difficulty managing even minor
tasks. Late-onset symptoms can at times involve movement
disorders including tremor, myoclonus, and parkinsonism (McCarthy
2001). Because the basal ganglia are so commonly involved in SLE,
up to 60% of patients may have tremor on examination. Additionally,
features of nystagmus, cerebellar ataxia, and pathologic reflexes
have been reported. Chronic and relapsing occurrences have not
been reported. However, recovering patients have also been noted
to manifest unstable emotions, difficulty with concentration, and
tremors (Roos 2005).
Diagnostic Criteria
SLE is defined by typical viral-related CSF changes and serum
IgM antibody for the SLE virus. In SLE, opening pressure is normal
to mildly elevated, CSF glucose levels are normal, and CSF protein
levels are normal to mildly elevated. Polymorphonuclear leukocytic
pleocytosis occurs initially and is followed by lymphocytic or
monocytic leukocytosis. In most cases, the CSF white blood cell
count is >200 cells/µL.
Demographics
SLE virus is predominantly found in the southeastern United
States, western Canada, and Mexico during summer and early
autumn. Symptomatic infections typically occur in individuals older
than age 50. The incubation period can last from 4 to 21 days (Roos
2005).
Neuroimaging
MRI brain scans of patients with SLE typically show symmetrical
involvement of basal ganglia, thalamus, or pons. T2-weighted and
FLAIR sequences show small areas of hyperintensity. Several case
reports have shown that SLE has a particular predilection for the
substantia nigra, causing neuronal degeneration, microglial
proliferation, and perivascular mononuclear infiltrate in that region
(McCarthy 2001).
Treatment
Treatment is supportive since there is no effective antiviral therapy
for SLE.
West Nile Virus

West Nile virus (WNV) encephalitis is an arthropod-borne
flavivirus inoculated via a mosquito bite (Roos 2005). WNV CNS
disease manifests with signs of meningeal inflammation, at times
developing into encephalopathy with either depressed or altered
levels of consciousness, lethargy, or personality change within 24
hours of infection. The most common symptoms include fatigue,
myalgia, and headaches, usually in frontal or retro-orbital regions.
Headache especially can be one of the persistent features of the
disease. Seizure activity is rare. WNV can also infect anterior horn
cells, leading to acute flaccid paralysis, which is not as commonly
seen in SLE. Behavioral changes manifest as irritability, confusion,
and disorientation. There have also been case reports of patients
with imbalance, gait abnormalities, and dyskinesia, symptoms also
reported in SLE. Movement disorders are frequently seen and
include tremors, myoclonus, and parkinsonism without resting
tremor. Cranial nerve and bulbar findings are also described. When
patients with severe WNV encephalitis were followed up to 8 months
after discharge from the hospital, many were found to continue to
experience persistent fatigue, myalgia, headaches, and cognitive
deficits. The most common chronic cognitive deficits include trouble
with short-term memory and slowed processing speed (McCarthy
2001).
Pathogenesis
WNV CNS infection initially involves cerebral capillary endothelial
cells with subsequent infection of neurons, choroid plexus, and
subependymal periventricular brain tissue (Roos 2005). Intracellular
spread typically involves dendritic or axonal processes.
Demographics
WNV infection is typically subclinical, but approximately one in
150 infected individuals goes on to develop neuroinvasive disease:
meningitis, encephalitis, or acute flaccid paralysis. The incubation
period ranges from 2 to 15 days. Older individuals with chronic
illnesses and immunosuppressed patients appear to be most
susceptible to developing neuroinvasive disease.
CSF and Plasma Biomarkers

Specific WNV biomarkers include the CSF PCR test; however,
this has unclear sensitivity and specificity. The best diagnostic test is
WNV IgM in CSF, keeping in mind that this may not be positive for
the first week after symptom onset (Roos 2005).
Neuroimaging
Although brain MRI in WNV encephalitis may appear normal, a
number of abnormalities may be detected, including bilateral focal
lesions in basal ganglia on both T2- and diffusion-weighted imaging,
as well as lesions on the thalamus and pons.
Treatment
WNV encephalitis has a guarded prognosis, with studies revealing
that at 6 months no residual symptoms remain. On average, normal
functioning typically occurs around 4 months (Saylor et al. 2015).
Additionally, severity of initial encephalopathy does not indicate poor
long-term outcome in all patients. Treatment involves supportive
care, as no definitive antiviral treatment is available.
Conclusion
Many pathogens infect the central nervous system, with some
causing acute, profoundly destructive infections and others resulting
in chronic infections that take their toll insidiously. The
neurocognitive and neurobehavioral manifestations of these
infections depend highly on the brain structures invaded and the
underlying pathological effects of that invasion. For example, acute
HSV-1 brain infection may lead to wholesale destruction of limbic
structures, leaving the patient with predictable sequelae based on
the structures destroyed. Unchecked brain HIV infection, on the
other hand, has a slowly progressive course leading to dementia
only after a number of years of infection. Central nervous system
infections are indeed a heterogeneous group of disorders with a
multitude of manifestations, although specific pathogens may exhibit
a tropism for specific brain regions resulting in predictable symptom
complexes.
References
Abers MS, Shandera WX, Kass JS: Neurological and psychiatric adverse effects of
antiretroviral drugs. CNS Drugs 28(2):131–145, 2014 24362768
American Academy of Neurology: Nomenclature and research case definitions for
neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1)
infection. Report of a Working Group of the American Academy of Neurology
AIDS Task Force. Neurology 41(6):778–785, 1991 2046917
Ances BM, Sisti D, Vaida F, et al; HNRC group: Resting cerebral blood flow: a
potential biomarker of the effects of HIV in the brain. Neurology 73(9):702–708,
2009 19720977
Anlar B: Subacute sclerosing panencephalitis and chronic viral encephalitis.
Handb Clin Neurol 112:1183–1189, 2013 23622327
Anthony IC, Ramage SN, Carnie FW, et al: Influence of HAART on HIV-related
CNS disease and neuroinflammation. J Neuropathol Exp Neurol 64(6):529–
536, 2005 15977645
Antinori A, Arendt G, Becker JT, et al: Updated research nosology for HIV-
associated neurocognitive disorders. Neurology 69(18):1789–1799, 2007
17914061
Apostolova N, Funes HA, Blas-Garcia A, et al: Efavirenz and the CNS: what we
already know and questions that need to be answered. J Antimicrob
Chemother 70(10):2693–2708, 2015 26203180
Appleby BS, Appleby KK, Crain BJ, et al: Characteristics of established and
proposed sporadic Creutzfeldt-Jakob disease variants. Arch Neurol 66(2):208–
215, 2009 19204157
Balasa M, Gelpi E, Rey MJ, et al: Clinical and neuropathological variability in
clinically isolated central nervous system Whipple’s disease. Brain Pathol
24(3):230–238, 2014 24320005
Becker JT, Kingsley L, Mullen J, et al; Multicenter AIDS Cohort Study: Vascular
risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men.
Neurology 73(16):1292–1299, 2009 19841381
Bissel SJ, Wiley CA: Human immunodeficiency virus infection of the brain: pitfalls
in evaluating infected/affected cell populations. Brain Pathol 14(1):97–108,
2004 14997942
Borchers AT, Keen CL, Huntley AC, et al: Lyme disease: a rigorous review of
diagnostic criteria and treatment. J Autoimmun 57:82–115, 2015 25451629
Brew BJ, Chan P: Update on HIV dementia and HIV-associated neurocognitive
disorders. Curr Neurol Neurosci Rep 14(8):468, 2014 24938216
Caniglia EC, Cain LE, Justice A, et al; HIV-CAUSAL Collaboration: Antiretroviral
penetration into the CNS and incidence of AIDS-defining neurologic conditions.
Neurology 83(2):134–141, 2014 24907236
Chahine LM, Khoriaty RN, Tomford WJ, et al: The changing face of neurosyphilis.
Int J Stroke 6(2):136–143, 2011 21371276
Ciccarelli N, Fabbiani M, Di Giambenedetto S, et al: Efavirenz associated with
cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology
76(16):1403–1409, 2011 21502598
Clifford DB, Ances BM: HIV-associated neurocognitive disorder. Lancet Infect Dis
13(11):976–986, 2013 24156898
Clucas C, Sibley E, Harding R, et al: A systematic review of interventions for
anxiety in people with HIV. Psychol Health Med 16(5):528–547, 2011 21777090
Compain C, Sacre K, Puéchal X, et al: Central nervous system involvement in
Whipple disease: clinical study of 18 patients and long-term follow-up. Medicine
(Baltimore) 92(6):324–330, 2013 24145700
Cruess DG, Evans DL, Repetto MJ, et al: Prevalence, diagnosis, and
pharmacological treatment of mood disorders in HIV disease. Biol Psychiatry
54(3):307–316, 2003 12893106
Cysique LA, Vaida F, Letendre S, et al: Dynamics of cognitive change in impaired
HIV-positive patients initiating antiretroviral therapy. Neurology 73(5):342–348,
2009 19474412
Dannemann BR, Israelski DM, Leoung GS, et al: Toxoplasma serology,
parasitemia and antigenemia in patients at risk for toxoplasmic encephalitis.
AIDS 5(11):1363–1365, 1991 1768386
Dantas-Torres F: Rocky Mountain spotted fever. Lancet Infect Dis 7(11):724–732,
2007 17961858
Davison JM, Subramaniam RM, Surasi DS, et al: FDG PET/CT in patients with
HIV. AJR Am J Roentgenol 197(2):284–294, 2011 21785073
Desplats P, Dumaop W, Smith D, et al: Molecular and pathologic insights from
latent HIV-1 infection in the human brain. Neurology 80(15):1415–1423, 2013
23486877
Gallego L, Barreiro P, López-Ibor JJ: Diagnosis and clinical features of major
neuropsychiatric disorders in HIV infection. AIDS Rev 13(3):171–179, 2011
21799535
Ghanem KG: Evaluation and Management of Syphilis in the HIV-Infected Patient.
Curr Infect Dis Rep 12(2):140–146, 2010 21308510
Grant I, Franklin DR Jr, Deutsch R, et al; CHARTER Group: Asymptomatic HIV-
associated neurocognitive impairment increases risk for symptomatic decline.
Neurology 82(23):2055–2062, 2014 24814848
Halperin JJ: Lyme disease: a multisystem infection that affects the nervous
system. Continuum (Minneap Minn) 18(6 Infectious Disease):1338–1350, 2012
23221844
Hansen K, Crone C, Kristoferitsch W: Lyme neuroborreliosis, in Peripheral Nerve
Disorders, Vol 115, 3rd Series. Edited by Said G, Krarup C (Handbook of
Clinical Neurology; Aminoff MJ, Boller F, Swaab DF, series eds). Amsterdam,
The Netherlands, Elsevier, 2013, pp 559–575
Heaton RK, Clifford DB, Franklin DR Jr, et al; CHARTER Group: HIV-associated
neurocognitive disorders persist in the era of potent antiretroviral therapy:
CHARTER Study. Neurology 75(23):2087–2096, 2010 21135382
Heaton RK, Franklin DR, Ellis RJ, et al; CHARTER Group; HNRC Group: HIV-
associated neurocognitive disorders before and during the era of combination
antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol
17(1):3–16, 2011 21174240
Hokkanen L, Poutiainen E, Valanne L, et al: Cognitive impairment after acute
encephalitis: comparison of herpes simplex and other aetiologies. J Neurol
Idro R, Marsh K, John CC, et al: Cerebral malaria: mechanisms of brain injury and
strategies for improved neurocognitive outcome. Pediatr Res 68(4):267–274,
2010 20606600
Kumar AM, Borodowsky I, Fernandez B, et al: Human immunodeficiency virus type
1 RNA Levels in different regions of human brain: quantification using real-time
reverse transcriptase-polymerase chain reaction. J Neurovirol 13(3):210–224,
2007 17613711
Landi G, Villani F, Anzalone N: Variable angiographic findings in patients with
stroke and neurosyphilis. Stroke 21(2):333–338, 1990 2305411
Letendre S, Marquie-Beck J, Capparelli E, et al; CHARTER Group: Validation of
the CNS Penetration-Effectiveness rank for quantifying antiretroviral
penetration into the central nervous system. Arch Neurol 65(1):65–70, 2008
18195140
Magaz Mde L, Wainsztein V, Maritano J, et al: Clinical characteristics of adult
patients with herpetic meningoencephalitis: a nested case control study [in
Spanish]. Rev Chilena Infectol 32(3):266–271, 2015 26230431
Maheshwari A, Fischer M, Gambetti P, et al: Recent US Case of Variant
Creutzfeldt-Jakob Disease-Global Implications. Emerg Infect Dis 21(5):750–
759, 2015 25897712
Marra CM: Neurosyphilis. Continuum (Minneap Minn) 21(6 Neuroinfectious
Disease):1714–1728, 2015 26633785
McArthur JC, Steiner J, Sacktor N, et al: Human immunodeficiency virus-
associated neurocognitive disorders: Mind the gap. Ann Neurol 67(6):699–714,
2010 20517932
McCarthy M: St. Louis Encephalitis and West Nile Virus Encephalitis. Curr Treat
Options Neurol 3(5):433–438, 2001 11487457
Mijch AM, Judd FK, Lyketsos CG, et al: Secondary mania in patients with HIV
infection: are antiretrovirals protective? J Neuropsychiatry Clin Neurosci
11(4):475–480, 1999 10570761
Panegyres PK, Edis R, Beaman M, et al: Primary Whipple’s disease of the brain:
characterization of the clinical syndrome and molecular diagnosis. QJM
99(9):609–623, 2006 16905752
Pavlovic D, Patera AC, Nyberg F, et al: Progressive multifocal
leukoencephalopathy: current treatment options and future perspectives. Ther
Adv Neurol Disord 8(6):255–273, 2015 26600871
Rabkin JG, Goetz RR, Remien RH, et al: Stability of mood despite HIV illness
progression in a group of homosexual men. Am J Psychiatry 154(2):231–238,
1997 9016273
Ragin AB, Du H, Ochs R, et al: Structural brain alterations can be detected early in
HIV infection. Neurology 79(24):2328–2334, 2012 23197750
Roos KL: Principles of Neurologic Infectious Diseases. New York, McGraw-Hill,
Medical Publishing Division, 2005
Russouw HG, Roberts MC, Emsley RA, et al: Psychiatric manifestations and
magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychiatry
41(4):467–473, 1997 9034541
Sattler FR, He J, Letendre S, et al; CHARTER Group: Abdominal obesity
contributes to neurocognitive impairment in HIV-infected patients with
increased inflammation and immune activation. J Acquir Immune Defic Syndr
68(3):281–288, 2015 25469522
Saylor D, Thakur K, Venkatesan A: Acute encephalitis in the immunocompromised
individual. Curr Opin Infect Dis 28(4):330–336, 2015 26098507
Schmidt H, Heimann B, Djukic M, et al: Neuropsychological sequelae of bacterial
and viral meningitis. Brain 129(Pt 2):333–345, 2006 16364957
Schneider T, Moos V, Loddenkemper C, et al: Whipple’s disease: new aspects of
pathogenesis and treatment. Lancet Infect Dis 8(3):179–190, 2008 18291339
Sherr L, Clucas C, Harding R, et al: HIV and depression—a systematic review of
interventions. Psychol Health Med 16(5):493–527, 2011 21809936
Simon RP: Neurosyphilis. Arch Neurol 42(6):606–613, 1985 3890813
Smurzynski M, Wu K, Letendre S, et al: Effects of central nervous system
antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS
25(3):357–365, 2011 21124201
Steinbrink F, Evers S, Buerke B, et al; German Competence Network HIV/AIDS:
Cognitive impairment in HIV infection is associated with MRI and CSF pattern
of neurodegeneration. Eur J Neurol 20(3):420–428, 2013 23095123
Thompson A, MacKay A, Rudge P, et al: Behavioral and psychiatric symptoms in
prion disease. Am J Psychiatry 171(3):265–274, 2014 24585329
Treisman G, Angelino A: Interrelation between psychiatric disorders and the
prevention and treatment of HIV infection. Clin Infect Dis 45 (suppl 4):S313–
S317, 2007 18190305
Valcour V, Watters MR, Williams AE, et al: Aging exacerbates extrapyramidal
motor signs in the era of highly active antiretroviral therapy. J Neurovirol
14(5):362–367, 2008 18989814
Wang GJ, Chang L, Volkow ND, et al: Decreased brain dopaminergic transporters
in HIV-associated dementia patients. Brain 127(Pt 11):2452–2458, 2004
15319273
Więdłocha M, Mcinowicz P, Stańczykiewicz B: Psychiatric aspects of herpes
simplex encephalitis, tick-borne encephalitis and herpes zoster encephalitis
among immunocompetent patients. Adv Clin Exp Med 24(2):361–371, 2015
25931371
Zerr I, Kallenberg K, Summers DM, et al: Updated clinical diagnostic criteria for
sporadic Creutzfeldt-Jakob disease. Brain 132(Pt 10):2659–2668, 2009
19773352
CHAPTER 15
Brain Tumors
Within weeks, an adult can pass from living a full and normal life
to being disabled and facing a terminal illness. The very first sign of
this change can be an epileptic seizure striking without warning.
Many tumors outside of the central nervous system (CNS) manifest
with insidious symptoms that patients may have privately
acknowledged as potentially serious. Tumors of the brain, by
contrast, often manifest with symptoms that first appear shortly
before diagnosis and arise in previously healthy individuals. Active
treatment involves—variously—physically traumatic neurosurgery,
neurotoxic chemotherapy and radiotherapy, high doses of
psychoactive drugs, or, not uncommonly, all four of these things
together. Small wonder that neuropsychiatric complications
consistently rank among the most frequently reported symptoms in
neuro-oncology.
In this chapter, I provide readers with a concise review and a
practical perspective on the evaluation and treatment of the
neuropsychiatric complications and comorbidities of brain tumors.
This is intended as a “big picture” overview with brief discussions of
selected clinical issues and a focus on primary (as opposed to
metastatic) tumors, and preference is given where appropriate to
more recent literature. Many important topics have inevitably been
left unexplored, and the interested reader is directed to the reference
list for further information.
Brain Tumors in Adults
Epidemiology
Among adult primary brain tumors, the single biggest histological
grouping is meningioma, accounting for 36.1%, with an incidence
rate of 7.9 per 100,000 persons. The vast majority of meningiomas
are benign. By contrast, glioma (incurable brain cancer) is the next
largest category, accounting for 28% of all primary and >80% of all
malignant primary brain tumors. Most gliomas are located in the
frontal and temporal lobes (Ostrom et al. 2016) (Figure 15–1).
FIGURE 15–1. Locations of benign and malignant brain tumors in adults.
In adults, benign brain tumors dominate the meninges and pituitary region, but
most malignant tumors are located in the frontal and temporal lobes. Figures are
percentages and do not add up to 100 because of rounding. “Other” includes
tumors in the spinal cord, ventricles, pineal gland, olfactory mucosa, cerebrum,
and other unspecified or unclassified locations. Pituitary region=pituitary gland and
craniopharyngeal duct.
Source. Adapted from Ostrom et al. 2016.
Gliomas are categorized by the predominant cellular type

observed through histology (principally, astrocytic, oligodendroglial,
or a mixture of both) and by the apparent level of malignancy (low- or
high-grade, as assessed histologically). Incidence varies according
to tumor type and the age of the patient. The overall figure is in the
order of five per 100,000 people, but the peak age of incidence rises
with the level of malignancy: the most malignant tumors are more
common in older patients. Glioblastoma multiforme is the most
frequent subtype and accounts for around 45% of gliomas. It is also
the most deadly, with median survival times from diagnosis barely
exceeding 1 year despite the best treatment. The natural history of
low-grade tumors is to progress slowly and transform after a period
of years into a higher (more proliferative) grade. Thus, the survival of
patients with a low-grade glioma is measured in years—sometimes
many years—rather than months.
The only known causes of primary brain tumors are ionizing
radiation and various inherited cancer syndromes (e.g.,
neurofibromatosis types 1 and 2, Von-Hippel-Lindau syndrome, and
Li-Fraumeni syndrome). Many environmental causative agents have
been hypothesized (e.g., mobile phones, cured meats, head trauma,
occupational exposure), but none have been proven to cause brain
tumor to date. Unlike most cancers, smoking is not thought to be a
risk factor for the development of a brain tumor. Meningioma occurs
more frequently in women, and glioma occurs slightly more
frequently in men (Ostrom et al. 2014).
Symptoms
The presenting symptoms of brain tumor are often subacute.
These symptoms may include focal neurological deficit (e.g.,
unilateral weakness or sensory loss, dysphasia, or gait disturbance),
headache, nausea, or visual field deficit. Alternatively, epileptic
seizures, which often complicate low-grade glioma in particular, can
trigger acute presentation. Although one may instinctively think of
these classically “physical” symptoms as archetypal for a patient
presenting with a brain tumor, in fact, the most frequently reported
symptom at presentation may be neurocognitive change. Posti et al.
(2015) reviewed the medical records of 142 Finnish glioma patients
to determine the frequency of manifesting symptoms. Cognitive
disorder (defined broadly by Posti et al. (2015, p. 89) as
“deterioration of intellectual functions, confusion, memory loss,
personality change, and apathy”) was documented in the largest
proportion of cases (57.0%). Neurocognitive change was
significantly more frequent in older patients and in those with higher-
grade (and thus faster growing) tumors. By contrast, any form of
seizure was documented in 52.8%, aphasia and/or motor paresis in
47.2%, and headache in only 19.7% of patients. These data seem
consistent with other studies and serve to highlight the potential
neurocognitive impact of a brain tumor.
Treatment
The medical oncological treatment landscape for glioma is
expanding rapidly as molecular stratification techniques identify
favorable prognostic groups. The complexity of these developments
can be bewildering even to specialists, and review of these
developments is well beyond the scope of this chapter. However, the
basic palette of treatment options remains simple. Most patients for
whom active treatment is indicated will receive a tailored mix of the
following: neurosurgery, sometimes conducted in cases of tumor in
the eloquent cortex on patients who are awake; radiotherapy on
varying schedules, with total doses depending on tumor histology
and patient infirmity; chemotherapy of various types (most
commonly, the alkylating agent Temozolomide for glioma); and
supportive medication, such as corticosteroids (to reduce brain
edema and alleviate neurological deficit) and antiepileptic drugs. In
some patients with lower-grade tumors, the treating team may elect
simply to follow up with the patient.
Many patients, even those presenting with neuropsychiatric
symptoms, may never see a psychiatrist during their treatment. Yet
brain tumors form part of the differential diagnosis of many
psychiatric disorders. More generally, there is perhaps a Western
cultural, clinical, and academic tendency to seek to link brain
abnormalities with psychopathology. It would be natural for
psychiatrists to be concerned that symptoms reported by their
patients might have a sinister physical explanation.
Does My Psychiatric Patient Have a Brain Tumor?

There is a clear association between the emergence of psychiatric
symptoms and the subsequent diagnosis of a brain tumor. Large
population-based record-linkage studies associate hospitalization for
depression with an increased risk of malignant brain tumor diagnosis
during the following year (Benros et al. 2009). The major problem for
the psychiatric clinician is that among his or her entire case load, the
patients whose symptoms are due to a developing brain tumor will
constitute only an elusive minority. The overwhelming majority of
patients—whether in clinic or a psychiatric ward—do not have a
brain tumor causing their symptoms. How can the few that do be
identified in a timely manner while avoiding indiscriminate
investigation of patients who may already be distressed?
Although not an exclusive list, a recent change of mental state
coinciding with any of the following symptoms would raise clinical
suspicion of brain tumor:
1. Headache. A headache caused by elevated intracranial

pressure (ICP) is classically worst when waking from sleep,
coughing, or straining on the toilet. Although headache is a
frequent symptom in these patients, its absence does not exclude
the presence of a brain tumor, and its presence alone certainly
does not confirm it. Common alternative reasons for headache in
psychiatric patients may include migraine and classic tension
headache, temporomandibular joint dysfunction secondary to
anxiety, somatization, fibromyalgia, and opiate medication
overuse.
2. Nausea or vomiting. In particular, clinical suspicion for a central
cause of nausea or vomiting (e.g., brain tumor) is higher among
patients in whom vomiting occurs suddenly and in the absence of
a clear gastrointestinal, metabolic, medication-related, or self-
induced cause.
3. Motor or sensory neurological deterioration. This is clearly a
broad category, and psychiatrists should be alert to any unusual
aspects of the clinical history. Hemiparesis can be a late sign;
earlier changes may include subtle clumsiness (“Have you
noticed any difficulty with keys, buttons, or the TV remote
control?”) or visual neglect (“Have you been bumping into
doorways? Is it always on the same side?”). Any new-onset focal
neurological signs should raise suspicion and prompt
investigation for an intracranial mass (e.g., a brain tumor) as well
as other causes of such signs.
4. New-onset seizure(s). In otherwise healthy people,
antidepressants are unlikely, at therapeutic doses, to lower
seizure threshold significantly (Alper et al. 2007). Some other
types of psychotropic medication, for example antipsychotics,
may have greater potential to cause seizures in susceptible
individuals. Nevertheless, the occurrence of new-onset seizures
in a patient with similarly recent-onset psychiatric/mental status
changes (as well as those without such changes) should prompt
investigation for their cause, including the possibility of a brain
tumor.
5. Unusual psychiatric symptoms. The literature is replete with
single case studies of psychiatric patients who were subsequently
found to have a brain tumor. Often symptoms were present that
“didn’t really fit,” such as (variously) musical or peduncular
hallucinations, palinopsia, automatisms, polyopic heautoscopy,
fantome de profil, anarchic hand syndrome, pathological laughter,
déjà vu, and other interesting phenomena.
6. New-onset psychopathology in an older patient without a prior
history. The late-life development of new psychiatric symptoms
that more typically begin in childhood, adolescence, or young
adulthood should prompt evaluation for neurological causes of
such symptoms (i.e., they should not first be taken as symptoms
of a late-onset idiopathic psychiatric disorder).
Critical signs to investigate on physical examination of psychiatric

patients whose history suggests the possibility of a brain tumor
include all of the following.
1. Papilledema. Funduscopic examination for papilledema, which

is caused by ICP, must be undertaken when a possible brain
tumor is suspected. See Madill et al. (2010) for an online tutorial
about this element of the physical examination.
2. Cranial nerve (CN) palsies. It is particularly important to
exclude diplopia, pupillary abnormalities, and ptosis when seeking
or addressing CN palsies. CN III and CN VI have the longest
intracranial course and the highest risk of compression from
elevated ICP.
3. Asymmetry of motor tone, power, or deep tendon reflexes.
Minor neurological abnormalities are common in psychiatric
patients and are nonspecific for identifying patients who need a
brain scan. For example, patients with first-episode psychosis
(and no brain tumor) have frequent subclinical abnormalities in
motor coordination or sensory integration or persisting
developmental reflexes (Dazzan and Murray 2002). However,
clear asymmetries of motor function or reflexes should prompt
evaluation of their possible cause/s, including brain tumor.
Even appropriately targeted computed tomography or magnetic

resonance imaging scans will occasionally identify incidental
(functionally silent and psychiatrically irrelevant) tumors. In
psychiatric patients, the frequency of incidental neuroradiological
abnormalities, excluding the nonspecific white matter changes, is
roughly 3% (Albon et al. 2008). The precise figure is unclear
because incidence varies according to scan sensitivity, but it is
probably similar to that of the general population. If there is clinical
doubt about the psychiatric relevance of a radiological abnormality,
neuroradiology or neuro-oncology services may be able to offer a
second opinion.
Does My Brain Tumor Patient Have a Psychiatric

Disorder?
Brain tumor patients are at high risk for developing psychiatric
disorders. This section will highlight three of the most commonly
encountered problems in clinical practice: personality and behavioral
change, depression, and anxiety. By way of context, most studies in
this literature have been conducted either on patients with various
types of glioma or on mixed populations of primary brain tumor
patients. The extent to which these problems arise in patients with
lower-frequency tumors (such as those of the pituitary, choroid
plexus, or pineal gland) is generally unknown.
Personality and Behavioral Changes

Background
Personality and behavioral changes are commonly reported in
persons with brain tumors. Reports describing such changes,
however, involve mostly small numbers of patients with
correspondingly wide confidence intervals on prevalence estimates.
The literature is also clouded by the difficulty of defining “personality.”
Studies make variable use of the partly overlapping concepts of
attitudinal change, behavioral change, and cognitive impairment.
Heterogeneity between study populations further reduces the
generalizability of any single prevalence estimate.
Despite these difficulties, a few rules of thumb can be outlined.
First, troublesome behavioral changes are reported across tumor
subtypes, ages, and stages of disease. Second, with the possible
exception of primary CNS lymphoma (in which behavioral changes
are reported in most patients), only a minority of patients present
with clear behavioral symptoms from the outset. Third, personality
and behavioral changes probably become more common as the
disease progresses. The extent to which behavioral changes are
independent of progressive cognitive impairment is unclear. What is
not in any doubt is the degree of distress experienced by the
caregivers and families of affected patients.
Etiology
Lesion location is sometimes invoked as the “cause” of
personality or behavioral changes. There is plainly a relationship of
sorts, and it may be tempting to draw analogies with neurology,
where destruction of a motor circuit or critical nucleus causes
predictable neurological signs. When predicting wider psychiatric
syndromes, however, the relationship is not as clear. The well-
rehearsed maxim that “frontal lobe tumors cause personality change”
is partly a legacy of pioneering autopsy studies of brain tumor
patients with mental state changes. Yet, in general, these studies
drew upon selected cohorts to describe historical psychiatric
syndromes. The recent literature linking tumor location with
behavioral phenotype consists mainly of case reports. In essence,
the evidence linking anatomical tumor location and a particular
psychiatric syndrome is mostly inconsistent.
For example, cerebellar tumors are well known to cause frontal-
type behavior changes. Similar changes have been reported for
tumors in nearly every other part of the brain including the brain stem
(Omar et al. 2007). Many patients with frontal tumors are meanwhile
surprisingly clinically unaffected by personality or behavior change.
Neither recent advances in knowledge of neural circuit dynamics
(Insel et al. 2010) nor the fascinating phenomenon of cerebral
diaschisis (Rozental et al. 1990) are especially well served by a rigid
lobe-based explanatory system. The critical factor may, instead, be
the extent to which tumors disrupt the functioning of particular
subcortical neural circuits that extend over wide areas of the brain.
Few studies, if any, have explored this in any great detail.
A few notable associations between tumor location and behavioral
change have been reported, however. One is the substantial
literature on the posterior fossa syndrome (see subsection “Posterior
Fossa Syndrome”). Another is the observation of an unusually high
risk of a disinhibition syndrome in patients with right
orbitofrontal/inferior temporal lesions and a family history of affective
disorder (Starkstein et al. 1987). This association generates the
caution that it may be reasonable to avoid antidepressants in these
patients unless necessary, but even here, we rely on a small
controlled study and some case reports.
Future longitudinal correlative studies will undoubtedly explore the
relationship between tumor location and behavioral phenotypes at
the level of functional neuronal circuitry. The advent of efficient,
precise, relatively unbiased analytic imaging methods such as voxel-
based lesion-symptom mapping may help (Bates et al. 2003). This
technique has recently been used to suggest that simple
mentalization abilities may be affected by tumors in the temporal and
insular regions, whereas higher-level mentalization abilities may be
differentially impaired by lesions in the prefrontal area (Campanella
et al. 2014). Currently, the molecular-, circuit-, and systems-level
biology that underlies behavior change and how altered dynamics of
these systems translate into symptoms remains undefined.
Assessment
There is general consensus between clinicians and
patient/caregiver representative groups that assessment of
behavioral change should be person centered and holistic,
encompassing behavior, cognitive functioning, and emotional state
(Figure 15–2). There is some evidence that functional analysis (an
appraisal of antecedent factors leading up to problem behavior, the
behavior itself, and its consequences for the patient) is effective in
reducing challenging behavior in patients with dementia and
improving aspects of caregiver stress (Moniz Cook et al. 2012). The
particular medical needs of brain tumor patients and the disease
tempo are different, but an A-B-C approach is unlikely to cause harm
and may offer a useful framework. A good history obtained from a
collateral source is essential because many patients will lack full
insight.
FIGURE 15–2. Cognitive/emotional/behavioral personality framework.
Assessment of personality change should be person centered and holistic.
Personality can be usefully broken down using a cognitive/emotional/behavioral
framework. Factors in squares are examples of things typically measured in
research. In the clinical setting, it may be more useful to frame the assessment in
terms more meaningful to the patient’s experience of “lived reality” (circles; the list
is far from exhaustive). The focus of such a review would generally be on finding
ways to reduce the troublesome behavior(s).
Reversible causes should be excluded or addressed. Patients are

likely to have several potentially reversible causes for behavioral
change (see Table 15–1). Commonly prescribed brain tumor
medication that may contribute to symptoms includes corticosteroids
and antiepileptic drugs, especially, it seems, levetiracetam
(Helmstaedter et al. 2008). However, these may also be essential
medicines for control of brain edema and epilepsy, so full discussion
with the treating team and a collaborative management approach are
vital.
TABLE 15–1. General clinical tips on the management of personality and

behavioral disturbance in brain tumor
• Commonly reported problems include irritability, anger, disinhibition, socially
inappropriate behavior, and apathy.
• Commonly prescribed medications that may contribute to these problems
include corticosteroids and antiepileptic drugs.
• Other reversible causes for challenging behavior include delirium, epilepsy,
depression, anxiety, cognitive impairment, frustration, and pain.
• Patients should receive both a neuropsychological and a neuropsychiatric
assessment to conceptualize what is contributing to the observed changes.
• Psychoeducation should be provided for the person and their family. Most
major brain tumor charities have leaflets to access online. A particularly
useful and pragmatic set of advice cards, developed and advocated by
clinicians, can be found here: http://www.cancerinstitute.org.au/patient-
support/patient-resources/brain-cancer-fact-sheets.
• Therapy should be delivered by professionally trained therapists. It may
involve both the individual and their family, focusing initially on the most
distressing behavioral changes.
• When delivering treatment, a flexible therapeutic approach is valuable. For
example, cognitive-behavioral therapy, mindfulness, and environmental
management may be used together for anger or impulsivity, while solution-
focused therapy and behavioral therapy could be combined for stress
management.
• Supportive counseling may also be useful for the individual (alone), family
member (alone), and/or couple/family, as appropriate.
Treatment
Despite the considerable personal impact, very few randomized
controlled trials (RCTs) have examined interventions for behavioral
syndromes in brain tumor. A multimodal home-based psychosocial
intervention (Making Sense of Brain Tumor program) has been
developed in Australia. The Making Sense of Brain Tumor program
combines neuropsychological assessment, psychological therapy,
and a person-centered approach. It has recently shown some benefit
in a single-center randomized wait-list controlled study (Ownsworth
et al. 2015).
Other researchers have focused on the cognitive aspects of
personality change. A handful of RCTs have shown limited efficacy
of brain tumor cognitive retraining programs. These can be delivered
successfully both in the early postoperative (Zucchella et al. 2013)
and the later outpatient phases of tumor treatment (Gehring et al.
2009). To date, the patients studied have generally shown
improvement in narrow psychometric parameters (mainly attention
and visual memory) rather than in the more complex social
behaviors underpinned by executive function and impulse control.
In general, though, there is a lack of specific psychological
therapy resources tailored to the problematic behavior changes often
encountered by patients and their families. Clinical management is
therefore mostly based on common sense, discussion with the
patient and family, and a pragmatic behavioral approach. Caregiver
education and support is essential. Some clinical and practical
suggestions are given in Table 15–1.
With the possible exception of antidepressants (see section
“Depression”), psychiatric medication should only rarely be
necessary in outpatient neuro-oncology. Most situations can be
managed by treating reversible causes, educating the patient and
caregiver, and using behavioral strategies. If regular sedation is
being considered by medical or surgical treating teams, patients
should be referred to specialist psychiatry services for review and
follow-up. When required as a last resort for behavioral disturbance,
a regular low-dose antipsychotic may be effective. Successful use of
risperidone to treat brain tumor–associated agitation has been
reported in the palliative care setting (Lee et al. 2001). As yet, there
are no data on the regular use of antipsychotics in brain tumor
outpatients or on the use of mood-stabilizing drugs other than as
antiepileptics. Risks should be weighed and minimized. Major
foreseeable risks of antipsychotic treatment include mobility
impairment and falls, worsening cognitive impairment, and a lowered
seizure threshold. If antipsychotics are contraindicated, propranolol
is an effective treatment for agitation and aggression in adults with
acquired brain injury (Fleminger et al. 2006). A trial of this drug could
therefore be considered, but medical comorbidities need to be
considered.
Behavioral agitation associated with the terminal stages of
disease can be complex to manage, and palliative care/hospice
services should be involved.
Depression
Background
Around 15%–20% of patients with glioma will develop clinical
depression during primary treatment of the tumor (Rooney et al.
2011a). Perhaps contrary to what might be expected, depression—at
least in the initial period of treatment—is therefore the exception
rather than the rule. Nevertheless, it occurs frequently enough to
maintain a high index of suspicion and is considerably more
prevalent in brain tumor patients than in the general population.
Subclinical depressive symptoms are more frequent, with a median
of 27% of patients scoring above threshold on a variety of rating
scales (Rooney et al. 2011a).
The frequency of suicidal ideation in brain tumor patients remains
unclear. Some prospective studies suggest a low frequency of
reported suicidal thoughts (Rooney et al. 2011a). Others report that
patients with a brain or CNS tumor are nearly eight times more likely
than control subjects to commit suicide in the first 12 weeks after
diagnosis (Fang et al. 2012). Either way, suicidal ideation is a cause
for concern and must be taken just as seriously in brain tumor
patients as it would be in the general psychiatric population.
Etiology
Most of what is currently known about depression in patients with
brain tumor is clinically focused. Questions directed at the level of
cell biology have largely not been asked, and the causes of
depression in these patients are therefore unclear. In clinical studies,
depression has generally not been found to be associated with
tumor-related variables such as grade of malignancy and histological
type. Unlike in community studies of depression, the sex ratio in
brain tumor populations appears to be equal, with men and women
at equal risk. Patients with larger tumors, significant functional or
cognitive impairment, and a prior history of depression appear to be
at higher risk of becoming depressed. Patients taking long-term
steroids and those with a frontal lobe tumor may also be at higher
risk, but the evidence for the latter association is still somewhat
muddy (Rooney et al. 2011a, 2011b). To date, the only study to
directly ask “What causes depression in brain tumor patients?”
concluded by proposing a mixture of neurological and psychological
causes (Armstrong et al. 2002).
Some patients for whom a diagnosis of depression seems fitting
at clinical interview demonstrate clear and pervasive anhedonia but
deny any lowering of mood (author’s unpublished observation).
Whether these patients have a common underlying pathophysiology
that is distinct from patients who report depressed mood is a matter
for future study. Other data suggest that serum levels of insulin-like
growth factor 1 (IGF1) and its binding partner IGFBP3 may be
significantly raised among newly diagnosed glioma patients with
depressive symptoms (a score >10 on the Hospital Anxiety and
Depression Scale) (Wang et al. 2014). The biological significance of
this association remains to be clarified.
Assessment
Making a confident diagnosis of depression in patients with brain
tumor can be difficult. First, nearly all of the symptoms that contribute
to major depressive disorder as outlined in DSM-5 (American
Psychiatric Association 2013) can also reasonably be attributed to
the tumor or its treatment. Second, an accurate history can be
difficult to obtain from a cognitively impaired patient. As with
dementia and epilepsy, a reliable collateral history is important.
Proxies tend to report greater severity of depressive symptoms than
brain tumor patients themselves. In particular, proxies are more
reliable on the objective symptoms of major depressive disorder:
sleep, appetite, psychomotor change, and fatigue (Rooney et al.
2013).
Other helpful diagnostic principles may include focusing on the
persistence and duration of symptoms, trusting in one’s clinical gut
instinct, and staying sanguinely mindful that the DSM criteria were
not designed with brain tumors in mind. The diagnosis of depression
is often essentially a difficult clinical judgment. Among the
psychological symptoms, intermittent waves of intense sadness at
the many losses that accompany a brain tumor diagnosis are
common and to be expected in the early stages of treatment.
Intermittent waves of guilt at being suddenly unable to fulfill work,
driving, or household roles are also typical. However, the defeated
hopelessness of clinical depression can still be sensed, and
pervasive guilt is not typical.
Treatment
Even with severe and persistent symptoms making for what—in a
psychiatric outpatient clinic—would be a fairly clear-cut case,
patients may sometimes be reluctant to accept a diagnosis of
depression. In some respects, this is completely understandable.
The validity of the concept of depression in medical illness can be
persuasively criticized (Horwitz and Wakefield 2007). From an
intellectual perspective, psychiatric dogmatism on the issue is
probably unwarranted. At the same time, professional opinions are
reached for a reason. A trial of treatment may be in the patient’s
interest. The best approach is to propose the diagnosis gently, listen
(and watch) carefully for any patient or caregiver unease, and, if
necessary, work toward a collaborative agreement that will preserve
the therapeutic alliance. Much as with discussing functional
symptoms, respecting the patient’s viewpoint and addressing
concerns from the start are likely to lead to clinical benefit in terms of
engagement with treatment. If a template “opening line” were of any
use, one possibility would be the following: “We know that
depression happens more often in people with brain tumors. It’s very
important to treat because that helps to improve quality of life.
You’ve had an awful lot going on recently, and maybe no one can be
certain about this, but on balance, I do think you have depression,
and I think that treatments could help. What do you think?”
If antidepressants are indicated, clinicians should weigh the
following considerations prior to selecting and initiating treatment
with these agents. First, no RCTs of antidepressants have been
conducted in depressed brain tumor patients (Rooney and Grant
2013). This means it is unknown whether antidepressants are
effective in the challenging scenario of cancer invading, distorting,
and metabolically altering brain tissue. The lack of RCTs means the
risk of precipitating epilepsy is also unclear. Antidepressants
generally do not lower seizure threshold in healthy patients, but they
can do so in overdose. Brain tumor patients are naturally at
extremely high risk of epilepsy. The epileptogenic potential at
therapeutic doses of antidepressants in such a vulnerable group is
not known. The best current evidence is from retrospective chart
reviews: these suggest that the risk of epilepsy is low (Caudill et al.
2011). Untreated depression is itself a risk factor for epilepsy
(Kanner 2008), so antidepressants could, by treating depression,
conceivably improve seizure control. These patients are often also
on chemotherapy and antiepileptic drugs. The cytochrome P450
(CYP450) interaction profile should be taken into account when
choosing a particular antidepressant. Most antidepressants are
enzyme inhibitors, so the theoretical interactive risk is of toxicity
rather than inefficacy. Nonetheless, it may be prudent to choose an
antidepressant with relatively few known effects on the CYP450
system as first-line treatment (e.g., sertraline). When treatment with
any antidepressant is begun, doses should start low and increase
slowly with regular clinical review.
Regarding nonpharmacological treatments for depression, an
important question is whether patients with cognitive impairment are
able to derive clinically significant benefit from intensive structured
psychotherapy. This question remains unresolved, again owing to a
lack of RCTs specifically focused on the brain tumor population. The
closest available evidence may be from patients with terminal
cancers of mixed histological types. Reviews in this wider population
provide moderate-level evidence that psychotherapy is effective for
treating depressive symptomatology as measured by rating scales.
Studies conducted on patients with terminal cancer and clinically
diagnosed depression are lacking (Akechi et al. 2008).
Anxiety
Background
The diagnosis of a brain tumor is naturally anxiety provoking. In
just the first few weeks after they present with symptoms, patients
must cope with waiting for a bewildering onslaught of scan and
histology test results, a multidisciplinary meeting to formulate
management, and uncertainty relating to prognosis. After initial
treatment, patients must also adjust to drastic changes in roles and
identity and come to terms with the ongoing risk of sudden
deterioration from tumor recurrence or epilepsy. Unsurprisingly, in
these circumstances, anxious symptomatology is common. Most
studies capture anxiety as part of its wider manifestation as “mixed
distress” rather than as a formal clinical diagnosis. The resulting
point prevalence estimates vary between 30% and 50% and may be
even higher in caregivers (Petruzzi et al. 2013). Anxiety may be
more frequent in patients with low-grade glioma, and in contrast to
depression, the sex balance is skewed: female patients seem at
higher risk of generalized anxiety than males (Arnold et al. 2008).
Higher premorbid IQ may protect against distress.
Treatment
No RCTs have examined the effectiveness of interventions for
anxiety in brain tumor patients, and again general management
principles from adult psychiatry must be applied. In a staggering
demonstration of anxiety management using psychological
principles, awake craniotomy has been shown to be possible with
only minimal analgesia and no sedation (Hansen et al. 2013). In a
small longitudinal pilot open-label study, pregabalin has been
associated with a reduction in anxiety concomitant with improved
seizure control (Maschio et al. 2012).
For a thoughtful and holistic clinical perspective on the impact of a
brain tumor on patients and families and the role of mental health
professionals in this setting, see Lucas (2013).
Brain Tumors in Childhood
Background
A review of the developmental biology and range of primary
neuro-oncological treatments of childhood brain tumors is outside
the scope of this chapter. As a starting point, the interested reader is
directed to a review of the treatment of childhood low-grade gliomas
(Bergthold et al. 2014). With treatment advances leading to improved
survival, however, an increasing number of childhood brain tumor
survivors will, in the future, present to adult psychiatrists and
neurologists alike. The long-term survival of many patients also
lends itself to the detailed longitudinal study of neuropsychiatric
sequelae. This characteristic feature of childhood brain tumors is
reflected in what is in some ways a higher-quality psychiatric
literature than currently exists for adults, although samples are
usually smaller.
The problem is essentially that healthy brain tissue is injured in
childhood as a necessary byproduct of the effective treatment of
brain tumor. In the long term, many survivors are left with significant
cognitive and neuropsychiatric difficulties. These difficulties
adversely affect social, emotional, behavioral, academic, and
vocational abilities. Survival is often secured at a cost for these
patients and their families.
Posterior Fossa Syndrome

The biggest immediate neuropsychiatric risk arising from the
treatment of childhood brain cancer, however, is of postsurgical
posterior fossa syndrome (PFS) (Pitsika and Tsitouras 2013). PFS—
which rarely also affects adults—consists of mutism together with
concurrent cognitive, emotional, and behavioral abnormalities.
Mutism can be complete and characteristically manifests within the
first few days following surgery. Interestingly, functional
neuroimaging in mute postoperative patients shows abnormalities
affecting multiple supratentorial sites during the acute episode
(Catsman-Berrevoets and Aarsen 2010). The observation that
single-photon emission computed tomography abnormalities resolve
in tandem with mutism has raised the hypothesis that the syndrome
arises from a cerebellar-cerebral diaschisis (De Smet et al. 2009).
PFS typically gradually resolves over several weeks, usually with a
period of dysarthria before recovery. After 1 year, however, many
children remain impaired in multiple cognitive domains (Palmer et al.
2010).
Long-Term Neurocognitive Impairment
Even in children who do not develop PFS, posterior fossa–
directed treatment carries a high risk of long-term, clinically
significant neurocognitive impairment. Indeed, studies consistently
report long-term cognitive impairments in survivors of childhood
brain tumors regardless of primary tumor site. Several high-quality
reviews summarize the extent of neurocognitive deficits and outline
possible mechanisms (see, e.g., Padovani et al. 2012).
It is likely that persisting cognitive dysfunction adversely affects
educational and social potential. These patients display impairments
(variously) in IQ, processing speed, working memory, reaction time,
adaptive behavior (e.g., communication skills), and/or attentional
abilities. Increasing radiation dose is associated with a greater
severity of symptoms, as is younger age at diagnosis, a history of
hydrocephalus, and prior chemotherapy or radiotherapy. In addition
to cognitive difficulties, emotional and behavioral functioning is often
affected. Schooling can be profoundly disrupted; there is a high
prevalence of acquired learning disability and frequent need for
educational support. Relatively few of these patients go on to
graduate from higher education. The child’s ability to form social
networks is often impaired, not least because many survivors have
significant hearing impairment. This panoply of disadvantages may
extend to an impact on general health, as shown by the startling
suggestion that the cardiorespiratory fitness of posterior fossa tumor
survivors is comparable to children with chronic heart disease (Wolfe
et al. 2012).
Adult Survivors
Patients with childhood brain tumor may survive to adulthood. In
these very long-term brain tumor survivors, clinically significant
levels of apathy are present in 35%—twice the level of sibling control
subjects. Apathy is particularly associated with females and lower IQ
(Carroll et al. 2013). Other significant issues that have been reported
in adult survivors include endocrinopathy, persisting cognitive
impairment, limited career options, ongoing financial dependence on
parents, and a need for counseling about fertility.
Proposed Mechanisms of Neurocognitive Impairment

Increasing effort is focused on understanding the cellular biology
of neuropsychological and neuropsychiatric impairments after
childhood brain tumor. Structural candidates include white matter
tract changes and atrophy of cortical and subcortical structures.
Functionally, both magnetoencephalography-recorded gamma
oscillations (Dockstader et al. 2014) and catechol O-methyl
transferase gene polymorphisms (Howarth et al. 2014) have been
differentially associated with neurocognitive symptoms following
cranial radiotherapy. The field of mechanistic candidates is
expanding quickly from the initial seminal discovery of the adverse
effects of radiotherapy on hippocampal neurogenesis (Monje et al.
2002). Many questions remain unanswered, however, and the “holy
grail” of an integrated mechanistic understanding that is detailed
enough to drive the development of novel, rational, neuroprotective
treatments is some distance in the future.
Treatment
There is relatively little high-quality evidence to guide current
management of neuropsychiatric problems in childhood brain tumor
survivors. There is preliminary evidence from small randomized
studies that computerized memory training may improve selective
aspects of memory (Hardy et al. 2013) and that methylphenidate
may improve attention and behavior over the short term, perhaps
especially in older boys of higher premorbid IQ (Smithson et al.
2013). Until high-quality science-based action plans are developed,
management is largely empirical. Strategies should be pragmatic,
individualized, problem focused, and underpinned by full discussion
about the relevant pros and cons. The child/young adult and his or
her parents should be involved as is appropriate for developmental
age and mental capacity. Care should be taken that
neuropsychological recommendations are feasible. As ever, the key
requirement is a holistic approach that encompasses cognitive,
emotional, behavioral, and socioeconomic interventions as
appropriate.
Conclusion
Researching the neuropsychiatric aspects of brain tumors is
fascinating but challenging. The many potential confounding factors
mandate large sample sizes for proper statistical control. Because
brain tumors are, in general, relatively rare, large samples require
either multicenter studies or long-term studies in a single institution.
Both options are expensive. Difficulty in securing funding is reflected
in a literature dominated by small and often single-center studies. If
basic and translational research is essential to find cures, then high-
quality neuropsychosocial research is essential to improve symptom
control and the “lived reality” for the many people who will get a brain
tumor before the cures are discovered.
One difficulty is the questionable validity of many of the described
neuropsychosocial outcomes. Subjective patient report is often used,
but the validity of self-report in these typically cognitively impaired
patients is unclear. Studies of neuropsychiatric outcomes based on a
diagnostic clinical interview are rare; studies of objectively
measurable endophenotypes are even rarer. This problem is not, of
course, unique in psychiatry. However, in neuro-oncology, there can
also be considerable difficulty in confidently diagnosing (for example)
depression, even through a supposed “gold-standard” diagnostic
interview. As discussed above, DSM diagnoses were not designed
with brain tumor patients in mind. The National Institute of Mental
Health Research Domain Criteria (Insel et al. 2010) may provide a
more secure footing for the linkage of tumor and its treatment with
neuropsychiatric outcomes.
A related challenge is how to unpack the biological mechanisms
that underpin the neuropsychiatric and neurocognitive consequences
of brain tumor. Until quite recently, there was a striking absence of
molecular biology from platform sessions devoted to issues related
to quality of life at the major international neuro-oncology
conferences. This situation is slowly changing. Detailed
understanding of homeostatic biological process that are affected by
brain cancer and its treatment will be necessary for the development
of treatments aimed at the root causes of symptoms such as
depression, fatigue, epilepsy, cognitive impairment, and behavioral
change. Neuropsychiatrists and behavioral neurologists alike need to
be involved in these developments.
New treatments need to be evidence based, and here, too, the
neuropsychosocial research has lagged well behind the considerable
activity of medical neuro-oncologists in subjecting new drugs or
modalities of treatment to trials. Partly because of difficulty securing
funding, RCTs for neuropsychiatric symptoms are rare. RCTs that
have been conducted are mostly Phase II or small Phase III trials. A
personal viewpoint on questions that might warrant further clinical or
mechanistic study is given in Table 15–2.
TABLE 15–2. Potential research questions for future study
Compared with control groups, what is the evidence that...
Immediate referral to a palliative care service at the point of tumor diagnosis
improves quality of life?
Antidepressants effectively treat depression without worsening epilepsy?
Family intervention programs improve their ability to cope with challenging
behavior?
Structured neurorehabilitation programs improve long-term social, academic,
or vocational outcomes in survivors of posterior fossa tumor?
What are the cellular and molecular mechanisms by which...
Radiotherapy and chemotherapy affect white matter tract biology?
Hippocampal neurogenesis is impaired after these treatments?
Personality and behavioral change arises in patients with a brain tumor?
Injury to the cerebellum causes changes in supratentorial brain structures?
Meeting these challenges—improving the measurement of

symptoms, defining their biological mechanisms, and conducting
clinical trials on new treatments—yoked to the fundamental
challenge of attracting sufficient funding to gather meaningful data
will be a major milestone on the road to better understanding of the
neuropsychiatry of brain tumors.
References
Akechi T, Okuyama T, Onishi J, et al: Psychotherapy for depression among
incurable cancer patients. Cochrane Database Syst Rev (2):CD005537, 2008
18425922
Albon E, Tsourapas A, Frew E, et al: Structural neuroimaging in psychosis: a
systematic review and economic evaluation. Health Technol Assess 12(18):iii–
iv, ix–163, 2008 18462577
Alper K, Schwartz KA, Kolts RL, et al: Seizure incidence in psychopharmacological
clinical trials: an analysis of Food and Drug Administration (FDA) summary
basis of approval reports. Biol Psychiatry 62(4):345–354, 2007 17223086
Armstrong C, Goldstein B, Cohen B, et al: Clinical Predictors of Depression in
Patients with Low-Grade Brain Tumors: Consideration of a Neurologic Versus a
Psychogenic Model. J Clin Psychol Med Settings 9(2):97–107, 2002
Arnold SD, Forman LM, Brigidi BD, et al: Evaluation and characterization of
generalized anxiety and depression in patients with primary brain tumors.
Neuro Oncol 10(2):171–181, 2008 18314416
Bates E, Wilson SM, Saygin AP, et al: Voxel-based lesion-symptom mapping. Nat
Neurosci 6(5):448–450, 2003 12704393
Benros ME, Laursen TM, Dalton SO, et al: Psychiatric disorder as a first
manifestation of cancer: a 10-year population-based study. Int J Cancer
124(12):2917–2922, 2009 19330831
Bergthold G, Bandopadhayay P, Bi WL, et al: Pediatric low-grade gliomas: how
modern biology reshapes the clinical field. Biochim Biophys Acta 1845(2):294–
307, 2014 24589977
Campanella F, Shallice T, Ius T, et al: Impact of brain tumour location on emotion
and personality: a voxel-based lesion-symptom mapping study on
mentalization processes. Brain 137 (Pt 9):2532–2545, 2014 25027503
Carroll C, Watson P, Spoudeas HA, et al: Prevalence, associations, and predictors
of apathy in adult survivors of infantile (<5 years of age) posterior fossa brain
tumors. Neuro Oncol 15(4):497–505, 2013 23502428
Catsman-Berrevoets CE, Aarsen FK: The spectrum of neurobehavioural deficits in
the Posterior Fossa Syndrome in children after cerebellar tumour surgery.
Cortex 46(7):933–946, 2010 20116053
Caudill JS, Brown PD, Cerhan JH, et al: Selective serotonin reuptake inhibitors,
glioblastoma multiforme, and impact on toxicities and overall survival: the mayo
clinic experience. Am J Clin Oncol 34(4):385–387, 2011 20859197
Dazzan P, Murray RM: Neurological soft signs in first-episode psychosis: a
systematic review. Br J Psychiatry Suppl 43:S50–S57, 2002 12271801
De Smet HJ, Baillieux H, Wackenier P, et al: Long-term cognitive deficits following
posterior fossa tumor resection: a neuropsychological and functional
neuroimaging follow-up study. Neuropsychology 23(6):694–704, 2009
19899828
Dockstader C, Wang F, Bouffet E, et al: Gamma deficits as a neural signature of
cognitive impairment in children treated for brain tumors. J Neurosci
34(26):8813–8824, 2014 24966381
Fang F, Fall K, Mittleman MA, et al: Suicide and cardiovascular death after a
cancer diagnosis. N Engl J Med 366(14):1310–1318, 2012 22475594
Fleminger S, Greenwood RJ, Oliver DL: Pharmacological management for
agitation and aggression in people with acquired brain injury. Cochrane
Database Syst Rev (4):CD003299, 2006 17054165
Gehring K, Sitskoorn MM, Gundy CM, et al: Cognitive rehabilitation in patients with
gliomas: a randomized, controlled trial. J Clin Oncol 27(22):3712–3722, 2009
19470928
Hansen E, Seemann M, Zech N, et al: Awake craniotomies without any sedation:
the awake-awake-awake technique. Acta Neurochir (Wien) 155(8):1417–1424,
2013 23812965
Hardy KK, Willard VW, Allen TM, et al: Working memory training in survivors of
pediatric cancer: a randomized pilot study. Psychooncology 22(8):1856–1865,
2013 23203754
Helmstaedter C, Fritz NE, Kockelmann E, et al: Positive and negative psychotropic
effects of levetiracetam. Epilepsy Behav 13(3):535–541, 2008 18583196
Horwitz AV, Wakefield JC: The Loss of Sadness: How Psychiatry Transformed
Normal Sorrow Into Depressive Disorder. New York, Oxford University Press,
2007
Howarth RA, Adamson AM, Ashford JM, et al: Investigating the relationship
between COMT polymorphisms and working memory performance among
childhood brain tumor survivors. Pediatr Blood Cancer 61(1):40–45, 2014
23956130
Insel T, Cuthbert B, Garvey M, et al: Research domain criteria (RDoC): toward a
new classification framework for research on mental disorders. Am J Psychiatry
167(7):748–751, 2010 20595427
Kanner AM: Depression in epilepsy: a complex relation with unexpected
consequences. Curr Opin Neurol 21(2):190–194, 2008 18317279
Lee MA, Leng ME, Tiernan EJ: Risperidone: a useful adjunct for behavioural
disturbance in primary cerebral tumours. Palliat Med 15(3):255–256, 2001
11407197
Lucas MR: What brain tumor patients and their families have taught me. J
Neurosci Nurs 45(3):171–175, 2013 23636071
Madill S, Kerrigan S, Grant R: Papilloedema. November 30, 2010. Available at:
https://www.youtube.com/watch?v=EWFFAtNenRQ. Accessed March 2, 2017.
Maschio M, Dinapoli L, Sperati F, et al: Effect of pregabalin add-on treatment on
seizure control, quality of life, and anxiety in patients with brain tumour-related
epilepsy: a pilot study. Epileptic Disord 14(4):388–397, 2012 23248037
Moniz Cook ED, Swift K, James I, et al: Functional analysis-based interventions for
challenging behaviour in dementia. Cochrane Database Syst Rev
(2):CD006929, 2012 22336826
Monje ML, Mizumatsu S, Fike JR, et al: Irradiation induces neural precursor-cell
dysfunction. Nat Med 8(9):955–962, 2002 12161748
Omar R, Warren JD, Ron MA, et al: The neuro-behavioural syndrome of brainstem
disease. Neurocase 13(5):452–465, 2007 18781444
Ostrom QT, Bauchet L, Davis FG, et al: The epidemiology of glioma in adults: a
“state of the science” review. Neuro Oncol 16(7):896–913, 2014 24842956
Ostrom QT, Gittleman H, Xu J, et al: CBTRUS statistical report: primary brain and
central nervous system tumors diagnosed in the United States in 2009–2013.
Neuro Oncol 18:v1–v75, 2016
Ownsworth T, Chambers S, Damborg E, et al: Evaluation of the making sense of
brain tumor program: a randomized controlled trial of a home-based
psychosocial intervention. Psychooncology 24(5):540–547, 2015 25251838
Padovani L, André N, Constine LS, et al: Neurocognitive function after
radiotherapy for paediatric brain tumours. Nat Rev Neurol 8(10):578–588, 2012
22964509
Palmer SL, Hassall T, Evankovich K, et al: Neurocognitive outcome 12 months
following cerebellar mutism syndrome in pediatric patients with
medulloblastoma. Neuro Oncol 12(12):1311–1317, 2010 20713408
Petruzzi A, Finocchiaro CY, Lamperti E, et al: Living with a brain tumor: reaction
profiles in patients and their caregivers. Support Care Cancer 21(4):1105–1111,
2013 23104453
Pitsika M, Tsitouras V: Cerebellar mutism. J Neurosurg Pediatr 12(6):604–614,
2013 24073751
Posti JP, Bori M, Kauko T, et al: Presenting symptoms of glioma in adults. Acta
Neurol Scand 131(2):88–93, 2015 25263022
Rooney AG, Grant R: Pharmacological treatment of depression in patients with a
primary brain tumour. Cochrane Database Syst Rev (5):CD006932 2013
23728663
Rooney AG, Carson A, Grant R: Depression in cerebral glioma patients: a
systematic review of observational studies. J Natl Cancer Inst 103(1):61–76,
2011a 21106962
Rooney AG, McNamara S, Mackinnon M, et al: Frequency, clinical associations,
and longitudinal course of major depressive disorder in adults with cerebral
glioma. J Clin Oncol 29(32):4307–4312, 2011b 21990406
Rooney AG, McNamara S, Mackinnon M, et al: Screening for major depressive
disorder in adults with glioma using the PHQ-9: a comparison of patient versus
proxy reports. J Neurooncol 113(1):49–55, 2013 23436131
Rozental JM, Levine RL, Nickles RJ, et al: Cerebral diaschisis in patients with
malignant glioma. J Neurooncol 8(2):153–161, 1990 2358850
Smithson EF, Phillips R, Harvey DW, et al: The use of stimulant medication to
improve neurocognitive and learning outcomes in children diagnosed with brain
tumours: a systematic review. Eur J Cancer 49(14):3029–3040, 2013
23831334
Starkstein SE, Pearlson GD, Boston J, et al: Mania after brain injury: a controlled
study of causative factors. Arch Neurol 44(10):1069–1073, 1987 3632381
Wang Y, Huang M, Jiao JT, et al: Relationship between concentrations of IGF-1
and IGFBP-3 and preoperative depression risk, and effect of psychological
intervention on outcomes of high-grade glioma patients with preoperative
depression in a 2-year prospective study. Med Oncol 31(5):921, 2014
24668415
Wolfe KR, Hunter GR, Madan-Swain A, et al: Cardiorespiratory fitness in survivors
of pediatric posterior fossa tumor. J Pediatr Hematol Oncol 34(6):e222–e227,
2012 22810754
Zucchella C, Capone A, Codella V, et al: Cognitive rehabilitation for early post-
surgery inpatients affected by primary brain tumor: a randomized, controlled
trial. J Neurooncol 114(1):93–100, 2013 23677749
CHAPTER 16
Endocrine Disorders
The relationship between endocrine disturbances and

psychiatric symptomatology has been recognized for centuries.
Indeed, it was these clinical observations and early controlled
studies that spawned the now established field of
psychoneuroendocrinology. The epidemiology and phenomenology
of psychiatric syndromes in the most common endocrine disorders
are reviewed as they occur in this chapter. Underlying
pathophysiology is discussed when there are data available, but
overall data are sparse. The cardinal signs and symptoms of each
disorder are presented together with the psychiatric findings to assist
clinicians in reviewing the context in which the psychiatric symptoms
manifest.
Diabetes Mellitus
The Centers for Disease Control and Prevention (2011) states that
“from 1980 through 2011, the number of Americans with diagnosed
diabetes has more than tripled (from 5.6 million to 20.9 million).”
Cardinal Features
Diabetes mellitus is a group of metabolic diseases, including type
1, type 2, and gestational diabetes, all of which are characterized by
hyperglycemia. Deficits in insulin secretion, insulin action, or a
combination of the two differentiate the disease processes and
ultimate choice of treatment modalities. Acute and long-term
complications of this illness are profound. Chronic hyperglycemia
affects multiple organ systems and can lead to retinopathy,
nephropathy, and peripheral neuropathy, as well as macrovascular
compromise. Diabetic patients are at increased risk for a number of
comorbid medical disorders, most notably coronary artery disease
and stroke.
One type of diabetes is classified as type 1 diabetes mellitus
(T1DM); it is subdivided into type 1A (immune mediated) and type
1B (other forms of diabetes with severe insulin deficiency). Patients
with T1DM are insulin deficient and require insulin to prevent weight
loss, ketoacidosis, and death. In contrast, type 2 is often
asymptomatic, being detected only through blood screening. Type 2
diabetes mellitus (T2DM) is the predominant form of diabetes
worldwide, accounting for 90% of cases globally. T2DM has been
viewed in the past as a disorder of aging, and this remains true
today. However, a disturbing trend has become apparent in which
the prevalence of obesity and T2DM in children is rising dramatically.
Reports suggest that as many as 8%–45% of children with newly
diagnosed diabetes have non–immune-mediated forms of the
disease (American Diabetes Association 2000).
Psychiatric Symptoms in Diabetes Mellitus

There is a considerable literature exploring the link between
psychiatric illness and diabetes. In an 18-month longitudinal study,
Fisher et al. (2012) assessed 506 patients with T2DM at 9-month
intervals for major depressive disorder (MDD), general anxiety
disorder (GAD), panic disorder, and dysthymia (persistent mood
disorder). Patients were interviewed with the Composite International
Diagnostic Interview. The study found a high prevalence of
psychiatric disorders that endured over time in diabetic patients
compared with control subjects: 60% higher for MDD, 123% higher
for GAD, 85% higher for panic disorder, and 7% higher for
dysthymia. There are also data available on the comorbidity of
diabetes and cognitive disorders.
Cognitive Disorders
There are many large cross-sectional and prospective studies that
have revealed significant cognitive deficits in patients with diabetes
type 1 and type 2. These deficits range from cognitive impairment
and decline among all ages to vascular dementia and Alzheimer’s
disease in older populations. Given the increasing incidence of
T2DM in the last three decades, many recent studies focus on this
subtype. However, when studies have been limited to either type 1 or
type 2, the findings have confirmed cognitive impairment in both.
Cognitive Disorders in Type 1 Diabetes

T1DM affects specific cognition subsets in adults and children,
including attention, psychomotor speed, cognitive flexibility,
intelligence, and visual perception. The cognitive dysfunction in
T1DM is indicative of slowing of mental speed and a diminished
mental flexibility, whereas learning and memory are spared (Patiño-
Fernández et al. 2010).
Diabetes is characterized by both chronic hyperglycemia and
intermittent episodes of hypoglycemia resulting from insulin therapy
and the insulin secretagogue drugs, the sulphonylureas and glinides
aimed at strict glycemic control. The negative impact of acute
hypoglycemia on cognitive and motor function for children and adult
patients with T1DM has been reported (Pramming et al. 1986).
Hypoglycemia acutely impairs cognition, but the impairment is
corrected upon return to a euglycemic state. The long-term effects of
hypoglycemia on cognition remain controversial. Several studies,
both cross-sectional and prospective with evaluation periods up to a
decade, have shown that recurrent severe hypoglycemic episodes
do not have an impact on cognition in adolescents diagnosed with
T1DM (Austin and Deary 1999; Diabetes Control and Complications
Trial Research Group 1996; Ferguson et al. 2003b; Reichard et al.
1996). However, numerous studies have obtained discrepant
findings (Blasetti et al. 2011; Golden et al. 1989; Hannonen et al.
2003; Hershey et al. 2003).
Cognitive Disorders in Type 2 Diabetes

Regarding the effects of T2DM on cognition, studies have
reported moderate deficits when comparing diabetic patients with
control subjects (Awad et al. 2004). However, there is heterogeneity
in the cognitive abilities found to be affected and the severity of
cognitive deficits reported. The most common cognitive deficits in
T2DM are found in verbal delayed memory and processing speed
(Awad et al. 2004). Findings on cognitive impairment in T2DM have
been inconsistent for immediate memory, nonverbal memory
arithmetic, verbal fluency, and executive function. Visuospatial
processing, long-term semantic memory, auditory and visual
attention, and language abilities are usually found to be intact. This
heterogeneity in findings is likely related to differences in
demographic data, diversity in neuropsychological tests used to
measure cognitive functioning, and differences in study
methodologies (Awad et al. 2004).
Long-Term Cognitive Effects of Diabetes

There is evidence to indicate that the mere presence of diabetes
imparts a risk of long-term cognitive impairment. Gregg et al. (2000)
in a prospective study found that the presence of diabetes for greater
than 15 years considerably increased the risk of major cognitive
decline.
Several biological mechanisms may contribute to the impaired
cognitive performance and development of dementia of patients with
T2DM, including insulin dysregulation (insulin resistance and
hypersinsulinemia), chronic hyperglycemia, inflammation, oxidative
stress, and vascular and microvascular damage. The prototypical
diabetic complications, including renal disease, stroke, hypertension,
hyperlipidemia, and ischemic heart disease, all likely contribute to
cognitive decline. These complications are largely secondary to
metabolic dyscontrol, such as ketoacidosis, hyperosmolar states,
chronic hyperglycemia, recurrent mild hypoglycemia, and
hypoglycemic seizures. Diabetes is associated with a 1.5- to 2.0-fold
increased risk of stroke. When present, strokes contribute
substantially to cognitive dysfunction in T2DM.
Many studies have identified a relationship between diabetes and
dementia. Large-scale longitudinal studies and systematic reviews
suggest that diabetes is associated with an increased incidence of
dementia. Overall, review of the literature suggests a stronger
association of diabetes with vascular dementia than Alzheimer’s
disease (Cheng et al. 2012).
The mechanisms associating T2DM with vascular dementia and
Alzheimer’s disease appear to differ. Vascular dementia is largely a
consequence of indirect neuronal damage via cerebral microvascular
and macrovascular atherosclerotic disease. With regard to
Alzheimer’s disease, however, there is emerging genetic and
biological evidence to support a possible common pathway leading
to the development of both T2DM and Alzheimer’s disease. Farris et
al. (2003) demonstrated that insulin-degrading enzyme catabolizes
β-amyloid. Insulin dysregulation and low function of the insulin-
degrading enzyme may impair β-amyloid clearance in the brain and
lead to plaque formation by regulating expression of, and competing
for, insulin-degrading enzyme. Additional mechanisms through which
insulin dysregulation may lead to Alzheimer’s disease and
cerebrovascular disease include the effects of insulin resistance and
hyperinsulinemia on cerebral glucose metabolism, vascular
dysfunction, dyslipidemia, oxidative stress, and inflammation.
Inflammation has been implicated in development of T2DM via
contributions to insulin resistance, and insulin dysregulation and
chronic hyperglycemia may, in turn, also promote inflammation (Craft
et al. 2013). The epsilon 4 allele of the apolipoprotein E gene
(APOE*E4) also has been associated with an increased incidence of
both impaired cognition and Alzheimer’s disease in patients with
T1DM and T2DM (Ferguson et al. 2003a).
Structural neuroimaging studies in patients with T2DM have
shown infarctions, cortical and subcortical cerebral atrophy, and
white matter lesions. The structural changes are correlated with
microvascular and macrovascular lesions caused by diabetes. The
association between T2DM and cerebral infarcts in structural
magnetic resonance imaging (MRI) studies is also consistent across
studies (van Harten et al. 2006). One consistent neuroimaging
finding is the presence of hippocampal atrophy in patients with
T2DM. The hippocampus is susceptible to acute metabolic changes
such as hypoglycemia, suggesting that it might be particularly
susceptible to diabetes-related metabolic and vascular change.
Hippocampal atrophy is one of the neuroanatomical features that
differ in T1DM versus T2DM. Both have reduced gray matter density
and white matter lesions, although cortical atrophy is generally more
pronounced in T2DM (possibly because this population is older on
average). Why the hippocampus is more affected in T2DM is
unclear, particularly because this region is susceptible to acute
metabolic change, which is a more prominent feature of T1DM.
Hypoglycemia
Because of the importance of sulfonylureas, glinides, and insulin-
induced hypoglycemia as a putative risk factor for the development
of cognitive impairment in diabetes, a brief discussion of the
phenomenology of hypoglycemia is warranted. Traditionally, the
signs and symptoms of hypoglycemia are divided into autonomic and
neuroglycopenic groups. The autonomic signs and symptoms
include diaphoresis, palpitations, tremor, and hunger, whereas the
neuroglycopenic symptoms include confusion, lethargy, speech and
behavioral changes, tingling, numbness, impaired vision, nightmares
or crying out during sleep, and incoordination. The episodes of
hypoglycemia are more common in T1DM, but individuals with
insulin-treated T2DM are also exposed to frequent hypoglycemic
events, many of which occur during sleep.
Hypoglycemia leads to cardiovascular and neurological
complications as well as physical trauma and accidents. Among the
neurological sequelae of hypoglycemia are seizures, coma, and
cognitive impairment. Hypoglycemia can interfere with daily
activities, jeopardize employment, and limit driving. Fear of
hypoglycemia can influence treatment, behavior, and self-
management of diabetes, leading to noncompliance with treatment.
Reactive hypoglycemia (postprandial hypoglycemia) is a relatively
rare, meal-induced hypoglycemic disorder occurring in patients with
diabetes mellitus, gastrointestinal disease, and hormonal deficiency
states, such as adrenal insufficiency or hypothyroidism. In these
states, hyperinsulinemia is responsible for the hypoglycemia.
Idiopathic postprandial hypoglycemia is a controversial entity with
uncertain validity. Factitious hypoglycemia due to exogenous insulin
administration is relatively uncommon but is suggested by the
presence of elevated insulin antibodies, hypoglycemia, and low C
peptide levels (Horwitz 1989).
Mood Disorders
Depression and Diabetes
The prevalence of depression is increased in diabetics. The
definition of the term depression differs across research studies,
ranging from symptoms of depressed mood to syndromal psychiatric
disorders such as persistent depressive disorder, MDD, and
adjustment disorder with depressed mood. Anderson et al. (2001)
performed a meta-analysis that included 20 controlled cross-
sectional studies of patients with T1DM and T2DM compared with a
nondiabetic group. Overall odds of depression were twice as high for
patients with diabetes compared with nondiabetic control subjects
(odds ratio [OR] 2.0, 95% confidence interval [CI] 1.8–2.2). There
were no differences between patients with T1DM and T2DM. The
sample sizes were relatively small, and only a minority of the studies
(n=20/48) compared prevalence data with a nondiabetes control
group, limiting the conclusions that can be drawn. In a large cross-
sectional study that included more than 200,000 adults from 47
countries, the associations between diabetes and an episode of
depressive symptoms were investigated. Both diabetes and
presence of an episode of depressive symptoms were determined by
self-report. Results showed that individuals with diabetes had
increased odds of an episode of depressive symptoms compared
with those without diabetes (adjusted OR 2.36, 95% CI 1.91–2.92).
Comparable associations were found in South American, Asian, and
European countries (Mommersteeg et al. 2013).
Depression and Type 1 Diabetes

Pouwer et al. (2010) examined the prevalence of depression in
T1DM using both diagnostic criteria and self-report questionnaires.
The prevalence of depressive affect was 25% and 30% for men and
women, respectively, in T1DM when using the Center for
Epidemiologic Studies Depression Scale (CES-D) questionnaire.
The prevalence of a major depressive disorder was 8% when using
the World Health Organization Composite International Diagnostic
Interview (CIDI). In this study, depression was associated with the
presence of proliferative retinopathy and suboptimal glycemic
control.
There is some evidence that the prevalence of depression is
increased in people with T1DM. However, the number of controlled
studies is limited, and most relied on self-report questionnaires to
assess depression.
Depression and Type 2 Diabetes

A recent systematic review and meta-analysis showed that the
prevalence of depression is increased in T2DM but not in those with
undiagnosed diabetes or impaired glucose metabolism (prediabetes)
compared with control subjects. This suggests that disturbed glucose
metabolism in the early phase of the disease is not associated with
depression. An important limitation of that systematic review is that
data on diabetes complications were not available (Nouwen et al.
2011). The findings of these studies support a bidirectional
relationship between diabetes and depression. The stressor of being
diagnosed and living with a chronic and debilitating illness has long
been believed to precipitate the onset of depressive symptoms.
However, in the last two decades, substantial evidence has also
emerged that supports the hypothesis that depression is a risk factor
for the onset and exacerbation of many medical illnesses, including
T2DM.
Comorbid diabetes and depression have been associated with
poorly controlled diabetes. However, the relationship between
glycemic control and depression in adults is complex. The data are
mixed linking depression and suboptimal glycemic control (Lustman
et al. 2007). Although there is a modest association between
depression and poorly controlled diabetes, the literature has shown a
stronger association between depressive symptoms and a range of
diabetes complications including retinopathy, sexual dysfunction, and
nephropathy. Given the negative impact of depression upon persons
with diabetes, groups of investigators have also documented that
patients with depression and diabetes suffer premature mortality
(Katon et al. 2005).
Multiple biological mechanisms may contribute to the relationship
between depression and diabetes. These include activation of
inflammatory processes and the hypothalamic-pituitary-adrenal
(HPA) axis as well as abnormalities in glucose metabolism, which
have been observed in both nondiabetic and diabetic depressed
patients (Okamura et al. 2000).
Depression and mental stress are associated with subclinical
hypercortisolism, blunted diurnal cortisol rhythm, or hypocortisolism
with impaired glucocorticoid sensitivity, and increased
catecholamines and inflammation secondary to the HPA axis
activation. Prolonged hypercortisolemia is associated with visceral
adiposity, insulin resistance, dyslipidemia, and hypertension. It can
also worsen atherosclerosis by increasing vessel fragility and
changes in lipids and catecholamines, which increase heart rate and
contribute to increased risk for thrombus formation (by increasing
platelet aggregation). Adipose tissue and damaged vessels then
release proinflammatory cytokines that can induce a behavioral
repertoire called “sickness behavior” that includes anhedonia,
anorexia, fever, sleep changes, and decreased social interaction.
Repetitive cycles with these characteristics can cause a myocardial
infarction or stroke (Dantzer and Kelley 2007).
All these aforementioned biological pathways are activated in
major depression and are associated with insulin resistance.
Treatment of Depression in Patients With

Diabetes
The psychopharmacological treatment of depression in diabetic
patients has been shown to be effective. However, it has mixed
effects on glycemic control, ranging from hyperglycemic effects with
tricyclic antidepressants to euglycemic or slightly hypoglycemic
effects with selective serotonin reuptake inhibitors (SSRIs) and
serotonin-noradrenaline reuptake inhibitors. Surprisingly, there are
few randomized double-blind placebo-controlled studies available
with respect to treatment of comorbid depression and diabetes
(Lustman et al. 2007).
In a recent Cochrane systematic review, Baumeister and
colleagues (2012) included randomized controlled trials that tested
psychotherapeutic and pharmacologic interventions for depression in
adults with diabetes and depression. Eight psychotherapy studies
showed beneficial effects on short-term (end of treatment), medium-
term (1–6 months after treatment), and long-term (more than 6
months after treatment) depression severity. Evidence regarding the
effect of psychotherapy on glycemic control was heterogeneous and
inconclusive. Eight trials compared pharmacologic interventions with
placebo, showing a moderate beneficial effect of antidepressant
medication on short-term depression severity. The
psychopharmacological treatment of depression in diabetic patients
requires some discussion because of the different effects of various
classes of antidepressants on appetite, body weight, glucose control,
cognition, cholinergic receptors, and sexual function and because of
their propensity to exacerbate autonomic neuropathy–mediated
orthostatic hypotension. Regarding the issues of appetite, weight,
and glucose control, monoamine oxidase inhibitors tend to
exacerbate hypoglycemia and are associated with significant weight
gain. Similarly, trazodone is also associated with weight gain and
orthostatic hypotension. Cognitive interactions between the
underlying illness and the selected medication need to be
considered as well. Medications with anticholinergic or sedating
properties are associated with greater cognitive impairment and can
interfere with the daily management of diabetes. Furthermore, the
impaired cognition often seen in diabetic patients may render
compliance with a monoamine oxidase inhibitor diet unattainable. In
addition to the adverse effects on cognition associated with
anticholinergic medications, the decrease in bowel motility caused by
such agents may worsen underlying diabetes-related gastroparesis
or constipation.
The use of tricyclic antidepressants (TCAs) in the diabetic
population remains controversial. Although they are certainly
effective in the treatment of depression, their side-effect profile
includes increased appetite, body weight, and blood glucose, all of
which are particularly problematic in the diabetic population. TCAs
are contraindicated in patients with cardiovascular disease, a very
common comorbidity in diabetic patients. However, controlled
studies have shown TCAs to be more effective than SSRIs. Although
there are no direct comparative trials, amitriptyline may have greater
efficacy in painful diabetic neuropathy than other TCAs. There is also
evidence for the efficacy of serotonin-noradrenaline reuptake
inhibitors, including duloxetine, venlafaxine, and milnacipran, in a
variety of pain states ranging from diabetic neuropathy to
fibromyalgia. Further studies are warranted in this area. Because of
the combined effects of demonstrated efficacy, safety, improved
glucose control, and minimal cognitive and anticholinergic effects,
SSRIs should be selected as the first-line antidepressants of choice
in treating the diabetic patient. Although the side-effect profile of
these medications is quite favorable, it is important to note that
SSRIs can often exert adverse effects on sexual function, which may
exacerbate sexual dysfunction associated with preexisting diabetic
neuropathy.
There are some data suggesting that certain antipsychotics and
antidepressants can increase the risk of developing diabetes.
Particularly, atypical or second-generation antipsychotic medications
are associated with a twofold to threefold increased risk of diabetes.
Cohort studies show a small increased risk of diabetes in those
receiving antidepressant medications. Randomized controlled trials,
however, have emphasized that antidepressants vary considerably in
their tendency for weight gain and glycemic effects, ranging from
hyperglycemic to hypoglycemic effects (Barnard et al. 2013). It
remains unclear whether the weight gain results from poorly treated
depression or a medication side effect. The precise mechanisms by
which these drugs may lead to weight gain and altered intermediate
metabolism are unknown, not least because they may affect multiple
neurotransmitter receptors simultaneously.
In addition to psychopharmacological treatment of depression,
psychotherapy treatment protocols for depression in diabetes have
mostly used cognitive-behavioral therapy delivered individually by
mental health providers or trained nurse case managers, and
cognitive-behavioral therapy has been shown to be effective in
reducing depressive symptoms in adults (van der Feltz-Cornelis et
al. 2010).
Anxiety Disorders
In a meta-analytic review of anxiety in adults with diabetes, which
included 18 studies and a combined population of 4,076, the
prevalence of GAD was 14%, and anxiety symptoms were
experienced by 40% of those in the population studied (Rosenberg
et al. 2002). The treatment of these disorders, in most cases,
parallels the treatment of these conditions in persons without
diabetes and with the caveats and approaches described for the
treatment of depression in persons with diabetes.
Hypothyroidism
Cardinal Features
Reduced production of thyroid hormones is the central feature of
the clinical state termed hypothyroidism. Primary hypothyroidism is
caused by destruction of the thyroid by irradiation injury or
autoimmune destruction. Central or secondary hypothyroidism is
caused by hypothalamic or pituitary disease, which results in
insufficient stimulation of a normal thyroid gland. Signs of
hypothyroidism include weight gain, hypothermia, bradycardia,
thickening of the nails, thinning of hair, dryness of the skin,
thickening of the tongue and facial skin, and a delayed relaxation
phase of deep tendon reflexes. Diagnosis depends on the
demonstration of decreased circulating thyroid hormone.
Overt and Subclinical Hypothyroidism

Hypothyroidism is classified as subclinical or overt. Subclinical
hypothyroidism is defined as a serum thyroid stimulating hormone
(TSH) level above the upper limit of normal despite normal levels of
serum free thyroxine as compared with overt hypothyroidism, which
requires low levels of free thyroxine. A diagnosis of subclinical
hypothyroidism is only applied when thyroid function has been stable
for weeks or more, the hypothalamic-pituitary axis is normal, and
there is no recent or ongoing severe illness. Prospective data have
shown an increased risk of coronary artery disease, depression, and
heart failure (Nemeroff et al. 1985) among affected adults.
Psychiatric Symptoms in Hypothyroidism

Patients with hypothyroidism frequently exhibit cognitive, affective,
psychotic, and anxiety symptoms. The medical literature includes
early reports that emphasized the psychotic and cognitive
manifestations of hypothyroidism, whereas subsequent larger cross-
sectional and longitudinal studies and small interventional studies
have attempted to enhance our understanding of the
phenomenology of psychiatric symptoms in hypothyroidism through
the use of more sophisticated assessment tools. Unfortunately,
because of the diversity of the studies, small samples, and cognitive
tests used with limited sensitivity, the data are inconsistent. Studies
have also shown different neuropsychiatric manifestations between
overt and subclinical hypothyroidism.
Cognitive Disorders
Disturbances in cognition are a commonly reported psychiatric
symptom in hypothyroidism. The severity of the disturbance varies
from mild subjective cognitive slowing to severe delirium and
encephalopathy. Cross-sectional studies have shown that overt
hypothyroidism affects different cognitive domains including
attention, concentration, memory, intelligence, visuospatial skills,
language, and executive and psychomotor function (Davis and
Tremont 2007). Subclinical hypothyroidism has been associated with
mild cognitive impairment.
Mood Disorders
Hypothyroidism is commonly associated with depression, and
symptoms and signs overlap. Mania and hypomania are quite
uncommon; however, they have been noted in case reports in the
literature. Depression and hypothyroidism have symptoms that
overlap, including fatigue and memory, attention, and concentration
deficits. Therefore, it is recommended that patients with psychiatric
symptoms be screened for thyroid disease (Bunevicius and Prange
2010).
In contrast to overt hypothyroidism, the literature is mixed with
respect to mood and anxiety symptoms in subclinical
hypothyroidism. Large cross-sectional studies have not shown a link
between depression and subclinical hypothyroidism (Joffe et al.
2013).
Anxiety
Anxiety occurs in approximately 30% of unselected hypothyroid
patients. No correlation between the severity of anxiety as measured
by the Hamilton Anxiety Scale and the severity of hypothyroidism
was noted in a sample of 30 hypothyroid patients (Jain 1972). Our
understanding of the phenomenology of anxiety in hypothyroidism is
limited by a paucity of data. Clinical experience suggests that anxiety
is often accompanied by significant depressive symptoms and is
more generalized.
Psychosis
Evidence suggests that 5%–15% of patients with hypothyroidism
may develop psychosis (Heinrich and Grahm 2003). No systematic
assessment of thought disorder symptoms in patients with
hypothyroidism is available.
Effects of Hypothyroidism Treatment

Patients with hypothyroidism are generally treated with a single
daily dose of synthetic levothyroxine (LT4). Treatment of
hypothyroidism with LT4 improves mood and cognitive symptoms.
However, some patients, despite reaching a euthyroid state indicated
by normal TSH, still complain of neuropsychiatric symptoms
(Panicker et al. 2009). Other thyroid hormone preparations are
available and include desiccated thyroid extract, triiodothyronine
(T3), and a mixture of thyroxine (T4) and T3. Because T4 is
converted to T3, ultimately near-normal concentrations of serum T3
can be restored by administering T4 alone in sufficient dosage.
There is an ongoing debate about whether combination T4 and T3
therapy might be somehow better than treatment with T4 alone. The
studies of the combined treatment with T4 and T3 to improve
neuropsychological symptoms have shown mixed results. The
results of these double-blind placebo-controlled studies failed to
demonstrate benefits in the treatment of mood and impaired
cognition. Recent studies have suggested that patients with
polymorphisms (Thr92Ala) in the thyroid hormone transporter genes
may have a positive response to T3 augmentation. Thyroid hormone
transporters are necessary for the uptake of thyroid hormone into
target tissues. Mutations on other transporters such as the
monocarboxylate transporter 8 (MCT8) have been correlated with
the Allan-Herndon-Dudley syndrome that is characterized by severe
psychomotor retardation and elevated serum 3,3′,5-triiodothyronine
levels (van der Deure et al. 2010).
Hyperthyroidism
Cardinal Features
Hyperthyroidism is defined as the excess production and release
of thyroid hormone, resulting in abnormally elevated thyroid levels.
The cardinal symptoms of hyperthyroidism vary, but the most
common manifestations include diaphoresis, heat intolerance,
fatigue, dyspnea, palpitations, weakness (especially in proximal
muscles), anxiety, weight loss despite an increased appetite,
hyperdefecation, oligomenorrhea or amenorrhea, and visual
complaints. Signs of hyperthyroidism include noticeable anxiety and
increased psychomotor activity; tachycardia, often with atrial
fibrillation; bounding peripheral pulses; moist and warm skin; thinning
of the individual hair shafts, as well as alopecia; tremor and
hyperreflexia; and eye findings ranging from simple retraction of the
upper lid with lid lag to overt exophthalmos with impairment of
extraocular movement. The most common causes are toxic goiter
(Graves’ disease), toxic multinodular goiter (Plummer’s disease),
and toxic adenoma. Thyrotoxicosis also refers to a hypermetabolic
state that results in excessive amounts of circulating thyroid
hormone but includes extrathyroidal sources of thyroid hormone
such as exogenous intake or release of preformed stored hormone.
Thyroiditis, inflammation of the thyroid gland resulting in release of
stored hormone, is a frequent cause of thyrotoxicosis. The clinical
presentation of thyrotoxicosis varies from asymptomatic (subclinical)
to life-threatening (thyroid storm).
Psychiatric Symptoms in Hyperthyroidism
Although many authors have emphasized the ubiquitous presence
of psychiatric symptoms in patients with hyperthyroidism, scrutiny of
the literature suggests that serious psychopathology occurs in only a
minority of patients. During the acute phase of hyperthyroidism,
patients can experience numerous symptoms that overlap with those
occurring in psychiatric illness, such as sleep disturbance, fatigue,
decreased concentration, weight loss, and irritability. Recognition of
this symptom overlap led investigators to attempt to delineate a
relationship between the illnesses. Initially, this effort yielded little
and resulted in the hypothesis that coexisting hyperthyroidism and
psychiatric illness are just that, comorbid but unrelated. In the last
decade, however, much evidence has accrued to the contrary,
supporting more than a coincident occurrence.
A Danish registry-based nationwide cohort study (Brandt et al.
2013) evaluated the association between hyperthyroidism and
psychiatric morbidity. The hyperthyroid patients had an increased
risk of being hospitalized with a psychiatric diagnosis and were more
likely than the control individuals to be taking antipsychotics,
antidepressants, or anxiolytics before they were diagnosed with
hyperthyroidism.
Cognitive Disorders
Cognitive changes associated with thyrotoxicosis range from
subtle defects in attention and concentration to overt delirium. Some
cross-sectional studies of overt thyrotoxicosis have shown
impairment in attention, concentration, and executive function
compared with control subjects. However, other studies have failed
to find deficits in cognition (Vogel et al. 2007).
Mood Disorders
Major depression is a common psychiatric manifestation of
hyperthyroidism, occurring in approximately 23% of patients with
Graves’ disease. Furthermore, the mood symptoms may precede the
development of physical signs and symptoms in some patients.
Mania and hypomania secondary to hyperthyroidism are distinctly
uncommon but are described in case reports (Bunevicius and
Prange 2010).
Anxiety
Anxiety due to hyperthyroidism generally has an insidious onset,
often preceding overt physical signs of the disorder. The anxiety
associated with thyrotoxicosis was indistinguishable from that
observed in primary anxiety disorders (Greer et al. 1973).
Psychosis
Psychosis is an uncommon manifestation of thyrotoxicosis.
Although estimates of prevalence have commonly been 15%–25%
based on studies performed in the 1960s, the symptoms reported in
those patients would be classified presently as affective disorders.
Accordingly, the frequency of psychosis in this context remains
uncertain but generally is taken to be low.
Hashimoto’s Encephalitis
Hashimoto’s encephalitis, or steroid-responsive encephalopathy
with autoimmune thyroiditis, is an unusual clinical syndrome that
warrants separate discussion. Patients with autoimmune thyroiditis
rarely manifest a subacute onset of confusion leading to delirium or
dementia. The clinical presentation often includes memory loss,
seizures, tremor, myoclonus, and ataxia. Several cases have been
reported of a severe encephalopathic state associated with the
presence of high titers of antithyroid antibodies, including
antithyroglobulin antibody (anti-Tg) and antithyroid peroxidase
antibody (anti-TPO). The pathophysiology and how the anti-TPO
and/or anti-Tg reacts with brain tissues are still unclear.
Hypothalamic-Pituitary-Thyroid Axis and Depression

Affective symptoms have long been identified in patients with
thyroid disease, leading many investigators to search for the role of
thyroid axis abnormalities in affective disorders. Thyroid hormone
supplementation has been found to increase the rapidity of action of
TCAs. T3 is an effective agent for augmentation of TCAs. However,
the data for T3 augmentation in the efficacy of SSRIs have been
mixed. Enhancement studies revealed that concurrent administration
of T3 at the inception of SSRI treatment leads to an acceleration of
response (Cooper-Kazaz et al. 2007). The evidence base for T3
augmentation of TCAs is considerable for acceleration of response
and efficacy. T3 augmentation/acceleration of SSRIs has been
investigated more recently, and no firm conclusions can be drawn
regarding its efficacy at this time.
Thus, the precise relationship between the hypothalamic-pituitary-
thyroid (HPT) axis and affective disorders remains unclear. The
complexities involved in this relationship are the following: 1)
Symptoms of depression occur in both hypothyroidism and
hyperthyroidism. 2) Most depressed patients have HPT axis
functions within the normal range (Esposito et al. 1997). 3) Elevated
levels of thyrotropin-releasing hormone have been reported in
cerebrospinal fluid of patients with major depression (Banki et al.
1988). 4) Patients with MDD exhibit a blunted TSH response to
exogenously administered thyrotropin-releasing hormone, whereas
depressed patients show an exaggerated response, which has been
associated with positive antithyroid peroxide antibodies (Carta et al.
2004). 5) The mechanism for the blunted TSH is unknown, but
elevated glucocorticoid levels in depression are known to inhibit the
thyroid axis; there is a higher prevalence rate of symptomless
autoimmune thyroiditis in depressed patients (Nemeroff et al. 1985).
6) Functioning of the HPT axis can be influenced by a variety of
states such as systemic or chronic illness, chronic physiological
stress, nutritional status, circadian rhythms, and cognitive processes
(Esposito et al. 1997). 7) Evidence suggests that thyroid hormones
affect neurotransmitter activity.
The brain’s serotonin system participates in the pathogenesis of
affective disorders. Some studies showed that thyroid hormone
abnormalities may be linked to reduced serotonin responsiveness.
Variation in thyroid hormone pathway genes and their effects on
clinical phenotypes is a recent area of research. Deiodinases are
selenocysteine enzymes that remove iodine molecules from thyroid
hormones. They are important for local T3 availability in the brain,
and thyroid hormone status has been associated with optimal
emotional and cognitive functioning. Three deiodinases have been
described (D1, D2, and D3). D1 and D2 play a role in the conversion
of T4 to T3. D3 is the main T3-inactivating enzyme, regulating the
conversion of T3 to T2 and T4 to reverse T3 (rT3). Single-nucleotide
polymorphisms (SNPs) have been identified in the deiodinases
genes. Panicker et al. (2009) demonstrated in a large cohort of
patients taking thyroid hormone replacement therapy that the D2-
Thr92Al polymorphism was associated with worse baseline General
Health Questionnaire scores in patients taking T4 replacement
therapy and improved response to combined T4-T3 therapy. No
impact of D1 or D3 polymorphisms on study outcomes was found. In
a relatively small population of patients with primary autoimmune
hypothyroidism (nZ141), D2 variants (D2-ORFa-Gly3Asp and D2-
Thr92Ala) have shown no association with well-being,
neurocognitive function, or preference for combined T4-T3 therapy
(Surks et al. 2004). The D1-C785T polymorphism was associated
with lifetime major depression in white female subjects from high-risk
cohorts (Philibert et al. 2002).
Organic anion-transporting polypeptides (OATPs) are proteins
capable of transporting thyroid hormone into the cell. Genetic coding
for OATP1C1 is located on chromosome 12p12, and the protein is a
thyroid hormone (T4 and rT3) transporter expressed at the blood-
brain barrier, considered to play a key role in delivering T4 to the
brain. A study found that the presence of the OATP1C1 SNP in
patients with primary autoimmune hypothyroidism was associated
with an increased frequency of hypothyroid symptoms, including
fatigue and depression (van der Deure et al. 2008). All of these
findings preclude a simple understanding of HPT axis dysfunction in
depression and emphasize the need for considerably more research
in this area.
Cushing’s Syndrome
Cardinal Features
Cushing’s syndrome is caused by prolonged exposure to elevated
levels of either endogenous or exogenous glucocorticoids. The most
common signs and symptoms of Cushing’s syndrome are centripetal
obesity, hirsutism, menstrual irregularities, decreased libido,
impotence, hypertension, proximal weakness, red to purple striae,
acne, and easy bruisability. Osteopenia and glucose intolerance may
also occur. Endogenous Cushing’s syndrome is classified as either
adrenocorticotropic hormone (ACTH) dependent or ACTH
independent. Most cases of Cushing’s syndrome are due to high-
dose corticosteroid administration, with adrenal carcinoma and
ectopic ACTH production occurring less frequently. The term
Cushing’s disease is reserved for cases of hypercortisolism due to
ACTH hypersecretion from a pituitary adenoma.
Psychiatric Symptoms in Cushing’s Syndrome

Psychiatric symptoms occurring in Cushing’s syndrome have
been well documented in the literature. In 1913, Harvey Cushing
noted psychiatric disturbance, particularly depression, in his first
description of the illness that bears his name (Cushing 1932). In the
decades since Cushing’s observations, substantial progress has
been made toward identifying the mechanisms by which excess
corticosteroids affect mood, anxiety, and cognition.
Mood and Anxiety Disorders

In a prospective study, Starkman (2013) found prominent
irritability and emotional lability in depressed patients with Cushing’s
syndrome. Patients also exhibited symptoms of generalized anxiety
and neurovegetative symptoms including insomnia, decreased libido,
and disturbances in appetite. Treating Cushing’s syndrome has been
shown to improve mood symptoms correlated with reduced
circulating cortisol levels.
Psychosis and Cognitive Disorder

Psychosis and overt delirium have rarely been reported in
individuals with Cushing’s disease (Rueda-Lara et al. 2003).
Psychotic symptoms in Cushing’s syndrome are usually associated
with affective syndromes.
Cognitive impairment in Cushing’s syndrome is reported relatively
infrequently, and when documented, impairment has been mild.
Attention has been focused on specific areas of the brain such as
the hippocampus, which plays a critical role in learning and memory
and is a major target of glucocorticoids. In a series of studies from
1981 through 2007, Starkman (2013) explored the neuropsychiatric
effects of elevated cortisol, especially with respect to cognition.
Starkman found that the hippocampal volume was negatively
correlated with serum levels of cortisol. Furthermore, verbal learning
and recall were positively associated with hippocampal volume. After
establishing a correlation between elevated cortisol levels, reduced
hippocampal formation volume, and memory dysfunction before
treatment of Cushing’s syndrome, Starkman (2013) then
demonstrated that hippocampal formation volume increased after
cortisol levels were returned to normal concentrations. These results
support the hypothesis that the hippocampus is particularly sensitive
to cortisol.
Exogenous Corticosteroid Administration

Psychiatric complications of corticosteroids were recognized
shortly after they were introduced into clinical practice in the 1950s.
Psychiatric symptoms are predominantly affective, although
cognitive changes, psychosis, delirium, and anxiety have also been
reported (Belanoff et al. 2001; Brown et al. (2002).
Despite widespread clinical use of corticosteroids, many of the
psychiatric side effects remain poorly characterized. Many groups of
researchers have attempted to address these issues. Naber et al.
(1996) and Wolkowitz et al. (1990) found that although depressive
symptoms exist, manic symptoms predominate in patients
undergoing short courses of steroid treatment. Other researchers
have studied the effects of long-term corticosteroid therapy (Brown
et al. 2002). Sleep disturbance and an increase in appetite and food-
seeking behavior are common side effects. When mood symptoms
are present, depressive symptoms are common. Cognitive
symptoms include word-finding difficulties and difficulties with
concentration and retaining information while reading.
Glucocorticoids regulate production and release of hypothalamic
corticotropin-releasing hormone and ACTH, modulate the activity of
several neurotransmitter systems, and act upon the plasticity and
circuitry of many brain regions. It is therefore not surprising that the
effects of glucocorticoid excess can be profound. Delineating their
complex role in central nervous system function has been an active
area of research for many decades. For example, observations of
the clinical impact of excess glucocorticoids on memory, coupled
with an emerging understanding of how memories are formed, have
led to detailed investigation of the cellular effects of glucocorticoids.
It appears that glucocorticoids are active in many processes within
the brain, including the mediation of neuron survival and death,
dendritic branching, synapse formation, operation of various second
messenger systems, and suppression of myelin content (Belanoff et
al. 2001).
Although the data are limited, a variety of strategies have been
employed to prevent steroid-induced psychiatric disturbances,
including administering divided doses, enteric-coated preparations,
lithium, chlorpromazine, valproic acid, lamotrigine, and olanzapine.
TCAs have been shown to exacerbate symptoms and are therefore
not a treatment option, and only have small benefit after the levels of
cortisol are reduced. The most effective strategy to treat
corticosteroid-induced psychiatric symptoms is reducing the dose of
steroids or adding a mood stabilizer/atypical antipsychotic (Brown et
al. 2004).
Addison’s Disease (Adrenal Insufficiency)
Cardinal Features
The symptoms of adrenal insufficiency are best understood in
terms of chronic and acute symptoms. Chronic adrenal insufficiency
is manifested by fatigue, malaise, weakness, weight loss, anorexia,
hyperpigmentation, hypotension, nausea, and vomiting.
Hyponatremia, hyperkalemia, metabolic acidosis, anemia, and
eosinophilia are often present on laboratory testing. Acute adrenal
insufficiency is manifested by more profound gastrointestinal
symptoms, including pain—which may mimic acute abdomen—fever,
and shock.
Psychiatric Symptoms in Adrenal Insufficiency

Primary hypoadrenalism refers to glucocorticoid deficiency
occurring in the setting of adrenal disease, whereas secondary
hypoadrenalism arises because of deficiency of ACTH. The
neuropsychiatric manifestations of adrenal insufficiency have not
been thoroughly studied. Reported symptoms include depressed
mood, sleep disturbances, and lack of energy. Addison’s (1868)
initial description of the disorder noted evidence of impaired
cognition.
Hypothalamic-Pituitary-Adrenal Axis and Depression

Observations of mood disturbance, both in patients with Cushing’s
syndrome and in those given exogenous steroids, led many
investigators to consider the role of cortisol in patients with primary
mood disorders. Hypercortisolemia has since been widely
documented in individuals with major depression and appears to
represent a state as opposed to a trait marker for depression
(Nemeroff et al. 1984). Several authors have postulated that
hypercortisolemia is a treatable factor, which can lead to
improvement in neuropsychiatric symptoms (Starkman 2013).
Hypercortisolemia is associated with hippocampal alterations and
deficits in verbal learning and memory in patients with depression.
MRI studies support this hypothesis in that patients with depression
have been shown to have smaller hippocampal volumes (Bremner
2002).
Clinical, epidemiological, and experimental studies have shown
that stressful life events activate the HPA axis. The autonomic
nervous system and HPA axis hyperreactivity, presumably due to
hypersecretion of corticotropin-releasing factor, may be a persistent
consequence of childhood abuse and contribute to the vulnerability
to psychopathological conditions in adulthood. Prolonged activation
of the HPA axis and the autonomic nervous system is associated
with changes in brain development and poor health outcomes (Heim
et al. 2010). These persistent neurobiological responses from early
life stress have been hypothesized to mediate vulnerability to
depression. However, not all victims of early life trauma develop
depression or any other psychiatric illness. The resilience of these
individuals appears to be associated with perceived personality style,
positive parental care, and the quality of peer and love relationships.
The variation of resilience among individuals is also likely explained
by genetic factors that moderate the relationship between early life
stress and depression. SNPs have been identified on four genes of
components of the HPA axis (i.e., CRHR1, NR3C2, NR3C1, FKBP5)
that modulate vulnerability to major depression after early life stress
(Pagliaccio et al. 2014). In summary, the association between the
stress of childhood trauma and depression is mediated by a number
of neurobiological pathways (e.g., corticotropin-releasing factor and
HPA axis dysregulation, immune system dysregulation) and
moderated by complex genetic mechanisms, including epigenetics.
Pheochromocytoma
Cardinal Features
Pheochromocytomas are rare, catecholamine-secreting, vascular
neuroendocrine tumors arising from chromaffin cells of the adrenal
medulla. The clinical symptoms are due to episodic release of
excess catecholamines into circulation. About 15%–20% of such
tumors are extra-adrenal in origin and are termed paragangliomas.
Common signs of pheochromocytoma include sustained or
paroxysmal hypertension, orthostatic hypotension, hyperhidrosis,
hypertensive retinopathy, pallor (very rarely flushing), Raynaud’s
phenomenon, and livedo reticularis. Prominent symptoms include
headache, diaphoresis, palpitations, tremulousness, abdominal or
chest pain, nausea, vomiting, and weakness. Diagnosis depends on
demonstration of elevated circulating catecholamines, after which
localization of the tumor is undertaken.
Psychiatric Symptoms in Pheochromocytoma
Anxiety is the most frequent psychiatric symptom in
pheochromocytoma, having been described in 22%–44% of patients
with this tumor (Modlin et al. 1979). Although anxiety symptoms are
frequently encountered in patients with pheochromocytoma, full
syndromal states resembling panic disorder or GAD are relatively
uncommon. Given the relative rarity of the syndrome even in
hypertensive populations, evaluation for pheochromocytoma should
probably be reserved for those patients whose anxiety symptoms are
accompanied by headache, palpitations, significant blood pressure
abnormalities, and diaphoresis.
Hyperprolactinemia
Cardinal Features
Prolactin is secreted by the lactotroph cells of the anterior pituitary
gland, and its secretion is caused by both physiological and
pathological conditions. The physiological stimuli include pregnancy,
stress, and nipple stimulation. Pathological hyperprolactinemia can
be caused by prolactinomas, decreased dopaminergic inhibition of
prolatic secretion, and decreased clearance of prolactin. The primary
consequence of hyperprolactinemia is gonadal dysfunction.
Amenorrhea and galactorrhea are the primary manifestations in
females, whereas impotence is the primary symptom in males,
although gynecomastia and galactorrhea can occur. Drug-induced
causes of hyperprolactinemia (e.g., antipsychotics) need to be
considered in the differential diagnosis, along with
hyperprolactinemia due to other endocrinopathies or due to hepatic
or renal disease. Idiopathic hyperprolactinemia and pituitary
adenomas constitute the remainder of cases. MRI of the sella is the
preferred modality for pituitary imaging. Treatment involves
administration of dopamine agonists or surgical resection.
Antipsychotics are known dopamine type 2 (D2) receptor
antagonists and raise serum prolactin by blocking the dopamine-
induced inhibition of prolactin secretion. Among newer
antipsychotics, the highest prevalence of hyperprolactinemia has
been observed with amisulpride, risperidone, and paliperidone,
whereas aripiprazole and quetiapine have the most favorable profile
(Peuskens et al. 2014).
Psychiatric Symptoms in Hyperprolactinemia

Compared with other endocrinopathies, the assessment of the
prevalence of psychiatric symptoms and syndromes in patients with
hyperprolactinemia has received little attention. Most of the literature
regarding psychiatric manifestations of hyperprolactinemia is
focused on symptoms such as aggression and hostility.
Bromocriptine, a dopamine agonist used in treating
hyperprolactinemia, has been demonstrated to reduce depression,
anxiety, and anger-hostility, based on the Symptom Questionnaire
(SQ; Kellner et al. 1984) scales; this improvement in symptoms
correlated with a reduced serum prolactin level. Taken together,
existing data suggest that hyperprolactinemia may contribute to
affective symptoms, although the precise relationship between
hyperprolactinemia and specific diagnostic syndromes remains to be
defined.
Hyperparathyroidism
Cardinal Features
The ability to diagnose primary hyperparathyroidism has changed
dramatically over the last several decades, primarily because of
automated screening laboratory panels. Most patients today either
are asymptomatic or have vague, nonspecific complaints. Fatigue,
malaise, weakness, and cognitive complaints are common. Other
manifestations include nephrolithiasis, proximal weakness of the
lower extremities, chondrocalcinosis, and band keratopathy.
Subperiosteal bone resorption and osteitis fibrosa cystica are rarely
seen today. Diagnosis depends on demonstration of elevated
circulating parathyroid hormone.
Psychiatric Symptoms in Hyperparathyroidism

A variety of psychiatric disturbances have been associated with
hyperparathyroidism, including mood, anxiety, psychotic, and
cognitive disorders. Most of the literature consists of case reports
and small case series. Okamoto et al. (1997) provided a
comprehensive review of the literature on the relation of primary
hyperparathyroidism to mild hypercalcemia and psychiatric
disturbances.
Review of the case literature reveals that psychological symptoms
in most patients improve with correction of serum calcium and
removal of the parathyroid adenoma. Other smaller case-control
studies have shown inconsistent results on improvement of
depression after parathyroidectomy.
Hypoparathyroidism
Cardinal Features
Hypoparathyroidism most commonly occurs as an idiopathic
variant in surgical patients after thyroidectomy. Its most prominent
feature is evidence of neuromuscular irritability, ranging from
paresthesias to muscle cramps, carpopedal spasm, laryngospasm,
and seizures. However, deep tendon reflexes are often decreased or
absent. Ocular findings include cataracts and, more rarely,
papilledema. Skin changes include alopecia; transverse nail growth;
dry, scaling, pigmented skin; and a propensity to develop candidal
infections.
Psychiatric Symptoms in Hypoparathyroidism
Numerous psychiatric symptoms have been reported in
hypoparathyroidism, including irritability and affective, anxiety,
psychotic, and cognitive disorders. Cognitive disorders are the most
frequently encountered syndromes.
The literature on psychiatric manifestations of hypoparathyroidism
continues to be dominated by the exhaustive study by Denko and
Kaelbling (1962). They reviewed 268 cases of hypoparathyroidism
selected for psychiatric symptoms and compared them with 58 cases
of pseudohypoparathyroidism and 11 cases of
pseudopseudohypoparathyroidism. Among patients with
hypoparathyroidism, these investigators noted severe intellectual
impairment in 56 patients, organic brain syndromes in 47, psychotic
symptoms in 29, and neurotic symptoms in 32. Fifty-seven patients
were considered to have undiagnosable psychiatric illness, yet
scrutiny of the data reveals that several of these patients had
affective and anxiety symptoms.
Improvement With Treatment

The overwhelming majority of the patients in the Denko and
Kaelbling (1962) series experienced improvement in their psychiatric
symptoms with treatment of the underlying hypoparathyroidism.
Conclusion
This review represents a clinically oriented discussion of the
prevalence and phenomenology of psychiatric symptoms in
endocrine disease. It remains unknown whether the associated
psychiatric disturbances are the direct result of primary metabolic
derangement in each endocrine disorder or are due to some
heretofore unknown factors. The pathophysiological mechanisms
involved in the development of psychiatric symptoms in endocrine
disturbances undoubtedly vary with the particular endocrine disorder.
Therefore, an understanding of the phenomenology of these
relationships is also critical to developing hypotheses concerning the
precise mechanisms by which endocrine disorders can produce
psychiatric symptoms.
It appears that the severity of the endocrine disturbance is often
correlated with the prevalence or severity of psychiatric symptoms,
although this is not always the case. In addition, it is important to
note that serious psychiatric syndromes are often present in only a
minority of patients. Potential risk factors (e.g., genetic
predisposition) for the development of psychiatric symptoms in
endocrine disease need to be identified as well. Clearly, further
research on pathophysiology and treatment is warranted.
References
Addison TW: Disease of the supra-renal capsules, in A Collection of the Published
Writings of the Late Thomas Addison, MD: Physician to Guy’s Hospital. Edited
by Addison TW, Wilks S, Daldy TM. London, The New Sydenham Society
1868, pp 209–239
American Diabetes Association: Type 2 diabetes in children and adolescents.
Diabetes Care 23(3):381–389, 2000 10868870
Anderson RJ, Freedland KE, Clouse RE, et al: The prevalence of comorbid
depression in adults with diabetes: a meta-analysis. Diabetes Care
24(6):1069–1078, 2001 11375373
Austin EJ, Deary IJ: Effects of repeated hypoglycemia on cognitive function: a
psychometrically validated reanalysis of the Diabetes Control and
Complications Trial data. Diabetes Care 22(8):1273–1277, 1999 10480770
Awad N, Gagnon M, Messier C: The relationship between impaired glucose
tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol
26(8):1044–1080, 2004 15590460
Banki CM, Bissette G, Arato M, et al: Elevation of immunoreactive CSF TRH in
depressed patients. Am J Psychiatry 145(12):1526–1531, 1988 3143269
Barnard K, Peveler RC, Holt RI: Antidepressant medication as a risk factor for type
2 diabetes and impaired glucose regulation: systematic review. Diabetes Care
36(10):3337–3345, 2013 24065841
Baumeister H, Hutter N, Bengel J: Psychological and pharmacological
interventions for depression in patients with diabetes mellitus and depression.
Cochrane Database Syst Rev (12):CD008381, 2012 23235661
Belanoff JK, Gross K, Yager A, et al: Corticosteroids and cognition. J Psychiatr
Res 35(3):127–145, 2001 11461709
Blasetti A, Chiuri RM, Tocco AM, et al: The effect of recurrent severe
hypoglycemia on cognitive performance in children with type 1 diabetes: a
meta-analysis. J Child Neurol 26(11):1383–1391, 2011 21572053
Brandt F, Thvilum M, Almind D, et al: Hyperthyroidism and psychiatric morbidity:
evidence from a Danish nationwide register study. Eur J Endocrinol
170(2):341–348, 2013 24282192
Bremner JD: Structural changes in the brain in depression and relationship to
symptom recurrence. CNS Spectr 7(2):129–130, 135–139, 2002 15220855
Brown ES, Suppes T, Khan DA, et al: Mood changes during prednisone bursts in
outpatients with asthma. J Clin Psychopharmacol 22(1):55–61, 2002 11799343
Brown ES, Chamberlain W, Dhanani N, et al: An open-label trial of olanzapine for
corticosteroid-induced mood symptoms. J Affect Disord 83(2–3):277–281, 2004
15555725
Bunevicius R, Prange AJ Jr: Thyroid disease and mental disorders: cause and
effect or only comorbidity? Curr Opin Psychiatry 23(4):363–368, 2010
20404728
Carta MG, Loviselli A, Hardoy MC, et al: The link between thyroid autoimmunity
(antithyroid peroxidase autoantibodies) with anxiety and mood disorders in the
community: a field of interest for public health in the future. BMC Psychiatry
4:25, 2004 15317653
Centers for Disease Control and Prevention: National diabetes fact sheet: national
estimates and general information on diabetes and prediabetes in the United
States, 2011. Available at:
https://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed March 3,
2017.
Cheng G, Huang C, Deng H, et al: Diabetes as a risk factor for dementia and mild
cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J
42(5):484–491, 2012 22372522
Cooper-Kazaz R, Apter JT, Cohen R, et al: Combined treatment with sertraline and
liothyronine in major depression: a randomized, double-blind, placebo-
controlled trial. Arch Gen Psychiatry 64(6):679–688, 2007 17548749
Craft S, Cholerton B, Baker LD: Insulin and Alzheimer’s disease: untangling the
web. J Alzheimers Dis 33 (suppl 1):S263–S275, 2013 22936011
Cushing H: The basophil adenomas of the pituitary body and their clinical
manifestations (pituitary basophilism). Bulletin of the Johns Hopkins Hospital
50:137–195, 1932
Dantzer R, Kelley KW: Twenty years of research on cytokine-induced sickness
behavior. Brain Behav Immun 21(2):153–160, 2007 17088043
Davis JD, Tremont G: Neuropsychiatric aspects of hypothyroidism and treatment
reversibility.. Minerva Endocrinol 32(1):49–65, 2007 17353866
Denko JD, Kaelbling R: The psychiatric aspects of hypoparathyroidism. Acta
Psychiatr Scand Suppl 38(164):1–70, 1962 14027013
Diabetes Control and Complications Trial Research Group: Effects of intensive
diabetes therapy on neuropsychological function in adults in the Diabetes
Control and Complications Trial. Ann Intern Med 124(4):379–388, 1996
8554246
Esposito S, Prange AJ Jr, Golden RN: The thyroid axis and mood disorders:
overview and future prospects. Psychopharmacol Bull 33(2):205–217, 1997
9230632
Farris W, Mansourian S, Chang Y, et al: Insulin-degrading enzyme regulates the
levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein
intracellular domain in vivo. Proc Natl Acad Sci USA 100(7):4162–4167, 2003
12634421
Ferguson SC, Blane A, Perros P, et al: Cognitive ability and brain structure in type
1 diabetes: relation to microangiopathy and preceding severe hypoglycemia.
Diabetes 52(1):149–156, 2003a 12502506
Ferguson IM, Deary IJ, Evans JC, et al: Apolipoprotein-e influences aspects of
intellectual ability in type 1 diabetes. Diabetes 52(1):145–148, 2003b 12502505
Fisher EB, Chan JC, Nan H, et al: Co-occurrence of diabetes and depression:
conceptual considerations for an emerging global health challenge. J Affect
Disord 142(suppl):S56–S66, 2012 23062858
Golden MP, Ingersoll GM, Brack CJ, et al: Longitudinal relationship of
asymptomatic hypoglycemia to cognitive function in IDDM. Diabetes Care
12(2):89–93, 1989 2702906
Greer S, Ramsay I, Bagley C: Neurotic and thyrotoxic anxiety: clinical,
psychological and physiological measurements. Br J Psychiatry 122(570):549–
554, 1973 4717027
Gregg EW, Yaffe K, Cauley JA, et al: Is diabetes associated with cognitive
impairment and cognitive decline among older women? Study of Osteoporotic
Fractures Research Group. Arch Intern Med 160(2):174–180, 2000 10647755
Hannonen R, Tupola T, Ahonen A Riikonen R: Neurocognitive functioning in
children with type-1 diabetes with and without episodes of severe
hypoglycaemia. Dev Med Child Neurol 45(4):262–268, 2003 12647928
Heim C, Shugart M, Craighead WE, et al: Neurobiological and psychiatric
consequences of child abuse and neglect. Dev Psychobiol 52(7):671–690,
2010 20882586
Heinrich TW, Grahm G: Hypothyroidism Presenting as Psychosis: Myxedema
Madness Revisited. Prim Care Companion J Clin Psychiatry 5(6):260–266,
2003 15213796
Hershey T, Lillie R, Sadler M White NH: Severe hypoglycemia and long-term
spatial memory in children with type 1 diabetes mellitus: a retrospective study.
J Int Neuropsychol Soc 95(5):740–750, 2003 12901780
Horwitz DL: Factitious and artifactual hypoglycemia. Endocrinol Metab Clin North
Am 18(1):203–210, 1989 2645127
Jain VK: A psychiatric study of hypothyroidism. Psychiatr Clin (Basel) 5(2):121–
130, 1972 5021364
Joffe RT, Pearce EN, Hennessey JV, et al: Subclinical hypothyroidism, mood, and
cognition in older adults: a review. Int J Geriatr Psychiatry 28(2):111–118, 2013
22410877
Katon WJ, Rutter C, Simon G, et al: The association of comorbid depression with
mortality in patients with type 2 diabetes. Diabetes Care 28(11):2668–2672,
2005 16249537
Kellner R, Buckman TM, Fava M, et al: Prolactin, aggression, and hostility: a
discussion of recent studies. Psychiatr Dev 2(2):131–138, 1984 6483849
Lustman PJ, Penckofer SM, Clouse RE: Recent advances in understanding
depression in adults with diabetes. Curr Diab Rep 7(2):114–122, 2007
17425915
Modlin IM, Farndon JR, Shepherd A, et al: Phaeochromocytomas in 72 patients:
clinical and diagnostic features, treatment and long term results. Br J Surg
66(7):456–465, 1979 466037
Mommersteeg PM, Herr R, Pouwer F, et al: The association between diabetes and
an episode of depressive symptoms in the 2002 World Health Survey: an
analysis of 231,797 individuals from 47 countries. Diabet Med 30(6):e208–
e214, 2013 23614792
Naber D, Sand P, Heigl B: Psychopathological and neuropsychological effects of 8-
days’ corticosteroid treatment: a prospective study. Psychoneuroendocrinology
21(1):25–31, 1996 8778901
Nemeroff CB, Widerlöv E, Bissette G, et al: Elevated concentrations of CSF
corticotropin-releasing factor-like immunoreactivity in depressed patients.
Science 226(4680):1342–1344, 1984 6334362
Nemeroff CB, Simon JS, Haggerty JJ Jr, et al: Antithyroid antibodies in depressed
patients. Am J Psychiatry 142(7):840–843, 1985 4014506
Nouwen A, Nefs G, Caramlau I, et al; European Depression in Diabetes Research
Consortium: Prevalence of depression in individuals with impaired glucose
metabolism or undiagnosed diabetes: a systematic review and meta-analysis of
the European Depression in Diabetes (EDID) Research Consortium. Diabetes
Care 34(3):752–762, 2011 21357362
Okamoto T, Gerstein HC, Obara T: Psychiatric symptoms, bone density and non-
specific symptoms in patients with mild hypercalcemia due to primary
hyperparathyroidism: a systematic overview of the literature. Endocr J
44(3):367–374, 1997 9279511
Okamura F, Tashiro A, Utumi A, et al: Insulin resistance in patients with depression
and its changes during the clinical course of depression: minimal model
analysis. Metabolism 49(10):1255–1260, 2000 11079812
Pagliaccio D, Luby JL, Bogdan R, et al: Stress-system genes and life stress
predict cortisol levels and amygdala and hippocampal volumes in children.
Neuropsychopharmacology 39(5):1245–1253, 2014 24304824
Panicker V, Saravanan P, Vaidya B, et al: Common variation in the DIO2 gene
predicts baseline psychological well-being and response to combination
thyroxine plus triiodothyronine therapy in hypothyroid patients. J Clin
Endocrinol Metab 94(5):1623–1629, 2009 19190113
Patiño-Fernández AM, Delamater AM, Applegate EB, et al: Neurocognitive
functioning in preschool-age children with type 1 diabetes mellitus. Pediatr
Diabetes 11(6):424–430, 2010 20456084
Peuskens J, Pani L, Detraux J, et al: The effects of novel and newly approved
antipsychotics on serum prolactin levels: a comprehensive review. CNS Drugs
28(5):421–453, 2014 24677189
Philibert R, Caspers K, Langbehn D, et al: The association of a HOPA
polymorphism with major depression and phobia. Compr Psychiatry 43(5):404–
410, 2002 12216017
Pouwer F, Geelhoed-Duijvestijn PH, Tack CJ, et al: Prevalence of comorbid
depression is high in out-patients with Type 1 or Type 2 diabetes mellitus.
Results from three out-patient clinics in the Netherlands. Diabet Med
27(2):217–224, 2010 20546267
Pramming S, Thorsteinsson B, Theilgaard A, et al: Cognitive function during
hypoglycemia in type I diabetes mellitus. Br Med J (Clin Res Ed) 292:647–650,
1986
Reichard P, Pihl M, Rosenqvist U, Sule J: Complications in IDDM are caused by
elevated blood glucose level: the Stockholm Diabetes Intervention Study
(SDIS) at 10-year follow up. Diabetologia 39(12):1483–1488, 1996 8960830
Rosenberg NL, Grigsby J, Dreisbach J, et al: Neuropsychologic impairment and
MRI abnormalities associated with chronic solvent abuse. J Toxicol Clin Toxicol
40(1):21–34, 2002 11990201
Rueda-Lara MA, Buchert S, Skotzko C, et al: Psychiatric symptoms masking
pituitary adenoma in Spanish speaking immigrants. Gen Hosp Psychiatry
25(5):367–371, 2003 12972230
Starkman MN: Neuropsychiatric findings in Cushing syndrome and exogenous
glucocorticoid administration. Endocrinol Metab Clin North Am 42(3):477–488,
2013 24011881
Surks MI, Ortiz E, Daniels GH, et al: Subclinical thyroid disease: scientific review
and guidelines for diagnosis and management. JAMA 291(2):228–238, 2004
14722150
van der Deure WM, Appelhof BC, Peeters RP, et al: Polymorphisms in the brain-
specific thyroid hormone transporter OATP1C1 are associated with fatigue and
depression in hypothyroid patients. Clin Endocrinol (Oxf) 69(5):804–811, 2008
18410547
van der Deure WM, Peeters RP, Visser TJ: Molecular aspects of thyroid hormone
transporters, including MCT8, MCT10, and OATPs, and the effects of genetic
variation in these transporters. J Mol Endocrinol 44(1):1–11, 2010 19541799
van der Feltz-Cornelis CM, Nuyen J, Stoop C, et al: Effect of interventions for
major depressive disorder and significant depressive symptoms in patients with
diabetes mellitus: a systematic review and meta-analysis. Gen Hosp Psychiatry
32(4):380–395, 2010 20633742
van Harten B, de Leeuw FE, Weinstein HC, et al: Brain imaging in patients with
diabetes: a systematic review. Diabetes Care 29(11):2539–2548, 2006
17065699
Vogel A, Elberling TV, Hørding M, et al: Affective symptoms and cognitive
functions in the acute phase of Graves’ thyrotoxicosis.
Psychoneuroendocrinology 32(1):36–43, 2007 17097812
Wolkowitz OM, Rubinow D, Doran AR, et al: Prednisone effects on neurochemistry
and behavior: preliminary findings. Arch Gen Psychiatry 47(10):963–968, 1990
1977371
CHAPTER 17
Sleep and Sleep-Wake Disorders

What is sleep? For most, one could paraphrase Supreme Court Justice
Potter Stewart—“I know it when I see it” (although he was referring to
obscenity). Sleep is characterized by typical changes in posture, reduced
motor activity, and a threshold for response to external stimuli that increases
progressively as sleep deepens (Datta 2010). Sleep was historically viewed
as a largely passive state, a mechanism for the brain to go “off-line.” We
now know that the brain functions in and transitions between three
physiologically distinct states, namely, wakefulness, non–rapid eye
movement (NREM) sleep, and rapid eye movement (REM) sleep. The
nuclei, networks, and neurotransmitters that generate and regulate the
transitions between these states are also integral to regulation of
homeostasis, sensorimotor function, emotion, behavior, and cognition
(Dyken et al. 2012). The process of sleep fundamentally affects the brain in
nearly every possibly way, from the regulation of genes to the plasticity of
widespread networks (Abel et al. 2013), and the quality and quantity of sleep
is a biomarker of the functional state of the brain and health in general
(Luyster et al. 2012). Thus, there is a reciprocal relationship between sleep
and the general medical, neurological, and psychological aspects of health
—you cannot have one without the other—and disturbances in one system
commonly cause disturbances in the other, either directly or indirectly.
Because sleep is so fundamental to health, the presence of sleep
disruption or disorder represents “low-hanging fruit”—a therapeutic target for
which the appropriate intervention, most often behavioral and noninvasive,
can have a beneficial impact on comorbid medical, neurological, or
psychiatric disorders and improve overall morbidity, mortality, and quality of
life (Bloom et al. 2009; Dyken et al. 2012; Schutte-Rodin et al. 2008; Watson
and Viola-Saltzman 2013). In this chapter, we review the physiological
aspects of sleep and the pathophysiology, diagnosis, and treatment of
common sleep-wake disorders, with an emphasis on the neuropsychiatric
aspects of sleep. The reader is also referred to the resources available from
the American Academy of Sleep Medicine (AASM), particularly the clinical
practice guidelines for the individual categories of sleep disorders
(https://aasm.org/clinical-resources/practice-standards/practice-guidelines/).
Sleep Physiology
The timing of the sleep-wake cycle results mainly from the interaction of a
homeostatic drive (process S)—originating in the basal forebrain and
promoting sleep in a near-linear fashion with time spent awake—and a
circadian drive (process C)—originating in the suprachiasmatic nuclei (SCN)
and promoting wakefulness in an oscillatory fashion with a period of about
24 hours. The state of NREM sleep is divided into N1 (characterized by
theta frequencies), N2 (characterized by the presence of sleep spindles and
K-complexes), and N3 stages, where N3 represents slow-wave sleep
(SWS), replacing the old nomenclature of stages 3 and 4. Periods of NREM
sleep alternate with periods of REM sleep (characterized by beta
frequencies) in a healthy human in roughly 60- to 90-minute cycles and in a
ratio of 3–4:1(Dijk and Lockley 2002).
Circadian Clock
The biological basis of the circadian clock and the rhythm it produces
rests in genetic feedback loops of relatively fixed timing; clock genes code
for clock proteins that are enzymatically transformed into transcription
factors that can repress or activate the expression of those of other clock
proteins (Lück et al. 2014). The resultant biological clock is resynchronized
to the day/night cycle by a variety of environmental cues termed zeitgebers.
The predominant zeitgeber is light itself (Duffy and Wright 2005), but
temperature, social interactions, exercise, and the timing of meals may exert
influence as well. The entrainment effect of light is mediated through
photosensitive retinal ganglion cells that project directly to the SCN via the
retinothalamic tract and affect abrupt changes in clock protein degradation
rates and gene expression. SCN inputs from the thalamus and midbrain
raphe allow for nonphotic entrainment to occur (Toh 2008). Conditions that
impact entrainment of the circadian clock, either from external factors (shift
work, living too near either pole) or internal factors (blindness, glutamate
antagonists—any process interfering with SCN inputs), can result in sleep
disruptions and somatic complaints. As clock genes are present in virtually
every tissue type in the body (Yamazaki et al. 2000), circadian disturbances
can trigger far-reaching and complex effects (Duguay and Cermakian 2009).
The SCN projects to other hypothalamic nuclei and the pineal gland that
secretes melatonin to regulate temperature, hormone fluctuations, and other
bodily functions. Melatonin acts as a signal for “biological night” for the rest
of the body (Arendt and Skene 2005).
Wake
The waking state is primarily driven by the ascending reticular activating
system (ARAS), a collection of neuronal circuits originating in the pontine
reticular formation (Schwartz and Roth 2008). Other areas, including the
locus coeruleus, dorsal raphe, median raphe, and hypothalamus, are
commonly included in the ARAS. The ARAS projections have two major
branches, the first of which consists of primarily cholinergic neurons
originating in the pedunculopontine and laterodorsal tegmental nuclei and
projects through synaptic relays in the rostral intralaminar and thalamic
nuclei to the cerebral cortex. The source neurons are most active during
wake and REM sleep and least active during NREM sleep. The second
branch of the ARAS projects to the lateral hypothalamus, basal forebrain,
and cerebral cortex. This branch carries noradrenergic inputs from the locus
coeruleus, serotonergic inputs from the dorsal and median raphe nuclei,
dopaminergic input from the ventral periaqueductal gray, and histaminergic
input from the tuberomammillary nucleus (TMN). The monoaminergic inputs
are most active during wake, are less active during NREM sleep, and go
silent during REM sleep. Other cortical afferents originating in the basal
forebrain (cholinergic and γ-aminobutyric acid [GABA]–ergic) follow the
same firing pattern as the cholinergic inputs to the primary ARAS branch,
active in wake and REM sleep (Table 17–1).
TABLE 17–1. Select neurotransmitter systems and their relative activity in wake and
in non–rapid eye movement (NREM) and rapid eye movement (REM) sleep
NeurotransmitterNuclei Target Wake NREM REM

Monoaminesa PAG, TMN, LC, Diffuse cortex; ++ + −
D/MR TMN→VLPO
nucleus
Acetylcholine PPT, LDT Diffuse cortex ++ − ++
Orexin Lateral Throughout CNS; ++ − ++
hypothalamus ARAS; cortex
GABA, VLPO nucleus TMN; lateral − ++ +
galanin hypothalamus
eVLPO nucleus Spinal − − ++
interneuronsb
and basal
forebrain
Note. Relatively more active (++), less active (+), and inactive (–) firing.
Abbreviations: ARAS=ascending reticular activating system; CNS=central nervous system;
D/MR=dorsal and median raphe; eVLPO=extended region of the ventrolateral preoptic;
GABA=γ-aminobutyric acid; LC=locus coeruleus; PAG=periaqueductal gray;
LDT=laterodorsal tegmental; PPT=pedunculopontine; TMN=tuberomammillary nucleus;
VLPO=ventrolateral preoptic.
aDopamine, histamine, epinephrine, norepinephrine, serotonin.
bIndirect target; see text for details.
An additional set of cortical afferents originates in the lateral

hypothalamus from orexin-producing cells.1 The afferents from orexin-
producing cells in the lateral hypothalamus follow the same firing pattern as
the cholinergic wake pathways (Sakurai 2007). These orexin-producing
neurons project widely throughout the central nervous system (CNS), with
particularly dense excitatory connections throughout the ARAS. During
wakefulness, the orexin-producing neurons appear to trigger increased
activation of the ARAS monoaminergic neurons, while the latter provide
feedback inhibition to the orexin-producing neurons. The result is
stabilization of the waking state. The orexin-producing neurons receive
direct inputs from the limbic system, providing a pathway for emotional
states to trigger increased alertness. The SCN projects to the nearby
subparaventricular zone, which, in turn, projects to the dorsomedial
hypothalamic (DMH) nucleus. The DMH nucleus has GABAergic projections
to orexin-producing neurons, providing a pathway for circadian influence
over this system.
Sleep and Flip-Flop Switches

A subgroup of GABAergic and galaninergic neurons projects to the
monoaminergic neuron systems, especially the TMN, as well as the lateral
hypothalamus (Schwartz and Roth 2008). The TMN, in turn, projects
histaminergic input to the VLPO nucleus. During sleep, increased firing by
the VLPO neurons suppresses monoaminergic cell firing, resulting in self-
disinhibition and a further increase in VLPO nucleus output. The VLPO
nucleus output also suppresses hypocretin output, further dampening the
ARAS and promoting sleep. With increased monoaminergic firing during
wakefulness, the VLPO nucleus is in turn inhibited, with resultant
disinhibition of the monoaminergic and hypocretin systems. The bidirectional
feedback loop creates a “flip-flop” switch between sleep and wake, allowing
for relative stability for each state once it is reached but working against any
intermediate state. The SCN (via the DMH nucleus) also connects to the
VLPO nucleus, allowing for another avenue of circadian influence. The
relative complexity of the various sleep and wake regulatory centers allows
for maintenance of critical physiologic cycles, but also permits flexible
adaptation to external influences and changes in the environment.
The extended portion of the VLPO (eVLPO) contains REM-active
GABAergic and galaninergic neurons, which project to an apparent “REM-
off” site within the ventrolateral periaqueductal gray (vlPAG) (Lu et al. 2006).
The vlPAG has dense GABAergic inhibitory projections to the
sublaterodorsal (SLD) nucleus within the mesopontine tegmentum, which, in
turn, projects similar inhibitory inputs back to the vlPAG. The SLD nucleus
contains two populations of glutamatergic neurons, one with descending
projections to spinal interneurons that appear to trigger REM atonia and a
second with ascending projections to the basal forebrain triggering the
cortical desynchronization seen on electroencephalogram (EEG) during
REM. The result of the feedback loop between the vlPAG and SLD nucleus
appears to be another flip-flop switch, this time supporting the oscillation
between REM and NREM sleep.
Table 17–1 lists the summary of overall changes in neurotransmitter
systems with respect to state (wake, NREM, and REM). Knowledge of the
role of the different systems can sometimes predict the likely adverse effects
of commonly used drugs (e.g., the sleepiness triggered by over-the-counter
antihistamines) or the impact of pathological states (e.g., hypocretin
depletion associated with narcolepsy).
Recent work has revealed that sleep is a dynamic state, specifically
dependent on preceding waking activity over specific areas of the cerebral
cortex (Clinton et al. 2011; Krueger and Tononi 2011). The accumulation of
sleep-regulatory substances, produced as a consequence of the normal
metabolic activity of neural networks, appears to trigger the entry of cortical
columns into local sleep while awake.
Classification of Sleep-Wake Disorders

There are three major organizing systems used in the classification of
sleep-wake disorders, each of which has recently been updated, reflecting
the rapid pace of progress in this field. Sleep medicine specialists commonly
use the International Classification of Sleep Disorders, now in its third
edition (ICSD-3; American Academy of Sleep Medicine 2014), while mental
health professionals may refer to the Diagnostic and Statistical Manual of
Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association
2013), and practitioners of all types refer to the International Classification of
Diseases, 10th Revision, Clinical Modification (ICD-10-CM; National Center
for Health Statistics 2017) for billing codes. A commonality between these
systems, and a departure from prior editions in the case of DSM, is
classification based on symptom clusters and comorbidity rather than on
presumptions of specific etiology. In ICSD-3, sleep disorders are classified
into one of seven categories: insomnias, sleep-related breathing disorders
(SRBDs), central disorders of hypersomnolence, circadian rhythm sleep-
wake disorders (CRDs), parasomnias, sleep-related movement disorders,
and other sleep disorders. ICSD-3 also includes appendixes of sleep-related
medical or neurological disorders and substance-induced sleep disorders
with an ICD-10 coding guide. DSM-5 generally parallels the ICSD-3
classification scheme but does not differentiate the various disorders of
hypersomnolence, nor does it include as thorough a classification in regard
to the parasomnias or sleep-related movement disorders. Unlike DSM-5 or
ICSD-3, ICD-10-CM continues to make a distinction between “organic” (G-
code) and “inorganic” (F-code) disorders.
Evaluation of the Patient With Sleep Complaints

Some basic principles of the evaluation of patients with sleep complaints
are presented here. (For a comprehensive review of this subject, see Reite
et al. 2009.)
History
Complaints presented by patients with sleep-wake disorders usually fall
into three categories: insomnia, hypersomnolence, and aberrant nocturnal
behaviors (Figure 17–1). Some patients may present with overlapping
symptoms—for instance, patients with difficulty sleeping at night may
present with excessive daytime sleepiness. Careful questioning can usually
elucidate the primary problem and guide further evaluation as outlined
below. Essential components of the history include review of the patient’s
daytime and nighttime symptoms, daily schedule, bedtime behaviors, sleep
environment, daytime napping, current medications or changes, and use of
alcohol, caffeine, over-the-counter medications or supplements, and illicit
drugs. Obtaining a family history also may help guide diagnoses.
FIGURE 17–1. Sleep complaints and differential diagnosis.
Insomnia
The definition for insomnia requires some form of daytime impairment for
diagnosis. Rare individuals that are genetically short sleepers seldom suffer
from deficiency in daytime performance. Patients with insomnia may
complain about difficulty falling asleep (sleep onset), staying asleep (sleep
maintenance), early awakening with difficulty returning to sleep, or any
combination of these. Each of these complaints may suggest different types
of sleep-wake disorders—for example, patients with restless legs syndrome
(RLS) often have sleep onset difficulty but usually do not complain of sleep
maintenance problems. Obstructive sleep apnea (OSA) leads to frequent
nocturnal awakenings and hence may present as sleep maintenance
difficulty. Early morning awakening is often associated with depression but
may also result from advanced sleep phase circadian disorder. Inquiring
about sleep hygiene—for instance, amount and timing of caffeine intake,
use of electronics at bedtime, and inconsistent bedtimes—is also useful.
Maladaptive sleep behaviors associated with anxious thoughts concerning
sleep point toward psychophysiological insomnia.
Hypersomnolence
Excessive daytime sleepiness is a common complaint reported in 5%–
20.6% of the population (Ohayon 2008). In general, daytime sleepiness can
result from nocturnal sleep disturbances or from an increased need for
sleep. It is critical to make this differentiation to guide rational investigation
and management. Nocturnal sleep disturbances could include sleep
deprivation or disruption of sleep by clinical sleep disorders. When daytime
napping is also nonrestorative, this usually indicates disruption of sleep by
clinical sleep disorders. However, patients with primary hypersomnia
(increased need for sleep) usually wake up refreshed from naps. Also,
associated symptoms like snoring, witnessed apneas, and frequent leg
movements at night provide information about clinical sleep disorders.
Aberrant Nocturnal Behaviors

Aberrant nocturnal behaviors constitute a diverse group of pathologies.
Particularly in those disorders that occur during REM sleep, the patient may
have insight and memory and be able to describe the problem. It is equally
important to obtain witnessed accounts. The pattern of aberrant behavior, its
timing and duration, patient responsiveness, and patient’s memory for the
event are all significant clues. Stereotypic behavior that is short, occurs in
clusters, and involves hypermotor manifestations or dystonic posturing
suggests nocturnal epilepsy, most commonly frontal lobe epilepsy. REM
sleep behavior disorder (RBD) usually presents as dream enactment
behavior with vivid recall, often occurring in middle-aged individuals,
especially in the latter half of the night. Non-REM parasomnias like
sleepwalking and sleep terrors are more often seen early in the night and
are less likely to be recalled by the patient.
Examination
In addition to routine physical examination, certain pertinent physical
findings can guide in the differential diagnosis of sleep-wake disorders.
Height, weight, and body mass index are important to note. Obesity is
commonly associated with OSA, narcolepsy, and nocturnal eating disorder.
Patients with body mass index greater than 35 kg/m2 are also at risk for
obesity-hypoventilation syndrome (Balachandran et al. 2014). Large neck
circumference (greater than 16 inches in men and 15 inches in women) is a
risk factor for OSA. Craniofacial anatomy, particularly structure of the maxilla
and mandible, the hyoid, tongue size, and uvula shape all affect the upper
airway resistance to airflow. Retrognathia and micrognathia are risk factors
for OSA. Patients with these anomalies are candidates for certain treatment
options that are not positive airway pressure (PAP) options, such as the
mandibular advancement device. Macroglossia is one of the contributing
factors to the development of OSA in patients with Down syndrome. Nasal
patency is assessed by having patients breathe through each nostril
separately. The oropharynx is commonly assessed by two methods, the
Mallampati classification (Mallampati et al. 1985) and the Friedman
classification (Friedman et al. 2002). Tonsillar and adenoidal hypertrophy is
a common cause of sleep-disordered breathing in young children. Features
of heart failure detected during the cardiopulmonary exam—for example,
bibasilar crackles and pedal edema—should raise suspicion for central
sleep apnea. In addition, chronic pulmonary obstructive disorders may also
coexist with OSA.
Careful neurological examination is essential. One of the most fascinating
disorders of sleep, RBD is closely related to parkinsonian syndromes.
Patients with RBD may present with hyposmia (i.e., impaired sensation of
smell) (Miyamoto et al. 2009). Examination of the first cranial nerve is hence
important along with the rest of the neurological exam. In patients with
clinical features of RLS, examination to detect neuropathy is necessary.
Attention should be paid to stigmata of neuromuscular disease, including
muscle atrophy, hyporeflexia in lower motor neuron disease, fibrillations,
fasciculations, and hyperreflexia in upper motor neuron disease, as well as
some characteristic features of individual syndromes. In addition to
predisposition to OSA caused by improper muscular tone in the upper
airway, these patients are also prone to developing hypoventilation,
especially during REM sleep. Obesity resulting from some of the
medications used for neurological disorders—for example, valproate for
epilepsy and steroids for certain neuromuscular disorders—may also
contribute to the development of OSA.
Investigations to Aid in Diagnosis

Use of sleep diaries can help characterize sleep complaints, provide
important information about sleep hygiene and circadian disorders of sleep,
and help track response to treatment (Schutte-Rodin et al. 2008). Some
commonly used questionnaires in sleep medicine history are the Epworth
Sleepiness Scale (to quantify daytime sleepiness), the Pittsburgh Sleep
Quality Index, the Insomnia Severity Index, the STOP-BANG Questionnaire
(a screening tool developed by anesthesiologists to preoperatively assess
the risk of SRBDs), and the Morningness-Eveningness Questionnaire (to
assess for CRDs).
Actigraphy is a good option to evaluate sleep patterns over prolonged
periods of time (Morgenthaler et al. 2007a). This is performed using portable
wristwatch-like devices that estimate sleep and wakefulness based on
motion. It has been validated in the diagnosis and therapeutic monitoring of
insomnia and CRDs.
Nocturnal, attended polysomnography (PSG) is considered the gold
standard test for many sleep-wake disorders. It is a comprehensive
assessment of many physiological parameters of sleep, including
electroencephalography, chin and limb electromyography,
electrooculography, electrocardiography, respiratory effort, respiratory flow,
oxygen saturation, and several other parameters like end-tidal capnography.
The AASM recommends criteria for the performance and analysis of PSG.
PSG is diagnostic in most instances and is usually followed by PAP titration
studies if the initial study demonstrates sleep-disordered breathing. This
paradigm is now undergoing change in the era of cost-effective medicine.
Portable sleep testing (limited channel cardiopulmonary testing) has been
developed as a tool of verification of diagnosis for patients who have a high
pretest probability of having SRBDs. This is a resource for patients that do
not have significant comorbid conditions like congestive heart failure or
neuromuscular disease. If confirmed to have OSA by portable sleep testing,
these patients may undergo treatment with auto-titrating PAP, without
undergoing PSG for PAP titration. AASM criteria have also been proposed
for patients who are suitable for portable sleep testing (Collop et al. 2007).
PSG is usually not indicated in the routine evaluation of insomnia. It has
some utility in paradoxical insomnia to convince patients of existence of
electrographic sleep. It is the test of choice for patients who are suspected
of having neurological disorders of sleep and SRBDs in the context of
complex medical conditions. The Multiple Sleep Latency Test (MSLT) is an
extended form of PSG that is used objectively to quantify daytime
sleepiness. The rationale behind the MSLT is that those patients who have
uninterrupted sleep at night and continue to demonstrate daytime sleepiness
have a centrally mediated increased need for sleep. Further testing with
dedicated EEG, cerebrospinal fluid testing, neuroimaging, endocrine and
genetic testing, arterial blood gas, pulmonary function testing, dedicated
electrocardiogram, echocardiogram, and serum chemistry may be
considered on the basis of individual diagnoses.
Common Sleep-Wake Disorders and Their

Management
In the following subsections, we describe common sleep disorders, based
on ICSD-3, and their management.
Insomnia
Most definitions of insomnia recognize this as a disorder of persistent
difficulty with sleep initiation, duration, consolidation, or quality that occurs
despite adequate opportunity for sleep and results in daytime impairment in
some form. The insomnia organization presented in ICSD-3 represents a
consolidation of the multiple chronic insomnia diagnoses in prior editions.
This was done both for the sake of simplicity and to be more in line with
clinical practice. Currently recognized subtypes of insomnia include chronic
insomnia, which requires the patient to have complaints for longer than 3
months, and short-term insomnia, which is of shorter duration as the name
implies. Another category of insomnia disorder is reserved for patients with
more nonspecific complaints that do not meet full criteria for either chronic
insomnia or short-term insomnia. Insomnia resulting from other medical and
psychiatric disorders or from the use of drugs or substances is
independently classified as such.
The previously delineated clinical and pathophysiological subtypes of
insomnia include psychophysiological insomnia—characterized primarily by
maladaptive behavior and heightened arousal surrounding sleep—and
paradoxical insomnia, also called sleep state misperception—characterized
by the patient’s inability to perceive neurophysiologically documented sleep
as the sleep state. Childhood insomnia has two main defined categories.
Sleep onset association type is consequential to the child’s dependence on
specific environmental circumstances for sleep. Limit-setting type is usually
seen as resistance to go to bed because of inadequate limit setting by the
parent.
The evaluation of insomnia, as outlined in the guidelines published by the
AASM (Schutte-Rodin et al. 2008), is based on published evidence
emphasizing that insomnia is primarily diagnosed by a clinical evaluation.
Supporting tools like questionnaires and technology help characterize
insomnia better but continue to be secondary.
The treatment of chronic insomnia involves a multimodality approach. In
addition to optimizing the treatment of comorbid sleep disorders and/or
medical disorders, the AASM clinical guidelines (Schutte-Rodin et al. 2008)
designate cognitive-behavioral therapy for insomnia (CBT-I; described
further below) as a first-line treatment of insomnia. This recommendation is
based on strong evidence from systematic reviews and meta-analyses that
established that CBT-I is effective (70%–80% of patients can be expected to
benefit) and durable (effects persist) and, when used as the only treatment,
may result in better long-term outcomes than pharmacotherapy alone or in
combination with CBT-I. The use of pharmacotherapy should be considered
as a short-term, adjunctive aid to cognitive and behavioral therapies
(Mitchell et al. 2012).
Pharmacotherapy
A wide array of agents are used in the pharmacological management of
insomnia. Table 17–2 provides characteristics of some of the more
commonly prescribed agents, although it should be noted that not all of the
agents listed are approved by the U.S. Food and Drug Administration (FDA)
for the treatment of insomnia. Current FDA-approved treatments include
several benzodiazepine receptor agonists (BzRAs), melatonin receptor
agonists (ramelteon), and the relatively new orexin (hypocretin) receptor
antagonists (suvorexant). Selection of an agent involves consideration of
several factors, including the type of insomnia, timing of symptoms (sleep
onset vs. sleep maintenance insomnia), comorbid disorders, adverse
effects, past treatment experience, contraindications and medication
interactions, cost, and patient preference. The recommendation is to begin
treatment with a short- or intermediate-acting BzRA or ramelteon. Low-dose
sedating antidepressants are used as second-line measures. Physicians
should be familiar with the nuances of using these medications—namely, the
potential for BzRAs to cause automatic behaviors and depress respiratory
drive (the patient must avoid concomitant use of alcohol or other sedative
agents; adequate sleep opportunity should be ensured), the potential for
daytime drowsiness and impaired psychomotor performance, and the
potential for tolerance with some of these agents as well as the dangers of
abrupt withdrawal.
TABLE 17–2. Selected hypnotic medications and their characteristics
Significant adverse
Medication class Medication Half-life (hr)Dose (mg) effects
Benzodiazepines Temazepam 8–20 15–30 Sleep
(BZDs) architecture
changes.
Residual
sedation,
amnesia,
abuse
potential,
automatic
behavior in
sleep, falls,
dizziness,
cognitive
effects
Non-BZD BZD- Zaleplon 1 5–20 Sleep
receptor architecture
agonists changes.
Residual
sedation,
amnesia,
abuse
potential,
automatic
behavior in
sleep, falls,
dizziness,
cognitive
effects;
metallic taste
(eszopiclone)
Zolpidem 1.5–2.4 5–10
Zolpidem CR 1.6–4.5 6.25–
12.5
Eszopiclone 6 1–3
Melatonin receptor Melatonin 0.6–1 0.3–10 Drowsiness,
agonists dizziness
Ramelteon 0.8–2 8
Significant adverse
Medication class Medication Half-life (hr)Dose (mg) effects
Sedating Trazodone 7–15 25–150 Dizziness,
antidepressants orthostatic
hypotension,
weight gain,
urinary
retention;
priapism
(trazodone)
Doxepin 15.3 3–6
Amitriptyline 1.5–4 10–100
Antihistamines Diphenhydramine 3.4–9.2 25–50 Sedation,
dizziness,
orthostatic
hypotension,
tachycardia,
urinary
retention
Doxylamine 10 25–50
Antipsychotics Quetiapine 7 25–200 Dry mouth,
tachycardia,
weight gain,
orthostatic
hypotension
Orexin receptor Suvorexant 12 10–20 Automatic
antagonists behavior,
cataplexy-like
symptoms,
sleep
paralysis,
sleep-related
hallucinations
Cognitive and Behavioral Management Strategies

The use of CBT-I is informed by multifactorial models that, in addition to
recognizing the role of precipitating stressors and predisposing trait
characteristics of the patient, emphasize the roles of maladaptive cognitions,
beliefs, attention to stimuli, coping strategies, and safety behaviors in the
process of conditioning insomnia (Perlis et al. 2011; Schutte-Rodin et al.
2008). For example, maladaptive strategies such as spending more time in
bed (e.g., going to bed earlier, sleeping in, taking naps) and staying in bed
while awake (e.g., tossing and turning attempting to force sleep) result in
decreased sleep efficiency and association of the bed with arousal and,
thus, can condition insomnia.
CBT-I includes three core components—sleep hygiene, stimulus control,
and sleep restriction therapy—and three adjunctive therapies—cognitive
therapy, relaxation training, and phototherapy (Perlis et al. 2011). Depending
on the problem and selected goals, the appropriate component or
combination can be implemented (Table 17–3). Sleep hygiene is the set of
routines and environmental factors that are conducive to circadian alignment
and the promotion of consolidated sleep, including keeping consistent
routines, avoiding maladaptive use of substances, and not spending
excessive time awake in bed. The aim of stimulus control therapy is to pair
the stimulus of the intended sleep environment to a sleep response by
reducing autonomic arousal and aligning intrinsic homeostatic and circadian
processes with the environment.
TABLE 17–3. Sleep improvement goals and suggested interventions
Sleep hygiene and other behavioral
Goal interventions CBT-I interventions
Create sleep- Keep the room dark and quiet (white Sleep hygiene
conducive noise is OK).
environment Use an eye mask and ear plugs.
Do not use the TV to fall asleep.
Avoid fluid intake in the evening.
Inpatient: minimize staff intrusions,
alarms, and bright light at night.
Facilitate circadian Keep a regular schedule (routine) for Sleep hygiene
rhythm bedtime, wake time, eating, and
entrainment activities.
Get bright light in the morning and avoid Phototherapy
bright light at night (including TV and
computer screens); use a night-light
(low light) if needed at night.
Increase drive for Get regular daytime exercise and avoid Stimulus control,
sleep at night exercise at night. sleep
Consolidate sleep at night and avoid taking restriction,
naps during the day. cognitive
therapies
If possible, dose sedating medications at
night and stimulating medications in
the morning.
Avoid caffeine or other stimulants after
noon.
Do not use tobacco.
Do not use alcohol to sleep (it disrupts
sleep continuity).
Decondition Use the bed for sleep (no TV, eating, or Stimulus control,
insomnia worrying allowed). sleep
restriction,
cognitive
therapies
Sleep when tired.
If awake >20 minutes, get up, do
something nonstimulating, and return
to bed when tired.
Sleep hygiene and other behavioral
Goal interventions CBT-I interventions
Relax, reduce Have a relaxing bedtime routine. Relaxation
autonomic training,
arousal hypnosis,
biofeedback,
Make a list of problems or worries for later. mindfulness
Avoid stressful or anxiety-provoking
conversations and media (e.g., books,
movies, news) before bed.
Note. CBT-I=cognitive-behavioral therapy for insomnia.
In sleep restriction therapy, homeostatic and circadian forces are

leveraged by first establishing a fixed wake time and a fixed sleep
opportunity—limited initially to a sleep diary–derived average of time spent
sleeping—and then progressively advancing the scheduled bed time while
maximizing sleep efficiency. (Because sleep deprivation may precipitate
mania or seizures, sleep restriction therapy is contraindicated for patients
with these conditions.)
Cognitive therapy consists of psychoeducation and guided identification
and restructuring of maladaptive thoughts through learning and practicing
specific skills, including paradoxical intention, attention bias, and imagery
rehearsal. Relaxation training aims to reduce the physiological arousal
associated with insomnia and may include progressive muscle relaxation,
diaphragmatic breathing, biofeedback, hypnosis, and mindfulness. A great
deal of practice in session and during waking hours is required to learn
these skills for them to be readily used and effective at bedtime and not to
be quickly abandoned or contribute to the already conditioned insomnia
response.
Phototherapy also may be helpful in insomnia or jet lag. This therapy
involves the use of bright light in the morning or evening depending on
whether there is a phase delay or phase advance component, respectively.
Hypersomnias
The central theme of these disorders is an increased need for sleep. The
main subtypes include narcolepsy (type I and type II), idiopathic
hypersomnia, Kleine-Levin syndrome, and hypersomnias secondary to
medical or psychiatric conditions and medications. The MSLT is the gold
standard test for defining daytime sleepiness. The clinical manifestations of
narcolepsy include excessive daytime sleepiness as the cardinal symptom,
and a mean sleep latency of less than 8 minutes and two or more sleep-
onset REM periods during the MSLT are required for the diagnosis of
narcolepsy. Although cataplexy (episodic, sudden loss of muscle tone with
retained consciousness often triggered by certain emotions, most commonly
laughter) is associated with narcolepsy type I, the latter may be diagnosed
even in the absence of cataplexy if associated with low serum hypocretin
levels. Other symptoms include sleep paralysis, sleep stage transition
(hypnagogic and hypnopompic) hallucinations, and disrupted nocturnal
sleep. Narcolepsy is also associated with the HLA DQB1*0602 or
DRB1*1501 allele (but this is not diagnostic; see Kumar and Sagili 2014).
Also associated are obesity, other primary disorders of sleep (e.g., REM
sleep behavior disorder), and anxiety disorders.
Stimulant medications like modafinil, methylphenidate, amphetamine, and
methamphetamine are used for the treatment of daytime sleepiness due to
narcolepsy (Morgenthaler et al. 2007b). Wake-promoting agents such as
modafinil or armodafinil have more favorable adverse effect profiles. Sodium
oxybate is effective for the treatment of cataplexy and daytime sleepiness
and for consolidating sleep in narcolepsy. Tricyclic antidepressants,
selective serotonin reuptake inhibitors (SSRIs), and venlafaxine may also be
effective for the treatment of cataplexy as well as sleep paralysis and
hypnagogic hallucinations. Scheduled naps can also ameliorate daytime
sleepiness.
There is less robust evidence for symptomatic treatment in other central
hypersomnias (Morgenthaler et al. 2007b). Modafinil has been found to
improve daytime sleepiness in patients with idiopathic hypersomnia. Lithium
carbonate is also thought to be effective for treatment of recurrent
hypersomnia and behavioral symptoms due to Kleine-Levin syndrome. This
rare syndrome is characterized by recurrent episodes of severe sleepiness,
in association with cognitive, psychiatric, and behavioral disturbances.
Sleep-Related Breathing Disorders

SRBDs include the OSA disorders, central sleep apnea syndrome, sleep-
related hypoventilation disorders, and sleep-related hypoxemia disorder.
Young et al. (1993) reported prevalence rates for OSA of about 9% in
women and 24% in men. Predisposing factors include obesity, craniofacial
abnormalities, male gender, and endocrine disorders. In younger children,
adenotonsillar hypertrophy is the most common cause of upper airway
narrowing. The pathophysiology of OSA involves repetitive, intermittent
upper airway obstruction during sleep. As implied, an apnea is characterized
by complete obstruction, whereas a hypopnea is a partial obstruction.
Typical symptoms of OSA include snoring, witnessed apneas, gasping
arousals, and daytime sleepiness. The spectrum of severity of upper airway
obstruction ranges from simple snoring to obesity hypoventilation syndrome
(associated with hypercapnia). OSA is associated with hypertension, atrial
fibrillation, type 2 diabetes, coronary artery disease, and congestive heart
failure, as well as mood disorders and pain disorders. Primary options for
OSA include PAP (continuous [CPAP], biphasic [BIPAP], or auto-titrating
[APAP]) therapy and lifestyle modification such as weight loss through
healthy diet and exercise. Although several surgical approaches have been
proposed, these usually remain second-line options after PAP therapy. The
exception is adenotonsillectomy in the pediatric population. Oral appliances
have demonstrated efficacy, particularly in mild, supine positional OSA.
Central sleep apnea syndromes are generally caused by a deficiency in
the ventilatory drive and are more prevalent in patients with congestive heart
failure, stroke, and/or opioid abuse or in premature infants. In some cases,
these syndromes may be a result of PAP treatment of OSA. Treatment
includes management of the underlying medical disorder with or without
PAP.
Parasomnias
Parasomnias are a fascinating group of disorders that are characterized
by undesirable behaviors or experiences that occur during sleep and/or
sleep-wake transitions; they are classified based on whether they occur in
NREM or REM sleep. NREM parasomnias include sleepwalking, confusional
arousals, sleep terrors, and sleep-related eating disorder. REM parasomnias
comprise RBD, recurrent isolated sleep paralysis, and nightmare disorder.
The entire spectrum of parasomnias is much more common in children.
These are also often found associated with other primary disorders of sleep
(e.g., OSA). Safety concerns and legal hazards should be addressed at the
very beginning. The diagnosis in many cases is purely clinical but in some
others (e.g., RBD) requires PSG. Multiple studies may be required to
capture an event. Effective treatments include benzodiazepines, tricyclic
antidepressants, and cognitive and behavioral therapies, but, depending on
the clinical situation and the presence or absence of medical comorbidity,
treatment may not be necessary and the focus may be on education and
reassurance.
Circadian Rhythm Sleep-Wake Disorders

CRDs are characterized by incongruence between the internal circadian
rhythm and timings required by the external environment (Morgenthaler et
al. 2007c). Clinically, these disorders often manifest as insomnia symptoms.
As with the insomnia group, impairment in functioning is requisite to the
diagnosis. Sleep logs and actigraphy are central to the diagnosis and
evaluation. Measurement of salivary or plasma dim-light melatonin onset
and urinary metabolites of melatonin are also used, most often in research.
Circadian chronotype can also be assessed using the Morningness-
Eveningness Questionnaire. Delayed sleep-wake phase disorder is most
often seen among adolescents and young adults. Social and behavioral
factors often play an important role in perpetuating the physiological shift
toward later sleep times that is seen in this age group. Advanced sleep-
wake phase disorder, in contrast, is often seen with advancing age. Irregular
sleep-wake rhythm disorder, as the name implies, is characterized by an
erratic sleep-wake cycle. Neurodegenerative disorders often predispose to
this form of circadian misalignment.
Therapeutic entrainment of circadian rhythms involves behavioral
interventions (most critically sleep hygiene), strategic use of zeitgebers (e.g.,
light therapy), and pharmacotherapy such as melatonin (dosed to
approximate dim-light melatonin onset, i.e., approximately 1 mg in the
evening, not at bedtime). High-dose melatonin given later in the night will be
soporific but can cause a phase delay and insomnia (Arendt and Skene
2005). Chronotherapy involves gradual advancing or delaying of bedtimes
as appropriate to counteract the disturbance. Non-24-hour sleep-wake
rhythm disorder is most often found in blind individuals. Recently,
tasimelteon, a melatonin receptor agonist, has been approved for the
treatment of this disorder. Shift work disorder is characterized by impaired
sleep and wake at desired times due to a misalignment between the
endogenous circadian clock and environmental time induced by the imposed
shift work schedule (Wright et al. 2013). Rapid travel across multiple time
zones results in a similar condition colloquially referred to as “jet lag.” The
circadian clock can typically adapt to such changes faster if aided by
strategic timing of zeitgebers (e.g., bright light, melatonin).
Sleep-Related Movement Disorders

The most common sleep-related movement disorders are RLS and
periodic limb movement disorder (Hornyak et al. 2006). Although the two
disorders are related, RLS is a sensorimotor disorder and a clinical
diagnosis, whereas periodic limb movement disorder is diagnosed when
PSG reveals periodic leg movements in sleep (PLMS) (>5 PLMS per hour of
sleep in children or >15 PLMS per hour of sleep in adults) and there is also
clinical evidence of functional impairment from nonrestorative sleep. RLS is
characterized by four cardinal criteria: 1) an urge to move the legs, caused
by a usually uncomfortable sensation in the legs, which 2) often begins or
worsens with rest or inactivity, 3) is at least partially relieved by movement,
and 4) often occurs predominantly in the evening or night. Patients with RLS
most often complain of sleep-onset insomnia. RLS may occur at any age,
occurs more often in women, and may also appear secondary to other
conditions like uremia and pregnancy. The prevalence of PLMS has been
found to increase with age. Low brain iron content, as reflected by serum
ferritin level, has been found in association with both RLS and PLMS. Iron
supplementation is recommended if serum ferritin is less than 50 μg/L.
Dopaminergic medications, anticonvulsants (e.g., gabapentin),
benzodiazepines, and opioids form the major groups of pharmacological
treatment (Aurora et al. 2012).
Sleep Disruption in Medical, Neurological, and

Psychiatric Disorders
Sleep in Medical Disorders

Sleep disruption is common in the medically ill, with over 90% reporting
symptoms of a sleep disorder (National Sleep Foundation 2002). Sleep is
especially problematic for hospitalized patients (Young et al. 2008). Such
sleep disruptions can lower the pain threshold, worsen cardiorespiratory
status, induce insulin resistance and predict the development of metabolic
syndrome, induce changes in cellular processing and production of free
radicals, increase the risk of cancer, disrupt autonomic tone, and contribute
to poor health and impaired functioning in general (Depner et al. 2014;
Luyster et al. 2012). The symptoms of a disorder (e.g., fever, hot flashes,
pain, heartburn, nocturia, thirst, dyspnea, and dystonia) or the side effects of
a drug (e.g., akathisia) can delay sleep onset or disrupt continuity.
Conversely, the physiological associations of normal sleep can
exacerbate some disorders. Examples include the skeletal muscle paralysis
and marked increase in blood pressure and heart rate associated with REM
sleep that can exacerbate pulmonary or cardiovascular and cerebrovascular
disorders, respectively. The former may produce arousals and sleep
deprivation and all of its sequelae, and the latter may contribute to the
increased risk of sudden cardiac death and stroke in early morning hours,
when REM is more prevalent (Verrier et al. 1996) and when coagulability is
increased because of circadian-neuroendocrine factors (Dyken et al. 2012;
Watson and Viola-Saltzman 2013).
Beyond these basic principles and examples, myriad associations exist
between sleep and individual medical disorders and have been well
reviewed elsewhere (Luyster et al. 2012; Parish 2009; Young et al. 2008). In
the following sections, we discuss the associations between sleep and
common categories of neurological and psychiatric disorders.
Sleep in Neurological Disorders

Sleep disruption and disorders can result from any focal lesion (e.g.,
stroke, CNS tumor, demyelination) or diffuse process (e.g.,
encephalopathy/delirium, neurodevelopmental disorders) that disturbs the
function of any of the sleep-wake and circadian centers and networks
described earlier in this chapter. The approach to such sleep disruptions can
be informed by the pathophysiology of the underlying neurological disorder
(Dyken et al. 2012; Watson and Viola-Saltzman 2013). In CNS infections
and autoimmune diseases, inflammation (perhaps mediated by IL-1β and
TNF-α) generally has a soporific effect, but a variety of sleep disturbances
are possible (e.g., Lyme disease causing poor sleep quality and RLS; HIV
causing insomnia in proportion to infection progression; and multiple
sclerosis causing disturbed sleep and fatigue and an increased incidence of
RBD and narcolepsy) (Parish 2009). Sleep and epilepsy are clearly
interrelated, because epileptic seizures commonly occur at least partially or
exclusively in sleep or may be precipitated by sleep deprivation, and there
are elevated rates of comorbid sleep disorders in patients with epilepsy,
including OSA, RLS, PLMS, RBD, and NREM parasomnias (Watson and
Viola-Saltzman 2013). Migraine, hypnic, and episodic (but not chronic)
cluster headaches are each closely associated with REM sleep, may be
exacerbated when REM sleep is increased, and have notable time-of-day
periodicity, suggesting roles for REM-promoting regions and SCN
dysfunction in these disorders. Neuromuscular diseases typically result in
hypersomnolence, strongly correlating with functional disability, either
directly by affecting the hypothalamus-hypocretin (orexin) system and
serotonergic dorsal raphe nuclei (as in myotonic dystrophy) or secondarily
from chronic hypercapnia and SRBD (as in amyotrophic lateral sclerosis
[ALS], muscular dystrophies, and myasthenia gravis).
The presence of idiopathic RBD is usually a harbinger of
neurodegenerative disease, including, most commonly, the
synucleinopathies (Watson and Viola-Saltzman 2013). In fact, RBD is a
“suggestive” diagnostic feature of dementia with Lewy bodies and is found in
about one-quarter of all patients with Parkinson’s disease. The disruption of
cholinergic tone, marking the progression of many dementias and other
neurodegenerative disorders, is associated with circadian misalignment
(e.g., phase delay in Alzheimer’s disease, phase advance in frontotemporal
dementia, and sleep-wake reversal in Parkinson’s disease and progressive
supranuclear palsy), reduced REM sleep, and the phenomena of
“sundowning,” and these disturbances may aggravate other symptoms, be a
major source of discouragement, increase caregiver burden, and lead to
earlier nursing home placement.
Contrary to popular belief, the need for sleep does not decrease for older
adults, and it would be unwise to dismiss a sleep complaint or take lightly
sleep changes in the elderly simply as expected age-related decline (Bloom
et al. 2009). Because of medical and psychosocial comorbidities, as well as,
in some individuals, loss of VLPO neurons, aging is associated with sleep
fragmentation and an increased predilection for CRDs, RLS, and other sleep
disorders.
Sleep in Psychiatric Disorders

Sleep disruption is a core diagnostic feature of mood disorders, but this
relationship is complex (American Psychiatric Association 2013; Sutton
2014). PSG changes, including reduced REM latency, SWS, total sleep
time, and sleep efficiency, are observed during both depressive and manic
episodes. This is consistent with evidence for hypothalamic dysfunction in
mood disorders and the cholinergic-monoaminergic imbalance hypothesis
for depression. The latter may also account for the disturbing dreams and
nightmares and the early awakenings associated with depression. This
balance is delicate, because treatment with antidepressants (especially
SSRIs) may incite insomnia, RLS, or somnambulism. While hypersomnia is
characteristic of atypical depression, insomnia is found in typical depression
and its severity predicts worse outcomes, including higher rates of suicide. A
single night of sleep deprivation, deprivation in the later part of the night, or
simply acute REM deprivation—perhaps by normalization of the increased
metabolic activity seen in the anterior cingulate gyrus—can temporally
relieve depression or can incite mania.
Insomnia is so strongly and bidirectional correlated, both temporally and
in severity, with anxiety disorders and posttraumatic stress disorder (PTSD)
that problems with insomnia are part of the diagnostic features of these
disorders and they are thought to share commonalities in their underlying
pathologies (Alfano and Mellman 2010). These disorders are associated
with hyperarousal, decreased sleep continuity and SWS, and increased
REM density, as well as narcolepsy and sleep paralysis. Secondary sleep
disruption by the symptoms of the respective disorder is common. Examples
include nocturnal attacks in panic disorder, nocturnal rituals diminishing the
time for sleep in obsessive-compulsive disorder and precipitating delayed
sleep-wake phase disorder, worry about sleep producing a conditioned
psychophysiological insomnia, or claustrophobia symptoms in PTSD that
limit compliance with PAP treatment (Sutton 2014).
Worsening insomnia is characteristic of the prodromal phase of
schizophrenia, and there is evidence for dysfunction of homeostatic and
circadian processes as well as sleep spindle production in this disorder
(Sutton 2014). When present at any phase, sleep disturbances are known to
dramatically increase the already elevated risk for suicide in schizophrenia,
perhaps 12-fold or more. Decreased dorsolateral prefrontal cortex activity in
schizophrenia, also found in REM sleep, may contribute to the experience of
hallucinations.
There may be common gene abnormalities shared by attention-deficit
hyperactivity disorder (ADHD) and delayed sleep-wake phase disorder
(Sutton 2014). ADHD is also associated with insomnia (generally a side
effect of stimulant treatment), RLS, and OSA.
Sleep-Wake Effects of Medications and Other

Substances
Many medications and abused substances cross the blood-brain barrier
and act on systems regulating wakefulness, homeostatic and circadian
drives, and REM/NREM balance (Conroy et al. 2010; Schweitzer 2011). The
overall effect on these systems varies by agent, timing of dosing and half-
life, patient genetic factors, comorbid conditions, and drug-drug interactions.
Through skillful psychopharmacology, medication effects can be harnessed
for the benefit of the patient, but failing to pay heed to these effects can lead
to harm, patient dissatisfaction, and noncompliance.
In general, medications that interfere with receptor-neurotransmitter
systems involved in wakefulness promotion (i.e., Ach, NE, DA, 5-HT, H1 or
H2, alpha1), such as most antipsychotics, tricyclic antidepressants, and
antiepileptic medications, are more likely to cause sedation, whereas
stimulators of these systems, such as procholinergic (e.g., donepezil) or
dopaminergic (e.g., L-dopa) agents, if dosed in the evening, may disrupt
sleep and cause disturbing dreams and, in the case of L-dopa,
hallucinations, agitation, and sleep attacks (see Table 17–1). Taking
advantage of this effect, use of donepezil in patients with Alzheimer’s
disease and OSA can stimulate respiratory drive and reduce apneic events
(Sukys-Claudino et al. 2012). Secondary effects of medications can disrupt
sleep-wake dynamics—for example, exacerbation of OSA secondarily by
the muscle-relaxing effects of benzodiazepines or by increased neck
circumference due to weight gain from atypical antipsychotics, mood
stabilizers, and some antidepressants.
The use of substances to induce sleep or promote wakefulness in our
modern society is pervasive and can be problematic. Alcohol is commonly
used to induce sleep but, unfortunately, results in a net decrease in total
sleep time with decreased sleep efficiency in the second half of the night,
reduced restorative (SWS) sleep, and early awakening, and alcohol is
associated with precipitating or worsening SRBD and PLMS (Conroy et al.
2010). Caffeine, as an adenosine receptor antagonist, is thought to promote
wakefulness by interfering with the homeostatic drive for sleep, and both
evening use and regular daily use are associated with disrupted sleep and
daytime sleepiness (Roehrs and Roth 2008).
Conclusion
Sleep is an indispensable physiological phenomenon with far-reaching
implications for the physical and mental well-being of an individual.
Evaluating and addressing sleep-wake disorders should be integral to health
care delivery in all specialties of medicine. There is robust evidence of
improvement in outcomes in many comorbid illnesses when sleep-wake
disorders are managed well. Referral to a specialist trained in the
management of sleep-wake disorders should also be considered in the
overall treatment paradigm.
References
Abel T, Havekes R, Saletin JM, et al: Sleep, plasticity and memory from molecules to whole-
brain networks. Curr Biol 23(17):R774–R788, 2013 24028961
Alfano CA, Mellman TA: Sleep in anxiety disorders, in Foundations of Psychiatric Sleep
Medicine. Edited by Winkelman JW, Plante DT. New York, Cambridge University Press,
2010, pp 286–297
American Academy of Sleep Medicine: International Classification of Sleep Disorders.
Darien, IL, American Academy of Sleep Medicine, 2014
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders,
5th Edition. Arlington, VA, American Psychiatric Association, 2013
Arendt J, Skene DJ: Melatonin as a chronobiotic. Sleep Med Rev 9(1):25–39, 2005
15649736
Aurora RN, Kristo DA, Bista SR, et al; American Academy of Sleep Medicine: The treatment
of restless legs syndrome and periodic limb movement disorder in adults—an update for
2012: practice parameters with an evidence-based systematic review and meta-
analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep
35(8):1039–1062, 2012 22851801
Balachandran JS, Masa JF, Mokhlesi B: Obesity Hypoventilation Syndrome Epidemiology
and Diagnosis. Sleep Med Clin 9(3):341–347, 2014 25360072
Bloom HG, Ahmed I, Alessi CA, et al: Evidence-based recommendations for the
assessment and management of sleep disorders in older persons. J Am Geriatr Soc
57(5):761–789, 2009 19484833
Clinton JM, Davis CJ, Zielinski MR, et al: Biochemical regulation of sleep and sleep
biomarkers. J Clin Sleep Med 7(5)(suppl):S38–S42, 2011 22003330
Collop NA, Anderson WM, Boehlecke B, et al; Portable Monitoring Task Force of the
American Academy of Sleep Medicine: Clinical guidelines for the use of unattended
portable monitors in the diagnosis of obstructive sleep apnea in adult patients. J Clin
Sleep Med 3(7):737–747, 2007 18198809
Conroy DA, Arnedt JT, Brower KJ: Sleep in substance use disorders, in Foundations of
Psychiatric Sleep Medicine. Edited by Winkelman JW, Plante DT. New York, Cambridge
University Press, 2010, pp 314–329
Datta S: Cellular and chemical neuroscience of mammalian sleep. Sleep Med 11(5):431–
440, 2010 20359944
Depner CM, Stothard ER, Wright KP Jr: Metabolic consequences of sleep and circadian
disorders. Curr Diab Rep 14(7):507, 2014 24816752
Dijk DJ, Lockley SW: Integration of human sleep-wake regulation and circadian rhythmicity.
J Appl Physiol (1985) 92(2):852–862, 2002 11796701
Duffy JF, Wright KP Jr: Entrainment of the human circadian system by light. J Biol Rhythms
20(4):326–338, 2005 16077152
Duguay D, Cermakian N: The crosstalk between physiology and circadian clock proteins.
Chronobiol Int 26(8):1479–1513, 2009 20030537
Dyken ME, Afifi AK, Lin-Dyken DC: Sleep-related problems in neurologic diseases. Chest
141(2):528–544, 2012 22315121
Friedman M, Ibrahim H, Bass L: Clinical staging for sleep-disordered breathing. Otolaryngol
Head Neck Surg 127(1):13–21, 2002 12161725
Hornyak M, Feige B, Riemann D, et al: Periodic leg movements in sleep and periodic limb
movement disorder: prevalence, clinical significance and treatment. Sleep Med Rev
10(3):169–177, 2006 16762807
Krueger JM, Tononi G: Local use-dependent sleep; synthesis of the new paradigm. Curr
Top Med Chem 11(19):2490–2492, 2011 21906015
Kumar S, Sagili H: Etiopathogenesis and neurobiology of narcolepsy: a review. J Clin Diagn
Res 8(2):190–195, 2014 24701532
Lu J, Sherman D, Devor M, et al: A putative flip-flop switch for control of REM sleep. Nature
441(7093):589–594, 2006 16688184
Lück S, Thurley K, Thaben PF, et al: Rhythmic degradation explains and unifies circadian
transcriptome and proteome data. Cell Reports 9(2):741–751, 2014 25373909
Luyster FS, Strollo PJ Jr, Zee PC, et al; Boards of Directors of the American Academy of
Sleep Medicine and the Sleep Research Society: Sleep: a health imperative. Sleep
35(6):727–734, 2012 22654183
Mallampati SR, Gatt SP, Gugino LD, et al: A clinical sign to predict difficult tracheal
intubation: a prospective study. Can Anaesth Soc J 32(4):429–434, 1985 4027773
Mitchell MD, Gehrman P, Perlis M, et al: Comparative effectiveness of cognitive behavioral
therapy for insomnia: a systematic review. BMC Fam Pract 13:40, 2012 22631616
Miyamoto T, Miyamoto M, Iwanami M, et al: Odor identification test as an indicator of
idiopathic REM sleep behavior disorder. Mov Disord 24(2):268–273, 2009 18972547
Morgenthaler T, Alessi C, Friedman L, et al; Standards of Practice Committee; American
Academy of Sleep Medicine: Practice parameters for the use of actigraphy in the
assessment of sleep and sleep disorders: an update for 2007. Sleep 30(4):519–529,
2007a 17520797
Morgenthaler TI, Kapur VK, Brown T, et al; Standards of Practice Committee of the
American Academy of Sleep Medicine: Practice parameters for the treatment of
narcolepsy and other hypersomnias of central origin. Sleep 30(12):1705–1711, 2007b
18246980
Morgenthaler TI, Lee-Chiong T, Alessi C, et al; Standards of Practice Committee of the
American Academy of Sleep Medicine: Practice parameters for the clinical evaluation
and treatment of circadian rhythm sleep disorders. An American Academy of Sleep
Medicine report. Sleep 30(11):1445–1459, 2007c 18041479
National Center for Health Statistics: International Classification of Diseases, 10th Revision,
Clinical Modification (ICD-10-CM), Hyattsville, MD, Centers for Disease Control and
Prevention, 2017. Available at: https://www.cdc.gov/nchs/icd/icd10cm.htm. Accessed
March 7, 2017.
National Sleep Foundation: 2002 “Sleep in America” poll. April 2002. Available at:
http://sleepfoundation.org/sites/default/files/2002SleepInAmericaPoll.pdf. Accessed
March 3, 2017.
Ohayon MM: From wakefulness to excessive sleepiness: what we know and still need to
know. Sleep Med Rev 12(2):129–141, 2008 18342261
Parish JM: Sleep-related problems in common medical conditions. Chest 135(2):563–572,
2009 19201722
Perlis ML, Aloia M, Kuhn BR: Behavioral Treatments for Sleep Disorders: A Comprehensive
Primer of Behavioral Sleep Medicine Interventions. Boston, MA, Academic, 2011
Reite M, Weissberg M, Ruddy JR: Clinical Manual for Evaluation and Treatment of Sleep
Disorders. Washington, DC, American Psychiatric Publishing, 2009
Roehrs T, Roth T: Caffeine: sleep and daytime sleepiness. Sleep Med Rev 12(2):153–162,
2008 17950009
Sakurai T: The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat
Rev Neurosci 8(3):171–181, 2007 17299454
Schutte-Rodin S, Broch L, Buysse D, et al: Clinical guideline for the evaluation and
management of chronic insomnia in adults. J Clin Sleep Med 4(5):487–504, 2008
18853708
Schwartz JR, Roth T: Neurophysiology of sleep and wakefulness: basic science and clinical
implications. Curr Neuropharmacol 6(4):367–378, 2008 19587857
Schweitzer PK: Drugs that disturb sleep and wakefulness, in Principles and Practice of
Sleep Medicine. Edited by Kryger MH, Roth T, Dement WC. Philadelphia, PA,
Saunders/Elsevier, 2011, pp 542–561
Sukys-Claudino L, Moraes W, Guilleminault C, et al: Beneficial effect of donepezil on
obstructive sleep apnea: a double-blind, placebo-controlled clinical trial. Sleep Med
13(3):290–296, 2012 22281004
Sutton EL: Psychiatric disorders and sleep issues. Med Clin North Am 98(5):1123–1143,
2014 25134876
Toh KL: Basic science review on circadian rhythm biology and circadian sleep disorders.
Ann Acad Med Singapore 37(8):662–668, 2008 18797559
Verrier RL, Muller JE, Hobson JA: Sleep, dreams, and sudden death: the case for sleep as
an autonomic stress test for the heart. Cardiovasc Res 31(2):181–211, 1996 8730394
Watson NF, Viola-Saltzman M: Sleep and comorbid neurologic disorders. Continuum
(Minneap Minn) 19(1 Sleep Disorders):148–169, 2013 23385699
Wright KP Jr, Bogan RK, Wyatt JK: Shift work and the assessment and management of shift
work disorder (SWD). Sleep Med Rev 17(1):41–54, 2013 22560640
Yamazaki S, Numano R, Abe M, et al: Resetting central and peripheral circadian oscillators
in transgenic rats. Science 288(5466):682–685, 2000 10784453
Young JS, Bourgeois JA, Hilty DM, et al: Sleep in hospitalized medical patients, part 1:
factors affecting sleep. J Hosp Med 3(6):473–482, 2008 19084897
Young T, Palta M, Dempsey J, et al: The occurrence of sleep-disordered breathing among
middle-aged adults. N Engl J Med 328(17):1230–1235, 1993 8464434
__________________
1Although often used interchangeably, hypocretin is now used to refer to protein
precursor products of the gene HCRT on chromosome 17 (i.e., hypocretin neuropeptide

precursor protein yields hypocretin-1 and -2), and orexin refers to their mature excitatory
neuropeptide (orexin-A and -B).
CHAPTER 18
Multiple Sclerosis
Multiple sclerosis (MS) is a clinically and pathologically

heterogeneous demyelinating disorder of the central nervous system
(CNS) with inflammatory and degenerative components. Although
formal proof of an autoimmune etiology remains elusive and
alternative theories of MS exist, autoimmune mechanisms are
strongly suspected based on the genetic association of MS with
major histocompatibility complex (MHC) class II alleles, the cellular
constituents of CNS infiltrates in MS patients, and similarities of MS
to animal models of experimental autoimmune encephalomyelitis
(Nylander and Hafler 2012). Autoimmune attack of the myelin-
oligodendrocyte complex is hypothesized to originate from a
breakdown of immune tolerance in susceptible individuals via
activation of autoreactive myelin lymphocytes by a foreign peptide
with structural homology to the myelin (molecular mimicry). Immune-
mediated demyelination interferes with saltatory axonal conduction in
the CNS, and diverse, paroxysmal neurological symptoms manifest
from reduced or blocked conduction, spontaneous discharge, and
ephaptic transmission.
Symptom relapses are the clinical manifestation of acute
inflammatory demyelinating focal lesions in the CNS. Remission (i.e.,
complete or partial clinical recovery from relapse) is associated with
dampening of acute focal inflammation, proliferation and spread of
sodium channels on axons, remyelination, and functional
reorganization of CNS functions. Importantly, disease activity is not
quiescent during clinical remission. New, clinically silent lesions
appear. At least in part independently of lesions, brain atrophy
increases and abnormalities in normal-appearing white matter
advance. Disease progression (i.e., the accumulation of irreversible
disability) is taken to signify demyelination, axonal loss, gliosis, and
diffuse pathology in the normal-appearing white matter and cortex.
The most common form of the disease, relapsing-remitting MS
(RRMS), is two to three times more common in females. Although
MS can occur at any age, the median and mean ages at onset are
23.5 and 30 years of age, respectively, with a peak age at onset
approximately 5 years earlier in women (Confavreux and Vukusic
2008). About half of patients become dependent on a walking aid
and may need a wheelchair after 15 years of disease (Weinshenker
et al. 1989). Median survival from symptom onset is 38 years, with a
mean age at death of 65 years and a standardized mortality ratio of
2.8 (Brønnum-Hansen et al. 2004).
Eighty-five percent of patients begin with an RRMS disease
course (Lublin et al. 2014). Individuals with RRMS experience clearly
delineated symptom relapses (one to two per year) with a stable
course between attacks. Recovery can be complete, or residual
deficits may persist. Most RRMS patients ultimately convert to a
secondary progressive MS (SPMS) disease course. Risk of
transition from RRMS to SPMS is approximately 2.5% per year.
Conversion occurs at a mean age of 40–44 years. SPMS is
characterized by progressively worsening baseline neurological
function. There may be occasional relapses, minor remissions, and
plateaus. The third major disease subtype, primary progressive MS
(PPMS), affects 10%–15% of patients. Unlike RRMS, a higher
proportion of patients are male. Disease onset is also generally later,
at an average age of 40 years. PPMS is characterized by a gradual,
continual worsening of neurological function from the time of
symptom onset. There are no discrete relapses.
Initial symptoms may be insidious or abrupt, monosymptomatic or
polysymptomatic. Common symptoms early in the disease include
paraethesiae, weakness, monocular visual loss with or without pain
(optic neuritis), diplopia, diminished dexterity, gait disturbance, and
ataxia. Any CNS function can be affected. Discrete symptom
episodes may be evident, with months or years passing between
attacks. In individuals with PPMS, the disease progression worsens
from the time of onset. Fatigue, pain, spasticity, and bladder
dysfunction may occur as the disease evolves. Neuropsychiatric
symptoms are common and a significant source of morbidity, but
they do not commonly constitute the initial presenting feature
(Feinstein 2007).
The 1965 Schumacher Committee criteria for the diagnosis of MS
established what remains the crux of clinical diagnosis: evidence of
CNS demyelinating activity disseminated in space (i.e., two or more
separate lesions) and disseminated in time (i.e., two or more
separate times), with no better explanation (Schumacher et al.
1965). The 1983 Poser Committee criteria (Poser et al. 1983)
incorporated laboratory data from evoked potential and
cerebrospinal fluid studies, and the 2001 McDonald Criteria and
2005 Revised McDonald Criteria (Polman et al. 2005)
operationalized magnetic resonance imaging (MRI) criteria. The
clinical diagnosis of MS per the 2010 revised McDonald criteria
(Table 18–1) requires the demonstration of at least two distinct
episodes of disease activity localizing to two or more CNS sites
typical of MS.
TABLE 18–1. The 2010 McDonald criteria for diagnosis of multiple sclerosis
(MS)
Additional data needed for MS

Clinical presentation diagnosis
1. ≥2 attacksa Nonec
2. Objective clinical evidence of ≥2
lesions
3. Objective clinical evidence of 1
lesion with evidence of a prior
attackb
1. ≥2 attacksa ≥1 T2 lesion in at least 2 of 4 MS-
typical regions of the CNS
(periventricular, juxtacortical,
infratentorial, or spinal cord)d
2. Objective clinical evidence of 1 Await a further clinical attacka
lesion implicating a different CNS site
1. 1 attacka Dissemination in time, demonstrated
by:
2. Objective clinical evidence of ≥2 Simultaneous presence of
lesions asymptomatic gadolinium-
enhancing lesions and
nonenhancing lesions at any time;
or
A new T2 and/or gadolinium-
enhancing lesion(s) on follow-up
MRI, irrespective of its timing with
reference to a baseline scan; or
Await a second clinical attacka
1. 1 attack Dissemination in space and time,
demonstrated by:
2. Objective clinical evidence of 1 For DIS:
lesion (clinically isolated
syndrome)
Additional data needed for MS
Clinical presentation diagnosis
≥1 T2 lesion in at least 2 of 4 MS-

typical regions of the CNS
(periventricular, juxtacortical,
infratentorial, or spinal cord) d;
Await a second clinical attacka that
implicates a different CNS site;
and
For DIT:
Simultaneous presence of
asymptomatic gadolinium-
enhancing and nonenhancing
lesions at any time; or
A new T2 and/or gadolinium-
enhancing lesion(s) on follow-up
MRI, irrespective of timing with
reference to a baseline scan; or
Await a second clinical attacka
1. Insidious neurological progression 1 year of disease progression
suggestive of MS (PPMS) (retrospectively or prospectively
determined), plus 2 of 3 of the
following criteriad:
1. Evidence for DIS in the brain
based on ≥1 T2 lesions in the MS-
characteristic (periventricular,
juxtacortical, or infratentorial)
regions
2. Evidence for DIS in the spinal cord
based on ≥2 T2 lesions in the
cord.
3. Positive CSF (isoelective focusing
evidence of oligoclonal bands
and/or elevated IgG index)
Note. CNS=central nervous system; CSF=cerebrospinal fluid; DIS=dissemination
in space; DIT=dissemination in time; IgG=immunoglobulin G; MRI=magnetic
resonance imaging; PPMS=primary progressive multiple sclerosis. If the criteria
are fulfilled and there is no better explanation for the clinical presentation, the
diagnosis is ‘‘MS’’; if MS is suspected but the criteria are not completely met, the
diagnosis is ‘‘possible MS’’; if another diagnosis arises during the evaluation that
better explains the clinical presentation, then the diagnosis is ‘‘not MS.’’
aAn attack (relapse; exacerbation) is defined as patient-reported or objectively
observed events typical of an acute inflammatory demyelinating event in the CNS,

current or historical, with a duration of at least 24 hours, in the absence of fever or
infection. It should be documented by contemporaneous neurological examination,
but some historical events with symptoms and evolution characteristic for MS, but
for which no objective neurological findings are documented, can provide
reasonable evidence of a prior demyelinating event. Reports of paroxysmal
symptoms (historical or current) should, however, consist of multiple episodes
occurring over not less than 24 hours. Before a definite diagnosis of MS can be
made, at least 1 attack must be corroborated by findings on neurological
examination, visual evoked potential response in patients reporting prior visual
disturbance, or MRI consistent with demyelination in the area of the CNS
implicated in the historical report of neurological symptoms.
bClinical diagnosis based on objective clinical findings for 2 attacks is most secure.
Reasonable historical evidence for 1 past attack, in the absence of documented

objective neurological findings, can include historical events with symptoms and
evolution characteristics for a prior inflammatory demyelinating event; at least 1
attack, however, must be supported by objective findings.
cNo additional tests are required. However, it is desirable that any diagnosis of MS
be made with access to imaging based on these criteria. If imaging or other tests
(for instance, CSF) are undertaken and are negative, extreme caution needs to be
taken before making a diagnosis of MS, and alternative diagnoses must be
considered. There must be no better explanation for the clinical presentation, and
objective evidence must be present to support a diagnosis of MS.
dGadolinium-enhancing lesions are not required; symptomatic lesions are
excluded from consideration in subjects with brain stem or spinal cord syndromes.
Source. Reprinted from Polman CH, Reingold SC, Banwell B, et al.: “Diagnostic
Criteria for Multiple Sclerosis: 2010 Revisions to the ‘McDonald Criteria.’” Annals
of Neurology 69(2):292–302, 2011. Copyright © 2011 American Neurological
Association. Used with permission.
The remainder of this chapter outlines the major neuropsychiatric

abnormalities that may accompany MS. These are broadly divided
into two categories: disorders of mood, affect, and behavior and
abnormalities affecting cognition (Feinstein 2007). With respect to
the former, because the majority of the literature is devoted to
depression, major depression is emphasized. Aspects of bipolar
disorder, euphoria, pseudobulbar affect, and psychosis are then
briefly covered. In the section on cognitive dysfunction, we review
the prevalence, nature, detection, and clinical correlates of cognitive
abnormalities. Recent advances in elucidating the cerebral
correlates of cognitive dysfunction are also summarized.
Major Depression
Evidence from hospital-based clinics, community samples, and
administrative databases confirm that approximately half of MS
patients will experience clinically significant depression in their
lifetime (Feinstein et al. 2014). This figure is considerably higher than
the lifetime prevalence of major depression in the general population
and may exceed that found in other chronic medical illnesses.
Nonetheless, depression remains underrecognized and undertreated
in MS patients, an omission with serious implications because
depression is the most significant predictor of suicidal ideation and
intent (Feinstein 2002), and suicide is a significant cause of mortality
in MS patients (Brønnum-Hansen et al. 2004). Depression in MS is
not consistently related to the severity of neurological impairment
and can occur at any stage of the disease, supporting the idea that it
is not simply a psychological reaction to the burden of a serious
neurological disorder. Depression is also linked to poor quality of life
in MS, for many individuals superseding physical disability and
objective cognitive dysfunction in this regard (Mitchell et al. 2005).
The basic phenomenology of depression in MS overlaps with that
found in primary depression. Irritability, frustration, and
discouragement, however, are more typical of depression in MS
patients than feelings of guilt and low self-esteem (Feinstein et al.
2014). In addition, classic neurovegetative symptoms of depression,
such as insomnia, appetite disturbance, and fatigue, may be equally
attributable to the MS itself. Mood-related symptoms (sadness and
irritability) in MS appear to fluctuate over time more than evaluative
(e.g., guilt, low self-esteem) and neuro-vegetative symptoms—
temporal variations that may relate, in part, to MS relapses (Moore et
al. 2012).
Rating scales validated for screening MS patients for depression
include the Beck Depression Inventory–II (BDI-II), the Beck Fast
Screen for Medically Ill Patients, the Hospital Anxiety and
Depression Scale (HADS), the Patient Health Questionnaire (PHQ-2
and PHQ-9), and the Center for Epidemiologic Studies Depression
Scale (CES-D). Each has strengths and drawbacks (Feinstein et al.
2014). The BDI-II is the most commonly employed depression rating
scale in MS research, and it has received the endorsement of the
American Neurological Association in their evidence-based
recommendations (Minden et al. 2014).
The Beck Fast Screen consists of a subset of 7 out of the original
21 BDI-II items and circumvents symptom overlap between
depression and MS. While the Beck Fast Screen correlates with
other depression measures and is sensitive to changes associated
with depression treatment, it has not been evaluated against a
reference standard such as the Structured Clinical Interview for DSM
Disorders (SCID).
The HADS, a 14-item scale with depression and anxiety
subscales, offers a significant advantage of also screening for
anxiety, which is often comorbid with depression. Like the Beck Fast
Screen, it does not include somatic symptoms such as fatigue or
sleep disturbance.
A potential limitation of the BDI-II, the Beck Fast Screen, and the
HADS, however, is that these scales are copyrighted and subject to
license fees for their use. In contrast, the PHQ-2, PHQ-9, and CES-
D are in the public domain.
Performance of the PHQ-9, PHQ-2, CES-D, and HADS was
recently evaluated relative to the SCID in MS (Patten et al. 2015).
Using the diagnosis of major depressive episode according to the
SCID as the gold standard, all of the scales performed reasonably
well in terms of sensitivity and specificity. It is important to
emphasize that a positive screen for depression by rating scale,
although useful for identifying patients who require further
evaluation, cannot be equated with a formal diagnosis of major
depression.
Depression in MS may co-occur with other symptoms and
syndromes. Anxiety disorders have been poorly studied in MS.
Lifetime prevalence of any anxiety disorder is nearly three times
higher in MS patients than in the general population (Korostil and
Feinstein 2007). Lifetime prevalences of specific anxiety disorders
are as follows: generalized anxiety disorder, 18.6% in MS patients
versus 5.1% in the general population; panic disorder, 10% in MS
patients versus 3.5% in the general population; obsessive-
compulsive disorder, 8.6% in MS patients versus 2.5% in the general
population; and social phobia, 7.8% in MS patients versus 13.3%
general population. Nearly half of depressed MS patients have
clinically significant anxiety symptoms; compared with those with
anxiety alone, MS patients with anxiety and depression have more
thoughts of self-harm, more somatic complaints, and greater social
dysfunction. Chronic pain and fatigue are common in MS and
correlate with depressive symptoms (Feinstein et al. 2014).
Depression in MS is also associated with poorer cognitive
functioning, particularly in domains of information processing speed,
working memory, and executive functioning (Feinstein et al. 2014).
Alcohol abuse in MS has been linked to depression, although rates
of the former do not appear to exceed those in the general
population.
The etiology of depression in MS is complex. Early neuroimaging
work reported that the presence of hyperintense lesions localized to
the left arcuate fasciculus was the single MRI variable that
distinguished patients with moderately severe depression, a finding
that could account for only 17% of the depression score variance
(Pujol et al. 1997). Subsequent data showed that more extensive
hyperintense lesion volume in the left medial inferior prefrontal cortex
together with atrophy affecting the dominant anterior temporal lobe
was associated with major depression (Feinstein et al. 2004). The
regression analysis accounted for 42% of the depression variance, a
considerable improvement over earlier efforts. More recent studies
have implicated hippocampal atrophy, particularly in CA2 and CA3
areas and the dentate gyrus, in the pathogenesis of depression in
MS (Gold et al. 2010). Interestingly, smaller volumes in these
hippocampal subfields were also associated with cortisol
hypersecretion, suggesting a neuroendocrine-limbic etiology of
depression in MS. A possible role of cytokines such as interleukin
(IL)-1, IL-6, and tumor necrosis factor α—activators of the
hypothalamic-pituitary-adrenal axis that promote cortisol secretion—
remains to be clarified in depression in MS. Newer imaging
techniques, such as diffusion tensor imaging, may also help to
further elucidate the neuroanatomical basis of depression. An
advantage to these techniques is that data may be gathered not only
with respect to the property of lesions but also in relation to normal-
appearing brain tissue.
Psychosocial data suggest that a constellation of perceived
helplessness, uncertainty, and perceptions of disability is also
important in explaining depression in MS patients (Lynch et al.
2001). The importance of psychosocial variables is underscored in
part by studies demonstrating that depressive symptomatology is
modulated longitudinally by coping strategies. Depressed MS
patients who utilize active compared with avoidant coping
mechanisms showed improvements in mood symptoms over time.
Depressed subjects have a more negative view of the world and of
their own health, and they may anticipate a significantly higher
proportion of negative MS-related future events (Feinstein et al.
2014). Depression may also impede physical progress in MS
patients because it reduces motivation and is associated with poorer
adherence to disease-modifying medication.
There are robust data from randomized controlled trials
supporting cognitive-behavioral therapy (CBT) in patients with MS
and depression. For example, after 16 weeks of treatment, CBT was
as effective as sertraline for depression in MS (Mohr et al. 2001).
The benefits of CBT were sustained over 6 months after the
treatment was completed. CBT administered via telephone to
patients whose immobility precludes regular and frequent clinic
attendance is also effective. Mindfulness training has been found to
improve depression, anxiety, fatigue, and quality of life for patients
with MS (Feinstein et al. 2014).
In contrast to the psychotherapy literature, there remains a
paucity of well-designed randomized, controlled trials of
pharmacotherapy for depression in MS. Only two trials meet the
quality threshold for Cochrane review approval. The tricyclic
antidepressant desipramine was found to be effective; however,
anticholinergic side effects precluded some patients from achieving
therapeutic doses (Schiffer and Wineman 1990). The selective
serotonin reuptake inhibitor paroxetine was compared with placebo
in a 12-week flexible dosing trial (Ehde et al. 2008). Although 57%
of the paroxetine-treated patients were deemed responders, this
response rate did not differ significantly from the 40% placebo
response rate. Open-label studies suggest that imipramine,
moclobemide, tranylcypromine, fluoxetine, sertraline, and duloxetine
are all effective (Feinstein 2007).
For MS patients with severe treatment-refractory depression that
has not responded to other treatments, electroconvulsive therapy
(ECT) should be considered, notwithstanding an absence of
randomized controlled trial data. In addition to the usual pre-ECT
workup, contrast-enhanced MRI should be completed to exclude
gadolinium-enhancing lesions, a sign of active disease that could be
exacerbated by ECT.
Bipolar Disorder
The prevalence of bipolar disorder in MS is twice that in the
general population (Feinstein 2007). Mania in the presence of MS
can occur in a number of scenarios: as a preexisting, separate
condition that is not correlated with the trajectory of MS and
manifests prior to MS onset; as a condition heralding the onset of
MS; or as a condition manifesting in later stages of the disease. Up
to a third of MS patients may develop manic symptoms in the context
of steroid and adrenocorticotropic hormone treatment (Minden et al.
1988). Screening for a personal and family history of mood disorder
may assist in identifying steroid-treated MS patients who may be
more likely to develop mania.
In the absence of published guidelines for the management of
mania in MS patients, the clinician is left to make an uncomfortable
retreat to the general psychiatry literature. Lithium, valproic acid,
carbamazepine, and atypical antipsychotics have been shown to be
effective in abating manic symptoms in MS patients in case reports
and series (Feinstein 2007). The choice of agent should be dictated
by symptom profile and tolerability. Thus, an atypical antipsychotic
would be a reasonable choice for an individual with mania with
psychotic features. Successful lithium treatment of MS patients with
manic symptoms due to adrenocorticotropic hormone has been
described, but one must be mindful of possible effects of lithium on
motor function, balance, coordination, and bladder functions.
Valproic acid may be equally effective and better tolerated.
Euphoria
Euphoria, an overly optimistic state of mental and physical well-
being in the presence of significant neurological disability, was for
many years considered the hallmark of abnormal mental status in
MS (Cottrell and Wilson 1926). In their seminal 1926 work, Cottrell
and Wilson delineated four states that affected two-thirds of their
sample: euphoria sclerotic (i.e., persistently cheerful mood); eutonia
sclerotic (i.e., lack of concern over physical disability); pes sclerotic
(i.e., optimism for the future irrespective of obvious physical decline);
and emotional lability, now considered to include the separate entity
of pseudobulbar affect (described in the next section). Subsequent
estimates of the prevalence of euphoria have declined, likely
because of the introduction of structured interviews, more precise
definitions, and improved sample selection. Rabins (1990) estimated
a 25% median rate of euphoria in MS.
Euphoria is considered a manifestation of advanced disease with
extensive cerebral damage, progressive disease course, greater
physical disability, and more cognitive impairment. It is important to
distinguish euphoria, a fixed state, from mania and hypomania with
features such as psychomotor agitation, pressured speech,
decreased need for sleep, and increased energy that fluctuate over
days to weeks. Reduced gray matter volume, ventriculomegaly,
more frontal lesions, and greater overall lesion load have been
associated with euphoria in MS (Feinstein 2007). There is no specific
treatment, but caregiver psychoeducation may be helpful.
Pseudobulbar Affect
Pseudobulbar affect (PBA), also referred to as pathological
laughing and crying, emotionalism, emotional incontinence,
involuntary emotional expression disorder, and a host of other
descriptors, denotes a syndrome of laughter without mirth and/or
tears without sadness. Poeck (1969) defined four constituents of
PBA: laughing or crying response to nonspecific stimuli, absence of
voluntary control of facial expression, lack of association between
subjective emotional state (mood) and the observed expression
(affect), and absence in corresponding change in mood exceeding
the period of laughing and/or crying. The four aspects of the
syndrome often co-occur to varying degrees along a spectrum of
severity. Approximately 10% of MS patients are affected by PBA
(Feinstein et al. 1997).
The precise etiology of PBA remains elusive. However, lesions
involving a widely dispersed neural network that includes frontal,
parietal, and brain stem regions were implicated in MS patients with
PBA versus an age-, gender-, disease duration–, physical disability–
matched group of MS patients without pathological affect (Figure 18–
1) (Ghaffar et al. 2008). Antidepressants and L-dopa have been
traditionally used to treat PBA. A double-blind, randomized, placebo-
controlled study of dextromethorphan/quinidine showed efficacy in
improving PBA, quality of life, and quality of relationships in MS
patients with PBA (Panitch et al. 2006).
FIGURE 18–1. Eroded brain images (radiological convention) denoting
semiautomatic brain region extraction with significantly greater lesion loads
(shaded) in pseudobulbar affect compared with control multiple sclerosis
subjects.
Psychosis
The long-held belief that psychosis is not increased in MS was
challenged by Patten et al. (2005), who reported rates of psychosis
of 2%–3% in MS patients compared with 0.5%–1% in the general
population. Individuals within the youngest cohort, 15–24 years of
age, had a greater comorbidity of psychosis and MS, and this co-
occurrence declined with age.
Few studies have examined the cerebral correlates of psychosis
in MS. Feinstein et al. (1992) conducted a case-control study of 10
MS subjects with psychosis compared with 10 without, matched for
age, gender, duration of MS, and physical disability. The most
common signs and symptoms in the psychotic group were lack of
insight (100%) and persecutory delusions (70%). Well-formed
hallucinations—auditory (20%) or visual (20%)—were less common.
MRI data revealed nonsignificant trends for greater lesion scores
globally, in periventricular areas, around the temporal horns
bilaterally, and in the left trigone. A statistically significant difference
between the psychotic and nonpsychotic groups emerged when
lesion scores for the left temporal horn and left trigone were
combined. It was speculated that a threshold of lesion volume in the
temporal lobes superimposed on a constitutional vulnerability may
underpin psychotic symptoms in individuals with MS.
In the absence of randomized controlled trials, antipsychotic
treatment remains the cornerstone of treatment of psychosis in MS
patients. Atypical antipsychotics with less liability for extrapyramidal
side effects are preferred.
Cognitive Dysfunction
Prevalence
Extensive research over the last 30 years has established a 43%–
65% point prevalence range for cognitive impairment in MS samples
(Feinstein 2007). Variability in this figure has been attributed to
differences in sample composition, with lower (43%–46%) and
higher (54%–65%) estimates being associated with community-
versus clinic-based samples, respectively. The latter group tends to
have higher proportions of individuals with more progressive disease
and neurological disability or to consist of MS patients specifically
referred for cognitive assessment at MS centers. Within specialty
clinics, the circumstances around recruitment are also associated
with variability in the frequency of cognitive impairment. In an MS
specialty clinic, paid research volunteers, patients referred for routine
monitoring, and patients referred for assessment of specific clinical
problems (for specific clinical questions around, e.g., driving or work
capabilities, disability evaluations) had different rates of cognitive
impairment (45.6%, 59.4%, and 65.6%, respectively) (Duquin et al.
2008).
Nature of Cognitive Deficits

The profile of cognitive deficits in MS differs from that observed in
“cortical dementias,” of which Alzheimer’s disease is the prototype.
As such, aphasia, apraxia, and agnosia are uncommon. Cognitive
dysfunction in MS is characterized by heterogeneous deficits in
complex attention, information processing speed, multiple memory
systems, and executive function. Basic attention, procedural
memory, linguistic ability, and general intellectual ability are generally
considered to remain preserved. DSM-IV dementia (dementia due to
a general medical condition), defined as marked impairment in
memory plus one other domain of cognitive function and consequent
disturbance in the activities of daily living (American Psychiatric
Association 2000), does occur in approximately one-fifth of MS
patients, but with a distinct quality and lesser severity compared with
Alzheimer’s disease (Benedict and Zivadinov 2011). Although many
MS patients who are deemed to have cognitive impairment may not
have deficits of sufficient severity to meet DSM-IV criteria for
dementia, the presence of neuropsychological deficits in MS patients
is associated with difficulties in employment, relationships, activities
of daily living, driving safety, medication adherence, and ability to
benefit from rehabilitation (Benedict and Zivadinov 2011). In DSM-V,
cognitive dysfunction of insufficient severity to meet criteria for
dementia (referred to as major neurocognitive disorder in DSM-V) is
subsumed under the new diagnosis mild neurocognitive disorder.
Cognitive impairment has emerged as a strong predictor of health-
related quality of life in individuals with MS (Mitchell et al. 2005).
Attention, Information Processing Speed, and

Working Memory
Attention is the means by which specific information from the
environment is selected for further processing. Most MS patients
typically perform normally on basic attention tasks such as simple
auditory span and visuospatial span. Impairment is more common on
tasks of complex aspects of attention, including sustained
attention/vigilance and selective attention. Attentional tests
themselves, however, are dependent on information processing
speed and working memory.
Information processing speed refers to the speed at which mental
activities are performed. Neuropsychological tasks that tap into
processing speed reveal deficits in 20%–30% of MS patients across
a range of tests (Benedict et al. 2006). Two categories of
neuropsychological tests have been used to evaluate information
processing speed, namely, reaction time tests and tests of rapid
serial processing.
Tests of reaction time distinguish between simple and choice
reaction time. In the former, subjects are required to respond only to
stimulus detection; there is no cognitive elaboration intended. In
choice reaction time, subjects are instructed in various ways to
selectively respond to some, but not all, stimuli, with an additional
layer of cognitive processing and decision making introduced.
Comparing simple and choice reactions allows separation of motor
slowing from cognitive slowing. MS patients are, not surprisingly,
affected by motor slowing. What studies using reaction time
paradigms have provided is firm evidence of specific cognitive
slowing (Feinstein 2007). Reaction time data also demonstrate that
eliciting deficits in information processing speed is dependent in part
on the nature of the choice reaction task. This has been referred to
as the “complexity effect” (Hughes et al. 2011). In other words,
differences in processing speed between patients and control
subjects increase in proportion to the cognitive demand of the task.
Thus, detecting slowed processing speeds in MS via reaction time
paradigms requires a sufficiently complex cognitive task.
The second category of tests assessing processing speed in MS
comprises those that utilize a rapid serial processing format. In these
tests, stimuli are presented sequentially with no variation in the
cognitive operation to be performed on each item. The cognitive
operation itself is not typically very difficult, but the participant must
complete as many items as possible in an allocated period of time.
Two rapid serial processing tests, the Paced Auditory Serial Addition
Task (PASAT) and the Symbol Digit Modalities Test (SDMT), are the
most commonly utilized cognitive tests in MS. The PASAT has been
used extensively in MS cognition and research, and its inclusion in
the MS Functional Composite makes it one of the most important
measures of cognition in MS. Performance on the PASAT can
distinguish MS patients from demographically matched
neurologically healthy control subjects with a medium effect size
(Benedict et al. 2006). Tapping into information processing speed,
divided attention, working memory, visual scanning, visual tracking,
and motor speed, the SDMT differentiates MS patients from healthy
control subjects with a very large effect size and is considered to be
the single most sensitive and reliable test for detecting cognitive
impairment in MS.
On the basis of effect sizes, rapid serial processing tests are more
sensitive than reaction time tests in differentiating MS patients from
control subjects. This has been attributed to the “compounding
effect” and the “augmentation effect” (Hughes et al. 2011). The
compounding effect refers to having to quickly repeat the same task
numerous times over a short period and may therefore be sensitive
to vigilance. The “augmentation effect” suggests that scanning
demands and distraction effects inherent in rapid serial processing
tests enhance their ability to distinguish patients and controls.
Working memory is defined as the temporary storage and
manipulation of information necessary for complex cognitive tasks.
Tasks probing processing speed (and many other cognitive
functions) are dependent on working memory. Working memory is
conceptualized as comprising two components. The first,
maintenance, is subserved by two “slave systems,” the visuospatial
sketchpad and the articulatory loop, that maintain visual and auditory
information, respectively. Manipulation, the second component, is
mediated by the “central executive” or “attentional controller.” An
episodic buffer that binds information from subsidiary systems and
from long-term memory to form integrated episodes was later
elaborated.
Research has attempted to measure the relative contribution of
processing speed and working memory problems in MS patients.
DeLuca et al. (2004) used two indices from the Weschler Memory
Scale, Third Edition—Processing Speed and Working Memory—to
do this. The principal finding was that RRMS patients with
information processing deficits generally had intact working memory,
whereas SPMS patients demonstrated impairments in both
processing speed and working memory. In MS patients, processing
speed impairments were always significantly greater than working
memory deficits.
An implication of the notion that a primary deficit in processing
speed underlies problems with working memory is that providing
individuals with additional time to complete tasks that deploy working
memory should result in performance benefits. This was
demonstrated in a study of 50 MS patients carrying out a
computerized task that systematically manipulated cognitive load
(Leavitt et al. 2011).
Memory
The encoding, storage, and retrieval of information may be
broadly divided into long-term memory and working memory.
Working memory replaces older terms, short-term or immediate
memory, and is described above. Long-term memory refers to the
more permanent or stable storage of information and is subdivided
into explicit (conscious or declarative) and implicit (unconscious,
nondeclarative, procedural) memory, the former involving the
intentional recollection of prior experiences and the latter denoting
skills, conditioning, and priming, which are not reliant on conscious
effort.
Procedural memory is generally intact in MS, as demonstrated by
studies examining motor skill learning and semantic priming. Deficits
in explicit memory, on the other hand, are a frequent finding and are
estimated to affect 40%–60% of patients (Benedict et al. 2006).
These deficits are found across verbal and visuospatial modalities.
Early studies pinpointed memory disturbances in MS to impairments
in the retrieval of information from long-term storage, the retrieval
failure hypothesis. This notion was supported by findings that MS
patients’ recognition memory is less impaired than their ability to
recall, implying that encoding may be relatively intact. However, a
meta-analysis by Thornton and Raz (1997) found that MS patients
showed significant deficits relative to healthy control subjects in both
recall and recognition. The retrieval failure hypothesis was further
challenged by studies for which information acquisition was
controlled.
Difficulties in processing speed and working memory contribute
significantly to memory impairment in MS. However, it is not
invariably the case that individuals with memory deficits will also be
impaired on tests of processing speed and working memory. MS
patients are also specifically impaired in their ability to utilize
strategies, such as semantic clustering and visual imagery, to
facilitate learning and memory (Benedict and Zivadinov 2011).
Executive Function
function in a supervisory capacity to manage purposeful, goal-
directed behavior. Executive functions are important in novel,
unfamiliar circumstances in which new strategies must be developed
and the effectiveness of these strategies monitored, in contrast to
performance of routine, well-learned behaviors. On
neuropsychological testing, executive dysfunction may be associated
with deficits in initiation, planning, organization, inhibition, set
shifting, flexibility, and error correction. A significant challenge in
interpreting tests of executive dysfunction is that, by definition,
executive tasks operate on other cognitive processes. Disentangling
whether failure on a test purported to measure executive function is
due to true executive dysfunction or to compromises in the more
elemental cognitive domains deployed in the task can be
challenging. Approximately 15%–20% of MS patients show evidence
of executive dysfunction (Benedict et al. 2006).
Language
Expressive and receptive language abilities generally remain
intact in most MS patients. Mild deficits in confrontation naming and
difficulties with more subtle aspects of language comprehension
have been reported in some samples. However, verbal fluency, the
ability to generate words in accordance with a set of phonemic or
semantic rules within a specified time period, is impaired in up to
25% of MS patients (Benedict et al. 2006). Verbal fluency tasks,
such as the Controlled Oral Word Association Test (COWAT),
engage working memory and executive function. The timed nature of
the tests also highlights the potential importance of slowed
processing speed.
Visuospatial Function
Visuoperceptual abnormalities in MS encompass a fairly broad
range of dysfunctions that are estimated to affect 20% of patients
(Benedict et al. 2006). Here too, processing speed deficits have
been implicated as an underlying contributing factor. Specific deficits
are found in facial recognition, visuospatial perception (e.g., judging
the orientation of lines), and object discrimination. These difficulties
can occur independently of visual acuity.
Risk Factors and Moderating Variables for Cognitive

Decline
Cognitive function decreases with age in healthy populations.
Some authors have linked age-related cognitive decline to slowed
information processing speed. Amato et al. (2001), in a 10-year
follow-up study of cognitive change in 50 early MS patients and 70
control subjects, found that age was associated with increased
decline on neuropsychological testing. Prakash et al. (2008), in a
meta-analysis including 57 studies with 3,891 participants, reported
that studies that recruited primarily females demonstrated greater
cognitive deficits as opposed to studies of mixed-gender samples.
The question of whether gender influences the prevalence of
cognitive dysfunction in MS remains unresolved, however. Of note is
that most studies have not reported a significant effect.
Cognitive dysfunction may occur at any stage of MS, including at
the time of clinically isolated syndromes. In general, patients with
RRMS fare better than those with chronic progressive illness, while
results for cognition in patients with PPMS compared with patients
with SPMS tend to favor a worse picture in the latter (Feinstein
2007).
A large number of studies have examined a possible correlation
between cognitive variables and the physical disability measured by
the Expanded Disability Status Scale (EDSS). Results have been
conflicting, with earlier studies tending to show stronger correlations.
More recent studies have used cognitive tasks selected specifically
to minimize any motor demands. Here, the relationship has been
weak. Relative independence of cognitive disability and physical
functioning is illustrated by benign MS; 47% of individuals with
benign MS were cognitively impaired at the 10-year point, with
significant drops from baseline in all cognitive domains (Amato et al.
2006).
Depression can adversely impact cognition (Feinstein et al. 2014).
Relative to nondepressed MS patients, those with depression
perform more poorly on tests of attention, information processing
speed, working memory, and executive function. Verbal and spatial
memory functions, on the other hand, do not differ between
depressed and nondepressed MS patients. It has been hypothesized
that depression may specifically impact the central executive
component of working memory, but further study is needed to clarify
the precise relationship between depression and cognition.
Cognitive reserve is defined as the difference between observed
neuropsychological performance and performance predicted on the
basis of brain pathology. Life experiences that seem to delay or limit
cognitive dysfunction have been delineated in Alzheimer’s disease.
More recently, the concept of cognitive reserve has been applied to
MS. Premorbid intelligence, cognitively stimulating leisure activities,
and occupational attainment were shown to independently account
for variance in cognitive function that was unexplained by brain
pathology (Benedict and Zivadinov 2011).
Assessment of Cognitive Function in MS

Measurement of cognitive function in MS is challenging because
the nature of the deficits is heterogeneous and may be subtle and
because physical symptoms may confound particular tests. Patients’
self-report of cognitive function is not associated with objective
neuropsychological performance and may be more closely allied with
depressive symptoms. Caregivers’ reports may be more reliable.
The Mini-Mental State Examination (MMSE) is not an adequate
screening method for cognitive deficits in MS irrespective of the cut
point used for impairment (Benedict and Zivadinov 2011).
Neuropsychological evaluation is the most sensitive means of
detecting cognitive difficulties, but testing is time-consuming,
expensive, and not always available. An expert panel proposed a 90-
min cognitive battery—the Minimal Assessment of Cognitive function
in MS (MACFIMS)—for clinical monitoring and research (Benedict et
al. 2006). This comprises seven tests covering five cognitive
domains that are commonly impaired in MS, namely, processing
speed, memory, executive function, visuospatial processing, and
word retrieval. The validity of the MACFIMS has been confirmed,
with MS patients showing significantly lower performance than
normal control subjects on all tests at medium to very large effect
sizes (Benedict et al. 2006).
Imaging Cognitive Dysfunction in MS

A large number of studies have correlated total hyperintense
lesion volumes with various cognitive indices. In general, patients
with greater lesion burden have significantly more cognitive
impairment than those with less lesion burden (Benedict and
Zivadinov 2011). The strength of the association is modest (r=0.3–
0.5). Determining regional affiliations of lesion burden with overall
cognitive dysfunction or specific cognitive deficits in MS has yielded
mixed results owing to the high number of intercorrelations between
regional and total lesion burden. Other factors potentially contributing
to the modest relationship between hyperintense lesions and
cognitive impairment in MS include difficulty in precisely quantifying
T2 lesions, pathological heterogeneity of hyperintense lesions, and
undisclosed disease in normal-appearing white matter and cortex.
The relationship of cognitive variables with hypointense lesions
has been investigated to a far lesser extent, with different studies
suggesting stronger or weaker associations relative to hyperintense
lesions. Disentangling the possible contribution of hypointense
versus hyperintense lesions has also been challenged by the very
high number of intercorrelations between the two (e.g., r=0.9)
(Benedict et al. 2004).
Early work involving linear measurement of third ventricular width
on computed tomography scans showed significant correlation with
cognition in MS patients. Benedict and coworkers (2004) used
regression models to determine the relative contribution of
hyperintense lesion volume, hypointense lesion volume, and brain
atrophy to cognitive outcome in MS patients as measured by the
MACFIMS battery. In this study, third ventricular width emerged as
the strongest predictor among the MRI variables tested, followed by
brain parenchymal fraction.
The association of brain atrophy in MS with cognitive variables
has been demonstrated in many studies using a variety of
methodologies to quantify volume loss. Atrophy of cortical gray
matter, white matter, and subcortical gray matter structures has been
found to correlate with cognitive indices. MS patients’ performance
on the SDMT is the most robust correlate of whole-brain atrophy.
Increased third ventricular width may relate in part to thalamic
atrophy. Follow-up work demonstrated a 16.8% decrease in
normalized thalamic volumes in MS patients compared with
neurologically healthy control subjects (Houtchens et al. 2007).
Cognitive performance was significantly associated with thalamic
volume in MS patients on all MACFIMS variables, although patients
and control subjects differed only on two indices. Relative to the
other MRI metrics, which included T1 lesion load, fluid-attenuated
inversion recovery lesion load, brain parenchymal fraction, and third
ventricular width, thalamic fraction correlated strongest with all
cognitive tests, although the differences in correlation coefficients
were not significant.
Temporal atrophy in MS is a significant predictor of both
auditory/verbal and visual/spatial memory impairments, whereas
frontal atrophy is associated with impairments in the consistency of
learning. Associations of memory indices in MS patients with
temporal atrophy have been detected using manual volumetry of the
temporal lobe in addition to more specific techniques, such as
manual hippocampal segmentation and segmentation of
hippocampal subregions. Complementing these data are voxel-
based morphometry studies showing more extensive volume
reductions in widespread gray matter regions in cognitively impaired
MS patients. However, the degree to which regional cortical volumes
can account for cognitive deficits above and beyond associations
with global cortical volume remains unresolved.
Diffusion tensor MRI data from studies have served to highlight
the potential importance of extralesional white matter abnormalities
to cognitive impairment in MS (Benedict and Zivadinov 2011). Not
surprisingly, in light of regional lesion and atrophy data, however, the
correspondence of tract-specific normal-appearing white matter
abnormalities to particular cognitive deficits is not consistently
strong.
Differences in patient samples, neuropsychological tests, and
imaging techniques could explain discrepancies between studies.
Functional MRI (fMRI) data have generally demonstrated that during
cognitive activation tasks, patients with MS recruit additional brain
regions or exhibit greater activation within the same regions as those
used by neurologically healthy control subjects (Benedict and
Zivadinov 2011). Analogous to fMRI studies of motor activity in MS,
this has been taken to represent cerebral reorganization aimed at
compensating for damage associated with the disease. Increased
activation may lessen as task difficulty increases or as disease
progresses beyond a certain threshold. This suggests that the
“functional reserve”—namely, the ability of the brain to meet
cognitive demands, is limited and decreases as the disease evolves.
This may account for the limitations in a purely lesion-based
approach to elucidating cognitive dysfunction.
Treatment of Cognitive Dysfunction

Cognitive dysfunction frequently coexists with depression,
although the precise relationship between these abnormalities
remains unclear. Whether treatment of depression in MS confers
cognitive improvements awaits further study. There is a paucity of
well-designed studies that examine potential cognitive improvement
with disease-modifying treatments (e.g., interferon β-1b, interferon
β-1a, glatiramer acetate). In a meta-analysis comparing all disease-
modifying drugs (Galetta et al. 2002), for example, only 3 out of 21
studies entered in the analysis could furnish useful cognitive data.
Acetylcholinesterase inhibitors used in Alzheimer’s disease, such
as donepezil, have been tested in MS patients with cognitive
dysfunction. With one exception, these have consisted of small,
open-label studies. In a randomized, double-blind, placebo-
controlled trial of 69 cognitively impaired MS patients, Krupp et al.
(2004) found marginal benefit of donepezil on a single cognitive
domain.
A number of new therapies for MS are in various stages of
development and testing. Some target specific elements of the
demyelinating or degenerative cascade, such as inflammatory cell
migration, activation, proliferation, and survival, whereas others are
aimed at enhancing neuroprotection and remyelination. The potential
of these advances to yield cognitive benefits to MS patients awaits
more definitive study.
Conclusion
Neuropsychiatric difficulties are integral to multiple sclerosis.
Ranging from disorders of mood and affect to a specific profile of
cognitive impairment, these difficulties can profoundly affect patients’
lives, adding to both morbidity and mortality. Fueled in part by rapidly
developing neuroimaging techniques, our understanding of the
neuropsychiatry of MS has advanced considerably of late. We now
have greater insight into the prevalence, pathophysiology, and
ecological validity of the many psychometric findings associated with
this disease.
Although further advancement in the field is clearly needed, it is
essential from the patient care perspective that therapeutics keep
pace with basic laboratory research.
References
Amato MP, Ponziani G, Siracusa G, et al: Cognitive dysfunction in early onset
multiple sclerosis: a reappraisal after 10 years. Arch Neurol 58(10):1602–1606,
2001 11594918
Amato MP, Zipoli V, Goretti B, et al: Benign multiple sclerosis: cognitive,
psychological and social aspects in a clinical cohort. J Neurol 253(8):1054–
1059, 2006 16609810
Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric
Association, 2000
Benedict RH, Zivadinov R: Risk factors for and management of cognitive
dysfunction in multiple sclerosis. Nat Rev Neurol 7(6):332–342, 2011 21556031
Benedict RH, Carone DA, Bakshi R: Correlating brain atrophy with cognitive
dysfunction, mood disturbances, and personality disorder in multiple sclerosis.
J Neuroimaging 14(3)(suppl):36S–45S, 2004 15228758
Benedict RH, Cookfair D, Gavett R, et al: Validity of the minimal assessment of
cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc
12(4):549–558, 2006 16981607
Brønnum-Hansen H, Koch-Henriksen N, Stenager E: Trends in survival and cause
of death in Danish patients with multiple sclerosis. Brain 127(Pt 4):844–850,
2004
Charcot J-M: Histologie de la sclérose en plaques. Gazette Hôpitaux 41:554, 557–
558, 1868
Confavreux C, Vukusic S: The clinical epidemiology of multiple sclerosis.
Neuroimaging Clin N Am 18(4):589–622, 2008 19068404
Cottrell SS, Wilson SA: Original papers: the affective symptomatology of
disseminated sclerosis: a study of 100 cases. J Neurol Psychopathol 7(25):1–
30, 1926 21611215
DeLuca J, Chelune GJ, Tulsky DS, et al: Is speed of processing or working
memory the primary information processing deficit in multiple sclerosis? J Clin
Exp Neuropsychol 26(4):550–562, 2004 15512942
Duquin JA, Parmenter BA, Benedict RH: Influence of recruitment and participation
bias in neuropsychological research among MS patients. J Int Neuropsychol
Soc 14(3):494–498, 2008 18419848
Ehde DM, Kraft GH, Chwastiak L, et al: Efficacy of paroxetine in treating major
depressive disorder in persons with multiple sclerosis. Gen Hosp Psychiatry
30(1):40–48, 2008 18164939
Feinstein A: An examination of suicidal intent in patients with multiple sclerosis.
Neurology 59(5):674–678, 2002 12221156
Feinstein A: The Clinical Neuropsychiatry of Multiple Sclerosis. Cambridge, UK,
Cambridge University Press, 2007
Feinstein A, du Boulay G, Ron MA: Psychotic illness in multiple sclerosis: a clinical
and magnetic resonance imaging study. Br J Psychiatry 161:680–685, 1992
1422619
Feinstein A, Feinstein K, Gray T, et al: Prevalence and neurobehavioral correlates
of pathological laughing and crying in multiple sclerosis. Arch Neurol
54(9):1116–1121, 1997 9311355
Feinstein A, Roy P, Lobaugh N, et al: Structural brain abnormalities in multiple
sclerosis patients with major depression. Neurology 62(4):586–590, 2004
14981175
Feinstein A, Magalhaes S, Richard JF, et al: The link between multiple sclerosis
and depression. Nat Rev Neurol 10(9):507–517, 2014 25112509
Galetta SL, Markowitz C, Lee AG: Immunomodulatory agents for the treatment of
relapsing multiple sclerosis: a systematic review. Arch Intern Med
162(19):2161–2169, 2002 12390057
Ghaffar O, Chamelian L, Feinstein A: Neuroanatomy of pseudobulbar affect: a
quantitative MRI study in multiple sclerosis. J Neurol 255(3):406–412, 2008
18297331
Gold SM, Kern KC, O’Connor MF, et al: Smaller cornu ammonis 2–3/dentate gyrus
volumes and elevated cortisol in multiple sclerosis patients with depressive
symptoms. Biol Psychiatry 68(6):553–559, 2010 20646680
Houtchens MK, Benedict RH, Killiany R, et al: Thalamic atrophy and cognition in
multiple sclerosis. Neurology 69(12):1213–1223, 2007 17875909
Hughes AJ, Denney DR, Lynch SG: Reaction time and rapid serial processing
measures of information processing speed in multiple sclerosis: complexity,
compounding, and augmentation. J Int Neuropsychol Soc 17(6):1113–1121,
2011 22040901
Korostil M, Feinstein A: Anxiety disorders and their clinical correlates in multiple
sclerosis patients. Mult Scler 13(1):67–72, 2007 17294613
Krupp LB, Christodoulou C, Melville P, et al: Donepezil improved memory in
multiple sclerosis in a randomized clinical trial. Neurology 63(9):1579–1585,
2004 15534239
Leavitt VM, Lengenfelder J, Moore NB, et al: The relative contributions of
processing speed and cognitive load to working memory accuracy in multiple
sclerosis. J Clin Exp Neuropsychol 33(5):580–586, 2011 21229437
Lublin FD, Reingold SC, Cohen JA, et al: Defining the clinical course of multiple
sclerosis: the 2013 revisions. Neurology 83(3):278–286, 2014 24871874
Lynch SG, Kroencke DC, Denney DR: The relationship between disability and
depression in multiple sclerosis: the role of uncertainty, coping, and hope. Mult
Scler 7(6):411–416, 2001 11795464
Minden SL, Orav J, Schildkraut JJ: Hypomanic reactions to ACTH and prednisone
treatment for multiple sclerosis. Neurology 38(10):1631–1634, 1988 2843795
Minden SL, Feinstein A, Kalb RC, et al; Guideline Development Subcommittee of
the American Academy of Neurology: Evidence-based guideline: assessment
and management of psychiatric disorders in individuals with MS: report of the
Guideline Development Subcommittee of the American Academy of Neurology.
Neurology 82(2):174–181, 2014 24376275
Mitchell AJ, Benito-León J, González JM, et al: Quality of life and its assessment in
multiple sclerosis: integrating physical and psychological components of
wellbeing. Lancet Neurol 4(9):556–566, 2005 16109362
Mohr DC, Boudewyn AC, Goodkin DE, et al: Comparative outcomes for individual
cognitive-behavior therapy, supportive-expressive group psychotherapy, and
sertraline for the treatment of depression in multiple sclerosis. J Consult Clin
Psychol 69(6):942–949, 2001 11777121
Moore P, Hirst C, Harding KE, et al: Multiple sclerosis relapses and depression. J
Psychosom Res 73(4):272–276, 2012 22980532
Nylander A, Hafler DA: Multiple sclerosis. J Clin Invest 122(4):1180–1188, 2012
22466660
Panitch HS, Thisted RA, Smith RA, et al; Psuedobulbar Affect in Multiple Sclerosis
Study Group: Randomized, controlled trial of dextromethorphan/quinidine for
pseudobulbar affect in multiple sclerosis. Ann Neurol 59(5):780–787, 2006
16634036
Patten SB, Svenson LW, Metz LM: Psychotic disorders in MS: population-based
evidence of an association. Neurology 65(7):1123–1125, 2005 16217073
Patten SB, Burton JM, Fiest KM, et al: Validity of four screening scales for major
depression in MS. Mult Scler 21(8):1064–1071, 2015 25583846
Poeck K: Pathophysiology of emotional disorders associated with brain damage, in
Handbook of Clinical Neurology: Disorders of Higher Nervous Activity. Edited
by Vinken PJ, Bruyn GW. Amsterdam, The Netherlands, North-Holland,
Elsevier Science Publishing, 1969, pp 343–367
Polman CH, Reingold SC, Edan G, et al: Diagnostic criteria for multiple sclerosis:
2005 revisions to the “McDonald Criteria.” Ann Neurol 58(6):840–846, 2005
16283615
Poser CM, Paty DW, Scheinberg L, et al: New diagnostic criteria for multiple
sclerosis: guidelines for research protocols. Ann Neurol 13(3):227–231, 1983
6847134
Prakash RS, Snook EM, Lewis JM, et al: Cognitive impairments in relapsing-
remitting multiple sclerosis: a meta-analysis. Mult Scler 14(9):1250–1261, 2008
18701571
Pujol J, Bello J, Deus J, et al: Lesions in the left arcuate fasciculus region and
depressive symptoms in multiple sclerosis. Neurology 49(4):1105–1110, 1997
9339697
Rabins PV: Euphoria in multiple sclerosis, in Neurobehavioral Aspects of Multiple
Sclerosis. Edited by Rao SM. New York, Oxford University Press, 1990, pp
180–285
Schiffer RB, Wineman NM: Antidepressant pharmacotherapy of depression
associated with multiple sclerosis. Am J Psychiatry 147(11):1493–1497, 1990
2221162
Schumacher GA, Beebe G, Kibler RF, et al: Problems of experimental trials of
therapy in multiple sclerosis: report by the Panel on the Evaluation of
Experimental Trials of Therapy in Multiple Sclerosis. Ann NY Acad Sci
31(122):552–568, 1965 14313512
Thornton AE, Raz N: Memory impairment in multiple sclerosis: a quantitative
review. Neuropsychology 11(3):357–366, 1997 9223140
Weinshenker BG, Bass B, Rice GP, et al: The natural history of multiple sclerosis:
a geographically based study, I: clinical course and disability. Brain 112(Pt
1):133–146, 1989 2917275
CHAPTER 19
Alcohol and Other Substance

Use Disorders
Most humans have used illicitly obtained opiates, stimulants, or

sedatives or legally obtained alcohol, nicotine, or caffeine at least
once to achieve pleasure and/or to attain altered states of
consciousness. Although most individuals use these substances
without difficulties, a small percentage develop substance use
disorders (SUDs), which can lead to considerable medical burden
and cost. Among the psychiatric disorders associated with these
substances are intoxication, dependence, and withdrawal and a
range of substance-induced neuropsychiatric disorders (NPDs)
(Table 19–1). These NPDs are most common with alcohol, partly
because of the relatively large doses of alcohol needed for
psychoactive effects, but NPD rates also vary depending on the
drug’s mechanism of action (Table 19–2).
TABLE 19–1. DSM-5 substance-related disorders: classification
Substance use disorders
Alcohol
Caffeine
Cannabis
Hallucinogens (e.g., phencyclidine, LSD, MDMA)
Inhalants
Opioids
Sedatives, hypnotics, and anxiolytics
Stimulants (cocaine and amphetamine-like substances)
Tobacco
Other (or unknown) substances
Substance-induced disorders
Substance intoxication
Substance withdrawal
Substance/medication–induced mental disorders
Psychotic disorder
Bipolar and related disorder
Depressive disorder
Anxiety disorder
Obsessive-compulsive and related disorder
Sleep disorder
Sexual dysfunction
Delirium (substance intoxication, substance withdrawal, medication-induced)
Major or mild neurocognitive disorders
Other (or unknown)
Note. LSD=Lysergic acid diethylamide; MDMA=3,4-
methylenedioxymethamphetamine.
TABLE 19–2. Substance mechanism(s) of action
Drug Target Primary action
Cocaine DAT/NET/SERT Increases synaptic
levels of DA, NE,
and 5-HT by
binding
transporters
blocking
presynaptic
reuptake.
Methamphetamine/amphetamine NET/DAT, Induces NE and DA
VMAT2, presynaptic
MAO release; reverses
transporters.
Tobacco/nicotine nAChR agonist Increases firing of
VTA DA neurons
through nicotinic
β2 receptors;
disinhibits DA
neurons via α4β2
receptors on VTA
GABAergic
neurons.
Opioids (morphine, heroin) μ receptor Increase DA release
agonist by disinhibition of
inhibitory
GABAergic
neurons through
μ receptors.
Cannabis CB1 receptor Increases DA by
agonist disinhibition of
VTA DA neurons
through CB1
receptors on
GABAergic
neurons.
Drug Target Primary action
Hallucinogens 5-HT2A receptor Hallucinogenic
agonist effects are
mediated through
(numerous other
stimulation of 5-
targets) HT2A receptors;
bind directly to all
DA receptor
subtypes; partial
agonist at DA1
and DA2
receptors.
Caffeine Adenosine A2A A2A receptor
antagonist activation
indirectly
increases
glutamate
release.
Benzodiazepines/barbiturates GABAA receptor Facilitate the
inhibitory effects
of GABA/GABA
agonists.
Alcohol Undefined Increases DA either
by direct action
on VTA neurons
or possibly by
disinhibition via
GABAergic
receptors.
Inhalants Undefined Increase DA by
directly
stimulating VTA
DA neurons or
through GABA
and NMDA
receptors.
Note. CB=cannabinoid; DA=dopamine; DAT=dopamine transporter; GABA=γ-
aminobutyric acid; 5-HT=serotonin; MAO=monoamine oxidase; nAChR=nicotinic
acetylcholine receptor; NE=norepinephrine; NET=norepinephrine transporter;
NMDA=N-methyl-D-aspartate; SERT=serotonin transporter; VMAT2=vesicular
monoamine transporter 2; VTA=ventral tegmental area.
In this chapter, we define SUD-relevant terms and provide an

overview of the neurobiology of SUDs. We then discuss making a
clinical diagnosis, providing in-depth information specific to each
drug class except for caffeine and tobacco, which rarely are
associated with development of NPDs. Because many patients who
develop significant NPDs also need attention to medically managed
withdrawal from alcohol, sedatives, and opiates, we cover their
management as well.
Definition of Terms
In DSM-IV (American Psychiatric Association 1994), substance
“abuse” was considered a mild form of addictive illness, whereas
“dependence” was viewed as a more severe form, but in DSM-5
(American Psychiatric Association 2013) these terms are no longer
used, and each “use disorder” simply has degrees of severity based
on how many of 11 possible symptoms are endorsed. Dependence
in DSM-5 includes pharmacological tolerance and withdrawal, and
the severity specifier ranges from mild (two symptoms) to severe
(more than five symptoms). Physical dependence typically leads to a
withdrawal syndrome when the drug is discontinued abruptly.
Dependence is not a diagnosis and can reflect a normal tolerance
response, such as the need for higher doses of opioids in pain
management as the treatment duration increases. Upon cessation of
the substance, most individuals do not experience a withdrawal
syndrome or drug craving. However, withdrawal can be precipitated
for some drugs with the use of antagonists such as naloxone for
opiates or flumazenil for benzodiazepines. “Addiction” or “addictive
disease” is not part of DSM-5, although it may be defined as a
specific abnormality of the reward system of the brain producing
repetitive use despite negative consequences.
Tolerance is a pharmacological term meaning that increased
amounts of the drug are needed to achieve the desired effect or that
diminished effects occur with continued use of the same amount of
the drug. Tolerance to respiratory depression and tolerance to
sedating and motor coordination effects may develop at different
rates, depending on the substance and the individual. Laboratory
tests may be helpful for determining tolerance. For example, high
blood levels of the substance with little evidence of intoxication
indicate tolerance. Tolerance may be metabolic, cellular and
functional, or behavioral. Metabolic tolerance means that the drug is
more rapidly changed into inactive substances, most often by the
liver. Cellular and functional tolerance is often put in terms of brain
receptor desensitization to or uncoupling of the receptor from its
second messenger system, such as cyclic adenosine
monophosphate. Behavioral tolerance is individual compensation for
drug effects through adjustments in behavior that are not directly
related to drug metabolism or changes in the cellular response to the
drug.
Withdrawal symptoms vary greatly across the classes of
substances, with marked and generally easily measured
physiological signs of withdrawal with alcohol, opioids, sedatives,
hypnotics, and anxiolytics. Withdrawal is often less apparent with
stimulants, tobacco, and cannabis. Significant withdrawal has not
been documented in humans after repeated use of phencyclidine,
other hallucinogens, and inhalants.
Craving, a feature newly introduced in DSM-5 as one of the 11
criteria symptoms for the diagnosis of an SUD, is a subjective
experience and a drug-acquisitive state that motivates drug use.
Real-time assessments of craving indicate that craving vacillates
substantially even within the course of a day and that reports of
craving obtained at different times have different meanings and
predictive power.
Neurobiology
Chronic substance use can produce structural and functional
brain abnormalities in overlapping brain circuits and be associated
with intense drug craving and compulsive use. Many abnormalities
that are associated with physical dependence resolve within days or
weeks after the substance use stops. The abnormalities that produce
drug craving, compulsive use, and neurocognitive dysfunction,
however, are more wide-ranging, complex, and potentially long-
lasting brain structural changes. These brain changes may be
amplified by environmental effects interacting with genetically
aberrant brain pathways and neurotransmitter sensitivities. Drug-
induced changes combined with genetic vulnerabilities can produce
craving that leads to relapse months or years after acute withdrawal
resolves.
The reinforcing effects of substances increase dopamine (DA) to
supraphysiological levels within several brain reward circuits,
particularly the ventral tegmental area (VTA) to the nucleus
accumbens (NAc) (Volkow et al. 2010). The postsynaptic binding of
DA activates the NAc, whereas presynaptic binding to the VTA
neurons can lead to feedback inhibition of further DA release from
the VTA (Figure 19–1). Other brain areas, such as the hippocampus
and amygdala, create a lasting memory called conditioned
association that links these good feelings and later craving with the
circumstances and environment in which they occur. These cravings
occur when the drug user reencounters those persons, places, or
things that were associated with their drug use. Finally, the action
decisions that lead to substance users making poor decisions and
seeking out more drugs in spite of many obstacles and adverse
health consequences involve a reduction in prefrontal cortex activity
that otherwise inhibits drug craving leading to relapse (Goldstein and
Volkow 2011). Thus, medication development to address
abnormalities in the neurocircuitry for various substance use
disorders is of primary importance.
FIGURE 19–1. Hypothetical representation of a dopamine (DA) neuron
projection from the ventral tegmental area (VTA) and its target neuron
located in the nucleus accumbens (NAc).
DA released by the presynaptic neuron may bind a number of DA receptor
subtypes (D1–D5) identified initially by the way in which they modulate the
conversion of adenosine triphosphate (ATP) to cyclic adenosine 3′,5′-
monophosphate (cAMP) and later confirmed through genetic cloning. DA is
inactivated by reuptake of DA through the dopamine transporter (DAT) back into
the presynaptic cell for recycling and repackaging into synaptic vesicles.
Intraneuronal DA is sequestered into the vesicles by the vesicular monoamine
transporter (VMAT). Cocaine blocks the DAT, increasing synaptic levels of DA (1).
High levels of DA then activate its respective receptors. Cocaine-induced
enhancement of dopamine activation of D1/D5 receptors increases cAMP via
adenylate cyclase (AC) through stimulatory G-protein (Gαs), whereas AC activity is
decreased through inhibitory G-protein (Gαi ) linked to D2/D3/D4 receptors. cAMP
can enhance or decrease the action of intracellular messengers that have
numerous targets, including acting on DNA to initiate or suppress gene expression
that alters cell activity. Methamphetamine and amphetamine (METH/AMPH) also
influence DA neurotransmission, however, through multiple mechanisms.
METH/AMPH reverses the DAT (1) and the VMAT (2), preventing DA from being
inactivated, and induces mobilization and release of vesicular DA (3), increasing
neurotransmitter levels in the synapse.
Positive subjective effects through brain reward circuitry are the

primary reason that some people continue to take drugs, particularly
in the early stages of drug use. However, the continued drive and the
compulsion to use drugs build over time and extend beyond simple
pleasure seeking. Chronic drug administration eventually leads to
abnormal synaptic plasticity and neurotransmission that contributes
to continued drug use. Reversal or normalization of this aberrant
neurotransmission is essential for treatment of drug-induced NPD
(Haile et al. 2012).
Clinical Diagnoses
Patients with an SUD need an assessment that can detect the
particular substance and develop a diagnosis with a rating of
severity. For an accurate diagnosis, various screening instruments,
such as the CAGE-D (CAGE adapted to include drugs) (Mayfield et
al. 1974), Michigan Alcoholism Screening Test (MAST; Selzer 1971),
or Alcohol Use Disorders Identification Test—Consumption (AUDIT-
C; Bush et al. 1998) for alcohol use disorder, can be very helpful with
a cooperative patient in a large-volume setting in which there is
limited time for screening and in-depth interviews. Urine toxicologies
can be invaluable to unmask SUDs, because both social stigma and
the illegality of some SUDs can lead patients to underreport their use
and associated complications of various drugs. These complications
include presenting complaints of mood problems, anxiety, sleep
difficulties, or symptoms of another psychiatric disorder, in addition to
an SUD.
Severity assessments also have several complicating
considerations. First, in DSM-5, low severity is described as mild
SUD rather than abuse, as in DSM-IV (American Psychiatric
Association 1994). Second, severity at the time of initial assessment
may differ from an assessment done during a baseline period of a
patient’s SUD. For example, if the patient is now presenting at the
emergency department (ED) with a catastrophic complication from
acute intoxication, withdrawal, or chronic use with an NPD, he or she
may have quite severe illness during that visit, but as little as a few
hours later the patient can recover and be given a diagnosis of mild
SUD. Overall, patient history and corroborating family member
information are critical, and questions must be asked with
nonjudgmental empathy and caring professional interest rather than
confrontational challenging. Finally, the emergence of agitation,
confusion, or delirium due to an unanticipated withdrawal syndrome
is not rare and requires both an accurate diagnosis and institution of
appropriate medical treatment for the withdrawal and for a follow-up
that will reduce or prevent relapse to drug taking.
Laboratory tests that assess biomarkers known to reflect drug
consumption are very helpful. For example, laboratory tests can
augment alcohol use disorder questionnaire screens. These alcohol-
related tests include γ-glutamyltransferase (GGT) and percent
carbohydrate deficient transferrin (%CDT). GGT is a membrane-
bound liver enzyme for the synthesis and degradation of glutathione,
and GGT levels are elevated in heavy drinkers. The %CDT is the
percentage of circulating glycoprotein transferrin that is carbohydrate
deficient. Serum %CDT is useful in detecting heavy drinking
because its levels correlate with alcohol consumption, especially in
patients with liver disease. Utilizing both biomarkers—GGT and
%CDT—enhances the sensitivity (90%) in detecting heavy drinkers
compared with either one alone (GGT 58%; %CDT, 63%).
Overall, the main goals of the clinical assessment are not just to
make an accurate diagnosis but also to engage the patient in the
treatment of the SUD. This engagement depends on the patient’s
acceptance of or motivation for treatment, the severity of his or her
problem, and the specific substance. The Patient Placement Criteria
algorithm developed by the American Society of Addiction Medicine
attempts to match patients to their optimal intensity of care as
defined within five levels of care (with sublevels) based on six
dimensions (Mee-Lee et al. 2001). Individuals placed in treatments
that are based on this algorithm have shown better outcomes than
mismatched patients. Spontaneous recovery, including participation
in self-help groups, also occurs in about 20% of SUD individuals.
Although this chapter will not detail all the various treatment
options for SUD, general principles of medical withdrawal treatment
deserve emphasis because, like severe intoxication, withdrawal can
be life-threatening and require emergent general medical care. To
prevent acute withdrawal, two principles apply. First, a cross-tolerant,
less harmful, and usually longer-acting medication can be
substituted for the abused drug, such as lorazepam for alcohol or
methadone or buprenorphine for heroin. The dosage is adjusted until
withdrawal symptoms are minimized, and then the medication is
gradually tapered off over several days. Second, non-cross-tolerant
medications can be used to reduce withdrawal symptoms, such as
clonidine for opioid withdrawal or carbamazepine for alcohol
withdrawal. These medications can be particularly useful for
outpatient procedures where the cross-tolerant medications have
their own misuse potential.
In DSM-5, the substance-related disorders include substance-
induced disorders such as intoxication, withdrawal, and psychotic,
bipolar, depressive, anxiety, obsessive-compulsive, sleep, and
sexual dysfunction disorders (Table 19–1). Many of these disorders
are transient and resolve without long-term complications, but some
unique NPD disorders occur for specific drugs that are reviewed
below.
DSM-5 lists specific symptoms for an SUD, as well as describing
a psychiatric disorder of intoxication that requires the substance
effect to be “clinically significant” and “maladaptive.” The specific
symptoms of an SUD fall into groupings of impaired control, social
impairment, risky use, and pharmacological criteria. Craving has
been newly added as a fourth criterion of impaired control, and this is
manifested by an intense desire or urge for the drug that is more
likely when in an environment where the drug previously was
obtained or used. Risky use occurs in situations that are physically
hazardous and involves continued use despite the knowledge of
having a persistent or recurrent physical or psychological problem
due to the substance. Pharmacological criteria include tolerance and
withdrawal, as defined earlier.
DSM-5 includes several different substance-related
neurocognitive disorders (NCDs), all of which require exclusion of
substance intoxication and withdrawal delirium, which tend to
develop quickly, are primarily attributable to active drug use, and
fluctuate considerably over the course of a day. DSM-5 then
differentiates normal neurocognitive function from mild NCD and
major NCD (or dementia). Major NCD is characterized by a
“substantial” decline in neurocognitive function from premorbid levels
in one or more ability areas (i.e., learning and memory, complex
attention, executive functions, language, perceptual-motor, and
social cognition) that disrupts normal everyday functioning.
Functional specifiers for major NCD range from mild (e.g., only
instrumental activities of daily living [ADLs] affected) to moderate
(e.g., basic ADLs affected) to severe (i.e., functionally dependent).
Minor NCD also requires neurocognitive decline in one or more
ability areas, but it differs from major NCD in that minor NCD deficits
are of a more “modest” severity and do not interfere meaningfully
with daily functioning. For both major and minor NCD, one can
specify whether behavioral disturbance (e.g., apathy, mood) is
present. Differentiating neurocognitive effects of SUD from those of
commonly comorbid neuropsychiatric (e.g., closed head injury) and
medical (e.g., HIV infection) conditions can be difficult clinically in
patients with these common comorbidities.
Neuropsychiatric Syndromes by Drug Class
Alcohol
The 2013 National Survey on Drug Use and Health indicated that
half of people age 12 and older were current alcohol drinkers, 60.1
million participated in binge drinking at least once in the past 30
days, and nearly 16.5 million reported heavy drinking (five or more
drinks on the same occasion on each of 5 or more days in the past
30 days).
Intoxication
Binge drinking frequently leads to intoxication, depending on
numerous factors such as body weight, amount and type of alcoholic
beverage, duration over which the alcohol was consumed, individual
tolerance, metabolism, sex, and genetic makeup. Clinical symptoms
of alcohol intoxication, particularly psychomotor impairment, vary
with blood alcohol concentrations (BAC, mg/dL) and the individual’s
tolerance from chronic alcohol use. Limits for legal intoxication are
well below BAC levels >400 mg/dL that lead to death from
respiratory depression. However, other lethal complications of
intoxication during chronic alcohol use may be associated with
cerebral atrophy, predisposing individuals to subdural hematomas
and disordered coagulation, rendering them liable to intracerebral
hemorrhage after a fall.
Withdrawal
Withdrawal symptoms generally occur within 8 hours after
stopping heavy or prolonged drinking and reach maximal intensity on
day two and typically resolve by day four or five. Severe withdrawal
can occur in about 5% of patients and can induce seizures or
delirium tremens (DTs), generally developing 24–72 hours after the
last drink. Worsening agitation, distractibility, and
illusions/misinterpretations generally precede DTs, which is
characterized by fluctuating disturbance of consciousness, changes
in cognition, severe autonomic symptoms (sweating, nausea,
palpitations, and tremor) and fear or terror (Schuckit 2009). Alcohol
withdrawal severity can be closely monitored using instruments such
as the Clinical Institute Withdrawal Assessment for Alcohol—
Revised scale (CIWA-Ar; Sullivan et al. 1989). Uncomplicated
withdrawal with tremor, vascular headache, photophobia, irritability,
and mild autonomic excitation generally does not require mediation.
More severe early-stage withdrawal includes hyperreflexia and
transient hallucinations. Generalized tonic-clonic seizures and
postictal confusion and disorientation are more obvious severe signs
and can be associated with disorientation and fluctuating levels of
consciousness. Finally, protracted withdrawal can begin 2–3 weeks
after the acute symptoms and last for months, with autonomic
dysfunction, sleep disturbance, fatigue, and impaired short-term
memory.
For treatment of the signs and symptoms of acute alcohol
withdrawal, comorbid psychiatric and medical conditions related to
nutritional and vitamin deficiencies need to be considered. Thiamine
(before glucose) should be administered to prevent potential
Wernicke’s encephalopathy and Korsakoff’s syndrome (as discussed
in the next subsections). Managing acute alcohol withdrawal typically
uses short- or long-acting benzodiazepines that are dosed based on
CIWA-Ar assessment of withdrawal severity.
Longer-term treatment to prevent relapse to alcohol SUD can
involve four medications that have U.S. Food and Drug
Administration (FDA)–approved indications. Two formulations of
naltrexone are available: oral and an extended-release injectable
(Rösner et al. 2010). The glutamate modulator acamprosate is
hypothesized to normalize glutamatergic/γ-aminobutyric acid (GABA)
dysregulation associated with chronic alcohol consumption and
withdrawal (Witkiewitz et al. 2012). Disulfiram blocks aldehyde
dehydrogenase, thereby increasing acetaldehyde and producing an
aversive reaction.
Neuropsychiatric Syndromes Associated With

Alcohol Use Disorder
Wernicke’s encephalopathy. Thiamine (vitamin B1) deficiency due
to poor nutrition and hyperemesis in individuals who are alcohol-
dependent can result in Wernicke’s encephalopathy, which can be
successfully reversed with vitamin supplementation. Onset may be
subacute or acute and is characterized by confusion, ataxia,
ophthalmoplegia, decreased level of consciousness, nystagmus,
memory disturbance, unexplained hypotension with hypothermia,
and possible withdrawal symptoms. Improvement in confusion
usually occurs in 1–2 days, and ocular abnormalities improve in days
to weeks, whereas ataxia usually responds within the first week but
can take months or much longer to resolve. Glucose/dextrose or
carbohydrate administration can facilitate the onset of Wernicke’s
encephalopathy; therefore, thiamine should always be administered
first. Magnesium levels should also be determined because sufficient
levels of both thiamine and magnesium are required for a positive
clinical outcome. If the encephalopathy is unrecognized and
untreated, approximately 80% of patients may develop Korsakoff
syndrome with profound anterograde amnesia and confabulation.
Korsakoff syndrome. Korsakoff syndrome is marked by
confabulation and a pervasive amnestic syndrome that profoundly
affects new learning and recall of both recent and remote events.
Semantic memory (i.e., memory for facts), IQ, basic attention, and
nondeclarative memory are relatively spared. Injury to diencephalic
structures (i.e., dorsomedial thalamus and mammillary bodies) is
widely thought to drive the amnesia of Korsakoff syndrome, but the
role of frontostriatal and temporolimbic systems cannot be excluded
(Sullivan and Marsh 2003).
Major neurocognitive disorders (i.e., dementia). Major NCDs,
which are evident in only a small proportion of individuals with
alcohol use disorder (<10%), have relatively heterogeneous
symptoms, including lack of interest in one’s appearance, impaired
judgment, attention deficits, slowed thought processes, and general
symptoms of frontal lobe dysfunction but without emotional lability or
grandiosity. Patients with major NCDs do not show aphasia and
have a clear sensorium. NCDs are slowly progressive and related to
Wernicke’s encephalopathy. Frontal lobe atrophy and ventricular
enlargement on MRI are not correlated with NCD severity. Alcoholic
patients without dementia may show brain volume reductions in the
prefrontal cortex, posterior parietal cortex, limbic system, and
cerebellum (Fama and Sullivan 2014). Minor NCDs are evident in
around 40% of individuals with alcohol use disorder of recent onset,
who show generally moderate deficits in executive functions, spatial
cognition, motor skills (e.g., gait and balance), information
processing speed, and memory (Stavro et al. 2013). Deficits in
emotional processing and social cognition may also be present
(Schulte et al. 2010). These neural changes and neurocognitive
impairments generally abate in a majority of patients with 1–2 years
of sobriety.
Alcoholic cerebellar degeneration. Alcoholic cerebellar
degeneration is a typically bilateral syndrome of gait ataxia and can
also include arm ataxia and dysarthria. It does not include the
oculomotor and mental deficits that accompany Wernicke’s
encephalopathy. The pathophysiology involves Purkinje cell
degeneration in the cerebellar cortex, and thiamine therapy may
provide some improvement.
Alcoholic polyneuropathy. Peripheral neuropathy may be
evidenced by muscular weakness, paresthesias, and decreased
peripheral sensation. The disorder tends to progress gradually in
sensory and motor neurons with deficits that are distal, bilateral, and
symmetric in a glove-and-stocking distribution. Autonomic nerves are
relatively spared.
Central pontine and extrapontine myelinolysis. Hyponatremia is
common in chronic beer drinkers because of the intake of large
volumes of water. Attempts to correct the electrolyte disturbance with
saline (particularly hypertonic saline) may result in demyelination,
which is considered to occur from complement-mediated
oligodendrocyte toxicity from rapid osmotic shifts in the brain, most
commonly in the pons. This demyelination can also occur in the
basal ganglia and thalamus.
Hepatic encephalopathy. Minimal hepatic encephalopathy may
affect 60% of patients with cirrhosis and includes psychomotor
slowing with deficits in attention and visual perception. With
recurrence, it can develop into dementia and may be accompanied
by asterixis, extrapyramidal rigidity, and choreoathetosis.
Cannabis
Cannabis use has increased partly because of changes in legal
status at the state level. The 2013 National Survey on Drug Use and
Health found that daily cannabis use in the past 12 months by
persons age 12 and older increased by 2.6 million users from 2006.
In addition, use of so-called synthetic cannabinoid-like compounds
(e.g., “K2” and “spice”) has also increased, but in contrast to
cannabis, these drugs are associated with psychosis and adverse
cardiovascular events (Mir et al. 2011). Indeed, drug-related ED
visits involving synthetic cannabinoids increased nearly 150% from
2009 to 2011.
Intoxication and Withdrawal

Acute intoxication with cannabis can lead to impaired motor
coordination, euphoria, and inaccurate time perception; these effects
are attenuated by pharmacological tolerance. Other signs include
conjunctival injection of the eyes, cannabis odor on clothing,
yellowing of fingertips from smoking joints, and less specific
symptoms, such as chronic cough, incense smell on the patient, and
exaggerated food craving, often at unusual times of the day or night.
Cannabis often is used to cope with mood, sleep, pain, or other
physiological or psychological problems. Withdrawal may contribute
to these same symptoms and includes irritability, anxiety, depressed
mood, decreased appetite, and sleep difficulty.
Neuropsychiatric Complications and Possible

Benefits of Chronic Cannabis Use
Cannabis can complicate schizophrenia and amotivational states
but also may have possible therapeutic benefits for headache, pain,
mood and anxiety disorders, and epilepsy. The conflicting literature
on the complications versus benefits of cannabis is not easily
resolved. Cannabis can augment the analgesic effects of opiates but
has very limited analgesic effects on its own. Other serious
conditions, such as epilepsy and psychiatric disorders, are more
likely worsened.
Neurocognitive Aspects of Chronic Cannabis Use

Adults who initiate cannabis use after their adolescence appear to
have no changes in brain structure, although the heavy cannabis
users may have mild deficits in attention and memory (Grant et al.
2003). Heavy cannabis use during adolescence can induce changes
in cortical gray matter volumes (e.g., prefrontal cortex, hippocampus)
and reduce white matter integrity (Lisdahl et al. 2014), both of which
are associated with lower IQ scores and neurocognitive deficits
(Meier et al. 2012). These deficits may interfere with academic
performance, vocational functioning, and the development of
essential everyday living skills. Whether full or partial recovery of
neural and neurocognitive function can occur in adolescent cannabis
users who are able to remain abstinent is not clear.
Stimulants
The stimulant-related disorders involve methamphetamine,
amphetamine, cathinone derivatives (“bath salts”), and plant-derived
drugs such as cocaine, ephedra, and khat. A recent Substance
Abuse and Mental Health Services Administration survey found that
14% of all individuals entering treatment had cocaine (7%) or
methamphetamine (7%) use disorder, and cocaine was the most
common illicit drug involved in drug-related ED visits.
Intoxication
The half-life of cocaine, which is significantly shorter (40–90 min)
than the half-life of methamphetamine/amphetamine (10–12 hours),
contributes to the duration of intoxication and toxicity, although both
substances produce similar symptoms. These stimulants drive the
central and sympathetic nervous systems, inducing euphoria,
increased energy, and hypersexuality. Hypersexuality leads to loss of
sexual inhibition and risk-taking behavior. Acute intoxication may
present with rambling speech, headache, transient ideas of
reference, and tinnitus. Individuals may develop paranoid ideation,
auditory hallucinations in a clear sensorium, and tactile
hallucinations. Threats or aggression may occur, although
depression with suicidal ideation is more common. Seizures and
psychosis are more common with amphetamine, including auditory,
visual, and tactile hallucinations, and delusions, resembling paranoid
schizophrenia. Stimulant intoxication and overdose can also cause
death from hyperthermia.
Withdrawal
Withdrawal symptoms following the cessation of stimulant use
include mostly dysphoric symptoms, such as an initial “crash” with
anxiety, agitation, depression, and, later, intense drug craving. The
time course is again influenced by the amount and frequency of drug
intake as well as the half-life of the stimulant ingested (Newton et al.
2004). Cocaine withdrawal is usually more abrupt than amphetamine
withdrawal, but both produce similar symptomology. Depression,
suicidal ideation, irritability, anhedonia, emotional lability, and/or
disturbances in attention and concentration commonly occur during
withdrawal. Mental disturbances associated with cocaine use usually
resolve hours to days after cessation of use but can persist for 1
month. Physiological changes during stimulant withdrawal
sometimes include bradycardia. Repeated panic attacks, social
anxiety disorder, and generalized anxiety syndromes are common,
as are eating disorders. Benzoylecgonine, a metabolite of cocaine, is
detectable in urine for about 1–3 days following the last dose;
amphetamine is detectable in urine for a longer time period.
Stimulant use can be detected for up to 90 days with hair analysis.
Neuropsychiatric Complications of Stimulant-

Related Disorders
Stimulants produce a range of disorders, including movement
disorders, more general neuropsychiatric impairment, and
psychoses. Movement disorders associated with stimulants include
chorea, dystonia, akathisia, choreoathetosis, eye blinking, and lip
smacking. These movements typically start within 2 hours of use and
spontaneously resolve. They are most likely related to DA
stimulation of the motor striatum, whereas the reinforcing effects of
these drugs are mediated by the mesolimbic system (Figure 19–1).
Another type of complication is psychosis that may be related to
sigma receptor binding, which is greater for amphetamine than for
cocaine. This psychosis typically resolves within 5–30 days, but it
can persist. Even without frank psychosis, stimulant abusers are
often tense and restless and can have delusions of persecution and
hallucinations of virtually any type.
Neurocognitive Aspects of Stimulant-Related

Disorders
Chronic stimulant users show mild to moderate neuroimaging
alterations in the structure and function of the fronto-striato-thalamo-
cortical loops, as well as alterations in the hippocampus and
posterior parietal cortex (Jernigan et al. 2005). Approximately 30%–
40% of chronic stimulant users demonstrate global but mild
neurocognitive deficits (Figures 19–2 and 19–3) (Scott et al. 2007).
The nature and extent of neurocognitive deficits in stimulant users do
not track reliably with onset, quantity, or frequency of use (Cherner et
al. 2010); however, the deficits appear to lessen in severity with
sustained abstinence (Iudicello et al. 2010). Consistent with the
frontal system’s neurotoxicity with chronic stimulant use (Volkow et
al. 2001), such neurocognitive deficits are most prominent in the
domains of episodic memory, executive functions (e.g., abstraction,
cognitive flexibility), attention/working memory, information
processing speed, and fine-motor skills.
FIGURE 19–2. Prevalence of methamphetamine-induced neurocognitive
disorders (NCDs) (N=91).
FIGURE 19–3. Profile of deficits among persons with methamphetamine-
induced neurocognitive disorders (N=224).
Opiates
Since 2007, prescription opiates have surpassed cannabis as the
most common illicit drug that adolescents initially abuse, leading to
an annual prevalence rate that is three times greater than the 0.14%
annual prevalence of heroin dependence in the United States.
Narcotic pain relievers and heroin accounted for 27.5% of all drug-
related ED visits in the United States in 2011. The most commonly
used opiates are diverted prescriptions for oxycodone, followed by
heroin and morphine use, and—among health professionals—
meperidine and fentanyl. Use disorders for the two opiate agonist
maintenance treatment agents—methadone and buprenorphine—
occur at substantially lower rates. One serious complication of opiate
use is the result of pregnant women consuming opioids throughout
pregnancy, which can lead to newborns who experience opioid
withdrawal and associated fatal seizures.
Intoxication
The “high” from opioids only occurs with a fast rate of change in
opiate brain levels (e.g., smoking or intravenous) that reduces GABA
activity and produces a burst of NAc activity. Oral and transdermal
opiate administration slowly increases opiate brain levels and does
not produce opiate euphoria. Intoxication produces a “rush” and
euphoria, followed by sleepiness (“the nod”). Heroin effects last 3–5
hours, and several doses a day are required to prevent withdrawal
emerging in dependent persons. Opiate overdose is managed with
the opiate antagonist naloxone, which has a short half-life and needs
to be given repeatedly.
Withdrawal
Tolerance and withdrawal commonly occur with 6–8 weeks of
chronic daily use. Tolerance appears to be pharmacodynamic rather
than pharmacokinetic, with relatively limited induction of the
cytochrome P450 2D6 and 3A4 systems. Tolerance to the mental
effects of opioids leads to the need for ever-increasing amounts of
drugs to sustain the desired euphoric effects as well as to avoid the
discomfort of withdrawal.
Symptoms of opioid withdrawal begin 8–10 hours after the last
dose of morphine and last 7–10 days. Many of these symptoms
resemble those of increased activity of the autonomic nervous
system. Protracted symptoms, characterized by hypotension,
bradycardia, hypothermia, mydriasis, and decreased responsiveness
of the respiratory center to carbon dioxide, can occur during 26–30
weeks of abstinence.
Pharmacotherapy can involve opioid detoxification or
maintenance treatment with agonists or antagonists. Agonists like
methadone and partial agonists like buprenorphine are long-acting
for preventing withdrawal symptoms and can typically be given once
daily, which facilitates both maintenance and detoxification. Other
medications that are used for detoxification include the α2-adrenergic
agonists clonidine and lofexidine, which have no narcotic action and
are not addictive. They are often combined with a range of other
symptomatic treatment agents. Orally acting antagonists such as
naltrexone are used postdetoxification orally three times a week at
doses of 100–150 mg or monthly by depot injection.
Maintenance treatment with methadone has been safely used for
more than 40 years. Methadone’s slow onset of action when taken
orally, long elimination half-life (24–36 hours), and production of
cross-tolerance at doses from 80 to 150 mg are the bases for its
efficacy. Sublingual buprenorphine maintenance also benefits from a
slow onset and long duration of action, and its partial agonism
reduces the risk of unintentional overdose. A subcutaneous
buprenorphine implant has also had favorable results but is not yet
FDA approved. However, patients must complete detoxification from
opiates before buprenorphine can be started. When any of these
medications are taken chronically for even years, they are safe, are
associated with few side effects (e.g., headache, nausea, abdominal
pain), and can be given to patients infected with hepatitis B or C
without producing hepatotoxicity.
Neuropsychiatric Complications of Chronic

Opiate Use
Neurological complications of chronic opiate use are rarely related
to the drug itself; they are related to common adulterants and
infectious complications such as HIV, endocarditis of the tricuspid
valve, brain syphilis, tetanus, and botulism. Injecting adulterants that
involve insoluble foreign material can lead to embolic strokes among
opiate users. Infectious agents and their toxins can pass into the
brain through arteriovenous shunts and result in abscess, meningitis,
diffuse vasculitis, and septic aneurysm of the brain or spinal cord.
Finally, during opiate overdose, brain hypoperfusion and
hypoventilation resulting in low oxygen levels can lead to ischemic
cerebral infarction.
Neurocognitive Aspects of Chronic Opiate Use

Chronic opiate users can show gray matter reductions in the
prefrontal and cingulate cortex that appear to be independent of
common comorbidities (e.g., HIV) and that persist after a few months
of abstinence (Yuan et al. 2009). The prevalence of neurocognitive
disorders per se among chronic opiate users is not known, but mild-
to-moderate deficits in information processing speed and various
aspects of executive functioning (e.g., decision making, planning)
are commonly reported, although findings across the literature are
mixed (Rass et al. 2014). Some aspects of neurocognitive functions
may improve with sustained abstinence, but mild deficits in higher-
order ability areas (e.g., executive functions) can persist (Cohen et
al. 2010).
Sedative-Hypnotics and Anxiolytics

About 1% of the U.S. population has used a benzodiazepine for a
year or longer; however, the rates are much greater among the
population with SUD. Approximately 15%–20% of alcoholic patients
presenting for treatment may be abusing benzodiazepines, and in
methadone clinics the rates of urine testing positive for illicit
benzodiazepines are reported as 30% and greater. Data from a
recent National Survey on Drug Use and Health indicated that 8% of
the U.S. population age 12 years or older used tranquilizers for
nonmedical purposes at some time in their lives, and
benzodiazepines were mentioned in 27% of suicide attempts (Center
for Behavioral Health Statistics and Quality 2012).
Sedative-hypnotics are anxiolytics, hypnotics, anticonvulsants,
muscle relaxants, and anesthesia induction agents. They include
four nonbenzodiazepine hypnotics: zopiclone, a cyclopyrrolone;
eszopiclone, a stereoselective isomer of zopiclone; zaleplon, a
pyrazolopyrimidine; and zolpidem, an imidazopyridine.
Intoxication and Overdose

With sedative-hypnotics and anxiolytics, as with most abused
drugs, rapid onset of action is associated with euphoria. Consistent
with that association, diazepam and alprazolam have higher abuse
potential than halazepam and oxazepam. The benzodiazepines have
less abuse liability than barbiturates and older sedative-hypnotics
(e.g., methaqualone, ethchlorvynol), while anxiolytics and hypnotics
that act via non-GABAergic mechanisms (e.g., buspirone,
antidepressants, ramelteon) lack abuse potential. Postmarketing
surveillance indicates a relatively low potential for abuse for
zolpidem considering how often it is prescribed. Barbiturates present
a more serious risk than benzodiazepines of central nervous system
depression, coma, and death when taken in high doses or with
ethanol or other sedative-hypnotics.
Acute benzodiazepine toxicity includes sedation, psychomotor
impairment, memory problems with anterograde amnesia, difficulty
acquiring new learning, and sedation affecting attention and
concentration. When high doses of benzodiazepines are ingested,
either as a therapeutic intervention or by overdose, initial signs of
toxicity are ataxia and impaired gag reflex. Sedative-hypnotics rarely
produce disinhibition or paradoxical excitement.
The Z-drugs—zolpidem, zopiclone, and zaleplon—are short-
acting GABA agonists that reduce sleep latency without disturbing
sleep architecture (Gunja 2013). These medications are implicated in
driving under the influence–related accidents, with impaired drivers
having high blood levels of the drug or combining the Z-drug with
alcohol or with other sedatives. Psychomotor impairment,
anterograde amnesia, and complex behaviors such as sleepwalking,
sleep-driving, and hallucinations occur more with zolpidem than with
zaleplon. Consistent with central nervous system depression, Z-
drug–impaired drivers in accidents may be able to understand and
respond to questions from police, whereas sleepwalkers are
completely unable to understand or interact with police. The Z-drug–
impaired drivers are often severely physically impaired and unable to
stand up or maintain balance, whereas sleepwalkers are able to
stand and walk unaided. The residual effect of Z-drugs on next-day
cognitive and psychomotor performance has significant impact on
lifestyle, safety, and occupational considerations, including motor
vehicle and machine operation.
Withdrawal
The most severe withdrawal syndrome following high-dose
chronic administration of diazepam can include grand mal seizures
and psychosis. When taken for short periods at therapeutic doses,
the withdrawal syndrome is usually mild, consisting of anxiety,
headache, insomnia, dysphoria, tremor, and muscle twitching. After
long-term treatment with therapeutic doses, the syndrome may
include autonomic dysfunction, nausea, vomiting, depersonalization,
derealization, delirium, hallucinations, illusions, agitation, and grand
mal seizures. Patients taking short-half-life agents (e.g., lorazepam,
alprazolam, temazepam) develop symptoms within 24 hours of
discontinuation, peaking at 48 hours. With longer-half-life agents,
such as diazepam, symptoms may develop a week after drug
discontinuation and last for several weeks. A prolonged withdrawal
syndrome may persist for several months, but it has not been clearly
distinguished from return of original anxiety symptoms.
Barbiturate withdrawal occurs after using 0.8–2.2 g/day oral doses
of secobarbital or pentobarbital for 6 weeks or longer and includes
apprehension, uneasiness, muscular weakness, coarse tremors,
postural hypotension, anorexia, vomiting, and myoclonic jerks lasting
up to 2 weeks. Grand mal seizures or delirium occurs within 2–3
days of discontinuation and lasts as long as 8 days to 2 weeks.
Management of the barbiturate withdrawal involves transition to an
equivalent dose of phenobarbital, determined either by a challenge
dose or with a loading dose procedure.
Neuropsychiatric Complications of Sedative-

Hypnotics and Anxiolytics
Withdrawal-related seizures are the most frequent
neuropsychiatric complication of sedatives. Seizures are produced
by excessive discharges of groups of neurons that can be focal or
generalized. Seizures often begin focally and quickly spread to
generalized seizures. These sudden generalized alterations in
cerebral function are the most common types in sedative withdrawal
and include incontinence and loss of consciousness and motor
control with tonic-clonic jerking of the extremities. These seizures
generally last a few minutes, but if they continue for more than 5
minutes without the patient regaining consciousness, this is called
status epilepticus. Focal seizures are very unlikely without a cerebral
lesion in addition to the drug withdrawal. Diagnostic
electroencephalographic studies are of limited use for sedative-
related withdrawal seizures because between seizures the
electroencephalogram is typically normal.
Neuropsychological Aspects of Sedative-

Hypnotics and Anxiolytics
Neuroimaging studies of chronic benzodiazepine use are sparse
and inconclusive. However, chronic benzodiazepine use does
appear to be associated with moderate deficits in a wide range of
neurocognitive functions, which are most reliably observed in the
areas of attention, psychomotor speed, spatial cognition, and
memory (Barker et al. 2004). As with other substances of abuse,
abstinence from benzodiazepines can be accompanied by some
recovery of neurocognitive function, but deficits in memory, for
example, are still evident even 6 months after last use (Barker et al.
2005).
Hallucinogens
Hallucinogens comprise a diverse group of substances that,
despite different chemical structures and possibly molecular
mechanisms, produce similar alterations of perception, mood, and
cognition in users. The main symptoms are visual hallucinations and
perceptual distortions that include depersonalization, derealization,
and sensory synesthesias such as seeing a loud automobile horn as
a bright light. These substances are typically used episodically,
perhaps because of the rapid tolerance that develops to
hallucinogens. Included among hallucinogens are two main chemical
classes: phenylalkylamines (e.g., mescaline, 2,5-dimethoxy-4-
methylamphetamine [DOM], 3,4-methylenedioxymethamphetamine
[MDMA], also called “ecstasy”) and the indoleamines, including
psilocybin (psilocin) and dimethyltryptamine (DMT), which are
tryptamines, and lysergic acid diethylamide (LSD) and morning glory
seeds, which are ergolines (Halberstadt and Geyer 2011). In
addition, there are miscellaneous other ethnobotanical compounds
that are classified as “hallucinogens,” of which Salvia divinorum and
Datura stramonium (jimsonweed) are two examples.
Little is known regarding the course of hallucinogen use disorder,
but it is generally thought to have low incidence, low persistence,
and high rates of recovery.
Hallucinogens are usually taken orally, but they can be smoked
(e.g., DMT, salvia). Some drugs (e.g., LSD, MDMA) produce effects
in users lasting hours to days, but tolerance quickly develops to both
autonomic and psychological effects. MDMA/ecstasy shares features
with amphetamines. The typical DSM-5 diagnostic elements are
tolerance, use despite physical or psychological problems,
hazardous use, and spending time engaged in drug-related
activities. Users most frequently endorse feeling depressed and
tired, having changed appetite, having trouble concentrating, feeling
anxious, having sleep difficulties, and having headaches.

Hallucinogen intoxication disorder reflects the drug used, its dose,
and the setting of use. The clinically significant behavioral and
psychological changes include dilated pupils, tachycardia, sweating,
palpitations, and tremors. These effects occur shortly after ingestion
of a hallucinogen and are followed by the perceptual distortions and
visual hallucinations produced by these drugs. Depending on the
specific hallucinogen, the intoxication may last only minutes (e.g.,
with salvia) or several hours or longer (e.g., with LSD or MDMA).
With these longer-lasting drugs, the excitation and impaired
judgment can result in serious adverse consequences, such as
jumping off a building because the user believes he or she can fly.
Symptoms typical of hallucinogens can also be produced by other
drugs such as phencyclidine and ketamine, highly potent cannabis,
and khat (cathinone). Toxicological tests can help in making this
distinction between hallucinogens and nonhallucinogens. Metabolic
derangements causing delirium that can resemble hallucinogen
intoxication can generally be distinguished by alteration in level of
consciousness associated with delirium. No withdrawal symptoms
occur from hallucinogens.
Neuropsychiatric Complications of
Hallucinogens
Regular use of the hallucinogens does not typically produce
neuropsychiatric complications. For example, the plant peyote used
as part of religious rituals is not linked to neuropsychological or
psychological deficits or toxicity. However, long-term neurotoxic
effects of MDMA/ecstasy use include mild-to-moderate impairments
in neurocognition (e.g., working memory, processing speed,
executive functions), mood, neuroendocrine function, and sleep
disturbance. Decreases in verbal memory, with adverse effects on
brain microvasculature, white matter maturation, and damage to
axons, may also be included among the MDMA/ecstasy neurotoxic
effects. With MDMA use, serotonergic neuron degeneration is
described in animals, but its clinical significance is unclear, and
perhaps the panic attacks observed in these users reflect this
neurotoxicity.
Hallucinogen persisting perception disorder can continue
episodically or continuously for weeks (or longer) after previous
intoxication. This perception disorder is usually associated with less
compelling visual hallucinations, perhaps verging into illusions,
compared with acute intoxication with hallucinogens. Most people
experiencing hallucinogen persisting perception disorder recognize
the symptoms and are not particularly disturbed by them. A related
phenomenon can be recurring flashbacks or transient perceptual
alterations involving flashes of color, after-images, or micropsia. The
flashbacks typically last seconds to minutes, can occur up to 5 years
after last hallucinogen use, and have a wide range of triggers.
Inhalants
Inhalant use disorder involves solvents (paint thinner), gases
(gasoline), cleaning agents (degreasers), aerosols (spray paint, hair
spray), anesthetics (nitrous oxide), glues (airplane glue), and
adhesives. Although rare, the disorder affects a very young and
vulnerable population, with 9% of 3 million persons age 12 and older
who used an illicit drug for the first time in the last 12 months
reporting inhalants as their first drug (Center for Behavioral Health
Statistics and Quality 2012). Inhalants may contain many toxic
chemicals. Products that contain toluene, acetone,
chlorofluorocarbons, benzene, xylene, hexane, and butane are
preferred chemicals of abuse by those with inhalant use disorder
(Howard et al. 2011). The neurobiological mechanisms that mediate
the reinforcing effects of inhalants are unknown. Much as with other
abused substances, studies in animals do indicate that inhalants
increase central DA, possibly through GABA and N-methyl-D-
aspartate (NMDA) receptors or by directly stimulating DA release in
mesolimbic circuits.

Acute inhalant intoxication produces dizziness, incoordination,
slurred speech, unsteady gait, depressed reflexes, generalized
muscle weakness, blurred vision, diplopia, and euphoria. Although
there is no clearly defined withdrawal syndrome for inhalant use,
some symptoms appear to be similar to cocaine withdrawal, just as
the intoxication resembles acute alcohol effects. No laboratory or
diagnostic tests identify inhalant use disorder; however, diagnosis
can be supported by the symptoms listed above, as well as by
possession of inhalants and their odors, and the presence of peri-
oral or peri-nasal (“glue sniffer’s rash”) lesions.
Neuropsychiatric Complications of Inhalants

Few empirical studies have investigated central nervous system
recovery following inhalant use. Case reports and group studies
report the severity of impairment related to the duration and severity
of misuse, blood lead levels among leaded petrol misusers, and only
partial recovery with prolonged abstinence. The severe neurological
impairment from lead encephalopathy that follows sniffing leaded
gasoline leads to abrupt damage to cerebellar neurons that may
never fully recover. Recovery from neuroanatomical damage may
not occur even with prolonged abstinence. Overall, chronic inhalant
use is associated with altered brain perfusion and blood flow and
structural abnormalities in specific areas linked to cognitive deficits.
Neurological symptoms associated with Parkinson’s disease—motor
impairment, decreased muscle strength, peripheral and sensorimotor
neuropathy, speech problems, and tremor—are associated with
inhalant use. Suicidal ideation, depression, and psychosis are
notable psychiatric consequences related to inhalants. Data from
inhalant cases reported to U.S. poison control centers indicate that
users of butane, propane, and air fresheners had the highest fatality
rates (Marsolek et al. 2010). Fatalities linked to inhalant use are
commonly a result of cardiovascular complications such as
myocardial ischemia from hypoxia, arrhythmias, and ventricular
fibrillation. Death can also result from anoxia, aspiration, asphyxia,
respiratory depression, and trauma.
Neuropsychological Aspects of Inhalants

Studies consistently find associations between inhalant use
among adolescents and lower IQ, as well as neurocognitive deficits
across a broad range of ability areas, including executive functions,
attention/working memory, psychomotor speed, spatial cognition,
and memory (Takagi et al. 2014). The higher-order deficits observed
in inhalant users appear to be independent of sociodemographic
factors and comorbid substance use (Rosenberg et al. 2002). The
extent to which neurocognitive deficits improve or normalize with
sustained abstinence is unclear.
Conclusion
We have reviewed the neuropsychiatric consequences (NPC) of a
wide range of abused substances but left out caffeine and nicotine,
because NPC are rarely associated with these licit drugs. Alcohol
has many NPC, however, probably related to the large dose of
alcohol that is needed for intoxication and its frequent daily use over
many years. Among the other abused drugs, sedatives can be
similar to alcohol in some of their NPC. However, opiates and
cannabis tend to have few NPC. In between alcohol and opiates are
the stimulants and inhalants, which can have a range of NPC,
including movement disorders, psychosis, anxiety, and depression,
with a pathophysiology of damage to dopamine neurotransmission
and demyelination, respectively.
References
1994
Barker MJ, Greenwood KM, Jackson M, et al: Cognitive effects of long-term
benzodiazepine use: a meta-analysis. CNS Drugs 18(1):37–48, 2004
14731058
Barker MJ, Greenwood KM, Jackson M, et al: An evaluation of persisting cognitive
effects after withdrawal from long-term benzodiazepine use. J Int Neuropsychol
Soc 11(3):281–289, 2005 15892904
Bush K, Kivlahan DR, McDonell MB, et al: The AUDIT alcohol consumption
questions (AUDIT-C): an effective brief screening test for problem drinking.
Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use
Disorders Identification Test. Arch Intern Med 158(16):1789–1795, 1998
9738608
Center for Behavioral Health Statistics and Quality: Treatment Episode Data Set
(TEDS): 2000–2010. National Admissions to Substance Abuse Treatment
Services. Rockville, MD, Substance Abuse and Mental Health Services
Administration, June 2012. Available at:
http://archive.samhsa.gov/data/2k12/TEDS2010N/TEDS2010NWeb.pdf.
Accessed March 7, 2017.
Cherner M, Suarez P, Casey C, et al; HNRC Group: Methamphetamine use
parameters do not predict neuropsychological impairment in currently abstinent
dependent adults. Drug Alcohol Depend 106(2–3):154–163, 2010 19815352
Cohen LJ, Nesci C, Steinfeld M, et al: Investigating the relationship between
sexual and chemical addictions by comparing executive function in subjects
with pedophilia or opiate addiction and healthy controls. J Psychiatr Pract
16(6):405–412, 2010 21107145
Fama R, Sullivan EV: Alcohol, in Neuropsychological Aspects of Substance Use
Disorders: Evidence-Based Perspectives. Edited by Allen DN, Woods SP. New
Goldstein RZ, Volkow ND: Dysfunction of the prefrontal cortex in addiction:
neuroimaging findings and clinical implications. Nat Rev Neurosci 12(11):652–
669, 2011 22011681
Grant I, Gonzalez R, Carey CL, et al: Non-acute (residual) neurocognitive effects
of cannabis use: a meta-analytic study. J Int Neuropsychol Soc 9(5):679–689,
2003 12901774
Gunja N: In the Zzz zone: the effects of Z-drugs on human performance and
driving. J Med Toxicol 9(2):163–171, 2013 23456542
Haile CN, Mahoney JJ III, Newton TF, et al: Pharmacotherapeutics directed at
deficiencies associated with cocaine dependence: focus on dopamine,
norepinephrine and glutamate. Pharmacol Ther 134(2):260–277, 2012
22327234
Halberstadt AL, Geyer MA: Multiple receptors contribute to the behavioral effects
of indoleamine hallucinogens. Neuropharmacology 61(3):364–381, 2011
21256140
Howard MO, Bowen SE, Garland EL, et al: Inhalant use and inhalant use disorders
in the United States. Addict Sci Clin Pract 6(1):18–31, 2011 22003419
Iudicello JE, Woods SP, Vigil O, et al; HIV Neurobehavioral Research Center
(HNRC) Group: Longer term improvement in neurocognitive functioning and
affective distress among methamphetamine users who achieve stable
abstinence. J Clin Exp Neuropsychol 32(7):704–718, 2010 20198527
Jernigan TL, Gamst AC, Archibald SL, et al: Effects of methamphetamine
dependence and HIV infection on cerebral morphology. Am J Psychiatry
162(8):1461–1472, 2005 16055767
Lisdahl KM, Wright NE, Kirchner-Medina C, et al: Considering cannabis: the
effects of regular Cannabis use on neurocognition in adolescents and young
adults. Curr Addict Rep 1(2):144–156, 2014 25013751
Marsolek MR, White NC, Litovitz TL: Inhalant abuse: monitoring trends by using
poison control data, 1993–2008. Pediatrics 125(5):906–913, 2010 20403928
Mayfield D, McLeod G, Hall P: The CAGE questionnaire: validation of a new
alcoholism screening instrument. Am J Psychiatry 131:1121–1123, 1974
Mee-Lee D, Shulman MJ, Fisherman M, et al: ASAM Patient Placement Criteria for
the Treatment of Substance-Related Disorders, 2nd Edition, Revised (ASAM-
PPC-2R). Chevy Chase, MD, American Society of Addiction Medicine, 2001
Meier MH, Caspi A, Ambler A, et al: Persistent cannabis users show
neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A
109(40):E2657–E2664, 2012 22927402
Mir A, Obafemi A, Young A, et al: Myocardial infarction associated with use of the
synthetic cannabinoid K2. Pediatrics 128(6):e1622–e1627, 2011 22065271
Newton TF, Kalechstein AD, Duran S, et al: Methamphetamine abstinence
syndrome: preliminary findings. Am J Addict 13(3):248–255, 2004 15370944
Rass O, Schacht RL, Marvel CL, et al: Opioids, in Neuropsychological Aspects of
Substance Use Disorders: Evidence-Based Perspectives. Edited by Allen DN,
Woods SP. New York, Oxford University Press, 2014, pp 231–253
Rosenberg NL, Grigsby J, Dreisbach J, et al: Neuropsychologic impairment and
MRI abnormalities associated with chronic solvent abuse. J Toxicol Clin Toxicol
40(1):21–34, 2002 11990201
Rösner S, Hackl-Herrwerth A, Leucht S, et al: Opioid antagonists for alcohol
dependence. Cochrane Database Syst Rev (12):CD001867, 2010 21154349
Schuckit MA: Alcohol-use disorders. Lancet 373(9662):492–501, 2009 19168210
Schulte T, Mũller-Oehring EM, Pfefferbaum A, et al: Neurocircuitry of emotion and
cognition in alcoholism: contributions from white matter fiber tractography.
Dialogues Clin Neurosci 12(4):554–560, 2010 21319499
Scott JC, Woods SP, Matt GE, et al: Neurocognitive effects of methamphetamine:
a critical review and meta-analysis. Neuropsychol Rev 17(3):275–297, 2007
17694436
Selzer ML: The Michigan alcoholism screening test: the quest for a new diagnostic
instrument. Am J Psychiatry 127(12):1653–1658, 1971 5565851
Stavro K, Pelletier J, Potvin S: Widespread and sustained cognitive deficits in
alcoholism: a meta-analysis. Addict Biol 18(2):203–213, 2013 22264351
Sullivan EV, Marsh L: Hippocampal volume deficits in alcoholic Korsakoff’s
syndrome. Neurology 61(12):1716–1719, 2003 14694035
Sullivan JT, Sykora K, Schneiderman J, et al: Assessment of alcohol withdrawal:
the revised Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-
Ar). Br J Addict 84(11):1353–1357, 1989 2597811
Takagi M, Lubman DI, Cotton SM, et al: Inhalants, in Neuropsychological Aspects
of Substance Use Disorders: Evidence-Based Perspectives. Edited by Allen
DN, Woods SP. New York, Oxford University Press, 2014, pp 448–462
Volkow ND, Chang L, Wang GJ, et al: Higher cortical and lower subcortical
metabolism in detoxified methamphetamine abusers. Am J Psychiatry
158(3):383–389, 2001 11229978
Volkow ND, Wang GJ, Fowler JS, et al: Addiction: decreased reward sensitivity
and increased expectation sensitivity conspire to overwhelm the brain’s control
circuit. BioEssays 32(9):748–755, 2010 20730946
Witkiewitz K, Saville K, Hamreus K: Acamprosate for treatment of alcohol
dependence: mechanisms, efficacy, and clinical utility. Ther Clin Risk Manag
8:45–53, 2012 22346357
Yuan Y, Zhu Z, Shi J, et al: Gray matter density negatively correlates with duration
of heroin use in young lifetime heroin-dependent individuals. Brain Cogn
71(3):223–228, 2009 19775795
CHAPTER 20
Alzheimer’s Disease
Alzheimer’s disease (AD), alone or in combination with other

pathology, is the most common cause of dementia in people over
age 65. The defining features of Alzheimer’s dementia are
progressive deficits in memory and other aspects of cognition,
typically including language, praxis, visual and spatial processing,
and executive function at some point during the course of the illness.
Noncognitive phenomena, including apathy and unawareness, are
important contributors to the burden of disease. At the same time,
elemental neurological function, and therefore the general
neurological exam, is usually normal, although paratonia and/or
myoclonus may be present. These deficits result in reduced ability to
perform daily activities, and most Alzheimer’s dementia patients will
become totally dependent on others unless they die of other causes
first.
The clinical presentation of Alzheimer’s dementia is the result of
synaptic dysfunction and neuronal loss that follow a predictable
distribution in the brain. The hippocampus, limbic cortex, and
polymodal association cortex sustain the greatest damage.
Dysfunction in these regions results in the characteristic clinical
pattern of Alzheimer’s dementia and assists in its clinical
differentiation from other dementing illnesses, which follow different
anatomical patterns of neuronal dysfunction.
Preclinical Alzheimer’s Disease

The existence of a preclinical stage of AD is supported by
evidence that its pathophysiological processes are detectable years
before the emergence of the symptoms. Evidence from genetic and
aging cohorts suggests that these processes may be present a
decade or more before onset of memory symptoms (Morris 2005).
We will be referring to the clinical stages of the disease for the
remainder of this chapter.
Diagnostic Criteria: DSM-5 Versus NIA-AA

The DSM-5 (American Psychiatric Association 2013) criteria for
diagnosis of major or mild neurocognitive disorder due to AD include
an acquired cognitive decline with an insidious onset and gradually
progressive course in one or more domains. Both involvement of one
or more cognitive domains and interference with a person’s everyday
independence are required for major neurocognitive disorder. Mild
neurocognitive disorder encompasses objective cognitive losses in
one or more domains that are in excess of the changes associated
with normal aging; the losses do not frankly compromise functional
independence but, instead, result in greater effort, the use of
compensatory mechanisms, or other accommodations to maintain
independence in activities of daily living (ADLs). The criteria for
probable AD are met when there is evidence of a causative AD
genetic mutation from family history or genetic testing or all three of
the following features are observed: 1) clear evidence of decline in
memory and learning; 2) steadily progressive, gradual decline in
cognition without extended plateaus; and 3) no evidence of mixed
etiology. Otherwise, the diagnosis remains possible AD. This
includes the caveats that the decline is independent of a delirium
and not better explained by another mental disorder. The
classification scheme includes specifications for “with” or “without”
behavioral disturbance, and in the case of major neurocognitive
disorder, severity may be specified as mild, moderate, or severe.
Severity is defined by the level of functional impairment as follows:
mild—difficulties with instrumental activities of daily living (IADLs)
like housework or managing money; moderate—difficulties with
basic ADLs like feeding and dressing; and severe—fully dependent
on others for ADLs (American Psychiatric Association 2013).
By comparison, the research-oriented National Institute on Aging–
Alzheimer’s Association (NIA-AA) 2011 diagnostic guidelines define
dementia as cognitive or behavioral symptoms that 1) interfere with
the ability to function at work or usual activities, 2) represent a
decline from previous levels of functioning, 3) are not explained by
delirium or major psychiatric disorder, 4) involve cognitive
impairment that is detected by history taking and cognitive
assessment, and 5) affect at least two cognitive or behavioral
domains. The diagnosis of mild cognitive impairment relies on the
determination that the cognitive impairments have minimal effect on
the person’s ability to function at usual daily activities. The criteria
also allow for statements regarding the likelihood that Alzheimer’s
dementia is the cause of the decline. Probable Alzheimer’s dementia
can be assigned as the diagnosis when a person’s symptoms meet
criteria for dementia along with insidious onset and clear-cut
worsening of symptoms, and when the deficits can be categorized as
amnestic or nonamnestic in a predictable pattern and are not
explained by any other concomitant disorder. Possible Alzheimer’s
dementia is diagnosed when the course is atypical or all criteria for
probable Alzheimer’s dementia are met and there is a concomitant
neurological explanation for the deficits. These criteria also allow for
focal presentations of Alzheimer’s dementia, which may include
impairment of language (e.g., logopenic primary progressive
aphasia) or visuospatial function (e.g., posterior cortical
atrophy/visual variant Alzheimer’s dementia). The use of biomarkers
can strengthen the diagnosis or increase certainty but is not
necessary for the diagnosis (McKhann et al. 2011).
Neurobiological Basis of Alzheimer’s Disease
Autopsy Pathology
The definitive diagnosis of Alzheimer’s dementia can only be
made by clinicopathological correlation and requires autopsy to
identify appropriate numbers of neuritic plaques and neurofibrillary
tangles in specified regions of the brain in a person whose
symptoms met the clinical criteria for dementia. A clinical history
consistent with dementia is required because some individuals with
heavy Alzheimer’s dementia pathological burden retain normal
cognitive function. Biopsy is not generally recommended for
diagnosis. Because of variability in the distribution of plaques and
tangles among individuals, a negative biopsy does not exclude
Alzheimer’s dementia, although a positive biopsy can confirm it.
However, the current state of dementia therapeutics argues that
biopsy results are not likely to alter treatment plans. Despite the
absence of a reliable laboratory test to definitively identify
Alzheimer’s dementia, clinical diagnosis yields an accuracy of >90%
with good concurrence among community-based providers and
experts (Mok et al. 2004).
On gross examination at autopsy, the brain of an individual with
Alzheimer’s dementia is usually atrophic with enlarged ventricles and
sulci (Figure 20–1). Total brain weight is invariably reduced, but there
is significant overlap with the range of brain weights for typically
aging older adults. The hallmark pathological features of Alzheimer’s
dementia remain the senile plaques and neurofibrillary tangles first
described by Alzheimer in 1906.
FIGURE 20–1. Gross pathology of Alzheimer’s disease.

Coronal pathological section of a patient with confirmed Alzheimer disease. The
section demonstrates hippocampal complex atrophy and dilatation of the temporal
horn of the lateral ventricle.
Source. Reprinted from Geldmacher DS: “Alzheimer Disease,” in The American
Psychiatric Publishing Textbook of Alzheimer Disease and Other Dementias.
Edited by Weiner MF, Lipton AM. Washington, DC, American Psychiatric
Publishing, 2009, pp. 155–172. Copyright © 2009 American Psychiatric Publishing.
Used with permission.
Senile Plaques
Senile plaques consist primarily of extracellular amyloid peptides
and cellular elements. The form of amyloid deposited in the brains of
Alzheimer’s dementia patients is known as β-amyloid (Aβ). Aβ is an
~4-kDa peptide that consists of 39–43 amino acid fragments
proteolytically derived from a transmembrane protein known as
amyloid precursor protein (APP).
Plaques are microscopic, ranging in diameter from 15 μ to 100 μ,
and are distributed in cortex and limbic nuclei (Figure 20–2). The
highest concentration is found in the hippocampus. Plaques with a
high proportion of distorted presynaptic neuronal elements—
dystrophic neurites—are known as neuritic plaques. Neurites include
intracellular elements of paired helical filaments, lysosomes, and
mitochondria. Activated microglial cells are typically found in and
around a dense core of extracellular amyloid, while fibrillary
astrocytes may be seen at the periphery. Other plaques that lack the
dense core of amyloid peptide are known as diffuse plaques. These
do not possess significant numbers of dystrophic neurites and are
not clearly associated with neuronal loss and cognitive dysfunction.
Amyloid can also accumulate in cerebral blood vessels, a condition
known as cerebral amyloid angiopathy. This leads to an increased
risk for microhemorrhages, microvascular ischemic changes, and,
rarely, large lobar hemorrhage.
FIGURE 20–2. Amyloid plaques in the cerebral cortex of a patient with
Alzheimer’s disease.
The section is immunostained for β-amyloid, which appears as dark extracellular
granular material. The plaques are large compared with surrounding cellular
nuclei.
In Vivo Amyloid Imaging
Three agents are approved in the United States to detect
abnormal amyloid accumulation on positron emission tomography
(PET). Amyloid-PET scans sensitively and specifically estimate the
brain Aβ neuritic plaque density in patients with cognitive
impairment. A negative scan indicates few to no neuritic plaques and
reduces the likelihood that any cognitive impairment is due to
Alzheimer’s dementia. A positive scan indicates moderate to
frequent plaques. This amount of Aβ plaque can be found in patients
with Alzheimer’s dementia, in patients with other types of cognitive
impairment, and in older people with normal cognition (10%–30%).
Because of payment limitations in clinical use, amyloid imaging is
used most frequently for selecting patients for anti-amyloid therapies
in clinical trials (Quigley et al. 2011).
Neurofibrillary Tangles
Neurofibrillary tangles (NFTs) are the second classical finding in
Alzheimer’s dementia (Figure 20–3). NFTs are intracellular
collections of abnormal filaments, which have a distinctive paired
helical structure in Alzheimer’s dementia. Although other
degenerative illnesses, such as progressive supranuclear palsy, also
have NFT pathology, the paired helical structure is unique to AD.
NFTs are found throughout the neocortex and limbic nuclei, and their
density correlates with the degree of neuronal loss. They are also
strongly represented in the basal forebrain, substantia nigra, raphe
nuclei, and locus coeruleus. NFTs occupy large areas within the cell
bodies of affected pyramidal neurons. This class of neurons is
responsible for long axonal projections that facilitate
interhemispheric and intrahemispheric communication and appears
especially sensitive to the effects of Alzheimer’s dementia.
FIGURE 20–3. Neurofibrillary tangles (Bielschowsky silver stain) in the
cerebral cortex of a patient with Alzheimer’s disease.
Tangles (arrows) are intraneuronal and consist of collapsed cytoskeletal elements,
including characteristic paired helical filaments. Tangle development interferes with
normal neuronal function through loss of axonal transport and other vital
homeostatic mechanisms.
In Vivo Tau Imaging

Ligands for tau imaging have not yet been approved for use in
humans but are being developed and tested in clinical trials at this
time.
Cerebrospinal Fluid Biomarkers of Alzheimer’s

Dementia
Additional biomarkers have been identified that may be useful in
identifying Alzheimer’s dementia pathology. The most reproducible of
these findings is a cerebrospinal fluid (CSF) profile, including
combined measurements of the CSF total tau, phosphorylated tau,
and Aβ levels. Aβ levels are decreased, probably because of
increased aggregation in the brain, whereas tau protein levels are
elevated, indicating neuronal injury (Hampel et al. 2008).
Synaptic Loss
Widespread cortical synaptic loss occurs in Alzheimer’s dementia
and is the major determinant of cognitive disability in the disease.
Oligomers of Aβ are now implicated as a direct synaptotoxin. The
deep layers of the temporal cortex and the hippocampus sustain the
greatest degree of synaptic loss. In addition, synaptic inputs to the
cortex are reduced up to 40% by the time of death. The amount of
synaptic loss in the frontal cortex correlates well with cognitive
impairment in Alzheimer’s dementia (DeKosky and Scheff 1990).
Substantial neuronal dropout also occurs in the basal forebrain
nuclei, such as the nucleus basalis of Meynert, which produces the
neurotransmitter acetylcholine (ACh). The number of NFTs in these
deep forebrain cholinergic nuclei closely relates to the degree of
cognitive dysfunction in Alzheimer’s dementia. A large proportion of
synapses and neurons are also lost in the locus coeruleus and the
raphe nuclei. Neurons in these brain stem nuclei produce
monoamine neurotransmitters and distribute them in the cerebral
cortex via long ascending axons. Losses of ACh, serotonin (5-HT),
and norepinephrine (NE) inputs to cerebral cortex contribute to the
expression of cognitive and behavioral symptoms in Alzheimer’s
dementia.
Pathophysiology
Both APP and Aβ are normal neuronal protein products. Aβ is
produced by the sequential action of β-secretase, also known as the
β-site APP cleaving enzyme, or BACE, and a second enzyme known
as γ-secretase (Stockley and O’Neill 2007). Functionally, γ-secretase
activity appears to result from a transmembrane protein complex
rather than a single enzyme (Verdile et al. 2007). The action of γ-
secretase produces the Aβ peptide, which normally ranges from 38
to 43 amino acids in length. A third enzyme, α-secretase, is also
involved in normal APP processing. The cleavage site for α-
secretase lies within the Aβ sequence, and the cleavage results in
nonamyloidogenic products.
In Alzheimer’s dementia, either an increased proportion of Aβ is
produced or there is reduced clearance of the Aβ, or there is some
combination of the two factors. In autosomal dominant forms of
Alzheimer’s dementia, mutations in and around the APP sequence
or in sequences associated with the presenilin component of γ-
secretase activity are associated with increased production of Aβ
peptides. The 42-amino acid Aβ species is the most likely to
associate into fibrils, which are the precursor to plaque formation.
Fibrils aggregate into extracellular deposits in an insoluble β-pleated
sheet configuration. Previously, parenchymal deposition of Aβ was
assumed to be the crucial step in the AD pathophysiology. There is
growing evidence, however, that prefibrillar, diffusible oligomeric
assemblies of Aβ are toxic to neurons and synapses, suggesting that
the disease process is under way prior to plaque formation.
The exact mechanism by which neuronal dysfunction and death
occur in AD is unknown. Glycoproteins similar to APP are associated
with cell surface interactions and nuclear signaling, which suggests
that APP or its normal derivatives might play a role in maintaining
synaptic function and neuronal health (Kamenetz et al. 2003). Aβ
also is an activating trigger for microglial cells, leading them to
produce several inflammatory cytokines with cytotoxic properties,
including tumor necrosis factor α. Activation of microglia may
contribute to a self-propagating cycle of local inflammation and
neuronal dysfunction (Block et al. 2007). Although most models of
AD pathophysiology place Aβ in a causative role, other approaches
suggest oxidative stress or bioenergetic failure as a triggering factor
in the amyloid cascade (Swerdlow and Khan 2004). It is possible that
Alzheimer’s dementia is a disorder with heterogeneous origins, with
different primary mechanisms resulting in similar patterns of
neuronal failure and pathological expression in different individuals.
Neurochemical Abnormalities
Acetylcholine
ACh is important for the cognitive functions of attention and
memory. Alzheimer’s dementia severity correlates with loss of
cerebral cortical markers for ACh metabolism. Choline
acetyltransferase (CAT), responsible for ACh synthesis, and
acetylcholinesterase (AChE), which degrades ACh, are both
depleted. The degree of cholinergic reduction in the cortex is closely
associated with the amount of cellular loss in the septal and basal
forebrain cholinergic (Ch) nuclei, where the neurons that produce
much of the cortical ACh are located. These include the septal
nucleus (Ch1) and vertical limb of the diagonal band of Broca (Ch2),
which supply the hippocampus; the horizontal limb of the diagonal
band of Broca (Ch3), which supplies the olfactory bulb; and the
nucleus basalis of Meynert (Ch4), which supplies extrahippocampal
limbic and paralimbic cortices and widespread neocortical areas.
Monoamines
Deficiencies in NE and 5-HT also contribute to both cognitive and
noncognitive symptoms, especially mood and anxiety. NE is
important for arousal, learning, and memory. The major site of
ascending NE projections is the locus coeruleus in the upper brain
stem, which undergoes significant cell loss in Alzheimer’s dementia.
Decreased markers of 5-HT activity in the cortex and loss of 5-HT–
producing cells in the median and dorsal raphe nuclei in the upper
brain stem are also observed in Alzheimer’s dementia.
Glutamate and Other Transmitters

There is conflicting evidence on the status of glutamate in the
brain of an individual with Alzheimer’s dementia. Glutamate is the
major excitatory neurotransmitter of the cerebral cortex, and
neuronal markers of glutamate activity generally decrease with
disease severity. However, some authors report that glutamate
clearance from the synapse is diminished in more advanced
Alzheimer’s dementia (Ellis et al. 2015). Residual synaptic glutamate
is thought to result in overexcitation and dysfunction of postsynaptic
neurons associated with excess calcium influx. Direct human data on
this hypothesis are limited. Other intrinsic classical
neurotransmitters, such as γ-aminobutyric acid (GABA), can also be
diminished, as are many cortically localized neuropeptides, such as
somatostatin and corticotropin-releasing factor. The role of these
changes in the Alzheimer’s dementia clinical syndrome is unknown.
Primary Clinical Manifestations of Alzheimer’s

Dementia
Although this chapter will address losses in domains like memory,
praxis, visual processing, and executive dysfunction separately, it is
important for clinicians to remember that intact human cognition is a
seamless and interdependent whole. Parsing cognitive function into
specific domains reflects the conveniences of taxonomy and testing
rather than physiological reality.
The DSM-5 criteria require evidence for impairments in memory,
learning, and at least one other cognitive domain (American
Psychiatric Association 2013) (Box 20–1). Factor analysis of
cognitive testing on 663 patients with probable AD revealed that
memory, language, and praxis are the principal cognitive deficits in
AD (Talwalker 1996). Although that study did not include careful
assessment of executive function, more recent studies indicate
executive dysfunction is present in a majority of Alzheimer’s
dementia patients (Stokholm et al. 2006). Other focal cognitive
deficits associated with temporoparietal lesions, such as spatial
disorientation, acalculia, and left-right disorientation, also develop in
many patients (Table 20–1).
BOX 20–1.DSM-5 Criteria for Major or Mild Neurocognitive

Disorder Due to Alzheimer’s Disease
A. The criteria are met for major or mild neurocognitive

disorder.
B. There is insidious onset and gradual progression of
impairment in one or more cognitive domains (for major
neurocognitive disorder, at least two domains must be
impaired).
C. Criteria are met for either probable or possible Alzheimer’s
disease as follows:
For major neurocognitive disorder:
Probable Alzheimer’s disease is diagnosed if either of the
following is present; otherwise, possible Alzheimer’s disease
should be diagnosed.
1. Evidence of a causative Alzheimer’s disease genetic

mutation from family history or genetic testing.
2. All three of the following are present:
a. Clear evidence of decline in memory and learning and at

least one other cognitive domain (based on detailed
history or serial neuropsychological testing).
b. Steadily progressive, gradual decline in cognition,
without extended plateaus.
c. No evidence of mixed etiology (i.e., absence of other
neurodegenerative or cerebrovascular disease, or
another neurological, mental, or systemic disease or
condition likely contributing to cognitive decline).
For mild neurocognitive disorder:

Probable Alzheimer’s disease is diagnosed if there is
evidence of a causative Alzheimer’s disease genetic mutation
from either genetic testing or family history.
Possible Alzheimer’s disease is diagnosed if there is no
evidence of a causative Alzheimer’s disease genetic mutation
from either genetic testing or family history, and all three of the
following are present:
1. Clear evidence of decline in memory and learning.

2. Steadily progressive, gradual decline in cognition, without
extended plateaus.
3. No evidence of mixed etiology (i.e., absence of other
neurodegenerative or cerebrovascular disease, or another
neurological or systemic disease or condition likely
contributing to cognitive decline).
D. The disturbance is not better explained by cerebrovascular

disease, another neurodegenerative disease, the effects of a
substance, or another mental, neurological, or systemic
disorder.
Coding note: For probable major neurocognitive disorder due to
Alzheimer’s disease, with behavioral disturbance, code first 331.0
(G30.9) Alzheimer’s disease, followed by 294.11 (F02.81) major
neurocognitive disorder due to Alzheimer’s disease. For probable
major neurocognitive disorder due to Alzheimer’s disease, without
behavioral disturbance, code first 331.0 (G30.9) Alzheimer’s
disease, followed by 294.10 (F02.80) major neurocognitive disorder
due to Alzheimer’s disease, without behavioral disturbance.
For possible major neurocognitive disorder due to Alzheimer’s
disease, code 331.9 (G31.9) possible major neurocognitive disorder
due to Alzheimer’s disease. (Note: Do not use the additional code
for Alzheimer’s disease. Behavioral disturbance cannot be coded
but should still be indicated in writing.)
For mild neurocognitive disorder due to Alzheimer’s disease, code
331.83 (G31.84). (Note: Do not use the additional code for
Alzheimer’s disease. Behavioral disturbance cannot be coded but
should still be indicated in writing.)
Reprinted from American Psychiatric Association: Diagnostic and
Statistical Manual of Mental Disorders, 5th Edition, Arlington, VA,
American Psychiatric Association, 2013. Copyright © 2013 American
Psychiatric Association. Used with permission.
TABLE 20–1. Domains of cognitive impairment in Alzheimer’s dementia
Domain Impairment Typical Onset
Memory Deficits in learning Early
Semantic knowledge failure Early
Repetitiveness Early
Orientation Distorted time sense Early
Language Anomia and word-finding difficulty Early
Poor speech content Early
Impaired prosody Late
Praxis Ideomotor apraxia Late
Ideational/conceptual apraxia Late
Limb-kinetic apraxia Late
Visual Impaired directed attention Early
processing
Poor object or person recognition Late
Spatial confusion Late
Executive Poor planning Early
function
Poor judgment Early
Impairment on complex tasks Early
Disinhibition Late
Memory
Memory dysfunction is usually the first symptom recognized in
Alzheimer’s dementia. It is detectable by neuropsychological tests
even in preclinical phases of the disease (Jacobs et al. 1995). The
typical memory impairment in Alzheimer’s dementia involves
difficulties with learning and retaining new information but relative
preservation of remote factual recall.
Alzheimer’s dementia–related memory change is often described
as “short-term memory loss.” Recent memories are impaired
because new information cannot be adequately stored for later
recall. This leads to the rapid forgetting characteristic of people with
Alzheimer’s dementia and their difficulty remembering recent events.
The span of the “short term” increases over time as the interval since
the last period of normal memory function becomes longer.
Declarative memory is most impaired in Alzheimer’s dementia. This
fact-oriented memory system allows us to store and recall specific
information and experiences. Declarative memory includes both
episodic and semantic memory. Episodic memory is recall of a
specific event, whereas semantic memory involves more general
knowledge. Both are affected early in the disease. Procedural
memory (e.g., knowing how to perform some task) is often better
preserved, which contributes to the superficial appearance of
normality in mild Alzheimer’s dementia. Emotionally toned memories
are often better maintained as well. For many individuals, subtle
deficits in learning occur prior to overt memory symptoms, but
familiar settings, old habits, and preserved social skills mask the
problem.
In patients with mild cognitive impairment, not only episodic but
also semantic memory is significantly impaired in patients who will
convert to Alzheimer’s dementia (Gainotti et al. 2014). Research
suggests the presence of semantic memory loss several years prior
to diagnosis (Verma and Howard 2012).
The character of memory loss changes over time. In the early
(mild) and moderate stages of the illness, recall of remote material,
learned before the onset of memory dysfunction, often appears to be
preserved. Detailed evaluation of patients reveals that subtle deficits
in recall of remote occurrences are frequently present, particularly for
specifics such as dates and the sequence of events (Storandt et al.
1998). In the late stages of Alzheimer’s dementia, memory
dysfunction extends to complete failure of recall for previously well-
remembered information, such as the names of the patient’s own
spouse or children.
Orientation
Although it is often considered a separate cognitive domain,
orientation to time and orientation to place represent specific types of
memory; orientation to person is different. A continuous process of
updating memory systems with the passage of time and changes in
location is required to maintain orientation. Orientation to time is
most vulnerable in early Alzheimer’s dementia, but persons often
dismiss deficiencies in this ability by stating that the day or date is
not important to them or that they have not looked at the news. For
healthy older adults, frequent reference to these external resources
is generally not required to maintain time and day orientation. More
relative concepts of time can also be distorted, such that people with
Alzheimer’s dementia may be unable to recount the hour of the day
or the time passed since a recent holiday. As the illness progresses,
orientation to place becomes more disrupted. This may result in
individuals becoming lost in familiar settings while driving or walking.
Spatial disorientation later becomes apparent on a smaller scale, like
the home environment. Family members often report this as
confusion or difficulty in locating rooms. Spatial disorientation is often
worse under conditions of low light and can be particularly
troublesome for families when the Alzheimer’s dementia patient
cannot find the bathroom. Loss of orientation to self is not typical
except in profound Alzheimer’s dementia, but language or response
disturbances may prevent more mildly affected individuals from
identifying themselves on questioning.
Language
Language impairments are a prominent part of the clinical picture
of Alzheimer’s dementia. They usually begin as word-finding difficulty
in spontaneous speech, which may later become severe enough to
interrupt the flow of speech and mimic dysfluent aphasia. Initially,
patients may complain of frequent tip-of-tongue experiences.
Circumlocution, when the patient substitutes a series of descriptions
or simpler words for the blocked one, becomes common. Some
healthy adults have verbal idiosyncrasies or mannerisms that have a
similar pattern. It is therefore useful to confirm with family members
that the worrisome verbal expression pattern represents a change.
The language of Alzheimer’s dementia patients becomes
progressively vague as access to semantics is lost. Patients’ verbal
output frequently lacks specifics, because they substitute generic
words or broad categories in place of more explicit nouns. Pronouns
(e.g., he, she, they) are often used in place of proper nouns. There is
also an increased use of automatic phrases and clichés, particularly
when the affected person is pressed for detailed information.
Prosody, the normal rhythm, melody, and emotional intonation of
speech, is affected in many Alzheimer’s dementia patients,
particularly in more severe stages. Reading skills and verbal
comprehension worsen as Alzheimer’s dementia progresses. In late
stages, global aphasia or muteness (aphemia) is common. When
present, disrupted communication patterns contribute to strain in
caregiving relationships.
Praxis
Apraxia is a disorder of on-demand, skilled purposeful movement
despite preservation of the motor abilities required by the task and
comprehension of the request to perform it. Nearly all Alzheimer’s
dementia patients will eventually develop apraxia in more severe
stages of the disease. Ideomotor apraxia, in which there is difficulty
in translating an idea into the proper spatially directed action, is most
common. This results in reduced ability to manage clothing fasteners
or eating utensils. Some patients will lose the conceptual basis of
tool use (conceptual apraxia) or the ability to perform multistep tasks
on demand (ideational apraxia). This is closely related to the loss of
semantic knowledge underlying the language and memory problems
in Alzheimer’s dementia (Chainay et al. 2006). Another common
manifestation of apraxia in more advanced Alzheimer’s dementia is
the inability to position parts of the body in space. This is a form of
limb-kinetic apraxia and can lead to problems in dressing. It also
contributes to difficulties in positioning the body, such as getting into
a car.
Higher Visual Function

Disorders of higher visual processing and visual impairment are
common in Alzheimer’s dementia and can be the manifesting
symptom in a variant known as posterior cortical atrophy. The
dysfunction is evident at the level of basic visual processing,
including impaired sensitivity to movement and visual contrast.
Deficits in depth perception are also observed. Visual processing
difficulties can be grouped in three main categories: 1) impaired
recognition, 2) impaired spatial processing, and 3) impaired visual
directed attention. These domains are differentially affected in
individual patents. Impaired recognition becomes evident as
agnosia, or the inability to recognize familiar objects. This should be
differentiated from anomia, in which the object is recognized but
cannot be named. The inability to recognize familiar faces
(prosopagnosia) may also evolve, typically in more advanced cases.
Problems in spatial processing contribute to spatial disorientation,
such as becoming lost in an otherwise familiar environment. Deficits
in directed attention become evident in impaired visual exploration,
which has important implications for functional tasks, such as driving,
that require active scanning of the environment.
When severe, spatial processing and directed attention deficits
may contribute to the development of Bálint’s syndrome in
Alzheimer’s dementia. This syndrome is defined by the triad of
simultanagnosia, the inability to perceive the visual field as a whole
despite preserved recognition of its components; oculomotor
apraxia, which describes difficulty with volitional gaze on command,
also known as “psychic paralysis of gaze”; and optic ataxia, the
inability to guide the hand toward an object using visual information
despite preservation of the visual, somatosensory, and motor
function required to do so.
Executive Function
manage and control other, relatively basic, cognitive functions and
that support purposeful goal-directed behaviors. These processes
are engaged most fully when confronting novel problems or
situations for which no previously established routines exist.
Executive function enables an individual to respond flexibly and
adaptively to the environment, to develop goals and anticipate their
consequences, and to direct cognition, emotion, and behavior in the
service of goal attainment.
Executive dysfunction, including problems with judgment, problem
solving, planning, and abstract thought, affects a majority of
Alzheimer’s dementia patients, beginning early in the disease course
(Stokholm et al. 2006). As a result of executive dysfunction, patients
develop difficulties in selecting tasks appropriately, sequencing their
execution, and monitoring performance to ensure successful
completion. Problems of these sorts commonly manifest as problems
with IADLs (e.g., failure to manage more complicated tasks like
family finances, meal preparation, scheduling activities and events,
and medication management). Executive function supports inhibition
of automatic, and potentially inappropriate, responses to people,
objects, and other environmental stimuli. Inhibitory failures
associated with executive dysfunction are manifested as socially
inappropriate behavior, disinhibition, and poor task persistence.
The presence of executive dysfunction predicts the transition from
more benign age-related cognitive changes to early dementia.
Executive dysfunction in Alzheimer’s dementia may result in both
positive symptoms with abnormally triggered behaviors and negative
symptoms characterized by a failure to respond to a normally
motivating circumstance.
Emotional and Behavioral Symptoms of

Alzheimer’s Dementia
Although not specifically included in the formal diagnostic criteria
for Alzheimer’s dementia, noncognitive or behavioral symptoms are
important aspects of the clinical expression of Alzheimer’s dementia
and sometimes the complaint that patients present with (Table 20–2).
As the disease progresses, these problems often account for a
larger proportion of the burden of care than cognitive dysfunction.
TABLE 20–2. Typical emotional and behavioral manifestations of

Alzheimer’s dementia
Neuropsychiatric
disturbance Manifestations Typical onset
Anosognosia Unawareness of illness Early
Apathy Poor initiation Early
Poor persistence Early
Psychosis Paranoid delusions Early or late
Delusional misidentification Late
Hallucinations (visual and/or Late
auditory)
Mood disorders Depression Early
Anxiety Early
Agitation Nonspecific motor behaviors, Late
including wandering and/or
pacing
Verbal aggression Late
Physical aggression Late
Sundowning Confusion and agitation Late
Apathy
While many clinicians think of agitation as the typical behavioral
symptom of Alzheimer’s dementia, personality changes involving
passivity and apathy are more frequent in the early phases of the
illness. Apathy is separable from depression and represents an
organic loss of motivation. It occurs in 25%–50% of Alzheimer’s
dementia patients. Apathy is defined as a reduction in goal-directed
thought, feeling, and action and manifests clinically in Alzheimer’s
dementia as diminished initiative, reduced emotional expression, and
decreased expressions of affection. Social withdrawal, mood
changes, and depression are common accompaniments of apathy in
Alzheimer’s dementia, being present in more than 70% of
Alzheimer’s dementia cases with a mean duration of more than 2
years prior to diagnosis (Jost and Grossberg 1996).
Unawareness of Deficits (Anosognosia)

Another common noncognitive problem in Alzheimer’s dementia is
unawareness of illness (anosognosia), which occurs in more than
50% of patients. This is often domain-specific—a patient will
acknowledge the presence of forgetfulness but will deny any
functional consequence of the impairment. In most cases,
unawareness of deficits appears to represent a self-monitoring deficit
of organic origin and should not be solely attributed to psychological
“denial.” Unawareness of illness is a major impediment to early
diagnosis and may reduce the effective implementation of
management strategies. Anosognosia is also associated with the risk
for dangerous behaviors in patients with dementia (Starkstein et al.
2007).
Psychosis
In contrast to apathy and unawareness, psychosis and agitation
tend to occur later in the disease course. Their emergence is
associated with more rapid global decline. Estimates of the
prevalence of psychotic features in AD vary widely and are prone to
selection bias. Population-based estimates suggest that the
prevalence of delusions is about 20%; hallucination prevalence is
estimated at about 15% (Bassiony and Lyketsos 2003). Delusions
are often paranoid in character and may lead to accusations of theft,
infidelity, and persecution. The delusion that caregivers or family
members are impostors or that one’s home is not one’s real home is
a common trigger for wandering or aggression. Hallucinations in AD
are more common in the visual domain but sometimes have auditory
components. Frequent themes include seeing deceased parents or
siblings, unknown intruders, and animals.
Depression and Anxiety

Estimates of depression prevalence in dementia vary widely, with
the frequency appearing to increase with disease severity. Major
depression was observed in about 20% of an Alzheimer’s dementia
sample with a mean Mini-Mental State Exam (MMSE) score of 18
(Zubenko et al. 2003). Patients with depression prior to the onset of
cognitive decline are more likely to experience major depression
during the course of their Alzheimer’s dementia. Anxiety can also be
expected in about 25% of Alzheimer’s dementia patients by the time
they reach moderate levels of cognitive impairment. Anxiety tends to
be more prominent in the later phases of the illness, but some
individuals with Alzheimer’s dementia will experience prominent
anxious symptoms early in the course of their illness. Catastrophic
reactions are intense emotional outbursts of short duration that are
associated with anxiety. They are characterized by the abrupt onset
of tearfulness, aggressive verbalizations or actions, and contrary
behaviors. These outbursts are often reactions to environmental
stressors, thwarted desires, or attempts at personal care.
Agitation and Sundowning

Agitation is reported in 50%–60% of Alzheimer’s dementia
patients. Sundowning, which is commonly used to describe
predictable increases in confusion and behavioral symptoms in the
afternoon and evening hours, is reported in up to 25% of Alzheimer’s
dementia patients. It is not a unitary symptom and often reflects
diurnal variation in other symptoms rather than a specific
pathophysiology.
Agitation does not represent a specific symptom; it can be divided
into several behavior classes: 1) physical aggression/assaultiveness,
2) verbal aggression and outbursts, and 3) nonaggressive physical
behaviors (Cohen-Mansfield and Deutsch 1996). Aggressive
behaviors are most clearly linked to delusions and delusional
misidentification. Verbal aggression is more common than physical
assault. Men and patients with more advanced functional decline are
more likely to demonstrate physical or verbal aggression. Aggressive
behaviors usually follow an escalating pattern, with verbal outbursts
preceding the physical acts. Many episodes of aggression are
triggered by attempted caregiver assistance with personal care,
especially bathing.
Wandering, pacing, and recurrent purposeless activities are
typical nonaggressive motor behaviors. Wandering is sometimes
associated with delusional misidentification; the affected person may
be trying to locate his or her “real” home or locate a “missing” loved
one. Wandering has also been associated with poor visuospatial
abilities, perhaps reflecting difficulty with incorporating visual
information into a coherent spatial map. Dim lighting conditions and
nighttime are therefore exacerbating factors for wanderers. Risks
resulting from wandering include getting lost outdoors and an
increased likelihood of fractures. Pacing is somewhat more
idiosyncratic, with fewer clearly associated neuropsychological
features. Constant movement or pacing contributes to accelerated
weight loss in some Alzheimer’s dementia patients, which can be
refractory to dietary interventions unless the locomotor activity is
reduced. A more benign form of physical nonaggressive behavior is
rummaging in drawers or closets. Patients who do this appear to be
searching for some item but are often unable to describe what it is.
This frequent sorting of personal effects is also associated with
delusions of theft.
Social Cognition
Social cognition is the ability to interpret and predict others’
behavior, based on their beliefs and intentions, and to interact in
complex social environments and relationships (Baron-Cohen 2000).
Deficits in social cognition can be attributed to difficulties in theory of
mind (i.e., the ability to attribute mental states to oneself and others)
and emotion recognition in both Alzheimer’s dementia patients and
patients with mild cognitive impairment (MCI). On the basis of
neuropsychological studies, these deficits seem to be secondary to
cognitive impairments and eventual difficulties with face perception
and verbal processing, rather than a primary impairment in theory of
mind in Alzheimer’s dementia (Kemp et al. 2012). The brain areas
commonly implicated in social cognition, particularly the frontal
lobes, are relatively spared in the early stage of the disease.
However, as the disease progresses and social cognition
deteriorates, this may lead to additional caregiver stress.
Physical and Neurological Findings of

Alzheimer’s Dementia
Physical Exam Findings

The general physical and neurological examination results remain
normal through most of the course of Alzheimer’s dementia.
Paratonia, which refers to an inability to volitionally inhibit movement
during assessment of resistance to passive manipulation, is a
common early finding associated with Alzheimer’s dementia.
Paratonia often manifests as facilitatory movement (i.e., mitgehen),
in which the patient automatically and involuntary assists the
examiner’s movement of the limbs despite explicit instructions not to
do so (e.g., “Relax and let me do all the work moving your arm”). It
also may manifest as oppositional movement (i.e., gegenhalten), in
which the patient automatically and involuntarily resists the
examiner’s movement of the limbs despite explicit instructions not to
do so. If not recognized correctly during the early portion of the
illness, paratonia may be misinterpreted as rigidity, which, in turn,
may lead to incorrect consideration of diagnoses in the parkinsonian
spectrum and therapeutic misadventures.
In the later stages of Alzheimer’s dementia, however,
extrapyramidal signs (e.g., rigidity) and gait disturbances may
develop. Myoclonus also is occasionally observed, with a point
prevalence of about 5% and worsening severity with more advanced
disease. Multifocal myoclonus may be difficult to distinguish from
seizures in late-stage patients. Epileptic seizures can be expected to
arise in 10%–20% of Alzheimer’s dementia patients; when such
seizures develop, they typically do so in the later stages of
Alzheimer’s dementia (Mendez et al. 1994).
Laboratory and Imaging Findings

There is no specific laboratory or imaging test that definitively
identifies AD. The American Academy of Neurology’s evidence-
based practice parameter for the diagnosis of dementia recommends
blood tests to exclude systemic illnesses as the cause of dementia.
These include a comprehensive chemistry panel, including hepatic
and renal function; complete blood count; thyroid function tests; and
vitamin B12 level (Knopman et al. 2001). Syphilis serology tests are
no longer considered part of the routine screening. Apolipoprotein E
genotyping has been suggested to reduce the rate of false-positive
diagnosis when used with clinical criteria (Mayeux et al. 1998), but
most health care insurance providers will not reimburse for the
testing, and its clinical value is questionable.
Imaging is recommended as a part of the routine assessment of
patients with dementia symptoms. Computed tomography or
magnetic resonance imaging (MRI) is useful to exclude structural
lesions that may contribute to the dementia, such as cerebral
infarctions, neoplasm, extracerebral fluid collections, and
hydrocephalus. Current evidence suggests that the presence of
mesial temporal atrophy on MRI strongly supports the likelihood of
Alzheimer’s dementia when appropriate clinical features are present
(Figure 20–4) (Duara et al. 2008; Wahlund et al. 2005).
Fluorodeoxyglucose positron emission tomography (FDG-PET)
scans reveal temporoparietal hypometabolism in patients with
Alzheimer’s dementia. In the United States, Medicare has approved
FDG-PET scanning for the specific indication of distinguishing AD
from frontotemporal degeneration.
FIGURE 20–4. Magnetic resonance imaging of the brain of a patient with
Alzheimer’s disease.
This T1-weighted coronal view (radiological orientation) at the level of the
hippocampus demonstrates mild bilaterally reduced frontal and lateral temporal
volumes and marked bilateral hippocampal volume loss (left greater than right),
consistent with Alzheimer’s disease.
CSF examination by lumbar puncture is not a routine part of the

dementia evaluation. Standard CSF tests have a low likelihood of
influencing diagnosis in most people with dementia. CSF
examination is more useful in cases with serological evidence of past
syphilis, as well as in patients with immunosuppression or atypical
dementia symptom patterns, such as young age at onset or very
rapid progression. CSF assays for soluble β-amyloid and tau are
commercially available (see subsection “Cerebrospinal Fluid
Biomarkers of Alzheimer’s Dementia” earlier in this chapter). Some
clinicians find them useful in cases of difficult differential diagnosis
between Alzheimer’s and non-Alzheimer’s causes of dementia, but
their utility in more routine clinical populations is unclear.
Electroencephalography is also not recommended as part of the
routine evaluation of dementia (Knopman et al. 2001).
Electroencephalographic findings are nonspecific. They are
frequently normal in early stages and evolve toward generalized
slowing.
Course of Disease
Most patients with Alzheimer’s dementia will pass through a
recognizable phase of MCI prior to diagnosis. In MCI, similar deficits
in cognition may be identifiable, particularly in the memory domain,
but the impairments do not cause disability in usual social or
occupational function.
A preclinical stage of AD may be detectable because of a patient’s
subjective memory impairment (Jessen et al. 2014) (see section
“Preclinical Alzheimer’s Disease” earlier in this chapter). Although
these patients do not have a measurable decline on testing, they are
concerned that their memory is worse. The pathophysiological
process is thought to begin years before the emergence of the
clinical phases of the illness.
Average survival for Alzheimer’s dementia is 8–12 years following
diagnosis. Many individuals will have prominent symptoms for
several years prior to diagnosis. Approximately half of Alzheimer’s
dementia patients will die of complications of global neurological
dysfunction like immobility and malnutrition; the other half have their
deaths attributed to other factors, typically other age-related
diseases such as stroke and cancer. Life expectancy is reduced by
about 50%.
Alzheimer’s dementia follows a relentlessly progressive course,
although there may be periods of relative symptom stability known
as plateaus. Symptoms tend to progress less rapidly in both early
and late disease, with more rapid losses—especially in ADLs—in
moderate disease. The course does vary by individual, and there
can be short periods of fluctuation, especially in the face of change
in external stressors (e.g., slight improvement with enjoyable
activities, worsening with illness).
AD is commonly broken into “stages” to facilitate communication
between providers. Because the pathological expression of the
illness follows a generally linear pattern, these stages do not have
clear biological correlates. Staging is defined by the level of
functional impairment and incorporated in the DSM-5 criteria.
Evaluation and Treatment of Cognitive,

Emotional, and Behavioral Manifestations
Evaluation
Mental Status
By definition, the diagnosis of dementia can only be made in the
presence of a clear sensorium. Clouding of consciousness suggests
a superimposed medical illness with delirium. Thought content is
often impoverished, but its organization is linear and logical.
Tangential thinking may be suspected, but this should be carefully
evaluated to exclude circumlocution related to word-finding
difficulties. Loosening of associations is not typical. Psychosis occurs
in a minority of individuals, usually in the setting of moderate or more
advanced stages of the disease. Delusions with a paranoid
character, particularly regarding theft of personal items, are most
common. In many cases, these misperceptions are propagated by
cognitive deficits. A typical pattern involves a patient forgetting where
they have placed an item and becoming suspicious that it was
stolen. This is often followed by progressively more elaborate hiding
of personal effects in obscure locations, which are then also
forgotten. Hallucinations are much less frequently observed during
examination and occur most often in the context of low illumination
and in severe dementia. Judgment declines with dementia severity.
Insight into impairments, especially losses in functional skills, is
reduced in more than half of Alzheimer’s dementia patients. Up to
40% of Alzheimer’s dementia patients will report low mood; euphoria
and hypomania are rare. Affect is usually appropriate to the
circumstances but may be blunt and superficial. Anxiety may be
provoked by the unfamiliarity of the testing process and environment.
Learning and Memory

The patient is typically asked to repeat and remember three
unrelated words. Word lists that are semantically related, such as
red, blue, and green or butter, eggs, and coffee, are less useful
because remembering their theme can aid recall. If word recall is not
being conducted as part of a structured examination like the MMSE,
the three memory items can be repeated as often as necessary to
ensure that the patient can repeat them all. Normal performance is to
learn and repeat all three words with the first exposure. After a
meaningful delay, generally 5 or more minutes of other mental state
testing, the patient should be asked to recall the three words. Normal
performance is to recall all three. For those that the patient cannot
remember, further steps may be taken to clarify the nature of the
memory impairment. The patient can be given a semantic clue, such
as “One of the words was a kind of flower.” Patients with Alzheimer’s
dementia are often not helped by semantic cues, whereas other
memory problems, such as those associated with healthy aging, are
more likely to benefit from cueing. Recognition memory can be
assessed by asking the patient to select the memory item from a list
of semantically related words.
Remote memory can be checked by asking the patient to name
the last five presidents. Alternatively, if a knowledgeable informant is
available to confirm the information, patients might be asked when
they were married or widowed, how many grandchildren they have,
or to provide details of their military service or employment history.
Nonverbal aspects of memory can be assessed by asking the
patient to observe while the examiner identifies and hides an object
in the examination room. The examiner might show a watch or
stethoscope to the patient and place it in a drawer. After a few
minutes of ongoing physical or cognitive examination, the patient can
be asked to recall what was hidden (object memory) and where
(spatial memory).
Because details are lost from remote memory in Alzheimer’s
dementia, it may be useful to ask the patient to provide details of
important historical events like the September 11, 2001, attacks or to
recall his or her own experience of learning about the 1963 Kennedy
assassination. It is impossible to know how accurately the patient
recalls his or her experience, but adults with intact memories are
usually able to give lucid and richly detailed recollections of how they
received the news, how they reacted, whom they were with, and so
forth. Those with poor declarative memory will often be very vague
or give temporally inappropriate replies (e.g., hearing about the Pearl
Harbor attack at work or on television).
Orientation
Orientation to time, especially dates, is lost early in the course of
Alzheimer’s dementia. Many patients with dementia try to minimize
aspects of disorientation. Excuses regarding a reduced need to keep
up with dates are common and are a cue that significant
disorientation may be present. The MMSE provides extensive
orientation testing. Additional inquiries about the approximate time of
day, what meal might be expected next, or what was the last major
holiday can augment the MMSE. Disorientation to self occurs only in
advanced dementia. Its presence in the context of mild or moderate
cognitive disability suggests delirium or a primary psychiatric
disturbance.
Language
Assessment of language includes naming, comprehension,
fluency and effortfulness of speech, sentence repetition, reading,
and writing. Language deficits are important in the consideration of
dementia because, unlike with memory, nearly all healthy older
adults have normal spontaneous language, with the exception of
momentary lapses in word finding, especially for proper names.
Impaired naming on examination often correlates with word-
finding difficulty in the spontaneous speech of the Alzheimer’s
dementia patient. This can be tested with everyday objects available
to the examiner, such as a jacket, shoe, or watch. Parts of objects
are more difficult to name than whole objects. Therefore, in addition
to a jacket as a whole, the patient might be asked to name the collar,
lapel, sleeve, pocket, and cuff. Responses should be considered
correct only if the patient provides a reasonable name for the item.
Descriptions of appearance or function (e.g., “It’s white” or “Doctors
wear it” for jacket) are incorrect. Education, culture, and
socioeconomic factors may influence naming of some items, but
most individuals without impairment should name most of the items
effortlessly.
Patients with Alzheimer’s dementia typically have fluent speech
that may seem empty, with reduced meaningful content. Except in
advanced stages, comprehension is usually sufficient to understand
basic conversation and to follow simple examination-related
commands. Comprehension of syntactically complex instructions is
more vulnerable. It can be tested with a two-step command in which
the word order does not reflect the order of the intended action (e.g.,
“Before pointing to the door, point to the ceiling”). This is somewhat
more language intensive and less memory dependent than the
three-step, syntactically straightforward command on the MMSE.
Praxis and Temporoparietal Function

A brief sequence of commands can further assess language
comprehension, ideomotor praxis, and left-right orientation. The
patient should be asked to carry out a different imagined action with
each hand (e.g., using a hammer to hit a nail or a key to open a
lock). A subsequent two-handed task, such as slicing bread, tests
the patient’s ability to integrate the actions of both hemispheres in a
single, spatially specific task. These can be followed with commands
that require the patient to correctly identify right and left, in reference
both to his or her own body (e.g., “Touch your right hand to your left
ear”) and to the examiner’s (e.g., “Point to my left hand with your left
hand”). Most cognitively normal adults will perform these tasks
effortlessly. Mildly affected Alzheimer’s dementia patients most often
perform poorly on the two-handed praxis test.
Visual and Spatial Processing

Many patients with Alzheimer’s dementia have problems in
processing perspective and apparent depth. This can be tested by
having the patient copy a drawing of a cube or other simple three-
dimensional figure. Normal performance is to accurately depict three
sides and three dimensions. Even mildly affected patients with
Alzheimer’s dementia may represent three visible surfaces with no
attempt to show their three-dimensional relationship.
The integration of motor behavior in space can be further tested
with a drawing task. The Clock Drawing Test (CDT) assesses
multiple realms of cognition, including executive function (planning),
spatial relationships, and semantic knowledge. Normal performance
involves placing all numbers and the hands in the correct positions.
Executive Function
Word-list fluency can provide useful information about executive
function. In this test, the patient is asked to state as many words as
he or she can that conform to a category set by the examiner. This is
a common neuropsychological test that can be abbreviated for use in
a medical assessment. The patient is asked to produce as many
words as possible that fit a semantic category, such as animals or
fruits. Patients who name fewer than 15 animal names in 1 minute
have a high likelihood of dementia (Canning et al. 2004).
Abstract Thought
Abstract reasoning can be assessed by asking the patient to
identify abstract similarities in word pairs (e.g., “How is a chair like a
table?” or “How is an apple like a banana?”). People with dementia
are apt to note the difference rather than a similarity. Alternatively,
they are likely to identify a concrete rather than an abstract similarity.
Examples of concrete responses would include that a chair and table
“go together” or that the apple and banana “have skin.” Interpretation
of proverbs is a common but less desirable test of abstract thought
because of cultural, educational, and generational biases.
Attention, Concentration, and Working Memory

To test these related parts of cognition, the patient can be asked
to add coins, specifically a penny, a dime, a nickel, and a quarter.
For this task, it is important that the names of the coins be used,
because the working memory system is engaged throughout the
subtly complicated process of translating the names to numerical
values, performing stepwise addition, and reporting the answer in a
unit different from what was provided. Patients without dementia are
not overly threatened by this task because it involves familiar items
and the everyday activity of adding pocket change. It is also
sufficiently familiar that a pencil and paper are not required for
normal performance. The patient who asks for writing tools, or who
dismisses the task as something he or she would need to write
down, should raise suspicion of impairment. This pocket change
addition task is useful as a cognitive screening tool because it can
assess calculation simultaneously with working memory. The patient
who answers “36 cents” can add numbers but has failed to include
all four coins.
Other tests of working memory or related aspects of attention can
be used if pocket change addition is inappropriate (e.g., the person
is unfamiliar with the common names of U.S. coins). Alternatives
include asking the patient to state the months of the year or days of
the week in reverse order. These do not, however, incorporate the
complexities of translation and addition of the four coins.
Digit span is a common test of primary memory that also depends
on attention. In this task, the patient is asked to repeat a string of
random digits in the order that he or she heard them. Normal
performance is to repeat strings of five or more correctly. Deficits
may be more pronounced when patients are asked to repeat digits in
reverse order. Normal performance in this task is to reach a span of
at least two digits less than the forward span.
Treatment
Optimal treatment for Alzheimer’s dementia involves both
pharmacological and nonpharmacological approaches (Doody et al.
2001). Currently approved therapies include members of the AChE
inhibitor and N-methyl-D-aspartate (NMDA) receptor antagonist
classes. These are generally classed as “symptomatic” therapies
and have not been demonstrated to alter the underlying pathological
process in Alzheimer’s dementia.
Treatment of emotional and behavioral symptoms in Alzheimer’s
dementia is also symptomatically oriented, and no drugs have been
specifically approved for this indication. However, because
depression may cause acceleration of decline if untreated, treatment
is highly recommended. Recreational programs and activity
therapies have shown positive results. Selective serotonin reuptake
inhibitors or serotonin-norepinephrine reuptake inhibitors should be
considered, with side-effect profiles guiding the choice of agent.
Sleep hygiene should be addressed, and if necessary,
pharmacological sleep aids with the least cognitively slowing effects
can be used. Antihistaminic/anticholinergic agents are relatively
contraindicated.
Agitation may be in response to physical or emotional discomfort.
Citalopram has shown efficacy in reducing agitation (Porsteinsson et
al. 2014). Antipsychotics should be used to treat agitation or
psychosis in patients with dementia where environmental
manipulation fails and with informed consent (usually from the
caregiver) regarding the potential complications of their use in older
patients. Atypical agents may be better tolerated compared with
traditional agents. Nonpharmacological strategies for the prevention
of agitation might include use of scheduled toileting and prompted
toileting for incontinence, offering graded assistance (as little help as
possible to perform ADLs), role modeling, cueing, providing positive
reinforcement to increase independence, and avoiding adversarial
debates by use of redirection instead. Caregivers should be advised
to maintain a calm demeanor and use the services of caregiver
support groups. Additionally, a systems-based approach to treatment
might decrease caregiver burden. Home health services or assisted
living facilities where multiple health care disciplines can become
involved in the care of the person with dementia are likely to prevent
caregiver burnout and subsequent skilled nursing facility placement.
Conclusion
While the breadth of knowledge about Alzheimer’s disease
pathophysiology is increasing, its prevalence continues to outpace
all treatment advances. The most promising developments in
disease-modifying therapies are focused on very mild impairment
and preclinical stages of the disease. Increases in awareness and
earlier diagnosis, therefore, will be necessary to implement these
therapies as they become available. The early psychiatric
manifestations of the disease, including anxiety, depression, and
apathy, are often the harbinger of progressive cognitive impairment.
Therefore, psychiatrists are well placed to assess for deficits
routinely.
References
Baron-Cohen S: Is Asperger syndrome/high-functioning autism necessarily a
disability? Dev Psychopathol 12(3):489–500, 2000 11014749
Bassiony MM, Lyketsos CG: Delusions and hallucinations in Alzheimer’s disease:
review of the brain decade. Psychosomatics 44(5):388–401, 2003 12954913
Block ML, Zecca L, Hong JS: Microglia-mediated neurotoxicity: uncovering the
molecular mechanisms. Nat Rev Neurosci 8(1):57–69, 2007 17180163
Canning SJ, Leach L, Stuss D, et al: Diagnostic utility of abbreviated fluency
measures in Alzheimer disease and vascular dementia. Neurology 62(4):556–
562, 2004 14981170
Chainay H, Louarn C, Humphreys GW: Ideational action impairments in
Alzheimer’s disease. Brain Cogn 62(3):198–205, 2006 16777309
Cohen-Mansfield J, Deutsch LH: Agitation: subtypes and their mechanisms. Semin
Clin Neuropsychiatry 1(4):325–339, 1996 10320435
DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer’s
disease: correlation with cognitive severity. Ann Neurol 27(5):457–464, 1990
2360787
Doody RS, Stevens JC, Beck C, et al: Practice parameter: management of
dementia (an evidence-based review). Report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology 56(9):1154–
1166, 2001 11342679
Duara R, Loewenstein DA, Potter E, et al: Medial temporal lobe atrophy on MRI
scans and the diagnosis of Alzheimer disease. Neurology 71(24):1986–1992,
2008 19064880
Ellis B, Hye A, Snowden SG: Metabolic modifications in human biofluids suggest
the involvement of sphingolipid, antioxidant, and glutamate metabolism in
Alzheimer's disease pathogenesis. J Alzheimers Dis 46(2):313–327, 2015
25835424
Gainotti G, Quaranta D, Vita MG, et al: Neuropsychological predictors of
conversion from mild cognitive impairment to Alzheimer’s disease. J
Alzheimers Dis 38(3):481–495, 2014 24002185
Hampel H, Bürger K, Teipel SJ, et al: Core candidate neurochemical and imaging
biomarkers of Alzheimer’s disease. Alzheimers Dement 4(1):38–48, 2008
18631949
Jacobs DM, Sano M, Dooneief G, et al: Neuropsychological detection and
characterization of preclinical Alzheimer’s disease. Neurology 45(5):957–962,
1995 7746414
Jessen F, Wolfsgruber S, Wiese B, et al; German Study on Aging, Cognition and
Dementia in Primary Care Patients: AD dementia risk in late MCI, in early MCI,
and in subjective memory impairment. Alzheimers Dement 10(1):76–83, 2014
23375567
Jost BC, Grossberg GT: The evolution of psychiatric symptoms in Alzheimer’s
disease: a natural history study. J Am Geriatr Soc 44(9):1078–1081, 1996
8790235
Kamenetz F, Tomita T, Hsieh H, et al: APP processing and synaptic function.
Neuron 37(6):925–937, 2003 12670422
Kemp J, Després O, Sellal F, et al: Theory of Mind in normal ageing and
neurodegenerative pathologies. Ageing Res Rev 11(2):199–219, 2012
22186031
Knopman DS, DeKosky ST, Cummings JL, et al: Practice parameter: diagnosis of
dementia (an evidence-based review). Report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology 56(9):1143–
1153, 2001 11342678
Mayeux R, Saunders AM, Shea S, et al; Alzheimer’s Disease Centers Consortium
on Apolipoprotein E and Alzheimer’s Disease: Utility of the apolipoprotein E
genotype in the diagnosis of Alzheimer’s disease. N Engl J Med 338(8):506–
511, 1998 9468467
McKhann GM, Knopman DS, Chertkow H, et al: The diagnosis of dementia due to
Alzheimer’s disease: recommendations from the National Institute on Aging-
Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s
disease. Alzheimers Dement 7(3):263–269, 2011 21514250
Mendez MF, Catanzaro P, Doss RC, et al: Seizures in Alzheimer’s disease:
clinicopathologic study. J Geriatr Psychiatry Neurol 7(4):230–233, 1994
7826492
Mok W, Chow TW, Zheng L, et al: Clinicopathological concordance of dementia
diagnoses by community versus tertiary care clinicians. Am J Alzheimers Dis
Other Demen 19(3):161–165, 2004 15214202
Morris JC: Early stage and preclinical Alzheimer disease. Alzheimer Dis Assoc
Disord 19(3):163–165, 2005 16118535
Porsteinsson AP, Drye LT, Pollock BG, et al; CitAD Research Group: Effect of
citalopram on agitation in Alzheimer disease: the CitAD randomized clinical
trial. JAMA 311(7):682–691, 2014 24549548
Quigley H, Colloby SJ, O’Brien JT: PET imaging of brain amyloid in dementia: a
review. Int J Geriatr Psychiatry 26(10):991–999, 2011 21905095
Starkstein SE, Jorge R, Mizrahi R, et al: Insight and danger in Alzheimer’s
disease. Eur J Neurol 14(4):455–460, 2007 17388998
Stockley JH, O’Neill C: The proteins BACE1 and BACE2 and beta-secretase
activity in normal and Alzheimer’s disease brain. Biochem Soc Trans 35(Pt
3):574–576, 2007 17511655
Stokholm J, Vogel A, Gade A, et al: Heterogeneity in executive impairment in
patients with very mild Alzheimer’s disease. Dement Geriatr Cogn Disord
22(1):54–59, 2006 16682794
Storandt M, Kaskie B, Von Dras DD: Temporal memory for remote events in
healthy aging and dementia. Psychol Aging 13(1):4–7, 1998 9533185
Swerdlow RH, Khan SMA: A “mitochondrial cascade hypothesis” for sporadic
Alzheimer’s disease. Med Hypotheses 63(1):8–20, 2004 15193340
Talwalker S: The cardinal features of cognitive and noncognitive dysfunction and
the differential efficacy of tacrine in Alzheimer’s disease patients. J Biopharm
Stat 6(4):443–456, 1996 8969979
Verdile G, Gandy SE, Martins RN: The role of presenilin and its interacting proteins
in the biogenesis of Alzheimer’s beta amyloid. Neurochem Res 32(4–5):609–
623, 2007 16944319
Verma M, Howard RJ: Semantic memory and language dysfunction in early
Alzheimer’s disease: a review. Int J Geriatr Psychiatry 27(12):1209–1217, 2012
22298328
Wahlund LO, Almkvist O, Blennow K, et al: Evidence-based evaluation of magnetic
resonance imaging as a diagnostic tool in dementia workup. Top Magn Reson
Imaging 16(6):427–437, 2005 17088692
Zubenko GS, Zubenko WN, McPherson S, et al: A collaborative study of the
emergence and clinical features of the major depressive syndrome of
Alzheimer’s disease. Am J Psychiatry 160(5):857–866, 2003 12727688
CHAPTER 21
Neurocognitive Disorders With

Lewy Bodies
Dementia With Lewy Bodies and
Parkinson’s Disease

The Lewy body disorders are a group of neurodegenerative

disorders that share the common pathology of fibrillar aggregates of α-
synuclein protein in selective populations of neurons and glia. The
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
(DSM-5; American Psychiatric Association 2013) presents current
criteria for major or mild neurocognitive disorder with Lewy bodies and
their applications in clinical practice. In this chapter, these conditions will
be collectively referred to as dementia with Lewy bodies (DLB) when
the cognitive-behavioral symptoms are the initial presentation and as
Parkinson’s disease (PD) or Parkinson’s disease with dementia (PDD) if
the movement disorder is the initial presentation and substantially
precedes cognitive-behavioral symptoms.
The underlying pathological lesion in these disorders is the
intracellular aggregation of α-synuclein. Aggregates of α-synuclein are
present in neurons as neocortical Lewy bodies and dystrophic Lewy
neurons in DLB, PD, and PDD, or as cytoplasmic inclusions in
oligodendrocytes in less common Lewy body disorders such as multiple
system atrophy. However, α-synuclein pathology can be present in
many other neurodegenerative diseases, such as Alzheimer’s disease
(AD) and Down syndrome (Table 21–1). The Lewy body disorders are
broadly characterized by variable degrees of progressive decline in
cognitive, motor, behavioral, and autonomic function.
TABLE 21–1. Disorders with synuclein pathology

Synuclein pathology commonly found Synuclein pathology may be found
Dementia with Lewy bodies Amyotrophic lateral sclerosis

Parkinson’s disease (with and without Pick’s disease
dementia)
Alzheimer’s disease (particularly Creutzfeldt-Jakob disease
autosomal dominant forms) Traumatic brain injury
Down syndrome
Multiple system atrophy
Pure autonomic failure
Idiopathic REM sleep behavior
disorder
Neurodegeneration with brain iron
accumulation
Note. REM=rapid eye movement.
Dementia With Lewy Bodies

DLB is probably the second most common cause of
neurodegenerative dementia after AD (McKeith et al. 2005). Neocortical
Lewy bodies were found, on autopsy, in up to 80% of males ages 95–99
with neurodegenerative disease (Karantzoulis and Galvin 2013;
Tarawneh and Galvin 2007). A significant delay in diagnosis occurs,
with patients generally seeing multiple physicians over many visits
before a DLB diagnosis is given; in a survey study, close to 70% of
caregivers reported that three or more doctors had been consulted
(Galvin et al. 2010). On average, it took physicians four office visits to
make the diagnosis, with 33% of the respondents reporting more than
six office visits. The majority of survey respondents had received a
diagnosis within 1 year (51%), and some even in the first month (19%);
however, a sizable minority of patients (31%) did not receive a
diagnosis for more than 2 years (Galvin et al. 2010). This leads to
significant stress for patients and caregivers (Zweig and Galvin 2014).
Clinical Features and Diagnostic Criteria

The consensus criteria for diagnosing DLB require criteria to be met
for major or mild neurocognitive disorder as well as an insidious onset
and gradual progression. In addition, probable or possible
neurocognitive disorder with Lewy bodies is determined based on core
and suggestive diagnostic features. For a probable diagnosis, one must
have two core features or one suggestive feature with one or more core
features. For possible diagnosis, one must have only one core feature
or one or more suggestive features (McKeith et al. 2005).
The three core diagnostic criteria include fluctuating cognition with
pronounced variations in attention and alertness (Ferman et al. 2004),
recurrent visual hallucinations that are well formed and detailed
(Ferman et al. 2013), and last, spontaneous features of parkinsonism.
Two clinically relevant suggestive diagnostic criteria include rapid eye
movement sleep behavior disorder (Boeve et al. 2001) and severe
neuroleptic sensitivity (McKeith et al. 2005). Additionally,
cerebrovascular disease, other neurodegenerative diseases, effects of
substances, and effects of other mental, neurological, and systemic
disorders must be ruled out first. Neuroimaging studies, particularly
modalities that examine dopaminergic systems, may distinguish AD and
DLB. Diagnosis of DLB may be enhanced with use of composite risk
scores that capture relevant signs and symptoms (Karantzoulis and
Galvin 2013).
Cognitive Profile
DLB is insidious in onset, with gradual progression. Whereas AD is
characterized by a cortical pattern of cognitive deficits, DLB often first
involves frontal-subcortical systems. The frontal-subcortical deficits
mediate executive and visuospatial functions in association with rapidly
fluctuating attentional deficits, as well as memory retrieval (Karantzoulis
and Galvin 2013). Over time, symptoms occur that are related to
extension of pathology to temporoparietal regions, leading to features of
aphasia, apraxia, and spatial disorientation. In the following
subsections, we describe the pattern of deficits in specific cognitive
domains. In Table 21–2, we compare the patterns of cognitive
impairment across various neurocognitive disorders.
TABLE 21–2. Patterns of cognitive impairment across neurocognitive disorders
Memory
Executive Attention and Visuospatialand Language and
Condition functioningconcentration abilities learning communication
Alzheimer’s + to + to +++ + to ++ +++ + to +++
disease +++
Parkinson’s 0 to ++ 0 to ++ 0 0 to + 0
disease
Parkinson’s ++ to ++ to +++ + to +++ 0 to 0 to ++
disease +++ +++
with
dementia
Dementia with ++ to ++ to +++ + to +++ 0 to 0 to ++
Lewy +++ +++
bodies
0=no impairment; +=mild impairment; ++=moderate impairment; +++=severe
impairment.
Executive Function and Attention and

Concentration
Patients with DLB often have impaired judgment and impaired
organizational and planning abilities. Attentional dysfunction is
prominent. Executive demands seem to affect attentional variability, and
greater performance variability is demonstrated in tasks that require
more active recruitment of executive control processes (Park et al.
2011).
Visuospatial Abilities
A consistent feature of DLB is impairment of visuospatial and
visuoperceptual function. Patients with DLB often have difficulty
navigating in their homes or even moving out of a bed or chair. Brief
cognitive screening tests may miss visuospatial or constructive deficits
at the very mildest stage, but visuospatial dysfunction can be readily
detected by testing with the Block Design or figure copying (i.e., cube,
intersecting pentagons) tasks.
Memory and Learning
Patients with pure Lewy body pathology have relative preservation of
memory in the early stages compared with patients with AD. Memory
impairment develops with disease progression, but early on, the
memory impairment in DLB predominantly reflects deficits in retrieval,
whereas the primary substrate of memory impairment in AD is impaired
encoding (Karantzoulis and Galvin 2013; Park et al. 2011).
Patients with DLB have poor initial learning and retrieval with mild
deficits in delayed recall. Relative preservation of verbal skills is an
important feature, and DLB patients show little or no impairment in
verbal memory and confrontation naming (Johnson et al. 2005).
The performance of patients with combined AD and Lewy body
pathology is similar to that of patients with AD on the subsets of verbal
memory, indicating that the additional Lewy body burden does not
negatively affect verbal performance in patients with AD. This finding is
in contrast to visuospatial dysfunction, on which the combined
pathology has an additive effect (Johnson et al. 2005).
Language and Communication

Compared with AD patients, patients with DLB have more severe
impairment in verbal fluency. In AD, category fluency is more severely
impaired than letter fluency; however, both appear to be affected to the
same degree in DLB. In addition, DLB patients may exhibit mild
confrontation naming deficits that improve with phonemic cues
(Karantzoulis and Galvin 2013).
Psychiatric Features
Visual hallucinations are frequently present early and occur
intermittently throughout the course of DLB (Ferman et al. 2013). These
hallucinations typically consist of fully formed, detailed, colored, three-
dimensional images of objects, persons, or animals. The emotional
response to hallucinations varies from indifference to excitement or fear,
and the patient may have some insight into their unreality.
Hallucinations can occur in other modalities, including auditory, tactile,
and olfactory, but auditory hallucinations rarely occur in the absence of
visual hallucinations.
Visual hallucinations occur in 59%–85% of autopsy-confirmed Lewy
body cases (Harding et al. 2002). The occurrence of visual
hallucinations in the first 4 years after dementia onset has positive and
negative predictive values for DLB of 81% and 79%, respectively
(Ferman et al. 2013).
A strong association exists between visual hallucinations and
cholinergic depletion in the temporal cortex and the basal forebrain
(Harding et al. 2002). Another suggested mechanism for visual
hallucinations is dysregulation of rapid eye movement (REM) sleep, with
the intrusion of dreams into wakefulness (Boeve et al. 2001).
Other psychiatric features in DLB include delusions. In contrast to the
vague persecutory delusions often seen in AD, which are based mostly
on confabulation and memory loss, delusions in DLB may be more
fixed, be more complex, and represent recollections of hallucinations
and perceptual disturbances (McKeith et al. 2000). A more common
delusion in DLB is the Capgras delusion, in which the patient believes
that a loved one has been replaced by an identical imposter
(Thaipisuttikul et al. 2013). Other psychiatric symptoms include
depression, anxiety, and apathy.
Motor Features
The distinction between DLB and PDD is based on the relationship of
dementia onset to motor impairment (Goldman et al. 2014). In DLB,
cognitive impairment precedes motor impairment by more than 12
months; the reverse is true for PDD (Emre et al. 2010; McKeith et al.
2005). The onset and severity of parkinsonism in DLB are highly
variable.
Many individuals with DLB develop a symmetric akinetic-rigid
syndrome. Tremor is less common than bradykinesia, facial masking,
and rigidity and tends to be maximal with posture/action rather than at
rest (Williams et al. 2006). Myoclonus is seen in 18.5% of DLB patients
and is rarely seen in PD patients who do not have dementia (Galvin
2006). Postural instability and gait difficulty are more prominent features
of DLB and PDD than of uncomplicated PD. Motor features in DLB
patients may be less responsive to dopaminergic treatment than are
those in PD patients.
Cognitive Fluctuations
Fluctuations in cognition (in the absence of clear precipitants) occur
commonly in DLB and manifest as waxing and waning of arousal, other
cognitive abilities, and functional status. Caregivers and other observers
describe these fluctuations, which alternate with episodes of lucidity and
capable task performance, as episodes of “staring into space” or
appearing “dazed,” or in other ways that suggest inattention, confusion,
incoherent speech, behavioral disorganization, and/or
hypersomnolence. These episodes can last minutes to days and can
vary from alertness to stupor. Transient episodes of disturbed
consciousness in which patients are found mute and unresponsive for a
few minutes may represent an extreme form of fluctuations. Among the
core features of DLB, cognitive fluctuations have the most significant
effect on cognitive performance (Escandon et al. 2010).
Excessive Daytime Drowsiness

Individuals with DLB often experience daytime drowsiness or
somnolence (Ferman et al. 2014), but it is important to rule out
secondary causes of daytime sleepiness. These include medications
and primary sleep disorders such as sleep apnea. Approximately three-
quarters of patients have a significant number of arousals not
accounted for by medication, periodic limb movements during sleep, or
sleep apnea (Boeve et al. 2001).
Rapid Eye Movement Sleep Behavior Disorder

REM sleep behavior disorder (RBD) is characterized by loss of
normal muscle atonia during REM sleep, associated with excessive
activity while dreaming. Increased muscle activity during REM sleep
occurs along with dream content and can range from elevated muscle
tone to complex behavioral sequences, such as acting out dreams.
RBD is associated with synucleinopathies, including DLB, PD, and
multiple system atrophy, and may precede the onset of other symptoms
by years, but it rarely occurs in tau-predominant conditions such as AD
(Boeve et al. 2001).
Autonomic Dysfunction
Autonomic dysfunction is a common feature in Lewy body disorders
(McKeith et al. 2005). Autonomic dysfunction is not specifically included
in the criteria, but some of the supportive features, such as recurrent
falls and transient loss of consciousness, might be explained by
autonomic dysfunction. Although many of these autonomic features
occur later in the disease process, there have been cases with early
and prominent involvement. There is also evidence of involvement of
the peripheral nervous system, with numerous Lewy bodies in the
sympathetic neurons and autonomic ganglia.
The most serious manifestation of autonomic dysfunction is
orthostasis, which is symptomatic in approximately 15% of patients with
DLB (Karantzoulis and Galvin 2013; McKeith et al. 2005). Other
features include decreased sweating, sialorrhea, seborrhea, heat
intolerance, urinary dysfunction, diarrhea, and erectile dysfunction. A
history of chronic constipation beginning two to three decades before
other symptoms is a common complaint.
Neuroleptic Sensitivity
Approximately 57% of patients with DLB, 39% of patients with PDD,
and 27% of patients with PD develop severe neuroleptic sensitivity
(Aarsland et al. 2005). It is not possible to predict the occurrence of
these adverse motor reactions, but they are generally more common
with the neuroleptics that are potent dopamine D2 receptor antagonists.
Both classic and atypical neuroleptics, as well as some antiemetics
(e.g., metoclopramide), can worsen parkinsonism and exacerbate other
features such as sedation and orthostatic hypotension (Zweig and
Galvin 2014).
The greatest concern with the use of typical neuroleptics in persons
with DLB is neuroleptic malignant syndrome (NMS), which is sometimes
fatal. NMS is caused by central blockade of dopamine and includes
muscle rigidity, hyperthermia, and autonomic instability. While NMS is
perhaps the most serious side effect, a similar but more common
adverse reaction, neuroleptic sensitivity reaction (NSR), can be seen in
DLB, PD, and PDD (Zweig and Galvin 2014). NSR, which can occur in
30%–50% of DLB patients, includes sedation, increased confusion,
rigidity, and immobility that may occur after taking a neuroleptic
medication. NSRs are just as likely to occur in patients with mixed
pathology, including AD, supporting the need for accurate diagnosis
(Aarsland et al. 2005).
Differential Diagnosis
Baseline and longitudinal differences in motor, cognitive, psychiatric,
and functional deficits may facilitate distinguishing between DLB and
AD. Motor features that facilitate distinguishing among these and other
neurodegenerative disorders are reviewed in Table 21–3. Men are more
likely to have DLB, whereas AD occurs more often in women. Patients
with DLB are more likely to exhibit psychiatric symptoms and greater
functional impairment in the early stages of DLB, whereas such
problems are more common in the later stages of AD. Furthermore, the
diffuse cortical and subcortical Lewy body pathology produces cognitive
impairment with predominant visuospatial and psychomotor deficits
(Johnson et al. 2005; Karantzoulis and Galvin 2013); although these
problems may develop in AD, they are not typical of this condition.
TABLE 21–3. Comparison of extrapyramidal features in neurocognitive
disorders
Condition Specific findings

Alzheimer’s disease Parkinsonism tends to be later in
course; rigidity, bradykinesia, and
tremor (resting or postural) most
obvious.
Parkinson’s disease Masked facies, stooped posture, and
reduced arm swing; unilateral or
asymmetric rigidity, bradykinesia,
resting tremor, and postural
instability; signs clearly are L-dopa
responsive.
Parkinson’s disease with dementia Same as in Parkinson’s disease, but
over time, bilateral involvement,
marked postural instability, and loss
of L-dopa responsiveness.
Dementia with Lewy bodies Masked facies, stooped posture, and
reduced arm swing similar to that in
Parkinson’s disease with or without
dementia, but tremor is less
asymmetric and more postural.
Multiple system atrophy Rigidity less asymmetric and minimally
L-dopa responsive in the
striatonigral variant; ataxia and
spasticity prominent in the
olivopontocerebellar atrophy
variant; orthostatic hypotension
prominent in the Shy-Drager
syndrome variant.
In a survey of 962 DLB caregivers, an initial diagnosis other than

DLB was given in 78% of cases: Parkinson’s disease (39%),
Alzheimer’s disease (26%), frontotemporal degeneration (4%), mild
cognitive impairment (6%), or other unspecified dementia (12%), as well
as primary psychiatric diagnoses (24%). The initial DLB diagnosis was
made by a neurologist the majority of the time (62%), followed by
psychiatrists, geriatricians, psychologists, and primary care providers.
Once the diagnosis was established, around 50% of DLB patients had
to see two or more clinicians for symptom management, and 58% of
caregivers reported difficulty with managing the care among different
providers (Galvin et al. 2010).
Parkinson’s Disease With Dementia

Up to 14% per year of patients with PD who are over age 70 will
develop at least mild dementia (Galvin 2006). No operationalized
criteria exist to characterize PDD or define the clinical boundaries
between pure PD and PDD, which differ only in whether the cognitive
impairment precedes or follows the motor signs by 12 months (McKeith
et al. 2005).
Both DLB patients and PDD patients may have psychiatric
symptoms, autonomic symptoms, RBD, cognitive fluctuations, and
neuroleptic sensitivity. The neuropsychological profiles in PDD and DLB
are similar, with prominent deficits in attention, executive function,
visuospatial function, language function, memory retrieval, and behavior
(Karantzoulis and Galvin 2013).
Risk Factors for Cognitive Decline in Parkinson’s

Disease
Dementia develops only in a subset of individuals with PD-related
cognitive impairment. Nonthreatening visual hallucinations, commonly
reported in PD even prior to the use of L-dopa, are the strongest clinical
predictor of dementia (Galvin et al. 2006). Advancing age is another
important risk factor for dementia in PD (Aarsland et al. 2004).
Advanced axial extrapyramidal involvement, such as bradykinesia,
rigidity, or postural instability, also appears to increase the risk of
dementia and the rate of cognitive decline once dementia develops.
Among the motor predictors, bilateral onset of motor symptoms and
declining response to L-dopa may also increase the risk of dementia.
Cognitive Profile
The cognitive profile of PDD is similar to that of DLB, with marked
executive dysfunction and marked impairment in attention and
visuospatial and constructional abilities (Johnson and Galvin 2011).
Aside from verbal fluency, cortical functions such as language, limb
praxis, and perceptual processing are relatively preserved in the early
stages. Memory impairment is less prominent than in AD, and recall
may be relatively preserved (Karantzoulis and Galvin 2013).
Compared with PD patients who do not have dementia, PDD patients
are more likely to have visual or auditory hallucinations, delusions, and
depression. They also tend to have a higher frequency of aphasia and
impairment in visuoconstructional tasks such as clock drawing. Other
distinctive clinical features of PDD include sensitivity to neuroleptic
medications, fluctuations in cognition, myoclonus, and sleep
disturbances (Galvin 2006; Goldman et al. 2014).
Executive Function
Patients with PD have impaired ability to plan, organize, and regulate
goal-directed behavior. Controlling for bradykinesia and tremor during
interpretation of psychometric testing is important to ensure that
changes in cognitive domains are measured rather than impairments in
motor control and speed.
Visuospatial Abilities
Impairment in visuoperceptual and visuomotor abilities is seen in PD
with and without dementia (Karantzoulis and Galvin 2013). These
deficits may precede impairments in other domains by several years
(Johnson and Galvin 2011).
Memory
Patients with PD have impaired semantic and episodic memory with
preserved recognition memory and benefit from cuing. The deficit in PD
is mostly associated with impaired registration or retrieval of information
during the early retention phase of short-term memory.
Language
Language processing and comprehension are relatively well
preserved in PDD compared with AD, but verbal fluency is more
compromised in the former. Patients with PDD have also been reported
to have naming deficits and difficulties with sentence comprehension.
Decreased content of spontaneous speech is also seen, but to a lesser
degree than in AD. These patients exhibit motor speech abnormalities
in the form of dysarthria, agraphia, decreased phrase length, and
impaired speech melody.
Psychiatric Features
Approximately 61% of patients with PD exhibit neuropsychiatric
disturbances. The most common are depression (38%), hallucinations
(27%), delusions (6%), anxiety, sleep disturbances, and inappropriate
sexual behavior. Visual hallucinations are aggravated by dopaminergic
treatment.
Cognitive impairment is the main risk factor for hallucinations induced
by L-dopa in PD patients. Other clinical correlates of psychosis in PD
are old age, advanced disease, a history of depression, and co-
occurring sleep disorder, including altered dream phenomena and sleep
fragmentation (Goldman et al. 2014).
Depression is common in patients with PD and appears to be
unrelated to the presence or absence of dementia or the severity of
motor impairment (Aarsland et al. 2004). Major or dysthymic (persistent)
depression can be seen in up to 39.9% of the PD patients, and panic
disorder can be seen in up to 30% of the patients (Nuti et al. 2004). It is
important to recognize depression as a confounding factor in cognitive
and motor impairment.
Fluctuations
PD patients usually have no cognitive fluctuations in the absence of
dementia. On the other hand, PDD produces a pattern of impairment
that is comparable to that of DLB.
Prominent autonomic dysfunction tends to occur later in PD, and
features such as orthostatic hypotension are related to disease severity
and duration. About one-third of patients have clinical features of
autonomic dysfunction. The most common autonomic features are
decreased gastrointestinal mobility and bladder dysfunction.
Constipation is very common, and serious complications, such as
intestinal pseudo-obstruction and toxic megacolon, can occur. Other
common features include bladder dysfunction with increased urgency,
frequency, and incontinence, and sexual dysfunction such as decreased
libido and erectile dysfunction. Almost 40% of patients with PD show
orthostatic hypotension (a fall in systolic blood pressure by ≥20 mm Hg)
(Bae et al. 2011).
Preclinical Cognitive Impairment

Early cognitive deficits are usually in visuospatial and executive
function and verbal memory (Johnson and Galvin 2011). These deficits
include decrements in planning, sequencing, concept formation, and
working memory. In general, rapid cognitive decline is associated with
more severe motor symptoms. In particular, motor symptoms mediated
by nondopaminergic mechanisms (e.g., gait, speech, and postural
control) are associated with accelerated cognitive decline in persons
with PD (Aarsland et al. 2004).
Neuropathology
Dementia With Lewy Bodies

Limbic and neocortical areas are preferentially involved in DLB, with
a variable degree of Lewy body pathology in the brain stem (McKeith et
al. 2005). Over 70% of Lewy body patients have concurrent AD
pathology. The neuritic plaques of AD include a dense core of amyloid-β
with neuritic processes composed of tau protein, but plaques in Lewy
body disease are typically diffuse. So-called Lewy neurites are
intracellular inclusions composed primarily of synuclein aggregated in
the neural processes. They are found in brain regions rich in perikaryal
Lewy bodies and preferentially affect limbic and temporal lobe
structures. Striatal Lewy neurites in DLB may contribute to the
extrapyramidal features. In addition to the involvement of the central
autonomic nuclei, early involvement of the peripheral postganglionic
autonomic neurons occurs in Lewy body disease (Tiraboschi et al.
2000).
Parkinson’s Disease With Dementia

The pathological substrates for PDD include cortical Lewy bodies,
Alzheimer’s pathology, and restricted subcortical pathology (Galvin et al.
2006). Roughly one-third of PDD cases are associated with only
neocortical Lewy bodies, and one-third meet criteria for both PD and
AD. The final third have only brain stem Lewy bodies (Braak et al.
2005).
The neuropathological hallmark of PDD is the presence of Lewy
bodies and neuronal loss in the substantia nigra. Cell loss is seen in the
substantia nigra as well as in the dorsal motor nucleus of the vagus, the
nucleus basalis of Meynert, and the locus coeruleus.
DLB, whether in a pure form or in combination with AD, appears to
begin rostrally and spread caudally, whereas the pathology of PDD
appears to begin in the brain stem and spread rostrally or to begin in the
olfactory bulb (Braak et al. 2005).
Clinicopathological Correlates
The density of Lewy bodies in multiple brain regions correlates with
the severity of cognitive impairment in Lewy body dementia. The total
Lewy body burden seems to correlate with disease duration. Consistent
correlations between the severity of neuropsychiatric symptoms and
Lewy body load have not been established. Many investigations point to
cholinergic depletion in the pathogenesis of fluctuations in DLB. The
response of these patients to cholinesterase inhibitors (McKeith et al.
2000) and the worsening of delirium with the use of anticholinergic
agents support this concept.
The presumed mechanism of RBD in DLB and PDD is damage to the
descending pontine-medullary reticular formation or sublaterodorsal
nucleus that leads to a loss of the normal REM sleep inhibition of the
spinal alpha-motor neurons. In humans, polysomnographic evidence of
REM sleep without atonia is considered the electrophysiological
substrate of RBD and is found in patients with or without florid RBD
(Boeve et al. 2001).
Neurochemical Changes
Although loss of the nigrostriatal dopaminergic pathway is mostly
responsible for the motor features of PD, the loss of mesocortical and
mesolimbic dopaminergic pathways contributes to PD-related cognitive
dysfunction. The striatal regions of DLB and PDD patients show a
varied decrease in dopamine D1 receptor in the caudate when
contrasted with control subjects. Dopamine D2 receptors, on the other
hand, have no differences in DLB and PDD patients. It should be noted
that dopamine D3 activity is significantly increased in the striatal region
(Sun et al. 2013).
DLB patients with fluctuating cognition show neurochemical
imbalances within the thalami and structures that connect the thalamus
to the frontal and parieto-occipital cortices (Delli Pizzi et al. 2015).
Ratios of N-acetyl-aspartate to creatine and of total choline to creatine
are increased in the thalami.
Diagnostic Evaluation
Structural Imaging
Results from radiological investigations, along with other findings,
may help in supporting clinical diagnosis (Table 21–4). Medial temporal
atrophy is noted to be less pronounced in DLB than in AD (Tam et al.
2005). The degree of ventricular enlargement or white matter changes
in DLB is comparable to that in AD (Barber et al. 2000).
TABLE 21–4. Comparison of neuroimaging findings in neurocognitive

disorders
Hypoperfusion (SPECT) or
Condition Pattern of atrophy (MRI) hypometabolism (FDG-PET)
Alzheimer’s Maximal in hippocampi, Maximal in temporoparietal
disease generalized cortical cortex
atrophy evolves over time
Parkinson’s Minimal to no significant Normal or minimally abnormal
disease cortical or hippocampal
atrophy
Parkinson’s Minimal to no significant Maximal in frontoparieto-
disease cortical or hippocampal occipital cortex
with atrophy
dementia
Dementia with Minimal to no significant Maximal in parieto-occipital
Lewy cortical or hippocampal cortex
bodies atrophy
FDG-PET=18F-labeled fluorodeoxyglucose positron emission tomography;

MRI=magnetic resonance imaging; SPECT=single-photon emission computed
tomography.
Magnetic resonance imaging shows putaminal atrophy in DLB but

not in AD (Cousins et al. 2003). Whole brain and caudate volumes are
significantly reduced in subjects with AD compared with subjects with
PD and control subjects, whereas both volumes are comparable among
control subjects, PD subjects, and PDD subjects.
Functional Imaging
Functional brain imaging using 18F-labeled fluorodeoxyglucose
positron emission tomography (FDG-PET) and 99mTc-
hexamethylpropylene amine oxime (99mTc-HMPAO) single-photon

emission computed tomography (SPECT) reveal only minor differences
between DLB and AD (Table 21–4). However, FDG uptake studies
demonstrate metabolic reduction in the visual association cortex in
Lewy body disease that does not appear in AD (Higuchi et al. 2000).
On PET imaging, hypometabolism of glucose is observed in the
primary visual cortex of DLB patients: a group of patients who showed
hypometabolism at baseline were followed for 3 years for cognitive
decline. Five out of 11 patients developed probable DLB, suggesting
that prodromal DLB subjects could show baseline hypometabolism as
well (Fujishiro et al. 2013).
Functional brain imaging using 99mTc-HMPAO and N-isopropyl-p-
[123I]iodoamphetamine (IMP) SPECT in patients with PD shows reduced
occipital perfusion as compared with other cortical areas (Matsui et al.
2005). A 99mTc-exametazime brain SPECT study showed a univariant
difference between AD and DLB, with AD showing decreased perfusion
in the left parahippocampal gyrus (Colloby et al. 2013). In fact, it has
been suggested that reduced flow in the medial occipital lobe, including
the cuneus and the lingual gyrus, can help discriminate DLB from AD
(Shimizu et al. 2005).
Therapeutics
Cognitive Symptoms
Acetylcholinesterase Inhibitors
Limbic and cortical cholinergic deficits are more severe in DLB than
in AD; augmentation of cholinergic function by inhibition of
acetylcholinesterase appears to provide symptomatic benefit. Benefit is
most likely seen in attention, apathy, excessive somnolence, and
hallucinations. In a double-blind, placebo-controlled multicenter trial of
patients with DLB, the subjects treated with rivastigmine 12 mg/day for
20 weeks had better performance on tests of attention, working
memory, and episodic secondary memory than the placebo group
(McKeith et al. 2000). A 24-week open-label study of galantamine
showed improvement in visual hallucinations, nighttime behaviors, and
fluctuating cognitive deficits.
Both rivastigmine and donepezil were evaluated in a randomized
controlled trial involving patients with PDD (Emre et al. 2004; Leroi et al.
2004). Results showed significant improvement in memory subscales
and a trend toward improvement in psychomotor speed and attention.
No differences were found between the treatment and placebo groups
in psychiatric status, motor activity, or activities of daily living at baseline
or at the endpoints. However, up to 25% of patients had side effects
requiring withdrawal of the medication; these included cholinergic side
effects and worsening of parkinsonism. The American Academy of
Neurology suggests the use of acetylcholinesterase inhibitors for the
treatment of PDD (Miyasaki et al. 2006), and rivastigmine is approved in
the United States for the treatment of PDD. There are no specific
approvals for the use of cholinesterase inhibitors in DLB, although off-
label use is common.
Memantine
Controlled clinical trials suggest that memantine, which may diminish
the toxic effects of glutamate, has a modest effect in DLB. In a
prospective study looking at the survival of patients with DLB taking
memantine, those judged to be responders at 24 weeks postbaseline
showed a marked increase in survival at 36-month follow-up compared
with nonresponders (Stubendorff et al. 2014). In a larger 24-week trial of
memantine 20 mg/day versus placebo in patients with DLB or PDD, the
DLB group had a mean 0.6-point improved score on the Clinical Global
Impression—Change scale, but no difference was seen in the PDD
group’s score (Emre et al. 2010).
Motor Symptoms
L-Dopa is the standard treatment for extrapyramidal symptoms in PD.
However, its use in DLB has been limited because of adverse effects on
cognitive and behavioral features and worsening of psychosis. There
have been reports of increased adverse events with the combined use
of L-dopa and cholinesterase inhibitors in patients with PD (Okereke et
al. 2004).
Although some reports suggest that dopaminergic treatment
increases impulsivity or decreases performance, neither of these side
effects has been confirmed. In fact, L-dopa replacement improves
working memory, particularly visuospatial and object tasks, in patients
with PD (Costa et al. 2003), and dopamine withdrawal may “unmask”
dysfunction in executive functions, spatial working memory, and thinking
time and accuracy.
Dopamine agonists have been less effective and less well tolerated
than L-dopa in persons with DLB. Therefore, if a trial of
pharmacotherapy for DLB-related motor symptoms is undertaken, then
L-dopa is recommended. When used, L-dopa is started at a low dose
and is titrated slowly to symptomatic benefit. Other PD medications,
such as amantadine, catechol O-methyltransferase (COMT) inhibitors,
monoamine oxidase inhibitors, and anticholinergics, tend to exacerbate
cognitive impairment and may worsen psychotic symptoms in DLB
(McKeith et al. 2000).
Behavioral Pathology
Anxiety and depression are common in patients with DLB and PDD,
and both groups respond to selective serotonin reuptake inhibitors and
anxiolytics. Benzodiazepines are better avoided given their risk of
sedation, paradoxical agitation, and falls.
Nonpharmacological Approaches
Education of caregivers is an essential part of managing behavioral
pathology. Often, patients’ behaviors are reactions to external stimuli
that can be identified and reduced or eliminated. Hallucinations and
delusions should not be confronted and argued about. Validation of
patients’ feelings and reassurance that their concerns are taken
seriously can often be calming. Although education can provide
caregivers with better understanding of the nature of the condition and
improve their skills in managing difficult situations, caregivers should
also be made aware of available support systems.
Pharmacological Approaches
Acetylcholinesterase inhibitors. A meta-analysis of large
acetylcholinesterase inhibitor trials in patients with AD showed that the
medications had a small but significant benefit in treating
neuropsychiatric symptoms (Trinh et al. 2003). Psychosis, agitation,
wandering, and anxiety are the most consistently responsive symptoms,
whereas depression, apathy, and eating behaviors are less responsive.
Antipsychotics. Visual hallucinations occur in up to 80% of patients
with DLB and have been suggested as predictors of a good response to
cholinesterase inhibitors (McKeith et al. 2004). The management of
psychosis in DLB has been mostly based on trials in AD. In addition,
some recommendations for the use of antipsychotics in DLB are based
on studies in PD because of its similar pathology. Treatment of
psychosis can be very challenging given the sensitivity of patients with
DLB to antipsychotics, as well as these patients’ complex
neurochemical and pathological deficits and wide phenotypic variations.
Typical antipsychotics such as haloperidol and atypical
antipsychotics with D2 receptor antagonism (e.g., olanzapine,
risperidone) should be avoided because of the risk of NMS,
parkinsonism, somnolence, and orthostatic hypotension. Experience
with atypical antipsychotics in Lewy body disease has been mixed.
Clozapine has been demonstrated to reduce psychosis in PD (The
Parkinson Study Group 1999). Quetiapine, which has little D2 activity
and does not require frequent monitoring of hematological status, has
been used frequently for psychosis in DLB, PD, and PDD (Fernandez et
al. 2002), although this constitutes off-label usage.
A potentially important addition to the pharmacotherapies for
psychosis in the Lewy body diseases is pimavanserin, a
nondopaminergic atypical antipsychotic that acts principally through
selective inverse agonism of serotonin 5-HT2A receptors. It
demonstrates a 40-fold greater selectivity for the 5-HT2A receptor than
for the 5-HT2C receptor and demonstrates no clinically significant
activity at 5-HT2B receptors or dopamine receptors. At the time of this
writing, pimavanserin is approved by the U.S. Food and Drug
Administration for the treatment of some patients with psychosis due to
Parkinson’s disease and is being studied as an adjunctive treatment for
schizophrenia. In the latter context, pimavanserin appears to potentiate
the antipsychotic effects of otherwise subtherapeutic doses of
risperidone and improves the tolerability of haloperidol by reducing the
development of extrapyramidal side effects. Although the role of
pimavanserin in the treatment of psychosis in DLB, PD, and PDD
requires further study, pimavanserin (and medications like it that are
likely soon to follow) represents a potentially important addition to the
pharmacotherapy of psychosis in this context.
Sleep Disorders
Clonazepam is the usual therapy for RBD, at 0.25–0.5 mg/night, but
dosages above 1 mg/night are necessary in some patients. Melatonin
may also offer some benefit as monotherapy or in conjunction with
clonazepam. There are reports of persistent efficacy beyond 1 year with
melatonin (Boeve et al. 2001). Other drugs reported to improve RBD
include pramipexole, donepezil, L-dopa, carbamazepine, triazolam,
clozapine, and quetiapine.
The treatment for insomnia should start with a review of sleep
hygiene and nonpharmacological approaches. The antidepressants
trazodone and mirtazapine have been used with some success. Short-
acting benzodiazepines and related γ-aminobutyric acid type A receptor
(GABAA) agonists (e.g., zolpidem) should be avoided in this population.
For excessive daytime sleepiness, treatment options include bupropion,
modafinil, and psychostimulants, but tolerability may be an issue.
Management of orthostatic hypotension includes measures such as
elevating the legs, using elastic stockings, increasing salt and fluid
intake, and avoiding medications that exacerbate orthostatic
hypotension. If these measures fail, midodrine or fludrocortisone can be
used.
Supine hypertension is a common manifestation of autonomic
dysfunction and can lead to serious complications. Treatment of supine
hypertension is difficult, and multiple trials of different medications may
be required. Simple measures include avoiding the supine position in
the daytime and using a tilt-up position at night, which will decrease
nocturnal natriuresis and may also improve morning orthostatic
hypotension.
Bladder dysfunction in Lewy body disease and Parkinson’s disease is
often associated with nocturia, urgency with or without urge
incontinence, and detrusor hyperreflexia. Decreasing fluid intake in the
evening can often improve nocturia. Medications with anticholinergic
activity can be used to treat urinary urgency, frequency, and urge
incontinence, but they can exacerbate cognitive problems. Other risks
include precipitating orthostatic hypotension if these drugs are used
early in the day. Although these medications are effective for detrusor
hyperreflexia, they may worsen urine retention in patients with detrusor
hyporeflexia or flaccid bladder. Another precaution concerns men who
have concomitant prostate hypertrophy or bladder outlet obstruction.
Anticholinergics should be avoided in this group, and urine retention
should be prevented by intermittent catheterization.
Constipation can usually be treated with exercise and dietary
modifications involving at least two high-fiber meals each day. Laxatives
such as lactulose at dosages of 10–20 g/day can be helpful. Cholinergic
stimulation by acetylcholinesterase inhibitors used for cognitive
treatment might improve constipation in some patients.
Although autonomic dysfunction plays a major role in impotence,
there is often a contribution from depression and nocturnal akinesia.
Treatment often necessitates specialized care with urological
consultation.
Conclusion
Dementia with Lewy bodies and Parkinson’s disease with dementia
are common causes of cognitive, behavioral, affective, movement, and
autonomic dysfunction in older adults. These syndromes are associated
with the accumulation of Lewy bodies in subcortical, limbic, and
neocortical regions and are characterized clinically by progressive
dementia, parkinsonism, cognitive fluctuations, and visual
hallucinations. There is essentially no difference in the clinical
phenotype between the two clinical entities. The presence of neocortical
Lewy bodies imparts a distinctive clinical phenotype that is well
captured by published criteria regardless of the temporal relationship of
motor to cognitive symptoms. An important goal is to widen the
spectrum of understanding of neurodegenerative diseases and change
concepts of Lewy body disease from a movement disorder to a disorder
associated with wider neuropsychiatric disturbances, impaired
cognition, episodic confusion, and the development of dementia. As the
ability to refine clinical and cognitive profiles of PDD and DLB increases,
the development of pharmacotherapeutic agents that may be more
selective or potentially specific to these syndromes becomes more
possible.
References
Aarsland D, Andersen K, Larsen JP, et al: The rate of cognitive decline in Parkinson
disease. Arch Neurol 61(12):1906–1911, 2004 15596611
Aarsland D, Perry R, Larsen JP, et al: Neuroleptic sensitivity in Parkinson’s disease
and parkinsonian dementias. J Clin Psychiatry 66(5):633–637, 2005 15889951
Bae HJ, Cheon SM, Kim JW: Orthostatic hypotension in drug-naïve patients with
Parkinson’s disease. J Mov Disord 4(1):33–37, 2011 24868389
Barber R, Ballard C, McKeith IG, et al: MRI volumetric study of dementia with Lewy
bodies: a comparison with AD and vascular dementia. Neurology 54(6):1304–
1309, 2000 10746602
Boeve BF, Silber MH, Ferman TJ, et al: Association of REM sleep behavior disorder
and neurodegenerative disease may reflect an underlying synucleinopathy. Mov
Disord 16(4):622–630, 2001 11481685
Braak H, Rüb U, Jansen Steur EN, et al: Cognitive status correlates with
neuropathologic stage in Parkinson disease. Neurology 64(8):1404–1410, 2005
15851731
Colloby SJ, Taylor JP, Davison CM, et al: Multivariate spatial covariance analysis of
99mTc-exametazime SPECT images in dementia with Lewy bodies and
Alzheimer’s disease: utility in differential diagnosis. J Cereb Blood Flow Metab
33(4):612–618, 2013 23361395
Costa A, Peppe A, Dell’Agnello G, et al: Dopaminergic modulation of visual-spatial
working memory in Parkinson’s disease. Dement Geriatr Cogn Disord 15(2):55–66,
2003 12566593
Cousins DA, Burton EJ, Burn D, et al: Atrophy of the putamen in dementia with Lewy
bodies but not Alzheimer’s disease: an MRI study. Neurology 61(9):1191–1195,
2003 14610119
Delli Pizzi S, Franciotti R, Taylor JP, et al: Thalamic involvement in fluctuating cognition
in dementia with Lewy bodies: magnetic resonance evidences. Cereb Cortex
25(10):3682–3689, 2015 25260701
Emre M, Aarsland D, Albanese A, et al: Rivastigmine for dementia associated with
Parkinson’s disease. N Engl J Med 351(24):2509–2518, 2004 15590953
Emre M, Tsolaki M, Bonuccelli U, et al; 11018 Study Investigators: Memantine for
patients with Parkinson’s disease dementia or dementia with Lewy bodies: a
randomised, double-blind, placebo-controlled trial. Lancet Neurol 9(10):969–977,
2010 20729148
Escandon A, Al-Hammadi N, Galvin JE: Effect of cognitive fluctuation on
neuropsychological performance in aging and dementia. Neurology 74(3):210–217,
2010 20083796
Ferman TJ, Smith GE, Boeve BF, et al: DLB fluctuations: specific features that reliably
differentiate DLB from AD and normal aging. Neurology 62(2):181–187, 2004
14745051
Ferman TJ, Arvanitakis Z, Fujishiro H, et al: Pathology and temporal onset of visual
hallucinations, misperceptions and family misidentification distinguishes dementia
with Lewy bodies from Alzheimer’s disease. Parkinsonism Relat Disord 19(2):227–
231, 2013 23182311
Ferman TJ, Smith GE, Dickson DW, et al: Abnormal daytime sleepiness in dementia
with Lewy bodies compared to Alzheimer’s disease using the Multiple Sleep
Latency Test. Alzheimers Res Ther 6(9):76, 2014 25512763
Fernandez HH, Trieschmann ME, Burke MA, et al: Quetiapine for psychosis in
Parkinson’s disease versus dementia with Lewy bodies. J Clin Psychiatry
63(6):513–515, 2002 12088163
Fujishiro H, Iseki E, Kasanuki K, et al: A follow up study of non-demented patients with
primary visual cortical hypometabolism: prodromal dementia with Lewy bodies. J
Neurol Sci 334(1–2):48–54, 2013 23927939
Galvin JE: Cognitive change in Parkinson disease. Alzheimer Dis Assoc Disord
20(4):302–310, 2006 17132978
Galvin JE, Pollack J, Morris JC: Clinical phenotype of Parkinson disease dementia.
Neurology 67(9):1605–1611, 2006 17101891
Galvin JE, Duda JE, Kaufer DI, et al: Lewy body dementia: the caregiver experience of
clinical care. Parkinsonism Relat Disord 16(6):388–392, 2010 20434939
Goldman JG, Williams-Gray C, Barker RA, et al: The spectrum of cognitive impairment
in Lewy body diseases. Mov Disord 29(5):608–621, 2014 24757110
Harding AJ, Broe GA, Halliday GM: Visual hallucinations in Lewy body disease relate
to Lewy bodies in the temporal lobe. Brain 125(Pt 2):391–403, 2002 11844739
Higuchi M, Tashiro M, Arai H, et al: Glucose hypometabolism and neuropathological
correlates in brains of dementia with Lewy bodies. Exp Neurol 162(2):247–256,
2000 10739631
Johnson DK, Galvin JE: Longitudinal changes in cognition in Parkinson’s disease with
and without dementia. Dement Geriatr Cogn Disord 31(2):98–108, 2011 21242691
Johnson DK, Morris JC, Galvin JE: Verbal and visuospatial deficits in dementia with
Lewy bodies. Neurology 65(8):1232–1238, 2005 16247050
Karantzoulis S, Galvin JE: Update on Dementia with Lewy Bodies. Curr Transl Geriatr
Exp Gerontol Rep 2(3):196–204, 2013 25379359
Leroi I, Brandt J, Reich SG, et al: Randomized placebo-controlled trial of donepezil in
cognitive impairment in Parkinson’s disease. Int J Geriatr Psychiatry 19(1):1–8,
2004 14716693
Matsui H, Udaka F, Miyoshi T, et al: N-isopropyl-p-123I iodoamphetamine single
photon emission computed tomography study of Parkinson’s disease with
dementia. Intern Med 44(10):1046–1050, 2005 16293914
McKeith I, Del Ser T, Spano P, et al: Efficacy of rivastigmine in dementia with Lewy
bodies: a randomised, double-blind, placebo-controlled international study. Lancet
356(9247):2031–2036, 2000 11145488
McKeith IG, Wesnes KA, Perry E, et al: Hallucinations predict attentional
improvements with rivastigmine in dementia with lewy bodies. Dement Geriatr
Cogn Disord 18(1):94–100, 2004 15087584
McKeith IG, Dickson DW, Lowe J, et al; Consortium on DLB: Diagnosis and
management of dementia with Lewy bodies: third report of the DLB Consortium.
Neurology 65(12):1863–1872, 2005 16237129
Miyasaki JM, Shannon K, Voon V, et al; Quality Standards Subcommittee of the
American Academy of Neurology: Practice Parameter: evaluation and treatment of
depression, psychosis, and dementia in Parkinson disease (an evidence-based
review): report of the Quality Standards Subcommittee of the American Academy
of Neurology. Neurology 66(7):996–1002, 2006 16606910
Nuti A, Ceravolo R, Piccinni A, et al: Psychiatric comorbidity in a population of
Parkinson’s disease patients. Eur J Neurol 11(5):315–320, 2004 15142224
Okereke CS, Kirby L, Kumar D, et al: Concurrent administration of donepezil HCl and
levodopa/carbidopa in patients with Parkinson’s disease: assessment of
pharmacokinetic changes and safety following multiple oral doses. Br J Clin
Pharmacol 58 (suppl 1):41–49, 2004 15496222
Park KW, Kim HS, Cheon SM, et al: Dementia with Lewy Bodies versus Alzheimer’s
Disease and Parkinson’s Disease Dementia: A Comparison of Cognitive Profiles. J
Clin Neurol 7(1):19–24, 2011 21519522
The Parkinson Study Group: Low-dose clozapine for the treatment of drug-induced
psychosis in Parkinson’s disease. N Engl J Med 340(10):757–763, 1999 10072410
Shimizu S, Hanyu H, Kanetaka H, et al: Differentiation of dementia with Lewy bodies
from Alzheimer’s disease using brain SPECT. Dement Geriatr Cogn Disord
20(1):25–30, 2005 15832032
Stubendorff K, Larsson V, Ballard C, et al: Treatment effect of memantine on survival
in dementia with Lewy bodies and Parkinson’s disease with dementia: a
prospective study. BMJ Open 4(7):e005158, 2014 24993765
Sun J, Cairns NJ, Perlmutter JS, et al: Regulation of dopamine D3 receptor in the
striatal regions and substantia nigra in diffuse Lewy body disease. Neuroscience
248:112–126, 2013 23732230
Tam CW, Burton EJ, McKeith IG, et al: Temporal lobe atrophy on MRI in Parkinson
disease with dementia: a comparison with Alzheimer disease and dementia with
Tarawneh R, Galvin JE: Distinguishing Lewy body dementias from Alzheimer’s
disease. Expert Rev Neurother 7(11):1499–1516, 2007 17997699
Thaipisuttikul P, Lobach I, Zweig Y, et al: Capgras syndrome in dementia with Lewy
bodies. Int Psychogeriatr 25(5):843–849, 2013 23211760
Tiraboschi P, Hansen LA, Alford M, et al: Cholinergic dysfunction in diseases with
Trinh NH, Hoblyn J, Mohanty S, et al: Efficacy of cholinesterase inhibitors in the
treatment of neuropsychiatric symptoms and functional impairment in Alzheimer
disease: a meta-analysis. JAMA 289(2):210–216, 2003 12517232
Williams MM, Xiong C, Morris JC, et al: Survival and mortality differences between
dementia with Lewy bodies vs Alzheimer disease. Neurology 67(11):1935–1941,
2006 17159097
Zweig YR, Galvin JE: Lewy body dementia: the impact on patients and caregivers.
Alzheimers Res Ther 6(2):21, 2014 25031635
CHAPTER 22
Huntington’s Disease
There are few examples of a condition that defines

neuropsychiatric illness and care as clearly as Huntington’s disease
(HD). This heritable disease produces neurodegeneration within
frontal-subcortical circuits that manifests as motor, cognitive,
emotional, and behavioral symptoms and signs, making it a
paradigmatic neuropsychiatric disorder. The individual and family
with HD present an opportunity for clinicians with neuropsychiatric
training to fully use their expertise and existing treatments to
alleviate suffering, even in the absence of a definitive cure for HD
itself. Research in HD is advancing quickly, and, as of this writing,
several symptomatic and disease-modifying therapies are being
studied for the condition.
In the meantime, the complex nature of HD and the
interrelatedness of the various neuropsychiatric disturbances it
produces necessitate a multidisciplinary approach to treatment—one
that accounts not only for the needs of the individual but also for
those of at-risk relatives and significant others as well as others
providing support and care. In this chapter, I review briefly the nature
of HD and the clinical issues necessary to address to develop an
evidence-informed approach to the treatment of individuals with HD.
Etiology
Individuals with HD carry an increased number of cytosine-
adenine-guanine (CAG) trinucleotide repeats on chromosome 4, the
“HD expansion mutation.” This mutation is inherited in an autosomal
dominant manner, meaning that each biological child of a person
with HD has a 50% chance of inheriting the mutation and developing
the condition, regardless of gender. Signs and symptoms of HD
usually appear in early or middle adulthood, although earlier and
later cases are reported. The number of CAG repeats correlates
inversely with age at onset of HD symptoms, such that a larger
number of CAG repeats in the HD gene is associated with younger
age at symptom onset. The HD gene also demonstrates length-
dependent intergenerational instability during gametogenesis, which
may increase the number of CAG repeats inherited by offspring
(especially those of men with HD). The expanded HD gene leads to
symptom onset at an even earlier age than that of the affected
parent, a process known as “anticipation.” This said, there is a great
deal of variability in age at onset for any given repeat length, making
the exact repeat number unhelpful in making prognoses about
disease onset in a specific individual (Rubinsztein et al. 1997).
Neuropathological changes begin years before motor symptom
onset, with loss of striatal neurons and cortical thinning among the
earliest changes (Vonsattel et al. 1985). Caudate degeneration is the
hallmark of HD, but cell loss occurs elsewhere in the striatum as
well. As the disease progresses, generalized cerebral atrophy
develops as a result of both primary effects on the neocortex and
secondary atrophy due to loss of corticostriatal projections (Rosas et
al. 2011). The mechanism by which the CAG expansion in the HD
gene leads to the neuropathology of HD remains uncertain.
However, possible mechanisms include toxic gain of function, loss of
function, huntingtin protein misfolding leading to dysfunction, or a
combination of cellular dysfunctions (Ross and Tabrizi 2011).
Genetic Testing
Genetic testing for HD may be performed when a patient is
showing signs or symptoms and seeks to know whether he or she
has the HD mutation expansion (i.e., confirmatory testing). HD gene
testing is also commonly undertaken when an individual at risk for
HD—for example, the adult child of a patient diagnosed with HD—
wants to know whether or not they will develop the condition (i.e.,
predictive testing). The first situation is more familiar, at least initially,
to clinicians: a patient with manifest symptoms of a disease presents
with symptoms suggestive of HD, the HD gene test is performed,
and a diagnosis of HD is rendered based on the results of that test.
Even in this familiar circumstance, however, it is imperative to remain
mindful that confirmatory testing provides information not only to the
patient but also to his or her blood relatives. When a patient’s HD
gene testing results become known to his or her family members,
those family members become aware that they are at risk for HD and
may, without further testing, be able to estimate that risk (i.e., 50%
risk in siblings and children, 25% risk in grandchildren). Accordingly,
engaging in genetic counseling in the evaluation process to provide
guidance and support about testing and testing results can be very
helpful to patients and their family members, including spouses and
other genetically unrelated family members, even in the setting of
(ostensibly) confirmatory testing.
The second situation—predictive HD gene testing in an
asymptomatic individual at risk for HD—is less familiar to clinicians
other than HD specialists. The Huntington’s Disease Society of
America (HDSA; hdsa.org) in conjunction with the U.S. Huntington’s
Disease Genetic Testing Group has promulgated guidelines to assist
health care providers in administering confirmatory, predictive, and
prenatal HD gene testing that are designed to protect the well-being
of those who choose to be tested. In this special circumstance, it is
recommended that the patient meet with a genetic counselor and
undergo a specific protocol for HD genetic testing that follows the
HDSA guidelines. A neurological exam is usually offered during the
testing process to see if symptoms are present, because individuals
at risk may not be aware that they have early signs or symptoms.
Psychiatric evaluation is also conducted to ensure that any
underlying depression, anxiety, substance abuse, or other
psychiatric disorder is treated before the individual undergoes testing
and receives a potentially life-altering result (Robins Wahlin 2007).
Most testing programs require a support person, such as a spouse,
close friend, or sibling, to be involved and accompany the individual
to testing visits and on the day results are given.
Reproductive Issues
The vast majority of HD mutation carriers opt to reproduce
naturally, without any intervention to prevent transmission of the HD
gene (Schulman and Stern 2015). For those who want to ensure
they will not have a child with the HD expansion mutation, in vitro
fertilization, sperm donation, adoption, and egg donation are all
options (de Die-Smulders et al. 2013). As noted above, the HDSA
has established guidelines for prenatal genetic testing; clinicians are
encouraged to review these guidelines in order to adhere to best
practices.
Motor Symptoms
Motor symptoms of HD include chorea, dystonia, impairment of
saccades, gait disorder, loss of coordination, dysphagia, and
dysarthria. Chorea is certainly the most common symptom of HD,
occurring in over 90% of patients. HD is the classic hyperkinetic
movement disorder, manifested by irregular, unpredictable dancelike
or writhing choreic movements. Chorea starts in the extremities and
face early in the course of the illness and progresses to involve the
trunk, where it can affect balance. Despite the sometimes dramatic
appearance of chorea, many patients are unaware they have this
symptom, or they minimize its severity. Snowden and colleagues
(1998) demonstrated that patients are likely to notice chorea only
when it has an impact on their surroundings (e.g., knocking over
dishes).
The decision to treat chorea is dependent on the wants and needs
of an individual patient and his or her family. Some patients seek
chorea suppression for minimal symptoms because they do not want
to appear “sick” or different, or they have employment where a
movement disorder would be unwelcome, such as teaching. Other
patients with more severe chorea have impairment in eating,
dressing, or bathing due to their movements. If the trunk and lower
extremities are affected, a choreic movement gait disorder can be
very disabling, and chorea suppression can partly correct this.
Choreic movements increase with anxiety, agitation, and fatigue, so
it is important to evaluate for these problems prior to initiating
treatment for choreic movements specifically; effective management
of these comorbidities may reduce the need for or dose of
medications targeting choreic movements. Many patients are not
interested in chorea suppression, and after careful discussion with
the patient and family, if there is no impact on function, then there is
no need to treat chorea (Burgunder et al. 2011; Jankovic and Roos
2014).
Chorea can be treated with haloperidol, benzodiazepines, or
tetrabenazine (a reversible vesicular monoamine transporter–2
[VMAT2] inhibitor that depletes dopamine). Treatment selection is
based principally on the favorability of the side-effect profile of each
of the available treatments given specific characteristics. If chorea
occurs only at night, use of a benzodiazepine only at bedtime, when
fall risk is reduced and sedation is beneficial, may be the best option.
For patients with prominent irritability, haloperidol may be the best
option for chorea suppression, because it will also help to ameliorate
this behavioral symptom.
Tetrabenazine carries a “black box” warning from the U.S. Food
and Drug Administration about treatment-associated increased risk
of depression and suicidality. The decision to prescribe
tetrabenazine for chorea must balance the risks of depression and
suicidality with the need for control of chorea. Tetrabenazine is
contraindicated in patients with active suicidality and individuals with
untreated or inadequately treated depression. Patients, family
members, caregivers, and clinicians should remain vigilant for the
emergence of such problems during treatment and intervene
promptly when they occur. Other possible side effects include
sedation, anxiety, and akathisia.
Dystonia (i.e., abnormal muscle tone resulting in muscular spasm
and abnormal posture) also develops commonly in persons with HD.
Dystonic posturing often involves the hands, arms, and feet and is
usually most evident during ambulation. Truncal dystonia can cause
leaning to one side and affect balance. Severe dystonia can cause
disability and pain. Treatment with botulinum toxin injections can
greatly alleviate dystonia symptoms (Adam and Jankovic 2008).
Gait abnormalities and impairments also are common in HD and
are usually the result of multiple factors, including chorea, dystonia,
and some medications (e.g., haloperidol, benzodiazepines). Physical
therapy and reduction of offending medications can be helpful in
reducing gait problems and improving the safety of patients, who are
very susceptible to subdural hematomas with falls, given the large
amount of generalized atrophy in the brain.
Loss of coordination impacts activities of daily life. Simple actions
such as bringing a spoon to the mouth can become impossible.
Physical and occupational therapy can help to provide new
strategies, and assistive devices that are easier to control, such as
weighted spoons and nonspill cups, can be used.
Nutrition consultations along with speech and swallowing
evaluations are helpful for dysphagia and dysarthria, which are a
major cause of morbidity in HD, because weight loss becomes a
problem as the disease progresses, as does choking.
Impairment of saccades is an early symptom of HD, starting with
slowed or interrupted saccades and eventually progressing to
diminished range of saccades. There are no established treatments
for these eye movement disturbances in HD, and the clinical
usefulness of this sign of HD is principally in diagnosis. Action
myoclonus is a rare symptom, seen in late disease. Seizures are
seen mainly in cases of juvenile onset (motor symptom onset before
age 18) and are treated with anticonvulsants.
Cognitive Symptoms
HD is often described as a subcortical dementia, in contrast to
cortical dementias such as Alzheimer’s disease. Subcortical
dementia manifests with slowness and inefficiency of information
processing, slowed psychomotor speed, difficulties initiating
cognitive processes, difficulty with the retrieval of previously learned
information, and executive dysfunction. Patients usually do not have
other typical features of cortical dementia, such as aphasia, impaired
new learning, or visuospatial deficits, until the late stages of HD.
Executive dysfunction is the earliest cognitive symptom in HD.
Patients and their caregivers often report, long before motor onset,
difficulties with multitasking, difficulty performing tasks requiring a
switch from one action to another, and difficulty with higher-level
organization (Papoutsi et al. 2014). Executive dysfunction may
substantially limit everyday functioning, sometimes resulting in
employment problems and job loss well before the development of
comparably disabling motor symptoms. Neuropsychological
assessment can be particularly useful in patients with cognitive
impairments—especially executive dysfunction—to identify
impairments for which function-preserving compensatory strategies
may be developed or application for disability benefits is required.
Unawareness of deficits (anosognosia) also develops relatively
early in many patients with HD. Anosognosic patients appear largely
unaware of their cognitive impairments and their functional
consequences. Although common, anosognosia is by no means
universal at the onset of HD-related cognitive impairments; some
patients with HD are very aware of their initial cognitive deficits.
Unfortunately, there are no established treatments for anosognosia
in HD.
Cognitive function is a strong predictor of overall functional status
in persons with HD. For instance, Rothlind et al. (1993) examined
motor and cognitive measures as predictors of independence in
activities of daily living and reported that psychomotor speed and the
ability to regulate attention may be particularly important
determinants of everyday functioning in mild HD.
At this time, there is no established pharmacological treatment for
the HD-related cognitive impairments. Trials of the
acetylcholinesterase inhibitors have not demonstrated benefits for
cognitive impairments due to HD (Cubo et al. 2006; Li et al. 2015).
Stimulant medications (e.g., methylphenidate), as well as stimulating
antidepressants (e.g., bupropion), are sometimes used to improve
attention and vigilance in individuals with early-stage HD. However,
the evidence base for these treatments is limited, and their use may
worsen irritability; accordingly, treatment with stimulants should be
avoided in patients with pretreatment irritability.
Behavioral Symptoms
Psychiatric symptoms are frequently reported and often precede
motor abnormalities of HD (Epping et al. 2016; Paulsen et al. 2013;
van Duijn et al. 2007). The manifestation and progression of these
symptoms are not influenced by CAG repeat length (Vassos et al.
2008). The psychiatric symptoms of HD contribute greatly to
caregiver burden and morbidity and are a cause of long-term care
placement. Unlike motor and cognitive symptoms, most behavioral
symptoms do not progress predictably from stage to stage. Apathy,
which worsens with advancing HD, is an exception to this general
rule.
Depression
Depression is common in HD, with more than half of patients with
HD experiencing depression at some point during their illness (van
Duijn et al. 2007). Treatment of depression follows that offered to
patients with idiopathic depression, with standard antidepressant
therapies and doses generally employed. Other mood disorders,
such as mania, are relatively rare in HD. Treatment for these other
mood disorders also follows that usually offered to patients with
idiopathic mood disorders.
Suicidality
Rates of self-harm and thoughts of suicide are increased in
people with HD and also in those who are genetically at risk for HD.
Suicide attempts occur at a rate of 10 times that of actual suicide
completion in the general population, and suicide attempts can result
in significant injury even if death does not result; accordingly, the
presence of suicidal thoughts or actions requires prompt evaluation
and management (Hawton et al. 1998). The frequency of suicide
attempts in those with symptomatic HD is 4.8%–17.7% during the
course of illness; rates vary with the methods of their categorization
in studies performed to date (Alonso et al. 2009; Dewhurst et al.
1970; Farrer 1986; Hayden et al. 1980; Hubers et al. 2013). Among
persons genetically at risk for HD, suicidality and suicide risk
increase as early signs and symptoms of HD manifest on
neurological exam (Paulsen et al. 2005). In a large study of
prodromal HD, PREDICT HD (Fiedorowicz et al. 2011), actual
suicide attempts in those at risk for HD were associated with
depression, history of prior suicide attempt, and incarceration.
Apathy
Apathy is a reduction of goal-directed cognition, emotion, and
behavior and is highly prevalent in patients with HD. It is the one
behavioral symptom that increases in severity in a linear manner
with disease progression, and apathy is the most common
neuropsychiatric symptom seen in advanced stages of the illness
(Thompson et al. 2012; van Duijn et al. 2014). Differentiating apathy
from depression can be challenging, but these symptoms are most
clearly distinguished by their respective emotional elements:
depression is a state of persistent and excessive sadness and/or
loss of the ability to experience pleasure (anhedonia), whereas
apathy is characterized by the absence of emotion and by reduced
emotional responsiveness to all stimuli, combined with diminished
spontaneous thoughts and actions (Levy et al. 1998; Naarding et al.
2009).
Pharmacological treatment of apathy is sometimes undertaken
using stimulants (e.g., methylphenidate); however, the evidence with
which to guide treatment of apathy in HD is very limited (Mestre et al.
2009). In general, treatment should be individualized to the patient
and his or her support system and environment and should include
multidisciplinary input, environmental modifications, and
psychosocial support. Education of family members is an essential
component of treatment. It begins by helping them understand that
the apathetic patient is not depressed, particularly to help them
understand that the apathetic patient with HD is not “lazy” or
intentionally uncooperative or nonparticipatory but, instead, is
disabled behaviorally by his or her disease. As caregivers begin to
better understand apathy, strategies to help them compensate for
the functional limitations it produces then may be implemented.
Irritability
Irritability in HD refers to a tendency to become easily irritated or
angered and is often associated with verbal or physical outbursts.
Irritability can be a purely internal state with little outward
manifestation. Irritability is highly prevalent in HD across stages of
the disease, with reported rates of irritability ranging from 40% to
70% (van Duijn et al. 2007). Recent work suggests irritability is an
early marker for HD progression (van Duijn et al. 2014). However,
and consistent with the common occurrence of anosognosia in HD,
patient-reported irritability and proxy (often family or caregiver)–
reported irritability are often discordant (Chatterjee et al. 2005).
Accordingly, interview of the patient and knowledgeable others is
necessary to fully evaluate irritability in HD.
There have been no studies of long-term follow-up and no blinded
treatment studies in HD. Treatment of irritability, based on clinical
experience, often leads to polypharmacy and inappropriate
treatments, resulting in sedation and other side effects. An algorithm
based on expert opinion has been published (Groves et al. 2011),
along with expert opinion reviews that are useful in guiding treatment
in the absence of controlled studies. The experts recommended an
antipsychotic drug as the first-line treatment of urgent aggressive
irritability. For patients for whom the need for treatment is not urgent
or emergent, selective serotonin reuptake inhibitors (SSRIs) were
regarded as first-line treatments by most respondents in North
America and Australia; in Europe, antipsychotics were endorsed as
first-line treatments for mild or moderate irritability. Anticonvulsant
mood stabilizers were also identified as possible treatments of mild
or moderate irritability. Although benzodiazepines were not regarded
as monotherapies for irritability, they were identified as possible
adjunctive treatments among patients with comorbid anxiety;
however, their use may increase fall risk and impair cognition,
making them less well suited for use in patients with HD-related gait
abnormalities and/or dementia. Mirtazapine was also identified as a
possible treatment, either as monotherapy or adjunctive therapy,
when insomnia is comorbid with irritability.
Psychosis
Prevalence of psychosis in HD varies between 3% and 11% (van
Duijn et al. 2007). Higher frequencies of psychosis are reported in
later-disease-stage populations, particularly those in institutional
settings (Zarowitz et al. 2014). Paranoid delusions (e.g., fear of food
being poisoned) and delusions of infidelity (i.e., spousal cheating)
are relatively common and generally uncomplicated (i.e., derive from
ordinary life experience). When psychotic symptoms develop
acutely, they often are indicators of delirium due to commonly
occurring late-stage medical illnesses (e.g., urinary tract infection,
pneumonia) or neurological injuries (i.e., occult traumatic brain injury
and/or subdural hematomas due to fall or assault).
Antipsychotic medications used for the treatment of chorea may
improve psychosis in HD. Newer antipsychotic medications like
olanzapine and aripiprazole may be effective and have a more
favorable side-effect profile for both psychosis and chorea than the
first-generation antipsychotics (Frank and Jankovic 2010).
Anxiety
Anxiety is common in HD but has received relatively little attention
(van Duijn et al. 2007). Chorea, like most movement disorders, will
worsen with anxiety. It is present in all stages of the illness and may
be seen in prodromal patients and in those who are considering
genetic testing (Paulsen et al. 2013; Vaccarino et al. 2011).
Treatment of anxiety follows guidelines for treatment in the general
population. Caution must be used when prescribing benzodiazepines
in light of their potential for increasing fall risk and impairing
cognition.
Repetitive Behaviors
Perseveration and obsessive and compulsive behaviors, formerly
a subset of anxiety disorders, are common in basal ganglia
disorders, including HD. Obsessions are intrusive, unwanted, and
repetitive thoughts (e.g., ceaseless worry about having hit someone
after driving over a bump in the road); compulsions are repetitive
behaviors that sometimes, but not always, are performed in
response to an obsession (e.g., changing clothing many times a day
either ritually [without obsession] or in response to a
contamination/soiling obsession). Perseveration is the repetition of a
behavior in response to a stimulus after the stimulus is no longer
present and the behavior is no longer relevant or adaptive (e.g.,
repeatedly asking a question despite understanding and recalling
answers previously provided). These types of repetitive behaviors,
which occur in as many as 50% of persons with HD, are associated
with the presence of other psychiatric symptoms, including
depression, and may worsen with disease severity (Anderson et al.
2001, 2010; Beglinger et al. 2007).
As with other behavioral symptoms in HD, controlled treatment
studies are lacking, but expert consensus guideline
recommendations are available (Anderson et al. 2011). These
guidelines identify SSRIs as first-line treatments for obsessive-
compulsive/repetitive behaviors in HD, although clomipramine may
also be useful as monotherapy. Antipsychotics and anticonvulsant
mood stabilizers may be considered augmentation strategies for
these behaviors when first-line interventions are only partially
effective.
Future Treatment Options
There are currently numerous agents under development for
treatment of HD symptoms and for slowing disease progression.
Improved approaches to symptomatic treatment are being developed
(e.g., modification of tetrabenazine to potentially decrease dose-
limiting side effects). Strategies to selectively lower the mutant
Huntingtin protein, modulate abnormal brain immune response,
increase neurotrophic factors, and address metabolic abnormalities
are all being pursued, as of this date (see Ross et al. 2014; Shannon
and Fraint 2015; and Wild and Tabrizi 2014 for reviews).
References
Adam OR, Jankovic J: Symptomatic treatment of Huntington disease.
Neurotherapeutics 5(2):181–197, 2008 18394562
Alonso ME, Ochoa A, Boll MC, et al: Clinical and genetic characteristics of
Mexican Huntington’s disease patients. Mov Disord 24(13):2012–2015, 2009
19672992
Anderson KE, Louis ED, Stern Y, et al: Cognitive correlates of obsessive and
compulsive symptoms in Huntington’s disease. Am J Psychiatry 158(5):799–
801, 2001 11329405
Anderson KE, Gehl CR, Marder KS, et al; Huntington’s Study Group:
Comorbidities of obsessive and compulsive symptoms in Huntington’s disease.
J Nerv Ment Dis 198(5):334–338, 2010 20458194
Anderson K, Craufurd D, Edmondson MC, et al: An International Survey-based
Algorithm for the Pharmacologic Treatment of Obsessive-Compulsive
Behaviors in Huntington’s Disease. PLoS Curr 3:RRN1261, 2011 21947193
Beglinger LJ, Langbehn DR, Duff K, et al; Huntington Study Group Investigators:
Probability of obsessive and compulsive symptoms in Huntington’s disease.
Biol Psychiatry 61(3):415–418, 2007 16839521
Burgunder JM, Guttman M, Perlman S, et al: An International Survey-based
Algorithm for the Pharmacologic Treatment of Chorea in Huntington’s Disease.
PLoS Curr 3:RRN1260, 2011 21975581
Chatterjee A, Anderson KE, Moskowitz CB, et al: A comparison of self-report and
caregiver assessment of depression, apathy, and irritability in Huntington’s
disease. J Neuropsychiatry Clin Neurosci 17(3):378–383, 2005 16179661
Cubo E, Shannon KM, Tracy D, et al: Effect of donepezil on motor and cognitive
function in Huntington disease. Neurology 67(7):1268–1271, 2006 17030764
de Die-Smulders CE, de Wert GM, Liebaers I, et al: Reproductive options for
prospective parents in families with Huntington’s disease: clinical,
psychological and ethical reflections. Hum Reprod Update 19(3):304–315,
2013 23377865
Dewhurst K, Oliver JE, McKnight AL: Socio-psychiatric consequences of
Huntington’s disease. Br J Psychiatry 116(532):255–258, 1970 4244788
Epping EA, Kim JI, Craufurd D, et al; PREDICT-HD Investigators and Coordinators
of the Huntington Study Group: Longitudinal Psychiatric Symptoms in
Prodromal Huntington’s Disease: A Decade of Data. Am J Psychiatry
173(2):184–192, 2016 26472629
Farrer LA: Suicide and attempted suicide in Huntington disease: implications for
preclinical testing of persons at risk. Am J Med Genet 24(2):305–311, 1986
2940862
Fiedorowicz JG, Mills JA, Ruggle A, et al; PREDICT-HD Investigators of the
Huntington Study Group: Suicidal behavior in prodromal Huntington disease.
Neurodegener Dis 8(6):483–490, 2011 21659725
Frank S, Jankovic J: Advances in the pharmacological management of
Huntington’s disease. Drugs 70(5):561–571, 2010 20329804
Groves M, van Duijn E, Anderson K, et al: An International Survey-based
Algorithm for the Pharmacologic Treatment of Irritability in Huntington’s
Disease. PLoS Curr 3:RRN1259, 2011 21975525
Hawton K, Arensman E, Wasserman D, et al: Relation between attempted suicide
and suicide rates among young people in Europe. J Epidemiol Community
Health 52(3):191–194, 1998 9616425
Hayden MR, Ehrlich R, Parker H, et al: Social perspectives in Huntington’s chorea.
S Afr Med J 58(5):201–203, 1980 6447366
Hubers AA, van Duijn E, Roos RA, et al; REGISTRY investigators of the European
Huntington’s Disease Network: Suicidal ideation in a European Huntington’s
disease population. J Affect Disord 151(1):248–258, 2013 23876196
Jankovic J, Roos RA: Chorea associated with Huntington’s disease: to treat or not
to treat? Mov Disord 29(11):1414–1418, 2014 25156927
Levy ML, Cummings JL, Fairbanks LA, et al: Apathy is not depression. J
Li Y, Hai S, Zhou Y, Dong BR: Cholinesterase inhibitors for rarer dementias
associated with neurological conditions. Cochrane Database Syst Rev
3(3):CD009444, 2015 25734590
Mestre T, Ferreira J, Coelho MM, et al: Therapeutic interventions for symptomatic
treatment in Huntington’s disease. Cochrane Database Syst Rev
(3):CD006456, 2009 19588393
Naarding P, Janzing JG, Eling P, et al: Apathy is not depression in Huntington’s
disease. J Neuropsychiatry Clin Neurosci 21(3):266–270, 2009 19776305
Papoutsi M, Labuschagne I, Tabrizi SJ, et al: The cognitive burden in Huntington’s
disease: pathology, phenotype, and mechanisms of compensation. Mov Disord
29(5):673–683, 2014 24757115
Paulsen JS, Hoth KF, Nehl C, et al: Critical periods of suicide risk in Huntington’s
disease. Am J Psychiatry 162(4):725–731, 2005 15800145
Paulsen JS, Nance M, Kim JI, et al: A review of quality of life after predictive
testing for and earlier identification of neurodegenerative diseases. Prog
Neurobiol 110:2–28, 2013 24036231
Robins Wahlin TB: To know or not to know: a review of behaviour and suicidal
ideation in preclinical Huntington’s disease. Patient Educ Couns 65(3):279–
287, 2007 17000074
Rosas HD, Reuter M, Doros G, et al: A tale of two factors: what determines the
rate of progression in Huntington’s disease? a longitudinal MRI study. Mov
Disord 26(9):1691–1697, 2011 21611979
Ross CA, Tabrizi SJ: Huntington’s disease: from molecular pathogenesis to clinical
treatment. Lancet Neurol 10(1):83–98, 2011 21163446
Ross CA, Aylward EH, Wild EJ, et al: Huntington disease: natural history,
biomarkers and prospects for therapeutics. Nat Rev Neurol 10(4):204–216,
2014 24614516
Rothlind JC, Bylsma FW, Peyser C, et al: Cognitive and motor correlates of
everyday functioning in early Huntington’s disease. J Nerv Ment Dis
181(3):194–199, 1993 8445379
Rubinsztein DC, Leggo J, Chiano M, et al: Genotypes at the GluR6 kainate
receptor locus are associated with variation in the age of onset of Huntington
disease. Proc Natl Acad Sci USA 94(8):3872–3876, 1997 9108071
Schulman JD, Stern HJ: Low utilization of prenatal and pre-implantation genetic
diagnosis in Huntington disease—-risk discounting in preventive genetics. Clin
Genet 88(3):220–223, 2015 25307798
Shannon KM, Fraint A: Therapeutic advances in Huntington’s Disease. Mov Disord
30(11):1539–1546, 2015 26226924
Snowden JS, Craufurd D, Griffiths HL, et al: Awareness of involuntary movements
in Huntington disease. Arch Neurol 55(6):801–805, 1998 9626771
Thompson JC, Harris J, Sollom AC, et al: Longitudinal evaluation of
neuropsychiatric symptoms in Huntington’s disease. J Neuropsychiatry Clin
Neurosci 24(1):53–60, 2012 22450614
Vaccarino AL, Sills T, Anderson KE, et al: Assessment of depression, anxiety and
apathy in prodromal and early Huntington disease. PLoS Curr 3:RRN1242,
2011 21731882
van Duijn E, Kingma EM, van der Mast RC: Psychopathology in verified
Huntington’s disease gene carriers. J Neuropsychiatry Clin Neurosci
19(4):441–448, 2007 18070848
van Duijn E, Craufurd D, Hubers AA, et al; European Huntington’s Disease
Network Behavioural Phenotype Working Group: Neuropsychiatric symptoms
in a European Huntington’s disease cohort (REGISTRY). J Neurol Neurosurg
Psychiatry 85(12):1411–1418, 2014 24828898
Vassos E, Panas M, Kladi A, et al: Effect of CAG repeat length on psychiatric
disorders in Huntington’s disease. J Psychiatr Res 42(7):544–549, 2008
17610899
Vonsattel JP, Myers RH, Stevens TJ, et al: Neuropathological classification of
Huntington’s disease. J Neuropathol Exp Neurol 44(6):559–577, 1985 2932539
Wild EJ, Tabrizi SJ: Targets for future clinical trials in Huntington’s disease: what’s
in the pipeline? Mov Disord 29(11):1434–1445, 2014 25155142
Zarowitz BJ, O’Shea T, Nance M: Clinical, demographic, and pharmacologic
features of nursing home residents with Huntington’s disease. J Am Med Dir
Assoc 15(6):423–428, 2014 24613270
CHAPTER 23
Frontotemporal Dementia
Frontotemporal dementia (FTD) is a common cause of young-onset dementia, affecting 20,000–

30,000 individuals nationwide (Knopman and Roberts 2011), and is the third most common
neurodegenerative cause of dementia after Alzheimer’s disease (AD) and dementia with Lewy bodies
(Snowden et al. 2002). In contrast to AD, FTD manifests with behavioral changes, language impairment,
and executive dysfunction with relative sparing of memory and visuospatial function. Furthermore, these
conditions may progress to involve motor systems of the brain, resulting in motor neuron disease and
parkinsonism.
AD is associated with a discrete neuropathological signature, namely, amyloid plaques and
neurofibrillary tangles; FTD, however, is more variable and may be characterized by the aggregation of
one of several possible proteins in the affected frontal or temporal cortices. The microtubule-associated
protein tau, transactive response DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS)
(Karageorgiou and Miller 2014) are the most commonly encountered protein deposits; other, less
common pathologies have been described. Frontotemporal lobar degeneration (FTLD) is the term for
the pathological process underlying a clinical FTD syndrome. There is no straightforward one-to-one
association between clinical phenotypes (e.g., behavioral-variant FTD, semantic-variant primary
progressive aphasia, or nonfluent-variant primary progressive aphasia; see section “Clinical Features”
below) and the underlying neuropathology (FTLD-tau, FTLD-TDP, or FTLD-FUS). For example,
behavioral-variant FTD patients with different molecular pathologies may exhibit similar clinical
phenotypes.
FTD may be further distinguished from AD by the strong genetic association that is found in 40% of
patients (Rabinovici et al. 2010). Often, patients may report an extensive history of family members
reeceiving what is, in retrospect, a misdiagnosis of AD or a psychiatric condition such as bipolar disorder
or schizoaffective disorder. Mutations in genes for tau (MAPT) or progranulin (GRN) account for many
cases of familial FTD (Karageorgiou and Miller 2014). More recently, a hexanucleotide repeat expansion
on chromosome 9 (C9ORF72) was identified as a cause of many cases of frontotemporal degeneration
with amyotrophic lateral sclerosis. Whereas MAPT mutations result in FTLD-tau pathology, GRN and
C9ORF72 mutations associate with FTLD-TDP (Karageorgiou and Miller 2014).
Although the current treatment for FTD is supportive care, the varied pathological targets associated
with these neurodegenerative processes present opportunities for future molecular-targeted or genetic
treatments. However, such treatment strategies first require an appreciation of the clinical phenotypes
and the characteristics of the three FTD syndromes (Table 23–1).
TABLE 23–1. Frontotemporal dementia (FTD) syndromes
Cognitive exam
FTD syndrome Symptoms findings Neuroimaging Motor findings Neuro
Behavioral-variant FTD Behavioral Deficits in Right-hemispheric Motor neuron FT
disinhibition executive tasks frontal and/or disease FT
Apathy or inertia Relative anterior (10%–15%)
temporal FT
preservation of Parkinsonism
Loss of sympathy atrophy,
(20%) or Oth
or empathy memory and particularly
visuospatial involving the supranuclear
Early
function orbitofrontal, gaze
perseverative, insular, and disturbance
stereotyped, or anterior
(less
compulsive cingulate
cortices common)
ritualistic
behaviors
Hyperorality
Nonfluent/agrammatic- Progressive Agrammatism Left posterior Right hemibody FT
variant primary expressive Inconsistent fronto- insular apraxia,
progressive aphasia aphasia atrophy on parkinsonism,
speech sound
characterized structural MRI dystonia,
by slow, errors and alien limb
Left posterior
effortful speech distortions and Progression to
fronto- insular
with decreased apraxia of
SPECT corticobasal
output;
speech syndrome or
dysarthria; and hypoperfusion
progression to Impaired or PET progressive
mutism comprehension supranuclear
hypometabolism
of syntactically palsy
complex
sentences
Spared single-
word
comprehension
and object
knowledge
Relative
preservation of
memory and
visuospatial
function
Cognitive exam
FTD syndrome Symptoms findings Neuroimaging Motor findings Neuro
Semantic-variant primary Left predominant Left predominant Asymmetric left Less common FT
progressive aphasia Word-finding Impaired and/or right
anterior and
difficulties confrontational
lateral temporal
Comprehension naming atrophy on
difficulties Impaired single- structural MRI
Right predominant word

comprehension
Prosopagnosia
Impaired object
Poor emotional
knowledge
recognition
Surface dyslexia
Disinhibition
Spared repetition,
Mental rigidity
grammar, and
Food fads
motor speech
Compulsions production
Relative
preservation of
memory and
visuospatial
function
Right predominant
Prosopagnosia
Impaired affect
recognition
Note. FTLD-FUS= frontotemporal lobar degeneration–fused in sarcoma; FTLD-tau=frontotemporal lobar degeneration–tau;

FTLD-TDP=frontotemporal lobar degeneration–transactive response DNA-binding protein 43; MRI=magnetic resonance
imaging; PET=positron emission tomography; SPECT=single-proton emission computed tomography.
Clinical Features
FTD comprises three distinct clinical syndromes: behavioral-variant frontotemporal dementia (bvFTD)
and two language variants, semantic-variant primary progressive aphasia (svPPA) and
nonfluent/agrammatic-variant primary progressive aphasia (nfvPPA). In 2011, revised consensus criteria
incorporating clinical symptoms, neuropsychological testing, and neuroimaging were published to guide
the diagnosis of bvFTD (Rascovsky et al. 2011).
Behavioral-Variant Frontotemporal Dementia

bvFTD is the most common type of FTD, responsible for slightly more than half of cases and more
commonly found in men (Rabinovici et al. 2010). Early onset at ages <65, impaired executive
performance on neuropsychological testing, and focal frontal or temporal lobe cerebral atrophy on
neuroimaging are key elements in distinguishing bvFTD from other neurodegenerative conditions. The
six major clinical features associated with bvFTD are early behavioral disinhibition; early apathy or
inertia; early loss of sympathy or empathy; early perseverative, stereotyped, or compulsive/ritualistic
behavior; hyperorality or dietary changes; and neuropsychological deficits that are predominantly
executive in nature, sparing episodic memory and visuospatial function. Almost universally, there is a
lack of insight on the part of the patient into the behavioral and cognitive changes that are observed by
others.
Behavioral disinhibition is the most widely recognized clinical characteristic of bvFTD and may be
manifested by overspending, sexually inappropriate remarks, and socially embarrassing behavior
(Rabinovici et al. 2010). Apathy, which may appear simultaneously with disinhibition early in the disease
or over time, is associated with decreased motivation, social isolation, and reduced emotional range.
Loss of empathy and sympathy is equally disturbing to caregivers, who complain about a lack of
response to grief or sadness experienced by loved ones. An increased predilection for sweets occurs
frequently, but it is nonspecific and is frequently observed in other neurodegenerative disorders such as
AD. In bvFTD, there is a pathological shift in feeding behaviors with the development of impaired satiety
and hyperphagia. These symptoms develop as a result of atrophy involving feeding centers within the
right ventral insula, striatum, and orbitofrontal cortex (Woolley et al. 2007). bvFTD leads to progressive
dysfunction of the frontal networks that regulate repetitive behaviors, producing compulsive motor
symptoms such as throat clearing, rubbing, picking, pacing, or wandering (Rabinovici et al. 2010).
Compulsive collecting, hoarding, shoplifting, and rummaging are also common.
Cognitive symptoms reflect prominent executive dysfunction with relative sparing of memory and
visuospatial function (Rascovsky et al. 2007). Specific cognitive deficits are found on frontal-based tasks
such as attention, working memory, set shifting, mental flexibility, response inhibition, and abstract
reasoning (Rabinovici et al. 2010). Poor attention often manifests as distractibility and impulsiveness.
While sparing of memory function is typical, 10%–15% of patients may present with episodic memory
deficits (Graham et al. 2005). Together, this spectrum of cognitive deficits renders a typical patient
unable to solve problems or to engage in complex tasks.
Primary Progressive Aphasia

M.-Marsel Mesulam offered the initial description of primary progressive aphasia (PPA) in 1982, a
condition characterized by progressive language decline over 2 years with relative preservation of
memory and visuospatial function (Mesulam 1982). Recent clinical observations have demonstrated that
PPA is a disorder with heterogeneous pathologies inclusive of both FTLD- and AD-specific findings
(Gorno-Tempini et al. 2004). PPA cases due to FTLD pathology include two distinct clinical phenotypes:
nfvPPA and svPPA. Of note, Gorno-Tempini and colleagues (2011) have published proposed criteria for
nfvPPA and svPPA as well as for logopenic aphasia caused by AD.
nfvPPA is a progressive, primary language disorder resulting from motor speech dysfunction and
characterized by effortful, nonfluent speech. Patients initially exhibit shortened phrase length, dysarthria,
phonemic paraphasias, and speech apraxia, with subsequent progression to mutism over time. In
addition to effortful speech, the other key clinical feature is agrammatism, with omissions of articles and
other syntactic words, leading to speech sometimes described as telegraphic (Gorno-Tempini et al.
2011). Comprehension is relatively spared compared with speech production, yet patients may struggle
to decode syntactically complex sentences (Gorno-Tempini et al. 2011). This condition localizes within
the left hemisphere prefrontal-perisylvian region of the cerebral cortex (Gorno-Tempini et al. 2004).
There is a female predominance for nfvPPA (Johnson et al. 2005). In contrast to bvFTD, social decorum
remains intact throughout the course of the disease. Neuropsychological testing reveals primary
expressive language impairment but may also show minor working memory and executive deficits
(Gorno-Tempini et al. 2004). At autopsy, nfvPPA is frequently associated with FTLD-tau pathology.
svPPA is distinct from nfvPPA, sparing speech fluency and instead resulting in impairments in
naming, object knowledge, and single-word comprehension. Patients with svPPA struggle with word
finding, particularly for nouns, leading to speech that is empty and impoverished, yet more fluent than
that seen in nfvPPA. Unlike a patient with AD, for whom a word may be at the tip of the tongue and
readily recognized from a list, a patient with svPPA loses not only the word itself but also the semantic
knowledge surrounding the noun in question. For example, the svPPA patient confronted with a picture
of a dog will neither generate the correct word nor succeed in choosing the word from a list; when told
that it is a dog, they may respond, “Dog...dog...what is a dog?” These deficits localize to the anterior
temporal lobes, which exhibit asymmetric atrophy that is worse in the left hemisphere in about three-
quarters of cases (Thompson et al. 2003). Particularly when the right temporal lobe is affected, svPPA
may involve behavioral symptoms, including strict routines, food fads, clock watching, and dieting
(Rabinovici et al. 2010). Prosopagnosia may be detected on evaluation. At autopsy, svPPA is frequently
associated with FTLD-TDP pathology (Davies et al. 2005).
Motor Symptoms
In addition to cognitive and behavioral impairment, FTD may result in progressive deterioration in
motor function. Approximately 10%–15% of patients with bvFTD will develop motor neuron disease
(amyotrophic lateral sclerosis) and experience dysphagia, dysarthria, limb weakness, or loss of dexterity
(Lomen-Hoerth et al. 2002). Respiratory weakness and impaired swallowing are frequently life-limiting
manifestations. In addition, 20% of patients with FTD will develop parkinsonian symptoms, including
tremor, rigidity, slowness, or imbalance. Followed longitudinally, nfvPPA may evolve into either a
progressive supranuclear palsy or corticobasal syndrome manifestation. Progressive supranuclear palsy
is characterized by the presence of axial rigidity, pseudobulbar affect, and supranuclear gaze palsy,
whereas corticobasal syndrome includes features of apraxia, myoclonus, limb dystonia, and alien limb
phenomenon.
Nomenclature
The nosology of the FTD clinical syndromes has evolved rapidly, reflecting in part a rapidly growing
understanding of these diseases and their interrelationships. Terms such as Pick’s disease, semantic
dementia, and progressive nonfluent aphasia are still actively used in the literature. In addition, the DSM
criteria were recently updated, in DSM-5 (American Psychiatric Association 2013), to include FTD as a
disorder, but the entity is referred to as frontotemporal neurocognitive disorder, designated as major or
mild, which comprises behavioral and language variants. (svPPA and nfvPPA are not differentiated
according to DSM-5.)
Therapeutic Approaches
In FTD, there are two general approaches to treatment: interventions that treat symptoms and those
that slow disease progression. While a symptomatic therapy may alleviate some disease manifestations,
it will have no impact on disease progression or mortality. When a symptomatic therapy is discontinued,
it is expected that the patient’s subsequent clinical course will reflect the natural history of the illness,
thus demonstrating the absence of any lasting treatment effect. By contrast, disease-modifying therapy
is an important and separate treatment goal, often targeting the very molecules that drive disease
pathogenesis. Such a therapy alters the fundamental course of the disease, offering lasting benefits for
the future. The ideal treatment approach to FTD would be two-pronged, combining both symptomatic
and disease-modifying drugs to address the mixture of cognitive and behavioral deficits as well as the
responsible molecular process.
Unfortunately, current treatment is limited to symptomatic therapy, as no disease-modifying agent for
FTD has yet emerged. Major challenges to identifying disease-modifying FTD treatments include not
only the complex and incompletely understood molecular underpinnings of the various FTD subtypes
(e.g., bvFTD, nfvPPA, svPPA) but also the difficulty in identifying the particular histopathological process
affecting a given patient. Essentially, the molecular steps leading to accumulation of tau, TDP-43, or
FUS are distinct and demand individual pharmacological approaches. For instance, a treatment directed
against FTLD-tau may be effective for the nfvPPA patient with a tau-driven disease process but will be a
fruitless strategy for svPPA patients with FTLD-TDP pathology. On the other hand, disease-modifying
drugs impacting a shared, common final pathway, such as cell death, may be effective for multiple
neurodegenerative diseases. Importantly, tau is implicated in both AD and some forms of FTD, and new
AD drugs targeting tau may be useful in diseases characterized by FTLD-tau pathology. In the coming
years, clinical trials of such tau-directed agents as well as of drugs targeting TDP-43 or other pathways
are expected to emerge (see section “Future Directions” below).
Nonpharmacological and pharmacological treatments may ameliorate FTD-associated symptoms.
Importantly, symptomatic treatment decisions should be based on which symptoms the clinician wishes
to treat, and the approach does not depend on whether the patient has bvFTD, nfvPPA, or svPPA.
Nonpharmacological Treatment
Limitations in pharmacological therapy for FTD underscore the importance of optimizing patient and
caregiver quality of life through nonpharmacological interventions. These treatments have a supportive
quality and are similar to those commonly recommended for other neurodegenerative conditions such
as AD.
Counseling and Education

FTD is a devastating disease that dramatically impacts lifestyle not only for the diagnosed individual
but also for the caregiver and family. Any new diagnosis should be accompanied by a formal family
meeting in which questions related to diagnosis, prognosis, and treatment can be addressed by the
health care professional. In certain cases, a referral to community resources such as the Alzheimer’s
Association may be helpful to reinforce the diagnosis and provide access to supportive resources. There
is evidence that the caregiver burden associated with FTD is greater than that associated with AD
(Wong et al. 2012), and providing access to regional caregiver support groups is highly recommended.
Social disinhibition is one of the most striking and debilitating symptoms associated with bvFTD. Such
behaviors may complicate public outings. Strategies to avoid embarrassing experiences include visiting
places where the patient is well known or establishments that are not crowded (Merrilees et al. 2010).
Families may carry a small business-size card that explains the patient’s diagnosis to strangers.
Individuals with FTD may be prone to agitation. Caregivers are encouraged to avoid triggers and when
confronted with an outburst not to escalate the situation but to remain calm and to acknowledge the
patient’s emotions. An effort should be made to limit potentially activating stimuli at home, such as loud
music or television (Merrilees et al. 2010).
As noted earlier, the epidemiology of FTD demonstrates several patterns of heritability. Given the
heritable nature of FTD, genetic counseling addressing the utility as well as consequences of genetic
testing should be offered to patients and their families.
Stimulation and Activity

Longitudinal cohort studies in healthy aging populations have shown that routine cognitive and
physical activity reduces the future risk of dementia. The majority of this research has been performed
with respect to development of AD and vascular dementia, but the same principles may be generalized
to other neurodegenerative diseases, including FTD.
Patients should be encouraged to remain physically active. Research suggests that moderate
physical activity positively impacts mood, sleep, functional ability, and cognition (Lautenschlager et al.
2008). The majority of beneficial activities studied in the literature are aerobic in nature (brisk walking,
hiking, aerobics, strength training, swimming, tennis doubles, yoga, martial arts, weight lifting, golfing
without a golf cart, and moderate use of exercise machines [e.g., exercise bike, treadmill, elliptical]).
Exercise at least three times a week in middle and late life has been shown to result in decreased risk
for dementia in longitudinal cohort studies (Laurin et al. 2001). Other research suggests that similar
levels of exercise may reduce the rate of decline among patients already diagnosed with dementia.
Participation in mentally engaging activities in late life is thought to maximize cognitive reserve by
enhancing neurogenesis and synaptogenesis. Observational studies have suggested that cognitively
intense leisure activities in the elderly, such as reading, writing, doing crossword puzzles, playing
board/card games, playing musical instruments, participating in group discussions, and dancing, are
associated with a decreased risk of dementia (Verghese et al. 2003). Furthermore, these activities
appear to reduce decline in global cognition, perceptual speed, and working memory (Wilson et al.
2002) and may help patients who already exhibit cognitive decline.
Patients with PPA, especially nfvPPA, may benefit from a course of speech therapy to optimize
expressive language. Therapists may be able to equip patients with a speech assist device. Recently
developed, affordable electronic devices with preprogrammed phrases and voice simulation have been
helpful in providing alternative means of communication for patients with nfvPPA.
FTD often produces motor impairments, typically weakness or parkinsonism. When motor
impairments are present and functionally limiting, physical, occupational, and/or speech therapy may be
helpful.
Safety
Establishing safety in the homes of persons with FTD and their families is critically important. A home
safety evaluation is recommended for patients with FTD to avoid potential accidents relating to
appliances and wandering behavior (Rabinovici et al. 2010). In addition, executive dysfunction has
specific implications in terms of medication compliance and chronic disease management. Medication
management support either through an individual’s caregiver or from a community-based support
organization (e.g., public health nurse, home care) should be established.
As a result of FTD-associated executive dysfunction, the provider should address transfer of
responsibility for cognitively demanding activities such as driving and finances. Consultation with
financial advisors and legal counsel, and discussion of conservatorship, may be appropriate. Individuals
should be encouraged to execute a durable power of attorney as appropriate. Another common safety
concern in FTD is reckless driving that places the patient, family members, and others at risk. All
patients should have their driving ability evaluated in an objective manner through a formal driving
evaluation. In more severe cases, car keys may be kept safely away from the patient (Merrilees et al.
2010).
Advance Care Planning

End-of-life treatment options and decisions need to take into account effective pain management and
the goals of the individual with dementia via advance directive. Decisions about resuscitation and
intubation in case of emergency should ideally be made during the earliest stages of the condition.
Clinical providers should refer individuals with FTD to advance care–planning resources to assure that
patients have tools and can execute documents that will guide their care when they are no longer
capable of doing so.
Pharmacological Treatments
There is no treatment approved by the U.S. Food and Drug Administration to treat symptoms or
modify disease progression in FTD. Rather, clinicians make use of the existing arsenal of psychoactive
drugs to treat a patient’s particular symptoms and improve quality of life to the extent possible,
prescribing drugs off-label in an attempt to provide relief to patients. Such drugs and the evidence to
support their use are considered here by drug class. Unfortunately, the level of evidence supporting the
use of most of the medications discussed below is modest, and most of what is discussed here is limited
to published case series and open-label studies. While most of the research outlined here has involved
patients with bvFTD (except as indicated), recommendations can reasonably be expected to extend to
patients with other FTD variants who exhibit the types of symptoms that these drugs are meant to target.
Serotonergic Medications
There are profound serotonergic abnormalities in FTD (Huey et al. 2006). Consequently, selective
serotonin reuptake inhibitors (SSRIs), which have a favorable side-effect profile with low risk of harm,
are widely used to treat a variety of behavioral symptoms in patients with FTD (Pasquier et al. 2003). In
an open-label study of 11 FTD patients treated with fluoxetine, sertraline, or paroxetine, most patients
experienced a reduction in disinhibition, depressive symptoms, carbohydrate craving, or compulsions,
and no subject worsened on these measures (Swartz et al. 1997).
Citalopram was studied in a 6-week open-label, uncontrolled study of 15 patients with FTD and
severe behavioral symptoms (Herrmann et al. 2012). Treatment was associated with a significant
reduction in disinhibition, irritability, depression, and other behavioral disturbances. Hermann et al.
attempted to document the degree of endogenous serotonin deficiency in subjects using a citalopram
challenge test; they found that greater citalopram efficacy correlated with greater endogenous
neurotransmitter deficiency. Citalopram can cause QT prolongation and risk for cardiac arrhythmia, and
dosing above 20 mg/day in elderly patients is discouraged.
Paroxetine may reduce repetitive, ritualistic behavior (Chow and Mendez 2002). In a randomized,
open-label study of 16 FTD patients comparing paroxetine with piracetam, improvements in behavioral
symptoms occurred in the paroxetine group (Moretti et al. 2003a). However, no effect of paroxetine
emerged from a randomized, double-blind, placebo-controlled trial of 10 FTD patients treated with
paroxetine at a higher dose (40 mg/day vs. 20 mg/day) (Deakin et al. 2004).
Sertraline has received less attention than paroxetine, but one open-label, uncontrolled study of the
drug suggests that it may be effective at reducing the compulsive, stereotypical motor behaviors that
can occur in bvFTD (Mendez et al. 2005). Other drugs that have shown possible benefits include
fluvoxamine (Ikeda et al. 2004) and trazodone (Lebert and Pasquier 1999).
Given the scant evidence currently available, there is no specific treatment recommendation
regarding the use of SSRIs to treat behavioral and psychological symptoms in FTD. These agents
appear safe, and the limited evidence reviewed above suggests possible efficacy.
Antipsychotic and Dopaminergic Medications

Antipsychotic medications have also been used to treat the behavioral symptoms of FTD, especially
agitation and disinhibition, although there is a general lack of supporting literature. Case reports with
risperidone (Curtis and Resch 2000) and aripiprazole (Fellgiebel et al. 2007; Reeves and Perry 2013),
as well as an open-label uncontrolled study of olanzapine (Moretti et al. 2003b), provide some very
limited support for their use. Importantly, patients with FTD may be exceptionally sensitive to the motor
side effects of antipsychotic medications, exhibiting high rates of extrapyramidal symptoms. In addition,
antipsychotic medications are associated with a risk of death in elderly patients. For these reasons, until
better evidence is available to reject the concern that risks outweigh benefits, antipsychotic drugs should
not be recommended for routine use in patients with FTD. Paradoxically, there is evidence that
dopamine agonists such as selegiline, a monoamine oxidase–B inhibitor that slows the metabolism of
dopamine, may reduce neuropsychiatric symptoms in FTD (Moretti et al. 2002).
Stimulant Medications
In part because of the pervasive apathy that occurs among many patients with FTD, some clinicians
have considered the use of psychostimulants. A single dose of methylphenidate appeared to reduce
risky decision making on a laboratory-based gambling task in a small, double-blind, placebo-controlled
experiment involving eight patients (Rahman et al. 2006). In another double-blind crossover trial of eight
patients with bvFTD alternately given quetiapine and dextroamphetamine, there was a significant
reduction in apathy and disinhibition associated with dextroamphetamine (Huey et al. 2008). Given this
limited research, and the possibility of adverse reactions to stimulant medications, no recommendation
can be made at this point regarding their use in the treatment of FTD.
Cholinesterase Inhibitors
Cholinesterase inhibitors, including donepezil, rivastigmine, and galantamine, are first-line
symptomatic therapies for AD. Their use in AD is scientifically rational, reflecting a profound cholinergic
deficit arising from the early demise of neurons in the nucleus basalis of Meynert. In FTD, there is a
relative preservation of cholinergic neurons in the brain and no a priori reason to expect a benefit from
cholinesterase inhibition (Huey et al. 2006).
Data regarding the efficacy of cholinesterase inhibitors in FTD are mixed and difficult to interpret
because of a lack of placebo-controlled studies. In one small open-label study (Lampl et al. 2004), nine
patients with bvFTD were given either donepezil or rivastigmine, and modest cognitive benefits were
observed, possibly more so among the four men in the study. In another 12-month open-label study, 20
bvFTD patients were given either rivastigmine or no cholinesterase inhibitor (Moretti et al. 2004), and
treatment-associated improvements in behavior, caregiver burden, and executive cognitive function
emerged for patients taking rivastigmine.
A study of galantamine in 40 patients with bvFTD or PPA revealed no evidence of benefit (Kertesz et
al. 2008). These patients were given escalating doses of galantamine during an 18-week open-label
phase and then randomly assigned to receive drug or placebo during an 8-week double-blind phase.
Galantamine produced no improvement in behavioral or language symptoms. A global severity score
trended better in the treatment group among the subset of patients with PPA. This is the largest and only
double-blind study of a cholinesterase inhibitor in FTD, and the results were negative.
Donepezil may worsen behavior in bvFTD. In a 12-patient open-label study of donepezil (Mendez et
al. 2007), the treated bvFTD group at 6 months exhibited no change in Mini-Mental State Examination
scores or in a measure of overall functioning relative to 12 matched, untreated bvFTD patients.
However, caregivers of the treated patients did endorse a higher level of disinhibition and
compulsiveness that reversed upon discontinuation of donepezil. In another study, discontinuation of
previously prescribed donepezil among patients with FTD led to improved neuropsychiatric symptoms
and reduced caregiver burden (Kimura and Takamatsu 2013).
Taken together with the lack of compelling evidence for a benefit of galantamine or rivastigmine,
these observations with donepezil have prompted a general recommendation to avoid cholinesterase
inhibitors in FTD. A further potential harm of cholinesterase inhibition is the risk of increasing oral
secretions and contributing to aspiration in the subset of FTD patients with associated motor neuron
disease. Finally, it is worth noting that in clinical cases in which AD and FTD are equal differential
considerations, a cholinesterase inhibitor cannot be used as a “litmus test” to aid in the diagnostic
construct because any beneficial response in a patient with AD is modest and evident only over time.
Memantine
Memantine in moderate to severe AD results in modest symptomatic improvements in cognition,
function, and behavior. Whereas this drug was designed as a low-affinity, use-dependent N-methyl-D-
aspartate (NMDA) glutamate receptor antagonist, its overall mechanism of action is not straightforward
(Parsons et al. 2007). Two randomized, placebo-controlled trials of memantine in FTD showed no
benefit on cognitive or neuropsychiatric endpoints (Boxer et al. 2013b; Vercelletto et al. 2011) and a
trend toward worsening cognition in one study (Boxer et al. 2013b). Therefore, memantine is not
recommended for the treatment of FTD.
Future Directions
Treatment options for FTD will become increasingly sophisticated as clinical trials identify candidate
disease-modifying therapies. Such therapies will likely be protein-specific, growing directly out of basic
science studies of FTLD-tau, FTLD-TDP, and FTLD-FUS.
One exciting current example is the introduction of drugs aimed at preventing tau aggregation. Such
therapy could potentially offer disease-modifying benefits both in AD and in a subset of FTD syndromes,
including some cases of bvFTD and most cases of nfvPPA. Davunetide was initially promising for this
indication but failed to help patients with progressive supranuclear palsy, an FTD-related tauopathy
(Boxer et al. 2014). Methylene blue is another agent that has been investigated for its potential to
reduce tau aggregation and slow AD progression, but a clinical trial of a second-generation version of
this compound was negative. Other potential therapeutic interventions include inhibition of enzymes that
contribute to tau phosphorylation (glycogen synthase kinase–3β [GSK3β] or cyclin-dependent kinase–
5), manipulation of tau-processing pathways (e.g., ubiquitination), reduction of tau expression, and other
approaches. There has been limited investigation into lithium and valproic acid, inhibitors of GSK3β, for
treatment of tauopathies.
FTLD-TDP neuropathology results in some cases from low levels of another protein, progranulin.
Loss-of-function mutations in progranulin result in a haploinsufficiency of the protein and cause familial,
autosomal dominant FTD with FTLD-TDP pathology (Baker et al. 2006; Cruts et al. 2006). Although the
exact function of progranulin is unknown, normalizing protein levels could be a potential therapeutic
strategy. A pilot study of amiodarone for this indication was negative (Alberici et al. 2014), and trials of
novel histone deacetylase inhibitors are under way.
As protein-specific therapies emerge, accurate in vivo diagnosis will be essential. Specifically, tools
that can differentiate FTLD-tau from FTLD-TDP are needed because most future disease-modifying
agents are likely to be targeted toward one pathway or the other. Neuroimaging will play a critical role in
this effort. Two large longitudinal studies patterned after and complementary to the Alzheimer’s Disease
Neuroimaging Initiative began recruiting patients with FTD to undergo sophisticated neuroimaging, with
a goal of characterizing the brain functionally and structurally over time and developing spinal fluid
biomarkers that may correspond to the underlying molecular pathogenesis (Boxer et al. 2013a). The
hope is that this study will yield not only new information on brain-behavior correlates but also strategies
for identifying the underlying proteinopathy in a specific patient and for monitoring the response to
emerging treatments.
Conclusion
Patients with FTD should be treated supportively and conservatively. Because of the absence of
disease-modifying pharmacological therapy or compelling evidence supporting drug efficacy for
reducing neuropsychiatric symptoms, nonpharmacological approaches should take priority. In a patient
with a neurodegenerative disease, the capacity to regain lost functions or to learn new behaviors is
fundamentally compromised. For this reason, the emphasis must be on tolerance of odd behaviors,
compensatory strategies for deficits, and modification of the environment to cope with new caregiving
realities.
In situations where neuropsychiatric symptoms interfere with safe caregiving or quality of life despite
optimal nonpharmacological interventions, a medication may be considered. Mood dysregulation,
obsessions, or compulsive behaviors may respond to SSRIs. There is no role for prescribing
cholinesterase inhibitors or memantine in FTD. There should be a conscious effort to avoid sedative
medications like antipsychotics, benzodiazepines, and anticholinergic medications, among others, given
the risk of worsening cognition and precipitating delirium. However, atypical antipsychotics may be
considered as a temporary measure when agitation interferes with safety.
References
Alberici A, Archetti S, Pilotto A, et al: Results from a pilot study on amiodarone administration in monogenic frontotemporal
dementia with granulin mutation. Neurol Sci 35(8):1215–1219, 2014 24569924
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition. Arlington, VA. American
Psychiatric Association, 2013
Baker M, Mackenzie IR, Pickering-Brown SM, et al: Mutations in progranulin cause tau-negative frontotemporal dementia
linked to chromosome 17. Nature 442(7105):916–919, 2006 16862116
Boxer A, Gold M, Huey E, et al: The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal
degeneration: the next therapeutic frontier). Alzheimers Dement 9(2):189–198, 2013a
Boxer AL, Knopman DS, Kaufer DI, et al: Memantine in patients with frontotemporal lobar degeneration: a multicentre,
randomised, double-blind, placebo-controlled trial. Lancet Neurol 12(2):149–156, 2013b 23290598
Boxer AL, Lang AE, Grossman M, et al; AL-108–231 Investigators: Davunetide in patients with progressive supranuclear
palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol 13(7):676–685, 2014 24873720
Chow TW, Mendez MF: Goals in symptomatic pharmacologic management of frontotemporal lobar degeneration. Am J
Alzheimers Dis Other Demen 17(5):267–272, 2002 12392261
Cruts M, Gijselinck I, van der Zee J, et al: Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia
linked to chromosome 17q21. Nature 442(7105):920–924, 2006 16862115
Curtis RC, Resch DS: Case of pick’s central lobar atrophy with apparent stabilization of cognitive decline after treatment with
risperidone. J Clin Psychopharmacol 20(3):384–385, 2000 10831030
Davies RR, Hodges JR, Kril JJ, et al: The pathological basis of semantic dementia. Brain 128(Pt 9):1984–1995, 2005
16000337
Deakin JB, Rahman S, Nestor PJ, et al: Paroxetine does not improve symptoms and impairs cognition in frontotemporal
dementia: a double-blind randomized controlled trial. Psychopharmacology (Berl) 172(4):400–408, 2004 14666399
Fellgiebel A, Müller MJ, Hiemke C, et al: Clinical improvement in a case of frontotemporal dementia under aripiprazole
treatment corresponds to partial recovery of disturbed frontal glucose metabolism. World J Biol Psychiatry 8(2):123–126,
2007 17455105
Gorno-Tempini ML, Dronkers NF, Rankin KP, et al: Cognition and anatomy in three variants of primary progressive aphasia.
Ann Neurol 55(3):335–346, 2004 14991811
Gorno-Tempini ML, Hillis AE, Weintraub S, et al: Classification of primary progressive aphasia and its variants. Neurology
76(11):1006–1014, 2011 21325651
Graham A, Davies R, Xuereb J, et al: Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain
128(Pt 3):597–605, 2005 15634737
Herrmann N, Black SE, Chow T, et al: Serotonergic function and treatment of behavioral and psychological symptoms of
frontotemporal dementia. Am J Geriatr Psychiatry 20(9):789–797, 2012 21878805
Huey ED, Putnam KT, Grafman J: A systematic review of neurotransmitter deficits and treatments in frontotemporal
dementia. Neurology 66(1):17–22, 2006 16401839
Huey ED, Garcia C, Wassermann EM, et al: Stimulant treatment of frontotemporal dementia in 8 patients. J Clin Psychiatry
69(12):1981–1982, 2008 19203481
Ikeda M, Shigenobu K, Fukuhara R, et al: Efficacy of fluvoxamine as a treatment for behavioral symptoms in frontotemporal
lobar degeneration patients. Dement Geriatr Cogn Disord 17(3):117–121, 2004 14739531
Johnson JK, Diehl J, Mendez MF, et al: Frontotemporal lobar degeneration: demographic characteristics of 353 patients.
Arch Neurol 62(6):925–930, 2005 15956163
Karageorgiou E, Miller BL: Frontotemporal lobar degeneration: a clinical approach. Semin Neurol 34(2):189–201, 2014
24963678
Kertesz A, Morlog D, Light M, et al: Galantamine in frontotemporal dementia and primary progressive aphasia. Dement
Geriatr Cogn Disord 25(2):178–185, 2008 18196898
Kimura T, Takamatsu J: Pilot study of pharmacological treatment for frontotemporal dementia: risk of donepezil treatment for
behavioral and psychological symptoms. Geriatr Gerontol Int 13(2):506–507, 2013 23551349
Knopman DS, Roberts RO: Estimating the number of persons with frontotemporal lobar degeneration in the US population. J
Mol Neurosci 45(3):330–335, 2011 21584654
Lampl Y, Sadeh M, Lorberboym M: Efficacy of acetylcholinesterase inhibitors in frontotemporal dementia. Ann Pharmacother
38(11):1967–1968, 2004 15479775
Laurin D, Verreault R, Lindsay J, et al: Physical activity and risk of cognitive impairment and dementia in elderly persons.
Arch Neurol 58(3):498–504, 2001 11255456
Lautenschlager NT, Cox KL, Flicker L, et al: Effect of physical activity on cognitive function in older adults at risk for
Alzheimer disease: a randomized trial. JAMA 300(9):1027–1037, 2008 18768414
Lebert F, Pasquier F: Trazodone in the treatment of behaviour in frontotemporal dementia. Human Psychopharmacology:
Clinical and Experimental 14(4):279–281, 1999
Lomen-Hoerth C, Anderson T, Miller B: The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology
59(7):1077–1079, 2002 12370467
Mendez MF, Shapira JS, Miller BL: Stereotypical movements and frontotemporal dementia. Mov Disord 20(6):742–745, 2005
15786492
Mendez MF, Shapira JS, McMurtray A, et al: Preliminary findings: behavioral worsening on donepezil in patients with
frontotemporal dementia. Am J Geriatr Psychiatry 15(1):84–87, 2007 17194818
Merrilees J, Klapper J, Murphy J, et al: Cognitive and behavioral challenges in caring for patients with frontotemporal
dementia and amyotrophic lateral sclerosis. Amyotroph Lateral Scler 11(3):298–302, 2010 20222805
Mesulam MM: Slowly progressive aphasia without generalized dementia. Ann Neurol 11(6):592–598, 1982 7114808
Moretti R, Torre P, Antonello RM, et al: Effects of selegiline on fronto-temporal dementia: a neuropsychological evaluation. Int
J Geriatr Psychiatry 17(4):391–392, 2002 11994896
Moretti R, Torre P, Antonello RM, et al: Frontotemporal dementia: paroxetine as a possible treatment of behavior symptoms:
a randomized, controlled, open 14-month study. Eur Neurol 49(1):13–19, 2003a 12464713
Moretti R, Torre P, Antonello RM, et al: Olanzapine as a treatment of neuropsychiatric disorders of Alzheimer’s disease and
other dementias: a 24-month follow-up of 68 patients. Am J Alzheimers Dis Other Demen 18(4):205–214, 2003b
12955785
Moretti R, Torre P, Antonello RM, et al: Rivastigmine in frontotemporal dementia: an open-label study. Drugs Aging
21(14):931–937, 2004 15554751
Parsons CG, Stöffler A, Danysz W: Memantine: a NMDA receptor antagonist that improves memory by restoration of
homeostasis in the glutamatergic system—too little activation is bad, too much is even worse. Neuropharmacology
53(6):699–723, 2007 17904591
Pasquier F, Fukui T, Sarazin M, et al: Laboratory investigations and treatment in frontotemporal dementia. Ann Neurol 54
(suppl 5):S32–S35, 2003 12833367
Rabinovici GD, Miller BL, Sarazin M, et al: Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and
management. CNS Drugs 24(5):375–398, 2010 20369906
Rahman S, Robbins TW, Hodges JR, et al: Methylphenidate (‘Ritalin’) can ameliorate abnormal risk-taking behavior in the
frontal variant of frontotemporal dementia. Neuropsychopharmacology 31(3):651–658, 2006 16160709
Rascovsky K, Salmon DP, Hansen LA, et al: Disparate letter and semantic category fluency deficits in autopsy-confirmed
frontotemporal dementia and Alzheimer’s disease. Neuropsychology 21(1):20–30, 2007 17201527
Rascovsky K, Hodges JR, Knopman D, et al: Sensitivity of revised diagnostic criteria for the behavioural variant of
frontotemporal dementia. Brain 134(Pt 9):2456–2477, 2011 21810890
Reeves RR, Perry CL: Aripiprazole for sexually inappropriate vocalizations in frontotemporal dementia. J Clin
Psychopharmacol 33(1):145–146, 2013 23288244
Snowden JS, Neary D, Mann DM: Frontotemporal dementia. Br J Psychiatry 180:140–143, 2002 11823324
Swartz JR, Miller BL, Lesser IM, et al: Frontotemporal dementia: treatment response to serotonin selective reuptake
inhibitors. J Clin Psychiatry 58(5):212–216, 1997 9184615
Thompson SA, Patterson K, Hodges JR: Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive
implications. Neurology 61(9):1196–1203, 2003 14610120
Vercelletto M, Boutoleau-Bretonnière C, Volteau C, et al; French research network on Frontotemporal dementia: Memantine
in behavioral variant frontotemporal dementia: negative results. J Alzheimers Dis 23(4):749–759, 2011 21157021
Verghese J, Lipton RB, Katz MJ, et al: Leisure activities and the risk of dementia in the elderly. N Engl J Med 348(25):2508–
2516, 2003 12815136
Wilson RS, Bennett DA, Bienias JL, et al: Cognitive activity and incident AD in a population-based sample of older persons.
Neurology 59(12):1910–1914, 2002 12499482
Wong C, Merrilees J, Ketelle R, et al: The experience of caregiving: differences between behavioral variant of frontotemporal
dementia and Alzheimer disease. Am J Geriatr Psychiatry 20(8):724–728, 2012 21941168
Woolley JD, Gorno-Tempini ML, Seeley WW, et al: Binge eating is associated with right orbitofrontal-insular-striatal atrophy in
frontotemporal dementia. Neurology 69(14):1424–1433, 2007 1790915
CHAPTER 24
Psychosis
Clinicians have defined the term psychosis in different ways

over the last two centuries. This term has been used variously as a
synonym for “gross impairment in reality testing” or “loss of ego
boundaries” sufficient to interfere with the capacity to meet the
demands of daily life; to denote the presence of delusions and/or
hallucinations; to indicate a category of psychiatric illnesses (“the
psychoses”); to describe the severity of delusional and “thought
disorder” symptomatology; and, more recently, to refer to a spectrum
of cognitive, emotional, behavioral, and motoric symptoms and
signs, each of which varies in character and severity in any given
patient (Arciniegas 2015).
Briefly reviewing the history of the term psychosis, Arciniegas
(2015) notes that by the mid-1990s, clinicians most commonly used
the term to define a population of patients with severe social and
personal impairment, characterized by social withdrawal and an
inability to perform typical daily activities at home or in the
workplace. He also notes that the American Psychiatric Association
(APA; American Psychiatric Association 2013) and the World Health
Organization (WHO; World Health Organization 1992) currently
apply narrow definitions of psychosis to the diagnoses they
recognize. Their definitions of psychosis require the presence of
delusions, insight-impaired hallucinations, or both. Impaired reality
testing remains central conceptually to psychosis in both of these
definitions, where delusions are fixed false beliefs that are
maintained despite evidence contrary to them and where
hallucinations (perceptions occurring in the absence of
corresponding external or somatic stimuli) are experienced without
insight into their pathological nature.
Although the APA and WHO acknowledge that “formal thought
disorder” (i.e., thought blocking, thought derailment, severely
disorganized thinking, or some combination of these disturbances)
occurs commonly among persons with psychotic disorders, they also
recognize that mildly disorganized speech is common and
diagnostically nonspecific. Accordingly, their definitions of psychosis
permit thought disorder to supplant the requirement for delusions
and insight-impaired hallucinations only when formal thought
disorder is accompanied by grossly disorganized behavior, catatonia
(for schizophrenia and schizophreniform and brief psychotic and
schizoaffective disorders), and/or negative symptoms (for
schizophrenia and schizophreniform and schizoaffective disorders
but not brief psychotic disorder), and when the severity of thought
disorder substantially impairs effective communication.
For the purposes of this chapter, then, psychosis will be used as
recommended by the APA and WHO and will refer narrowly to the
presence of delusions or hallucinations without insight. This use will
apply to psychosis arising as an idiopathic psychiatric disorder
(primary psychoses) as well as psychosis developing in the context
of a neurological condition (secondary psychoses).
Clinical tradition in psychiatry and neurology generally divides the
psychoses into two broad categories: primary and secondary.
Primary psychoses define the schizophrenia spectrum disorders
(e.g., delusional disorder, schizotypal disorder, schizophrenia,
schizoaffective disorder) and arise in mood disorders (e.g., major
depressive disorder, bipolar disorder) and other idiopathic psychiatric
disorders. Secondary psychoses, in contrast, are associated with
developmental, degenerative, and acquired neurological conditions
such as adrenoleukodystrophy, Alzheimer’s disease (AD), Lewy
body diseases, stroke, traumatic brain injury, epilepsy, multiple
sclerosis, and autoimmune encephalidities, among others. As the
science of psychosis evolves, it is increasingly clear that division of
psychoses into primary and secondary types is artificial, at best.
However, this division, nevertheless, remains useful for
characterizing clinical phenotypes and ensuring that the underlying
illness is optimally treated even when the psychosis itself must be a
target of intervention.
Although phenomenology does not always reliably differentiate
between primary and secondary psychoses, certain differences are
generally apparent. The primary psychoses usually (although not
invariably) begin in late adolescence or early adulthood and often
feature a family history of phenomenologically similar psychoses.
The secondary psychoses usually (although not invariably) begin in
late adulthood and are associated with a known or identifiable
neurological illness. Hallucinations are predominantly (although not
exclusively) auditory in the primary psychoses, and delusions are
often bizarre and complex. In the secondary psychoses,
hallucinations are more often visual, and delusions are often simpler
and more contextually or environmentally dependent (e.g., delusions
of theft in a patient with AD as memory impairment and executive
dysfunction develop). Treatment of the primary psychoses usually
requires antipsychotic medications, whereas treating the underlying
disease process may be sufficient to diminish or ameliorate
delusions and hallucinations in some (but not all) of the secondary
psychoses.
Schizophrenia
Schizophrenia is a common illness, affecting 0.5%–1.0% of the
general population worldwide, with typical onset in late adolescence
and early adulthood. The core features of schizophrenia include
delusions, hallucinations (without insight), disorganized speech (e.g.,
frequent derailment or incoherence), grossly disorganized or
catatonic behavior, and negative symptoms (i.e., diminished
emotional expression or avolition). For DSM-5 criteria for
schizophrenia to be met, two or more of these symptoms must be
present for a significant portion of time during a 1-month period (or
less if successfully treated) amid at least 6 months of continuous
signs of the disturbance, and at least one of the symptoms must be
delusions, hallucinations (without insight), or grossly disorganized
speech. Additionally, these symptoms must be severe enough to
markedly interfere with previously achieved function in one or more
major areas of daily functioning (e.g., work, interpersonal relations,
self-care), or, if onset occurs in childhood or adolescence, to
preclude attainment of expected levels of interpersonal, academic, or
occupational functioning (American Psychiatric Association 2013).
Schizophrenia has long been regarded as the archetypal primary
psychotic disorder; however, DSM-5 reframed schizophrenia as one
of several psychotic disorders existing on a spectrum of
psychopathology. Although the schizophrenia spectrum disorders
differ with respect to type, number, complexity, severity, and duration
of the psychotic symptoms and associated features that define them,
they all feature hallucinations, delusions, disorganized thinking (i.e.,
“formal thought disorder,” which is usually inferred from an
individual’s speech), grossly disorganized or abnormal motor
behavior (including catatonia), and negative symptoms. Conditions
on the mild end of the schizophrenia spectrum feature fewer, less
complex, and shorter-duration psychotic symptoms, whereas those
on the severe end entail a larger number of, more complex, severe,
and persistent psychotic symptoms.
Delusions and Hallucinations

Delusions are “fixed beliefs that are not amenable to change in
light of conflicting evidence” (American Psychiatric Association
2013). There are many types of delusions, some examples of which
can be found in Table 24–1. Delusions are considered bizarre if they
are clearly implausible and do not derive from ordinary life
experience, even after the patient’s sociocultural belief system is
taken into account. Examples of bizarre delusions include thought
insertion (i.e., the belief that an external force is placing thoughts in
one’s mind against one’s will), thought withdrawal (i.e., the belief that
one’s thoughts have been removed by an outside force), and bizarre
somatic delusions (e.g., the belief that key internal organs have been
removed from one’s body by an outside force). In schizophrenia,
delusions are often complex or systematized. For instance, a patient
with schizophrenia may report that his internal organs have been
secretly replaced by the military in order to spy on him.
TABLE 24–1. Common delusions
Type Description
Control Another person, group, or external
force is controlling one’s thoughts,
feelings, and/or behaviors.
Cotard One does not exist or has died.
Erotomanic Another person, usually of higher
social status or fame, is in love
with the patient (also known as
De Clérambault’s syndrome).
Grandiose One has exceptional abilities, wealth,
fame, or power.
Jealousy One’s spouse or lover is having an
affair (when he or she is not doing
so).
Nihilistic Things, including oneself, do not
exist or are unreal.
Paranoid (persecutory) One is being followed, harassed,
conspired against, spied on,
attacked, cheated, poisoned or
drugged, or otherwise obstructed
in the pursuit of one’s goals.
Phantom intruder (boarder) Others (usually unwelcome) are
living in one’s home.
Referential Otherwise mundane or innocuous
gestures, comments,
environmental cues, events, and
so forth are directed at oneself
and/or have special and personal
meaning.
Somatic One’s body is somehow diseased,
abnormal, or changed.
Theft Others are stealing or hiding one’s
things.
Thought broadcasting Others can hear or are aware of
one’s thoughts.
Type Description
Thought withdrawal Another person or entity is removing
thoughts directly from one’s mind.
Thought insertion Another person or entity is placing
thoughts directly into one’s mind.
Verbal auditory hallucinations are thought to occur in 50%–70% of

patients with schizophrenia. In 25%–30% of cases, these
hallucinations are refractory to medication treatment (Brunelin et al.
2012). Voices may appear to originate from animals, from inanimate
objects, or from no clear source. The patient may or may not
recognize the speaker. The patient often has no voluntary control
over the voices and may consider them threatening and upsetting.
Sometimes the voices may issue commands or instructions to the
patient that may be harmful to the patient or to others. The voices
often form one aspect of a complex delusional system.
Imaging studies have found that the presence of auditory
hallucinations in schizophrenia is associated with cerebral
hyperactivity in the left temporal and parietal regions (Silbersweig et
al. 1995). Investigators have hypothesized that decreasing cerebral
activation in the left temporal and parietal regions may suppress
auditory hallucinations. Brunelin et al. (2012) reported a mean
reduction in auditory hallucinations of 31% using the therapeutic
modality of transcranial direct current stimulation. In this study, the
scalp electrode was placed in such a way that the excitability of the
underlying cortex was reduced. In a meta-analysis of repetitive
transcranial magnetic stimulation (rTMS) over the left
temporoparietal cortex (between T3 and P3 in the 10–20
International System of Electrode Placement) for the treatment of
auditory verbal hallucinations (AVHs) in schizophrenia, Slotema and
colleagues (2014) reported a mean weighted effect size of 0.63
(moderate to large) for a 10-day course of 1-Hz rTMS treatment of
AVHs in patients with schizophrenia. In this meta-analysis, left
temporoparietal rTMS did not outperform sham with respect to other
symptoms of schizophrenia, and right rTMS was no better than sham
with respect to AVHs in schizophrenia. In addition to the clinical
implications of these findings, they support the thesis that AVHs in
schizophrenia (and, by extension, other psychoses) are associated
with abnormalities of left temporoparietal function.
Hallucinations, particularly visual hallucinations, are also a
common symptom of secondary psychotic disorders. Cummings and
Mega (2003) hypothesized that hallucinations in the secondary
psychoses could be correlated with a few basic mechanisms: 1)
perceptual release, or the release of spontaneous neurological
activity in the presence of decreased sensory input; 2) ictal
discharges; 3) dream intrusions; or 4) neurochemical effects. The
possible neurobiology of secondary psychosis is further explored
later in this chapter.
Behavior
Patients with schizophrenia are often characterized as being “odd”
or “eccentric” in appearance and behavior. This is frequently due not
to any major transgression on the part of the patient but to a more
general impression of disorderliness or “off” behavior. Such an
appearance may result from the patient’s lack of certain sets of
social skills derived from theory of mind, which encompasses an
array of cognitive processes responsible for discerning the mental
states of others. Byom and Mutlu (2013) parse theory of mind into
three related components: 1) knowledge of the shared social
context, 2) perception of social cues, and 3) interpretation of the
actions of others. An impaired theory of mind has profound
implications for behavior. In their examination of subjects enrolled in
the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-
SNIP) studies, Ruocco et al. (2014) explored the ability of subjects to
correctly identify facial expressions. The researchers found that
schizophrenia subjects exhibited marked impairment in their ability to
recognize facial expressions, especially those faces expressing fear,
happiness, and sadness. A schizophrenia patient’s inability to
accurately gauge another person’s cognitive or emotional state may
lead to interpersonal misunderstandings resulting in others viewing
the patient as odd or eccentric.
Abnormal movements have also been described in patients with
schizophrenia. These movements have included withdrawn catatonia
(i.e., patient awake but immobile and relatively mute), catalepsy (i.e.,
waxy flexibility), agitated catatonia (i.e., patient paces rapidly but
remains uncommunicative), and choreic/athetoid-like movements.
Peralta et al. (2010) found that 31 motor signs in drug-naive
schizophrenia spectrum disorder patients fell into specific categories
using factor analysis. Five of these categories—abnormal involuntary
movements, hypokinesia, retarded catatonia, excited catatonia, and
echo phenomenon—improved when medication therapy was
initiated. One category, parkinsonism, worsened. These findings
would seem to confirm that abnormal movements in schizophrenia
reflect a vulnerability in the neuronal circuits linking basal ganglia to
cortex and cerebellum.
Impaired Prefrontal Lobe Function

Abnormal thought processes in schizophrenia have also been
linked to frontal lobe dysfunction. A number of clinical features
observed in schizophrenia have long been associated with
dysfunction of the prefrontal lobe areas. Such clinical features have
included impaired problem solving, blunted affect, social withdrawal,
reduced motivation, distractibility, attentional deficits, and impaired
insight (Weinberger et al. 1991). These clinical observations have
been supported by functional imaging studies. Importantly, early
regional blood flow studies found that hypofrontality is generally seen
primarily when patients are engaged in certain cognitive tasks known
to activate prefrontal cortex, such as the Wisconsin Card Sorting
Task (WCST). Of further interest is the observation that drug-naive
schizophrenic subjects generally demonstrate less prefrontal
activation during the WCST than medicated subjects. This would
suggest that antipsychotic medications may improve symptoms in
part by improving frontal lobe activation (Berman et al. 1992).
More recent studies indicate that cognitive difficulties extend
beyond those generally associated with frontal dysfunction.
Fatouros-Bergman et al. (2014) performed a meta-analysis of
cognitive performance in a large number of medication-free subjects
using a standard test battery. In general, subjects scored worse in all
cognitive domains but were especially impaired in the areas of verbal
memory, speed of processing, and working memory. Mesholam-
Gately et al. (2009) observed that memory impairment was generally
more evident in subjects at risk for psychosis, while executive
deficits such as those associated with frontal dysfunction were more
apparent in subjects who had already transitioned to psychosis.
Imaging Studies in Schizophrenia

Early computed tomography scans of schizophrenia patients
indicated ventricular enlargement. More recent magnetic resonance
imaging (MRI) studies have not only confirmed this increase in
ventricular volume but also further suggested reduced volume of the
medial temporal structures, hippocampal formation, amygdala, and
parahippocampal gyrus (Kuperberg et al. 2003). Investigators from
the B-SNIP study (Padmanabhan et al. 2015) performed a cross-
sectional analysis of cortical density and volume across subject
groups with clinically diagnosed schizophrenia, bipolar disease, and
schizoaffective disorder, as well as control subjects. Positive
symptom scores correlated inversely with gray matter volume and
cortical thickness of frontal and temporal areas. Negative symptoms
correlated inversely with gray matter volume–cortical surface area.
There was no significant interaction between illness severity and
MRI structural factors.
Recent brain imaging studies have found that certain cerebral
areas remain active even though control subjects are simply resting
quietly. Investigators further noted that these cerebral centers then
“deactivated” when subjects were asked to attend to specific types of
motor or cognitive tasks. It has been argued that these centers form
a unique interconnected cerebral network, “the default network”
(Buckner et al. 2008). Although functions of this network have only
recently been explored, one of its most crucial functions may be to
support internal mentation, both related and unrelated to the
immediate external environment. Such internal mentation could
include conducting mental simulations based on autobiographical
memory. These reflections may form the bases for self-reflective
thought, judgment, and inferred emotional and social context.
Problems with the default network may underlie some of the most
important symptoms of schizophrenia. Ordinarily, the dorsolateral
prefrontal cortex (DLPF) is activated during certain cognitive tasks
and deactivated during rest. Because the opposite pattern is seen in
the default network, researchers believe there may be something of
a reciprocal “anticorrelation” between the default network and the
DLPF. Whitfield-Gabrieli et al. (2009) propose that because the
DLPF is necessary for working memory and other cognitive tasks,
cognitive deficits in schizophrenia could in part be due to
hyperactivity and hyperconnectivity of the default network. In other
words, patients experiencing hyperactivity of the default network may
be overly attentive to internal fantasy states, rendering them unable
to appropriately attend to external environmental stimuli. Among
other problems, such overactivity could result in the misattribution of
internal thoughts or emotional states to external situations.
Somewhat paradoxically, other studies have shown that this
increased functional connectivity is accompanied by decreased
structural connectivity in the same clinical samples (Fornito and
Bullmore 2015). These latter findings suggest a “decoupling” of
functional from structural connectivity in schizophrenia. Fornito and
Bullmore (2015) speculate that schizophrenia neuropathology
reflects a compromise of structural connectivity between network
connector hubs located in association cortices. Loss of structural
connectivity at a busy network hub might paradoxically result in an
increase in functional connectivity through the hub if the signal-to-
noise ratio is improved by the removal of less relevant information.
Taken together, these studies suggest that hyperactivity and
hyperconnectivity of the default network in schizophrenia not only
may be associated with overattentiveness to internal thought but
may result in impairment of frontal executive function as well.
Genetics
Twin studies have demonstrated an increased risk of illness in
first-degree relatives and identical twins. Cardno and Gottesman
(2000) found concordance rates of 41%–65% in monozygotic twins
and 0%–28% in dizygotic twins. Overall heritability was estimated at
80%–85%. In a Finnish study, Tienari et al. (2003) found that 5.3% of
children adopted away from mothers with schizophrenia were
eventually diagnosed with the disease, whereas only 1.74% of
children adopted away from control mothers were so affected.
However, when the definition was broadened to schizophrenia
spectrum disorder, the rates for adopted children were 22.46% for
affected mothers and 4.36% for non-affected mothers. Despite a
strong genetic contribution to disease risk, no single genetic marker
has been identified to explain this risk. In a recent meta-analysis,
Gatt et al. (2015) found that 97 genetic variants had been studied in
schizophrenia, with conflicting null studies for 27 of these variants.
Some of the variants that had been the subject of a number of
studies included variants of the genes for methylenetetrahydrofolate
reductase, brain-derived neurotrophic factor, and catechol O-
methyltransferase. Studies have suggested genetic “hot spots” that
may harbor multiple structural variants associated with
schizophrenia. Understanding the genetic variants associated with
schizophrenia may eventually help better explain the neurobiology of
the illness.
A recent genome-wide association scan in a large cohort of
patients with schizophrenia and control subjects identified 108
regions of interest. One of the strongest areas of association was in
the major histocompatability complex on chromosome 6. This area is
also associated with genetic coding for complement factor, part of
the innate immune system. Complement factor may also play a role
in cerebral development perhaps explaining some of the
developmental abnormalities seen in schizophrenic patients
(Dhindsa and Goldstein 2016).
Secondary Psychoses
Cases
The task of defining “psychosis” becomes still more challenging
when one is dealing with specific neurological diseases, such as
epilepsy or Parkinson’s disease (PD). The two cases presented
below explore the boundaries of the definition of “psychosis.”
Case Example 1
A middle-aged woman had a long history of complex partial
seizures originating in the temporal lobe. She had several
hospitalizations for status epilepticus with ictal and postictal paranoid
psychosis. This paranoid psychosis would resolve completely after a
few weeks if her seizures were kept under control. One interesting
feature of her seizure management, however, was that she would
from time to time experience a period of days or weeks in which she
believed that the license plate numbers on vehicles she saw on the
street publicly displayed information about her personal life.
Fortunately, she had the insight to contact her neurologist when she
began to experience this paranoid delusion, and her anticonvulsant
medications were adjusted appropriately. If her anticonvulsants had
not been quickly adjusted, she would have experienced a seizure
and a postictal period of severe paranoia.
Case Example 2
An elderly man with Lewy body disease (LBD) had mild cognitive
impairment but no overt dementia. On occasion, he would
experience brief, nonthreatening visual hallucinations. One particular
delusion/hallucination of fascination to his family and physicians alike
was his belief that he could talk at will and without a phone to his
sister, who lived 1,000 miles away. When asked to do so, he would
stop, look up, and say, “Hello, Sadie, is that you?” He would then
have a conversation for several minutes, during which observers
would have the impression of listening to half of a perfectly normal
telephone conversation. The patient had no insight into the
extraordinary nature of these calls and merely accepted this skill at
face value.
The first case raises the important question of insight. The patient
experienced well-defined paranoid delusions that were likely
precipitated by ictal discharges, increasing in frequency during the
prodromal ictal state. However, although the delusion reoccurred,
her insight was not immediately impaired. This case suggests that
insight is not binary (present vs. absent), and it need not exist in
lockstep with delusion.
The second case raises the question about the applicability of the
term “psychosis.” The patient was not at all distressed by his
“telephone skills.” Because the patient was participating in activities
that were clearly impossible, and because his insight was impaired,
he could be described as psychotic. However, because the patient
experienced no distress due to this isolated delusion and, in fact,
initiated the experience himself, one could question the applicability
of the term “psychosis” in this case. In fact, his clinicians chose not
to treat this particular symptom of his LBD.
Psychosis and Sleep
Psychotic or psychotic-like behavior may occur during abnormal
or normal sleep. During prolonged sleep deprivation, a patient may
experience intermittent hallucinations. These hallucinations may be
due to the intrusion of sleep and dream material into wakefulness.
Non–rapid eye movement (non–REM) sleep parasomnias include
sleepwalking and confusional arousals. Patients may exhibit
prolonged bizarre behavior during these parasomnias, such as sleep
eating behavior. Even violent behavior resulting in injury or death has
occasionally been described (Siclari et al. 2010). Nocturnal panic
attacks or night terrors may result in disturbing nighttime
experiences.
It is of interest that hallucinations are more common in those
dementia syndromes associated with an increased risk for sleep
disorders. It is possible that there is a link between visual
hallucinations and disordered sleep in these illnesses. For example,
REM sleep behavior disorder (RSBD)—the failure to suppress motor
tone during REM sleep—occurs with sufficient regularity prior to the
onset of other clinical features of LBD that some investigators feel
that RSBD should be considered a key diagnostic feature of the
disorder. As in confusional arousals or sleep walking, the dream
enactment behavior of RSBD may appear bizarre and psychotic.
In patients with advanced dementia or severe encephalopathy, the
breakdown in the distinction between the states of wakefulness,
REM sleep, and non-REM sleep may become particularly severe,
resulting in status dissociatus (Mahowald and Schenck 1991). In this
state, patients may appear encephalopathic, psychotic, or both.
Although seen during the course of some acute withdrawal
syndromes, this condition is especially problematic when it occurs
during the course of severe dementia. Rather than experience brief
episodes of hallucinations or confusion, patients may continue in a
dreamlike state without end; they have lost the normal experience of
the distinction between sleep and wakefulness.
Patients with RSBD may also at times exhibit a complex and
disabling array of symptoms known as parasomnia overlap disorder
(Schenck et al. 1997). These patients may exhibit features of
sleepwalking, sleep terrors, and confusional arousals.
Further strengthening the association between psychosis and
sleep disorder are the clinical symptoms occurring due to “top of the
basilar artery” syndrome (Caplan 1980). Some patients who suffer a
stroke involving the bifurcation of the basilar artery, in addition to
other symptoms, may experience somnolence, vivid hallucinations,
and dreamlike behavior. These symptoms are probably due to
ischemia of upper midbrain and diencephalic structures, which
contain anatomical neural centers and pathways for sleep regulation.
Epilepsy and Psychosis

Epilepsy was one of the first disorders to be linked to psychosis,
and current estimates indicate it is present in approximately 4%–
10% of patients with epilepsy (Krishnamoorthy 2002). Psychosis in
epilepsy can be classified based on its temporal relationship with
seizures: ictal psychosis, postictal psychosis, or chronic interictal
psychosis (Nadkarni et al. 2007).
Ictal psychosis, the occurrence of psychotic behavior during a
seizure, is relatively rare. Patients will typically experience auditory
or visual hallucinations and illusions combined with affective
changes including agitation, fear, or paranoia (Nadkarni et al. 2007).
When ictal psychosis occurs, the seizure focus is usually localized to
the limbic system and neocortical temporal lobe and can be
prolonged if the patient is in partial or partial complex status
epilepticus. It can also be associated with generalized epilepsy,
including absence status epilepticus.
Postictal psychosis is defined as psychosis that occurs within 1
week of a seizure and has a duration of 1 day to 3 months. It occurs
in approximately 2%–7.8% of epilepsy patients but can rise to 18%
in patients with medically intractable focal epilepsy (Nadkarni et al.
2007; Trimble et al. 2010). Postictal psychosis is usually associated
with complex partial seizures and often follows a cluster of seizures.
There is often a lucid interval during which the patient may be mildly
subdued or confused although he or she displays ostensibly normal
mental health and behavior. This interval may last up to 72 hours
and rarely even longer. The mean duration of postictal psychosis
ranges from 3 to 14 days but can last up to 90 days. During these
psychotic episodes, patients often experience significant mood
alterations, including depression and mania. Delusions may be
present and can be paranoid, persecutory, grandiose, or religious in
nature. Religious delusions, in particular, which typically come with a
fear of impending death, may occur in up to 25% of patients with
postictal psychosis, compared with only 2% of patients with interictal
psychosis (Trimble et al. 2010). Both visual and auditory
hallucinations occur. In addition, patients may become aggressive or
violent. Postictal psychosis usually begins to occur after more than
10 years of epilepsy, and as its frequency increases, so does the risk
of developing chronic interictal psychosis. The patient in Case 1
above was probably experiencing subclinical ictal activity, which
triggered her delusions regarding the license plate numbers.
Most studies have linked postictal psychosis to medial temporal
limbic structures, but the laterality is less clear. Several
electroencephalographic studies have linked postictal psychosis to
bilateral independent interictal and ictal foci. Imaging studies using
single-photon emission computed tomography (SPECT), however,
have shown increased blood flow to the right temporal lobe (Trimble
et al. 2010).
The underlying mechanism of postictal psychosis is not clear. The
lucid period between the associated seizure and its onset would
argue against simple overstimulation and fatigue as the cause.
Trimble et al. (2010) hypothesized that the mechanism of postictal
psychosis could be similar to forced normalization. Forced
normalization is a phenomenon in which a patient develops
psychosis after his or her seizures are successfully treated with
antiepileptic medications. It can develop suddenly with severe
delusions, despite clear consciousness and a normal
electroencephalogram.
Chronic interictal psychosis can occur in approximately 5% of
patients with a long history of uncontrolled seizures (Nadkarni et al.
2007). Persecutory auditory hallucinations are common in these
patients, while the negative symptoms of schizophrenia are less so.
Interictal psychosis is most often associated with complex partial
seizures involving the temporal lobe, perhaps with a left medial
temporal predominance. It has, however, also been described with
extratemporal ictal foci and generalized epilepsy. Risk factors include
onset of seizures in early adolescence, female gender, left medial
temporal seizure focus, left-handedness, cognitive impairment, and
presence of psychic auras (Cummings and Mega 2003).
As for postictal psychosis, the underlying mechanism for interictal
psychosis has yet to be fully elucidated. One hypothesis is the
kindling model: frequent seizures would stimulate and alter the limbic
structures leading to psychotic symptoms (Lancman 1999). An
alternative hypothesis is that a single lesion that predates the onset
of seizures is responsible for the development of both psychosis and
epilepsy.
Alzheimer’s Disease With Psychosis

In 1907, Dr. Aloysius Alzheimer described a 51-year-old patient
who presented with striking symptoms: inexplicable jealousy toward
her husband and worsening memory loss (Strassnig and Ganguli
2005). As her disease progressed, she developed agitation,
paranoia, and likely auditory hallucinations. After her death, she was
found to have the now well-recognized senile plaques and
neurofibrillary tangles of AD. While AD is characterized by
progressive memory loss and further cognitive impairment,
symptoms of psychosis are also common—just as Alzheimer’s first
patient may have experienced paranoid delusions. The estimated
prevalence of psychotic symptoms in AD varies, but the authors of a
review of published studies from 1990 to 2003 found a median
prevalence of 41.1% (range=12.2%–71.1%) (Ropacki and Jeste
2005). This would make AD the second most prevalent psychotic
disorder in the United States after schizophrenia (Murray et al.
2014).
Common psychotic symptoms in AD include delusions, visual
hallucinations, and misidentification syndromes. In contrast to the
bizarre, complex delusions of schizophrenia, the delusions of AD are
typically simple, loosely held, transient, and related to their
immediate environment (Cummings and Mega 2003). For instance,
patients may believe that an unwelcome stranger is coming into their
house and stealing or that their spouse is unfaithful. Although visual
hallucinations are the most common in AD, hallucinations are known
to occur in all sensory modalities. The misidentification delusional
syndromes, such as Capgras syndrome, are also common and will
be discussed in a later section.
Psychosis in AD presents added difficulties beyond the psychotic
symptoms themselves, as it is associated with greater cognitive
impairment and a more rapid decline (Murray et al. 2014). Moreover,
psychosis in AD is tied to the behavioral symptoms of agitation and
aggression, along with depression and apathy. The combination of
these symptoms leads to greater rates of institutionalization and
mortality.
Although the pathogenesis of psychosis in AD is not yet fully
understood, it does appear to be most associated with the
dysfunction of the neocortex—especially the dorsolateral prefrontal
cortex and the heteromodal association areas—as opposed to the
medial temporal lobe structures. This has been shown with
functional imaging as well as with pathological evidence, including
increased neurofibrillary tangle density in the neocortex but not the
medial temporal structures (Murray et al. 2014). These findings
suggest that in AD, psychosis is not primarily due to limbic system
dysfunction.
Researchers have found many neurotransmitter abnormalities
that may be associated with AD with psychosis. For instance, AD
patients with delusions have shown an increase in muscarinic
acetylcholine M2 receptor density in the orbitofrontal cortex and
middle temporal gyrus. There may also be an association with the
density of dopamine D3 receptors in the nucleus accumbens and
reduced serotonin in the ventral temporal cortex and proscubiculum.
In addition, there appears to be genetically mediated risk of
psychosis in AD, as the estimated heritability is 30% for a single
psychotic symptom and 61% for recurrent or multiple symptoms.
Although no specific genes have been definitively identified, the
dopamine receptor gene DRD1 polymorphism may be associated
with hallucinations and the DRD3 polymorphism with delusions.
Notably, the apolipoprotein E epsilon 4 allele, which is a genetic risk
factor for late-onset AD, is not associated with psychosis (Murray et
al. 2014).
Parkinson’s Disease With Dementia and Lewy Body

Disease
Parkinson’s disease is a neurodegenerative disorder
characterized by movement abnormalities (resting tremors,
bradykinesia, and rigidity) (see Chapter 21, “Neurocognitive
Disorders With Lewy Bodies”). The pathological hallmark is the Lewy
body, a cytoplasmic inclusion predominantly made up of the protein
α-synuclein. Pathology of the substantia nigra in the midbrain is
associated with decreased levels of the neurotransmitter dopamine,
resulting in the disease’s well-known motor symptoms. Although PD
is primarily a movement disorder, it can also have cognitive and
behavioral features. Psychosis is common, affecting approximately
one-third of patients on dopaminergic therapy (Goldman et al. 2011).
LBD shares the same Lewy body pathology as PD (see Chapter
21). The difference is one of location; whereas PD pathology is more
prevalent in the brain stem, LBD has more cortical pathology. In
addition, cognitive symptoms occur earlier in LBD than in PD.
Psychosis is very common in LBD, occurring in 57%–76% of patients
(Assal and Cummings 2002). In fact, visual hallucinations are part of
the diagnostic criteria, along with parkinsonism and fluctuations in
cognition.
The most common psychotic symptom in PD and LBD, again in
contrast to schizophrenia but similar to AD, is visual hallucinations.
These range from mild symptoms, such as illusions and passage or
presence hallucinations, to more complex, well-formed
hallucinations. A passage hallucination is the sensation of a person
passing through one’s peripheral vision, whereas a presence
hallucination is the sensation that another being is present in one’s
immediate environment. The formed visual hallucinations of PD are
typically of people or animals, such as children playing in the yard.
These hallucinations usually last a few seconds to several minutes,
and they can worsen at night. Visual hallucinations occur in about
30% of patients with PD taking dopaminergic mediations; however,
they are much more common in patients with LBD (prevalence:
14%–92%) (Jellinger 2012). Hallucinations can, however, occur in
other sensory domains as well. In addition, delusions occur in
approximately 5%–10% of PD patients who receive dopaminergic
therapy. Common delusions in PD and LBD include paranoid or
persecutory delusions and the misidentification syndromes such as
Capgras or Frégoli syndromes (see Table 24–2) (Jellinger 2012).
TABLE 24–2. Delusional misidentification syndromes
Type Description
Capgras syndrome Belief that a spouse, family member,
or other familiar individual has
been replaced by an impostor
who is physically, but not
psychologically, identical to the
replaced person
Clonal pluralization of the self Belief that there are multiple copies
of oneself that are identical both
physically and psychologically but
physically separate and distinct
Frégoli syndrome Belief that different people are in fact
a single person (usually a
persecutor or other threatening
individual) who changes
appearance or is in disguise
Intermetamorphosis syndrome A variant of the Frégoli syndrome in
which the patient believes that
others change into someone else
in both external appearance and
internal personality
Mirrored self-misidentification Belief that one’s own appearance in
the mirror is that of someone else
(“mirror sign”)
Reduplicative paramnesia Belief that one’s current location is
actually located adjacent to (or
part of) another location, usually
closer to home
Syndrome of subjective doubles Belief that a physical double of
oneself exists (doppelgänger),
although usually with different
personality traits, carrying out
independent actions; also known
as the subjective Capgras
delusion
One might be tempted to conclude from the above that
dopaminergic treatments are, if not the sole contributing factor, then
one of the major contributing factors to the development of psychosis
in PD. Indeed, it was hypothesized that these treatments lead to
psychosis by rendering mesolimbic receptors hypersensitive. There
are, however, several factors that challenge the notion that
dopaminergic medications alone are the primary cause of psychosis
in this disease: 1) there is evidence that the daily dose of dopamine
replacement may not differ between patients with psychosis and
those without; 2) high-dose intravenous levodopa does not induce
psychosis (Goldman et al. 2011); and 3) there are reports of patients
with PD developing psychosis prior to the advent of dopaminergic
medications. What is more, there are known risk factors involved in
the manifestation of psychosis in PD other than medication: 1) longer
duration and severity of the disease, 2) greater cognitive impairment,
3) decreased visual acuity, and 4) greater degree of depression. The
single most important risk factor, however, is dementia—and
hallucinations and delusions are often a sign of progression to
dementia. The estimated prevalence of psychosis among patients
with PD without dementia is 7%–14% but rises to 29%–54% in
patients with Parkinson’s disease with dementia (Assal and
Cummings 2002).
Even if mesolimbic hypersensitivity from dopaminergic
medications is not the primary cause of psychosis in PD and LBD,
dopamine is clearly involved. Evidence of this is that all classes of
dopaminergic enhancers are associated with inducing or
exacerbating psychosis, and the removal of or decrease in these
agents may improve psychotic symptoms. An alternative theory of
psychosis in PD is that there is a loss of balance between the
cholinergic and dopaminergic systems. In PD and LBD, there is a
degeneration of the ascending cholinergic system from the basal
forebrain. This loss of cholinergic activity in the presence of
dopaminergic replacement may lead to psychotic symptoms.
Supporting this is the fact that anticholinergic medications can
induce psychosis, and increasing acetylcholine with cholinesterase
inhibitors has been shown to improve these symptoms. A proposed
mechanism for this is that acetylcholine enhances the neuronal
signal-to-noise ratio. If acetylcholine is reduced, the noise of
irrelevant internal or sensory information may reach conscious
awareness (Goldman et al. 2011).
The serotonergic system is also implicated in psychosis in these
disorders. In PD, there is a loss of the serotonergic raphe nucleus,
with its projections to the frontal and temporal lobes, and putamen.
Dopaminergic therapy lowers the serotonin-to-dopamine ratio further
and may also lead to hyperstimulation of 5-HT2A receptors.
Hyperstimulation of these serotonergic receptors modulates
dopamine neurons in the ventral tegmentum, leading to excitation of
the limbic area and inhibition of the prefrontal cortex (Goldman et al.
2011). Other studies using positron emission tomography (PET)
scans have shown increased 5-HT2A receptors in the ventral visual
processing pathway, dorsolateral prefrontal cortex, medial
orbitofrontal cortex, and insula, all areas important for visual and
cognitive processing and for behavior. A final role of serotonin is its
involvement in REM sleep and the potential that visual hallucinations
may be REM intrusions (see section “Psychosis and Sleep” earlier in
this chapter). Further supporting the serotonergic hypothesis is the
efficacy of atypical antipsychotics such as clozapine, quetiapine, and
pimavanserin, all of which have high 5-HT2A activity.
The brain is organized into two visual processing streams: a
ventral occipitotemporal lobe “what” visual stream and a dorsal
occipitoparietal lobe “where” visual stream. Given the well-formed
visual hallucinations that often involve movement in PD and LBD, it
might be predicted that there would be abnormalities in both of these
processing streams. In fact, hallucinations in PD are associated with
both decreased volume and activation on imaging of the occipital,
parietal, and temporal regions. There is also evidence that
hallucinating PD patients have decreased volume of the
hippocampus, limbic system, and neocortex. Finally, there is
evidence that the frontal lobes have increased activation in PD with
hallucinations (Goldman et al. 2011).
Nagahama et al. (2010) were able to correlate the anatomy of
psychosis even further in LBD. Using SPECT imaging, they divided
psychotic symptoms into visual hallucinations, delusions, and
misidentification syndromes. As with PD, visual hallucinations were
associated with hypoperfusion in the ventral visual stream (left
ventral occipital gyrus) and dorsal stream (bilateral parietal cortices).
This seems to follow Cummings and Mega’s (2003) perceptual
release explanation for hallucinations. The hypoperfusion of the left
ventral occipital gyrus seems to coincide with the face recognition
pathway. It has been hypothesized that the decrease in cholinergic
inputs from the basal forebrain and brain stem in LBD may lead to
this hypoperfusion of the visual pathways. Interestingly, delusions of
theft and persecution were associated with relative hyperperfusion of
the frontal cortex compared with the posterior regions, but these
delusions were associated with hypoperfusion when compared with
the frontal lobes of control subjects. Relative hypoperfusion of frontal
areas has been associated with delusions in other conditions, such
as AD and schizophrenia. From these findings, Nagahama et al.
(2010) hypothesize that the delusions in LBD are due to incorrect
causal attributions to external people based on impaired source
monitoring and insufficient episodic memory from frontal lobe
dysfunction.
Misidentification Syndromes
In 1907, Professor Arnold Pick described a 67-year-old woman
with senile dementia who had developed a fixed belief that her
Prague hospital and her physicians had been simultaneously
duplicated and that she was being treated in her hometown rather
than in Prague. This was the first description of reduplicative
paramnesia. Later, in 1923, Drs. Joseph Capgras and Jean Reboul-
Lachaux described a 53-year-old woman who believed everyone
close to her, including her husband and daughter, had been replaced
by various doubles or imposters. Later known as Capgras syndrome,
this, along with reduplicative paramnesia, form part of the group of
delusional misidentification syndromes, which are characterized by a
misidentification or doubling of a person or place (Harciarek and
Kertesz 2008). Additional common misidentification syndromes are
listed in Table 24–2.
Originally thought to be due to psychiatric disorders like
schizophrenia, misidentification syndromes are now commonly
associated with neurological disorders. These syndromes are
common in AD (15.8%) and LBD (16.6%) (Harciarek and Kertesz
2008) but have also been described in Parkinson’s disease with
dementia, semantic dementia, vascular dementia, traumatic brain
injury, epilepsy, stroke, pituitary tumor, multiple myeloma, multiple
sclerosis, viral encephalitis, migraine, tuberous sclerosis,
neurocysticercosis, and frontal lobe pathology (Cummings and Mega
2003).
The misidentification syndromes can be split into two groups
based on sense of familiarity. The first group has in common that
patients feel decreased familiarity for a person or place. This group
includes syndromes such as Capgras syndrome and the mirror sign.
The second group involves abnormally increased familiarity for a
person or place. This group includes Frégoli syndrome,
intermetamorphosis, and reduplicative paramnesia.
Lesions causing misidentification syndromes are strongly
associated with the right hemisphere. It has been reported that in
patients with reduplicative paramnesia, approximately 52% had
lesions in the right hemisphere, 41% had bilateral lesions, and only
7% had left hemisphere lesions (Devinsky 2009). Similarly, in
patients with Capgras syndrome, 32% had right hemisphere lesions,
62% had bilateral lesions, but only 7% had left-side-only lesions.
More specifically, the right frontal lobe appears to be particularly
involved in Capgras syndrome. In a study of 29 patients, 10 out of
the 29 (34.5%) had exclusively frontal lobe lesions, 6 of which were
bifrontal and 4 of which were right frontal only. None of the patients
had lesions sparing the frontal lobes (Devinsky 2009).
Although the frontal lobes may be involved in the generation of
misidentification syndromes, the temporal lobes may determine the
level of familiarity a patient experiences. One study of
misidentification syndromes showed that temporal lesions were
present in 64% of patients who had decreased familiarity, whereas
they were present in only 14% of patients who had increased
familiarity (Devinsky 2009). This could indicate that if a patient has a
temporal lesion, the delusional misidentification is more likely to have
decreased familiarity, whereas if the patient’s temporal lobe is
spared, he or she may experience increased familiarity. Of interest is
the fact that the perirhinal parahippocampal cortex is activated by
familiar stimuli and evokes a sense of déjà vu if electrically
stimulated.
It has been hypothesized that frontal lobe dysfunction may cause
misidentification syndromes through impairment of reality, memory,
and familiarity monitoring. However, frontal lobe dysfunction does not
always lead to misidentification. Harciarek and Kertesz (2008) did
not find any misidentification syndromes in behavioral-variant
frontotemporal dementia or in primary progressive aphasia, both of
which are predominately associated with frontal lobe pathology.
Alternatively, the misidentification symptoms could be an attempt by
the impaired brain to resolve conflicting information. For example,
Capgras syndrome has been described as the opposite of
prosopagnosia, which is the inability to recognize faces due to
lesions of the ventral visual stream (Harciarek and Kertesz 2008).
Often, patients with prosopagnosia will maintain their familiarity with
a person, even though they cannot recognize that person’s face.
This may be due to an intact more dorsal secondary visual stream
through the inferior parietal lobule connecting the occipital lobe to
limbic structures. In Capgras syndrome, the opposite may occur.
Because of a malfunction of the more dorsal pathway, patients may
retain their recognition of the person’s face but lose the associated
feeling of familiarity and emotional significance. To resolve this
conflicting information, patients may conclude that the person is an
impostor.
It may be that misidentification syndromes require a double-hit
pathology, such as baseline generalized atrophy with a subsequent
right hemisphere lesion (Devinsky 2009). Functional imaging
supports the involvement of multiple areas of dysfunction. In a study
of patients with AD using PET imaging, patients with misidentification
syndromes had hypometabolism of the bilateral paralimbic structures
(orbitofrontal and cingulate) and left medial temporal areas (Mentis
et al. 1995).
Stroke and Psychosis

Although the prevalence of a psychotic syndrome in stroke is
relatively low—between 0.4% and 3.1%—it is associated with
increased mortality (Hackett et al. 2014). Individual symptoms of
psychosis are more common, with delusions occurring in
approximately 3%–10% of patients and hallucinations in
approximately 4%. Delusions and hallucinations are usually
associated with lesions to the right hemisphere, whereas ideas of
reference and persecution may be associated with the left
hemisphere (Cummings and Mega 2003).
Delusions have accompanied strokes to the right frontal,
temporal, and parietal lobes, as well as the subcortical limbic
structures (Devine et al. 2014). Recently, there has been increasing
evidence that the right inferior frontal gyrus may also be involved.
Devine et al. (2014) used a lesion overlap analysis to associate
persistent poststroke delusions with the right inferior frontal gyrus
and its underlying white matter. An earlier study associated
delusions with right caudate infarctions and hypometabolism of the
inferior frontal gyrus (McMurtray et al. 2008). These abnormalities
are similar to what is found in AD and are consistent with the
hypothesis that delusions are due to a disruption of the prefrontal
lobe function of reality monitoring and testing. Anton’s syndrome
occurs with bilateral occipital lobe lesions and is associated with
cortical blindness and confabulation of visual images; patients will
report that they can see visual stimuli when they, in fact, are
completely blind. Visual hallucinations can also be present with
unilateral infarcts, however, and occur in 12% of occipital lobe
strokes (Hackett et al. 2014). Patients may report complex visual
phenomena in their blind hemifield, although patients usually
recognize that their visual experiences are not real. This type of
hallucination fits the perceptual-release hypothesis. Auditory
hallucinations are less common, occurring in approximately 0.8% of
cortical strokes (Hackett et al. 2014).
Traumatic Brain Injury and Psychosis

Psychosis can also be a sequela of traumatic brain injury (TBI),
occurring in 0.9%–8.5% of closed-head injuries (Fujii and Ahmed
2014). There are two categories of psychotic symptoms in TBI:
delusional disorder and schizophrenia-like psychosis. Patients with a
delusional disorder most commonly suffer from Capgras syndrome
and/or reduplicative paramnesia, each of which occurs in
approximately 32% of patients. Delusional jealously is less common,
occurring in 16% of patients. The schizophrenia-like psychosis of TBI
is characterized by both hallucinations and delusions. Of these
patients, 97% experience hallucinations, the majority of which are
auditory (88%), but visual hallucinations are also present (22%).
Delusions are present in 85% of cases and are often persecutory
(65%). Bizarre delusions, ideas of reference, and grandiose
delusions—more typical of primary psychosis—also occur (Fujii and
Ahmed 2014).
Ninety-four percent of delusional disorders in TBI have structural
MRI abnormalities, the most common of which are lesions in frontal
(75%) and temporal lobes (56%). In contrast, patients with
schizophrenia-like psychoses after TBI are less likely to have
structural lesions on neuroimaging and much more likely (86% of
patients) to exhibit abnormalities on functional imaging
(SPECT/PET), particularly in temporal lobes. Delusional disorders
tend to occur within the first year of a patient’s injury, while
schizophrenia-like psychosis will typically have a more delayed
onset, often somewhere in the range of 3–4 years after the injury
was sustained. It is important to distinguish psychosis due to TBI
from the psychotic symptoms that might occur in posttraumatic
stress disorder, seizures, and substance abuse, as these all often
co-occur in this patient population (Fujii and Ahmed 2014).
Miscellaneous Other Causes of Psychosis

There are several other, secondary causes of psychosis that are
worth briefly exploring. Besides AD, PD, and LBD, other
degenerative diseases, such as Huntington’s disease or
frontotemporal dementia (FTD), can produce psychosis.
Huntington’s disease is an autosomal dominant neurodegenerative
disorder characterized by chorea and behavioral changes (see
Chapter 22, “Huntington’s Disease”). It has been reported that a
schizophrenia-like psychosis may develop in 4%–12% of patients
(Cummings and Mega 2003). Frontotemporal dementia is a
neurodegenerative disorder characterized by progressive behavioral
or language decline and atrophy of the frontal and anterior temporal
lobes (see Chapter 23, “Frontotemporal Dementia”). It was originally
believed that psychosis in FTD was rare, but recent evidence has
shown that psychosis may have often gone unrecognized and is
particularly prevalent in certain pathological and genetic subtypes
(Shinagawa et al. 2014). The overall prevalence of psychosis in FTD
has been reported at 10%–15%, but in carriers of the C9ORF72
mutation (related to TDP-43 [transactive response DNA-binding
protein 43] type B pathology), the prevalence may be up to 50%
(Shinagawa et al. 2014). Additional variants commonly associated
with psychosis include the progranulin gene (GRN) mutation (related
to TDP-43 type A pathology) and the fused in sarcoma pathology
(Shinagawa et al. 2014). Imaging studies in FTD have shown an
association between visual hallucinations and atrophy of the medial
right temporal lobe.
Herpes simplex encephalitis is a viral infection that preferentially
affects the medial temporal lobe and inferior frontal lobes. It will
frequently manifest with psychosis, with auditory hallucinations and
delusions as initial symptoms (Cummings and Mega 2003).
Additional infections that may cause psychosis include rabies,
mumps, syphilis, and HIV encephalopathy, among others.
A recently described form of autoimmune encephalitis presents
with psychosis even more frequently than herpes encephalitis: anti–
N-methyl-D-aspartate (anti–NMDA) receptor encephalitis. Anti–
NMDA receptor encephalitis is a paraneoplastic syndrome often
associated with ovarian teratomas in young women. Psychosis is a
common initial symptom and in one series was present in 68% of
subjects, all of whom had (typically auditory) hallucinations (Gable et
al. 2009).
Additional paraneoplastic and autoimmune causes of psychosis
include voltage-gated potassium channel encephalitis, Hashimoto’s
encephalitis, and systemic lupus erythematosus. There are also
many metabolic causes of psychosis. Psychosis may be a
presenting symptom of Wilson’s disease, caused by abnormal
copper metabolism. Patients with this disorder frequently present
with psychiatric symptoms and may have paranoid delusions and
auditory hallucinations very similar to schizophrenia (Cummings and
Mega 2003). Other metabolic causes of psychosis include kidney
and liver disease, electrolyte abnormalities, endocrine disturbances,
nutritional deficiencies, myelin-affecting disease, genetic metabolic
disorders, and medications.
Treating Psychosis
Regardless of whether patients are diagnosed with primary or
secondary psychosis, treatment is generally the same. Although
there is an extensive literature on the treatment of schizophrenia,
there have been far fewer studies examining the relative efficacy of
the drugs used to treat psychosis in patients with known neurological
disorders (secondary psychoses). Nevertheless, drugs used to treat
schizophrenia are generally effective, although to varying degrees, in
other primary and secondary psychoses—especially in treating
delusions and/or hallucinations.
The efficacy of both the older first-generation antipsychotics and
newer atypical drugs is largely mediated by D2 receptor antagonism,
with some exceptions. Clozapine has been found to be superior in
treating refractory schizophrenia, but there is a general consensus
among clinicians that there are relatively few differences in efficacy
between the first- and second-generation antipsychotics in the
treatment of psychotic symptoms. However, the second-generation
antipsychotics may be superior with respect to their effects on
cognition and negative symptoms. Additionally, the second-
generation antipsychotics (or at least those that are relatively modest
D2 antagonists) are associated with fewer adverse motor effects and
a lower risk of tardive dyskinesia.
In LBD and AD, psychotic symptoms may sometimes improve in
response to treatment with acetylcholinesterase inhibitors. In LBD,
antipsychotics are largely contraindicated because of increased
sensitivity to side effects. Both quetiapine and clozapine, however,
may be used cautiously in this condition.
New drugs are under study that may benefit cognitive function as
well as psychosis (Bruijnzeel et al. 2014). Among these, a potentially
important addition to the pharmacotherapies of psychosis is
pimavanserin, a nondopaminergic atypical antipsychotic that acts
principally through selective inverse agonism of serotonin 5-HT2A
receptors. It demonstrates a 40-fold greater selectivity for the 5-HT2A
receptor than for the 5-HT2C receptor and demonstrates no clinically
significant activity at 5-HT2B receptors or dopamine receptors. At the
time of this writing, pimavanserin is approved by the U.S. Food and
Drug Administration for the treatment of some patients with
psychosis due to Parkinson’s disease and is being studied as an
adjunctive treatment for schizophrenia. In the latter context,
pimavanserin appears to potentiate the antipsychotic effects of
otherwise subtherapeutic doses of risperidone and improves the
tolerability of haloperidol by reducing the development of
extrapyramidal side effects. While the role of pimavanserin in the
treatment of primary and secondary psychoses requires further
clarification, it represents an important development in the
pharmacotherapy of psychoses that may portent similar near-term
advances in this area of neuropsychiatric treatment.
Behavioral therapies have also been found to be of benefit in
some patients with primary psychosis, including versions of
cognitive-behavioral therapy developed specifically for the treatment
of psychosis (Mehl et al. 2015) and cognitive remediation and
psychiatric rehabilitation strategies for persons with schizophrenia
(Wykes et al. 2011). These interventions are important elements of
the treatment of schizophrenia and related psychoses, but they
remain underdeveloped and infrequently provided as treatments for
secondary psychoses. Also, as noted earlier in this chapter,
transcranial direct current stimulation and rTMS may prove useful in
suppressing auditory hallucinations in patients with schizophrenia.
The potential applications of psychological, behavioral, and
neurostimulation interventions to the treatment of primary and
secondary psychoses remain to be elucidated but appear promising
as potential adjuncts and/or alternatives to the pharmacotherapy of
psychosis.
Conclusion
Over the last 200 years, the term psychosis has either been
applied broadly to the presence of a spectrum of cognitive,
emotional, behavioral, or motoric symptoms or more narrowly to the
presence of insight-impaired delusions often with content-congruent
hallucinations. Studies of psychosis or schizophrenia largely depend
on the choice of narrow or broad enrollment criteria. However, at its
core, psychosis is largely identified by the presence of delusions of
bizarre, strongly held beliefs that are not amenable to reason or
persuasion.
Schizophrenia is a medical illness that is strongly associated with
delusions and hallucinations consistent with psychosis. However,
schizophrenia is often associated with a characteristic age range of
onset, positive family history for psychiatric disorders, thought
disorder, poor social skills, motor symptoms, and cognitive
dysfunction (often with a frontal-executive pattern). However, no
pathophysiological process has been identified yet as an etiology for
schizophrenia.
Careful evaluation is critical to determine a possible secondary
cause for psychosis. The most important secondary etiologies to
consider include the following: drug effects, dementia, delirium,
infection, sleep disorders, seizure disorders, or focal neurological
deficits such as strokes.
References
Arciniegas DB: Psychosis. Continuum (Minneap Minn) 21(3 Behavioral Neurology
and Neuropsychiatry):715–736, 2015 26039850
Assal F, Cummings JL: Neuropsychiatric symptoms in the dementias. Curr Opin
Neurol 15(4):445–450, 2002 12151841
Berman KF, Torrey EF, Daniel DG, Weinberger DR: Regional cerebral blood flow in
monozygotic twins discordant and concordant for schizophrenia. Arch Gen
Psychiatry 49(12):927–934, 1992 1360197
Bruijnzeel D, Suryadevara U, Tandon R: Antipsychotic treatment of schizophrenia:
an update. Asian J Psychiatr 11:3–7, 2014 25216917
Brunelin J, Mondino M, Gassab L, et al: Examining transcranial direct-current
stimulation (tDCS) as a treatment for hallucinations in schizophrenia. Am J
Psychiatry 169(7):719–724, 2012 22581236
Buckner RL, Andrews-Hanna JR, Schacter DL: The brain’s default network:
anatomy, function, and relevance to disease. Ann NY Acad Sci 1124:1–38,
2008 18400922
Byom LJ, Mutlu B: Theory of mind: mechanisms, methods, and new directions.
Front Hum Neurosci 7:413, 2013 23964218
Caplan LR: “Top of the basilar” syndrome. Neurology 30(1):72–79, 1980 7188637
Cardno AG, Gottesman II: Twin studies of schizophrenia: from bow-and-arrow
concordances to star wars Mx and functional genomics. Am J Med Genet
97(1):12–17, 2000 10813800
Cummings JL, Mega MS: Neuropsychiatry and Behavioral Neuroscience. New
York, Oxford University Press, 2003
Devine MJ, Bentley P, Jones B, et al: The role of the right inferior frontal gyrus in
the pathogenesis of post-stroke psychosis. J Neurol 261(3):600–603, 2014
24449063
Devinsky O: Delusional misidentifications and duplications: right brain lesions, left
brain delusions. Neurology 72(1):80–87, 2009 19122035
Dhindsa RA, Goldstein DB: Schizophrenia: from genetics to physiology at last.
Nature 530(7589):162–163, 2016 26814972
Fatouros-Bergman H, Cervenka S, Flyckt L, et al: Meta-analysis of cognitive
performance in drug-naïve patients with schizophrenia. Schizophr Res 158(1–
3):156–162, 2014 25086658
Fornito A, Bullmore ET: Reconciling abnormalities of brain network structure and
function in schizophrenia. Curr Opin Neurobiol 30:44–50, 2015 25238608
Fujii DE, Ahmed I: Psychotic disorder caused by traumatic brain injury. Psychiatr
Clin North Am 37(1):113–124, 2014 24529427
Gable MS, Gavali S, Radner A, et al: Anti-NMDA receptor encephalitis: report of
ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis
28(12):1421–1429, 2009 19718525
Gatt JM, Burton KL, Williams LM, et al: Specific and common genes implicated
across major mental disorders: a review of meta-analysis studies. J Psychiatr
Res 60:1–13, 2015 25287955
Goldman JG, Vaughan CL, Goetz CG: An update expert opinion on management
and research strategies in Parkinson’s disease psychosis. Expert Opin
Pharmacother 12(13):2009–2024, 2011 21635198
Hackett ML, Köhler S, O’Brien JT, et al: Neuropsychiatric outcomes of stroke.
Lancet Neurol 13(5):525–534, 2014 24685278
Harciarek M, Kertesz A: The prevalence of misidentification syndromes in
neurodegenerative diseases. Alzheimer Dis Assoc Disord 22(2):163–169, 2008
18525289
Jellinger KA: Cerebral correlates of psychotic syndromes in neurodegenerative
diseases. J Cell Mol Med 16(5):995–1012, 2012 21418522
Krishnamoorthy E: Neuropsychiatric disorders in epilepsy—epidemiology and
classification, in The Neuropsychiatry of Epilepsy. Edited by Trimble MR,
Schmitz B. New York, Cambridge University Press, 2002, pp 355–317
Kuperberg GR, Broome MR, McGuire PK, et al: Regionally localized thinning of
the cerebral cortex in schizophrenia. Arch Gen Psychiatry 60(9):878–888, 2003
12963669
Lancman M: Psychosis and peri-ictal confusional states. Neurology 53(5) (suppl
2):S33–S38, 1999 10496232
Mahowald MW, Schenck CH: Status dissociatus—a perspective on states of
being. Sleep 14(1):69–79, 1991 1811323
McMurtray AM, Sultzer DL, Monserratt L, et al: Content-specific delusions from
right caudate lacunar stroke: association with prefrontal hypometabolism. J
Mehl S, Werner D, Lincoln TM: Does cognitive behavior therapy for psychosis
(CBTp) show a sustainable effect on delusions? a meta-analysis. Front Psychol
6:1450, 2015 26500570
Mentis MJ, Weinstein EA, Horwitz B, et al: Abnormal brain glucose metabolism in
the delusional misidentification syndromes: a positron emission tomography
study in Alzheimer disease. Biol Psychiatry 38(7):438–449, 1995 8672604
Mesholam-Gately RI, Giuliano AJ, Goff KP, et al: Neurocognition in first-episode
schizophrenia: a meta-analytic review. Neuropsychology 23(3):315–336, 2009
19413446
Murray PS, Kumar S, Demichele-Sweet MA, et al: Psychosis in Alzheimer’s
disease. Biol Psychiatry 75(7):542–552, 2014 24103379
Nadkarni S, Arnedo V, Devinsky O: Psychosis in epilepsy patients. Epilepsia 48
(suppl 9):17–19, 2007. 18047594
Nagahama Y, Okina T, Suzuki N, et al: Neural correlates of psychotic symptoms in
dementia with Lewy bodies. Brain 133(Pt 2):557–567, 2010 19920063
Padmanabhan JL, Tandon N, Haller CS, et al: Correlations between brain structure
and symptom dimensions of psychosis in schizophrenia, schizoaffective, and
psychotic bipolar I disorders. Schizophr Bull 41(1):154–162, 2015 24907239
Peralta V, Campos MS, De Jalón EG, et al: Motor behavior abnormalities in drug-
naïve patients with schizophrenia spectrum disorders. Mov Disord 25(8):1068–
1076, 2010 20222137
Ropacki SA, Jeste DV: Epidemiology of and risk factors for psychosis of
Alzheimer’s disease: a review of 55 studies published from 1990 to 2003. Am J
Psychiatry 162(11):2022–2030, 2005 16263838
Ruocco AC, Reilly JL, Rubin LH, et al: Emotion recognition deficits in
schizophrenia-spectrum disorders and psychotic bipolar disorder: Findings
from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP)
study. Schizophr Res 158(1–3):105–112, 2014 25052782
Schenck CH, Boyd JL, Mahowald MW: A parasomnia overlap disorder involving
sleepwalking, sleep terrors, and REM sleep behavior disorder in 33
polysomnographically confirmed cases. Sleep 20(11):972–981, 1997 9456462
Shinagawa S, Nakajima S, Plitman E, et al: Psychosis in frontotemporal dementia.
J Alzheimers Dis 42(2):485–499, 2014 24898651
Siclari F, Khatami R, Urbaniok F, et al: Violence in sleep. Brain 133(Pt 12):3494–
3509, 2010 21126993
Silbersweig DA, Stern E, Frith C, et al: A functional neuroanatomy of hallucinations
in schizophrenia. Nature 378(6553):176–179, 1995 7477318
Slotema CW, Blom JD, van Lutterveld R, et al: Review of the efficacy of
transcranial magnetic stimulation for auditory verbal hallucinations. Biol
Psychiaty 76(2):101–110, 2014 24315551
Strassnig M, Ganguli M: About a peculiar disease of the cerebral cortex:
Alzheimer’s original case revisited. Psychiatry (Edgmont) 2(9):30–33, 2005
21120106
Tienari P, Wynne LC, Läksy K, et al: Genetic boundaries of the schizophrenia
spectrum: evidence from the Finnish Adoptive Family Study of Schizophrenia.
Am J Psychiatry 160(9):1587–1594, 2003 12944332
Trimble M, Kanner A, Schmitz B: Postictal psychosis. Epilepsy Behav 19(2):159–
161, 2010 20727828
Weinberger DR, Berman KF, Daniel DC: Prefrontal coretx dysfunction in
schizophrenia, in Frontal Lobe Function and Dysfunction. Edited by Levin HS,
Eisenberg HM, Benton AL. New York, Oxford University Press, 1991, pp 275–
287
Whitfield-Gabrieli S, Thermenos HW, Milanovic S, et al: Hyperactivity and
hyperconnectivity of the default network in schizophrenia and in first-degree
relatives of persons with schizophrenia. Proc Natl Acad Sci USA 106(4):1279–
1284, 2009 19164577
World Health Organization: World Health Organization: International Statistical
Classification of Diseases and Related Health Problems, 10th Revision.
Geneva, World Health Organization, 1992
Wykes T, Huddy V, Cellard C, et al: A meta-analysis of cognitive remediation for
schizophrenia: methodology and effect sizes. Am J Psychiatry 168(5):472–485,
2011 21406461
CHAPTER 25
Mood Disorders
Mood disorders are characterized by abnormalities of mood and

affect regulation, cognitive changes, motor activity alterations, sleep
abnormalities, appetite changes, and other disturbances of
homeostatic/drive states (e.g., libido, motivation). Although the
etiology of mood disorders in most patients is “idiopathic,”
neuropsychiatric disorders are commonly associated with
disturbances of mood and affect, especially depressive syndromes.
A growing literature supports a similar neurobiological basis for
mood disorders, regardless of etiology. However, rather than defining
a single causative “lesion” or neurochemical abnormality, current
models propose an integrated set of distinct but interconnected
neural systems underlying the phenomenological features of mood
disorders. Each of these systems may be more or less disturbed,
resulting in variable symptomatic presentation and treatment
response. Mood disorders (major depressive disorder, persistent
depressive disorder [dysthymia], and bipolar disorder) are a
pervasive and costly public health concern. Mood disorders have a
12-month prevalence rate of about 10% and a lifetime prevalence
rate of about 20%. Mental and behavioral disorders, especially major
depressive disorder, are the leading cause of disability in the United
States and present a significant economic burden nationally and
globally.
Current and developing mood disorder treatments are based on
the complex interplay of anatomy, biochemistry, and phenomenology
of mood disorders. By analogy, the treatments for many neurological
disorders, such as Parkinson’s disease (PD), vary depending on the
paradigm on which an intervention is based, such as biochemistry
(e.g., dopamine agonists, enzyme inhibitors, anticholinergic
medication), anatomy, or neurocircuitry (e.g., ablation, deep brain
stimulation [DBS]). Similarly, greater acknowledgment of the intricate
neurobiology of mood disorders will likely generate many diverse
and hopefully effective treatments.
Clinical Features of Mood Disorders

On the basis of the American Psychiatric Association’s Diagnostic
and Statistical Manual of Mental Disorders, 5th Edition (DSM-5;
American Psychiatric Association 2013), mood disorders are
characterized by the types of mood episodes that occur over the
course of the illness. Thus, major depressive disorder (MDD) is
categorized by one or more major depressive episodes (MDEs),
where as bipolar I disorder is categorized by at least one manic
episode and the possible occurrence of depressive or hypomanic
episodes.
In DSM-5, prior diagnoses of dysthymia and chronic MDD are
now subsumed under persistent depressive disorder. Although
criteria for MDD have remained unchanged from DSM-IV (American
Psychiatric Association 1994), a specifier, “with mixed features,” has
been added to indicate the presence of an MDE with at least three
manic symptoms (inadequate to fulfill criteria for a manic episode).
Similarly, in bipolar I disorder, the specifier “mixed episode” was
discarded in lieu of a new specifier, “with mixed features,” to describe
individuals with episodes of hypomania/mania in the presence of
depression. Bipolar I disorder no longer requires that individuals’
symptoms simultaneously meet full criteria for both mania and an
MDE to be considered “mixed.” For both bipolar and depressive
disorders, specifiers were added for “anxious distress.”
This classification of mood disorders is useful for both clinical and
research purposes but belies the phenomenological complexity of
mood disorders. Two patients with MDD, for example, may present
with very different symptoms of an MDE. One may have decreased
sleep with early morning awakening, severe psychomotor
retardation, profound anhedonia, absence of mood reactivity, and a
distinct quality of “depressed” mood that differs from normal sadness
(e.g., melancholic features). The other may present with sad mood
and atypical features consisting of increased sleep, appetite, and
mood reactivity. Although both patients’ symptoms meet criteria for
an MDD diagnosis, the manifestations of the two illnesses appear
quite distinct and reflect a biological difference between subtypes of
depression. When mood disorders manifest in the context of
neuropsychiatric conditions (such as PD), they can have even
greater variability in presentation, given the overlap between
psychiatric and neurological symptoms.
Mood Disorders Associated With

Neuropsychiatric Conditions
Correctly diagnosing a mood disorder in the neuropsychiatric
patient can be difficult because symptoms of the neurological illness
may mimic or mask the symptoms of mood disturbance. Thus, when
the clinician is evaluating patients with neuropsychiatric disease, it is
important to be vigilant for any and all symptoms of depression,
paying particular attention to symptoms less likely to be
independently associated with the underlying neurological illness,
including mood disturbance, anhedonia, excessive guilt, and
suicidality.
In patients with neurological illness, depression may result from
the pathophysiology or treatment of the underlying neurological
illness, reaction to the psychosocial stress of having the underlying
illness, recurrence of a premorbid depressive disorder, or a
combination of all of these. Table 25–1 lists common associations of
depression with various neuropsychiatric illnesses and treatments. In
many patients, the etiology of depression will be multifactorial.
TABLE 25–1. Common associations with depression in neuropsychiatric
patients
Psychiatric (idiopathic)
Major depressive disorder
Bipolar disorder
Persistent depressive disorder (dysthymia)
Cyclothymic disorder
Pharmacological/iatrogenic
Corticosteroids
Thyroid ablation
α-Interferon
Deep brain stimulation (especially of subthalamic nucleus)
Substance intoxication/withdrawal
Neurological
Basal ganglia disease, especially,
Parkinson’s disease
Huntington’s disease
Wilson’s disease
Cerebrovascular disease, especially,
Frontal cortical/subcortical stroke
Basal ganglia stroke
Multiple sclerosis
Infectious encephalitis
Neoplasm
Traumatic brain injury
Dementia
Epilepsy
Other
Hypothyroidism
Cushing’s syndrome
Vitamin deficiency (e.g., B12)
Autoimmune disease
Neurochemical abnormalities in patients with neurological disease
mimic those in patients with idiopathic depression. All three
monoamines are disrupted in PD, which is highly associated with
depression. Serotonergic dysfunction has also been linked to
poststroke depression. Huntington’s disease has been less clearly
associated with monoaminergic abnormalities; however,
abnormalities of corticotropin-releasing factor and glutamate function
have been suggested.
The structural and functional neuroanatomical changes resulting
from depression associated with neurological disease also share
similarities with those of idiopathic depression. Computed
tomography and magnetic resonance imaging (MRI) studies in
stroke patients with and without mood disorders have demonstrated
a high association of mood changes with infarctions of the left frontal
lobe and basal ganglia, the severities of which correlated with lesion
proximity to the left frontal pole (Starkstein et al. 1987). Studies of
individuals with head trauma, brain tumors, or ablative neurosurgery
further suggest that dorsolateral prefrontal lesions, particularly on the
left, are associated with depression and depressive-like symptoms.
A number of functional imaging studies of depressed patients with
neurological disease have been conducted in order to evaluate
depression-associated functional abnormalities without the confound
of gross cortical lesions. These studies have typically investigated
PD, Huntington’s disease, and lacunar strokes of the basal ganglia—
disorders with known or identifiable neurochemical,
neurodegenerative, or focal changes that spare frontal cortex (the
region repeatedly implicated in idiopathic depression studies). These
data have demonstrated that depressed patients with PD have
selective hypometabolism involving the caudate nucleus and
prefrontal and orbitofrontal cortices. Depressed patients with
Huntington’s disease show decreases in paralimbic orbitofrontal and
inferior prefrontal cortices (as well as caudate abnormalities inherent
to the disease). Patients with depression following stroke also show
cortical hypometabolism (Mayberg 1994), suggesting that subcortical
lesions can affect function throughout a network of brain regions
involved in mood regulation. These data suggest that the depressive
syndrome, regardless of etiology, is associated with similar regional
brain changes (Figure 25–1).
FIGURE 25–1. Common glucose metabolic positron emission tomography

findings in neurological and idiopathic depression.
Decreased prefrontal, dorsal cingulate, and temporal cortical metabolism is a
common finding across different depressive syndromes, including patients with
Parkinson’s disease, Huntington’s disease, and idiopathic unipolar depression.
Together, imaging data for depressed patients with neurological

disease support that cortical, subcortical, and limbic-paralimbic
networks are involved in mood regulation. These data also support
the notion that disturbance of the network at any critical node can
result in behavioral effects and “downstream” activity changes
consistent with idiopathic depression.
Neurobiology of Mood Disorders
Neurochemical Findings
Depression has been associated with dysfunction of the
monoamine neurotransmitter systems (i.e., serotonin,
norepinephrine, dopamine). Growing evidence suggests that the
glutamatergic system also plays an important role (Caddy et al.
2014). Of the monoamine neurotransmitter systems, serotonin has
received the greatest attention, and there is strong evidence that
serotonergic dysfunction plays a major role in the pathophysiology of
depression.
Data supporting norepinephrine and dopamine dysfunction in the
pathophysiology of depression are more limited but suggest a
significant role for these neurotransmitters (Morilak and Frazer
2004). Medications that selectively block norepinephrine reuptake
are effective in treating depression, as are bupropion and
mirtazapine, which also act on the noradrenergic system. In
depressed patients taking noradrenergic antidepressants and
euthymic patients with a history of depression, catecholamine
depletion can result in depressive relapse. Various studies suggest
dopamine transporter activity may be reduced in patients with
depression. Medications targeting the dopamine system, such as
monoamine oxidase inhibitors (MAOIs), have shown antidepressant
efficacy.
Glutamate, an excitatory neurotransmitter, has been implicated in
mood disorders, memory, and cognition (Sanacora et al. 2012). A
proliferation of studies have explored medication that targets a
specific glutamate receptor type, the N-methyl-D-aspartate (NMDA)
receptor. In individuals with depression, changes in glutamate level
have been identified in brain tissue, cerebrospinal fluid, and plasma
concentration. In addition, decreased glutamate and glutamine have
been noted in the hippocampus, amygdala, anterior cingulate cortex,
left dorsolateral prefrontal cortex, dorsomedial prefrontal cortex, and
ventromedial prefrontal cortex of patients with major depression.
Neuroendocrine systems have been implicated in the
pathophysiology of mood disorders. The hypothalamic-pituitary-
adrenal (HPA) axis is clearly dysfunctional in at least some patients
with depression (Pariante and Lightman 2008). Severely depressed
patients with prior unsuccessful medication trials may have a
hyperactive HPA axis, evidenced by cortisol levels and impaired
feedback response using the prednisolone suppression test. Recent
reports of alterations in cortisol regulation associated with transient
stress in patients with a history of early-life trauma or abuse further
suggest that HPA axis dysregulation may be an important marker of
vulnerability to various types of affective disorders in later life (Heim
and Binder 2012); these data also suggest that HPA axis
abnormalities may be causal for certain types of depression rather
than the reverse. Corticotropin-releasing factor—the hormone
responsible for adrenocorticotropin hormone release—has been
shown to be an important modulator of monoaminergic activity.
A growing database supports a role for inflammatory processes in
mood disorders, especially depression (Rosenblat et al. 2014).
Certain immune mediators and inflammatory markers have been
clearly associated with depressive and other mood disorder
symptoms. Inflammatory pathways may interact with stress-
response systems (i.e., HPA axis) to mediate effects on mood and
behavior. Investigations of these targets continue, with many studies
exploring the use of anti-inflammatory medications such as
acetylsalicylic acid, celecoxib, minocycline, antitumor necrosis factor
α agents, curcumin, and omega-3 polyunsaturated fatty acids for
mood disorders.
An increasing number of studies have focused on dysregulation of
second messenger systems, gene transcription, various neurotrophic
factors, and cell turnover in mood disorders. Such pathways have
been more extensively studied in bipolar disorder, where
medications (e.g., lithium) are known to have effects on these cell-
signaling systems (Einat and Manji 2006).
Genetics
The heritability of depression is 33%–50% (Levinson 2006), and
the heritability of bipolar disorder may be as high as 80%–90%
(McGuffin et al. 2003). When the variability of mood disorders and
their complex patterns of inheritance are taken into account, these
illnesses likely involve multiple genes and important genetic-
environmental interactions.
The genetic literature suggests that depression variability might
best be explained by a three-factor model, parsing out the
psychomotor/cognitive, mood, and neurovegetative symptom
clusters of depression. Data also suggest that specific
polymorphisms are associated with distinct personality traits and
symptoms of mood disorders, including neuroticism (Heim and
Binder 2012) and suicidality (Levinson 2006). Consistent with this
concept, several genes involved in monoamine function have been
implicated in vulnerability to depression and bipolar disorders.
Genetic polymorphisms associated with serotonin transporter
inefficiency may contribute to genetic depression vulnerability (see,
e.g., Caspi et al. 2003).
With the recognition that monoamine dysfunction cannot fully
explain the neurobiology of mood disorders, genes for other
neuromodulators are another focus of investigation (Levinson 2006).
For example, a functional polymorphism of the promoter region for
the brain-derived neurotrophic factor gene may cause susceptibility
to mood disorders. Thus, consideration has been given to
conceptualizing mood and genetic risk in the context of
developmental vulnerability, gene-environment interactions, and
epigenetic mechanism (Heim and Binder 2012).
Neuroanatomical Findings
The neuroanatomy of mood disorders has been of interest for
more than a century. Advances in structural and functional
neuroimaging have allowed increasingly detailed investigation of
brain anatomy and have greatly advanced our understanding of how
parts of the brain are involved in the pathophysiology of depression.
The most common structural abnormalities associated with
depression include decreased volumes of the prefrontal cortex,
hippocampus, amygdala, and various basal ganglia structures,
although data are inconsistent (Wise et al. 2014). Most studies
investigating hippocampal abnormalities have shown that patients
with unipolar but not bipolar depression tend to have reduced
hippocampal volume. Some research has also shown decreased
volume of various systems in the prefrontal cortex. Investigations of
the anterior cingulate cortex have likewise been tentatively
implicated; although some meta-analyses using region-of-interest
measurements show no significant change, voxel-based
morphometry meta-analyses show significant volume reduction.
Also, variability in the structure of brain regions involved in mood
regulation may be related to genetic factors—with polymorphisms of
the promoter region for the serotonin transporter gene associated
with differences in volume of the subgenual cingulate cortex and
amygdala in healthy subjects (Rodríguez-Cano et al. 2014).
Functional neuroimaging research has emphasized the role of a
network of brain regions in the pathophysiology of depression. The
“default mode network” refers to a set of interconnected neural
regions that remain active when subjects are awake and not
engaging with any tasks or stimuli (Raichle and Snyder 2007).
Several functional MRI (fMRI) studies have supported the idea that
depression is associated with increased functional connectivity
between the anterior cingulate cortex, as well as other prefrontal
cortex structures, and the default mode network (Greicius et al.
2007). Validating these findings, successful treatment for depressive
symptoms has been shown to normalize default mode network
activity (Dichter et al. 2015). The most common functional
neuroanatomical abnormality that is associated with depression is
resting state hypometabolism and reduced connectivity between the
cortical and limbic systems (Wang et al. 2012). A recent meta-
analysis posits that depression is associated with hypometabolism in
the superior temporal gyrus and the insula (Chen et al. 2015).
However, hyperactivity of the prefrontal cortex has also been
reported (Brody et al. 2001). Depression has also been associated
with the dysfunction of various subcortical limbic systems (Wang et
al. 2012).
Taken together, these data suggest that depression (as a
syndrome) is best characterized not by any single functional
neuroanatomic abnormality but rather by a pattern of brain activity
changes that includes decreased activity in dorsal regions and
increased activity in ventral and limbic-paralimbic regions of a mood
regulation network. Even in subjects who fail to show this typical
pattern, abnormal activity is seen in similar frontal cortical-subcortical
brain regions.
Observations of patients undergoing surgery to alleviate
treatment-refractory depression provide complementary evidence for
this neural systems conceptualization of the depression syndrome
(Mayberg et al. 2005). These studies suggest that surgical
modulation of a putative mood regulation network (e.g., through
tractotomy, vagus nerve stimulation [VNS], or DBS) can alleviate
depression—perhaps through “downstream” effects throughout this
network.
This multidirectional mood network model has been well
supported in recent investigations of emerging treatments for
depression. Neuroanatomical targets for mood disorder treatments
were determined empirically based on brain imaging data and have
been validated by the success of focal stimulation treatment. For
example, on the basis of this model, DBS of the subgenual cingulate
cortex (Brodmann area 25) was developed and has shown promising
antidepressant effects in patients with treatment-resistant
depression; these antidepressant effects were associated with
systemwide changes in regional brain activity consistent with the
effects of combinations of multiple treatments (Holtzheimer et al.
2012). These treatment effects were well maintained in long-term (3-
year) follow-up research. From imaging data, researchers
hypothesize that DBS’s efficacy lies in the subgenual region’s strong
links to structures implicated in mood disorders, including the
nucleus accumbens, amygdala, hypothalamus, and prefrontal cortex.
This supposition might explain behavioral and neurological evidence
that DBS reduces patients’ negative self-bias (Hilimire et al. 2015). In
some other, albeit smaller, trials of DBS, stimulation of the ventral
capsule/ventral striatum, nucleus accumbens, and medial forebrain
bundle/nucleus accumbens have demonstrated antidepressant
effect. Repetitive transcranial magnetic stimulation has
demonstrated utility in providing antidepressant effect, with the left
dorsolateral prefrontal cortex (DLPFC) as the most common target.
The DLPFC is implicated in regulating blood-flow response in the
anterior cingulate cortex based on prior transcranial magnetic
stimulation/positron emission tomography studies (Barrett et al.
2004). Investigations of VNS provide similar evidence that abnormal
cerebral blood flow is associated with depression; several studies
show that the action of VNS mimics cerebral blood flow effects of
antidepressant medications (Conway et al. 2012).
Generally, brain regions implicated in bipolar depression
significantly overlap with those identified in unipolar depression
(Strakowski et al. 2012); this finding is supported by evidence that
patients with unipolar and bipolar depression respond favorably to
DBS of the subgenual cingulate cortex and to right-side prefrontal
transcranial magnetic stimulation. Interestingly, during mania, activity
of prefrontal cortical regions may decrease (as often seen in
depression), perhaps suggesting a valence-independent change in
cortical activity during mood episodes, although lateralization of
decreased activity is dependent on mood state (either manic or
depressed). Decrease in subgenual cingulate cortical volume, seen
after onset of mania, has also been implicated in bipolar disorder.
Abnormalities in limbic structure have also been observed. Some
research suggests that abnormally large prefrontal and
parahippocampal volumes might predict onset of bipolar disorder,
and reduced amygdala volume is consistently associated with
bipolar diagnosis.
From these data, it can be concluded that mood disorders cannot
be simply explained by a “single lesion” model of regional brain
dysfunction (just as no single neurotransmitter abnormality can
explain all depressive syndromes). Rather, the functional
neuroanatomy of mood disorders involves a diverse set of brain
structures, including the prefrontal cortex, anterior cingulate cortex,
subgenual cingulate cortex, medial temporal cortex, parietal cortex,
hippocampus, and amygdala, as well as subcortical structures,
including the ventral striatum, thalamus, hypothalamus, and brain
stem. Additionally, there is notable variability in neuroanatomical
findings reported to date. Although some of this variability might be
explained by inconsistencies in imaging technique and analysis, it is
likely that this discordance results from underlying biological
heterogeneity across mood disorder patients.
Neurobiology of Symptom Domains

Another approach to the study of mood disorders has been to
focus on the neurobiology of specific symptom clusters—based on
the presumption that there will be greater homogeneity in the neural
basis for a specific symptom than for the larger syndrome (in which
symptom manifestation may differ between subjects with the same
disorder). In this section, we review symptom clusters relevant to
mood disorders and neuropsychiatric conditions, followed by the
neurobiological bases of each cluster.
Mood and Affect

Disturbances of mood and affect are fundamental to mood
disorder diagnoses. Essentially, every mood disorder requires a
specific alteration of mood to justify the diagnosis (with the notable
exception of MDD, which allows for no alteration of mood as long as
anhedonia is present). Although the terms mood and affect are often
used interchangeably, it is useful to make a semantic distinction
between the two. Mood is sometimes used to refer to the subjective
emotional state experienced by an individual (e.g., the subject feels
happy, sad, anxious, numb). Affect is more objective and refers to
the individual’s emotional state as it appears to an outside observer
(e.g., the subject looks happy, sad, anxious, numb). Importantly,
affect can also be defined by the range of emotional states a subject
demonstrates (e.g., during an interview), its stability and consistency
over time, and how appropriate affect is, given the conversation,
stated mood, and so forth. Alternatively, mood may be defined as the
sustained, pervasive emotional baseline (the “emotional climate”)
within which moment-to-moment changes in emotion, or affect, occur
(the “emotional weather”) (American Psychiatric Association 2013;
Arciniegas 2013). Within this conceptualization, both mood and
affect have objective and subjective components—namely, the
expression of emotion and the experience of emotional feeling. This
is a critical point discussed in more detail below.
Mood and affective states associated with specific mood episodes
often are clinically straightforward to assess, and, typically, mood
and affect correspond. Thus, patients diagnosed with depression
often describe their mood as “sad,” “blue,” or simply “depressed,”
and their affect expresses sadness, sometimes accompanied by
restricted emotional range. Similarly, patients with mania or
hypomania usually describe elevated moods and often appear
excited and euphoric. Patients in mixed episodes often describe their
moods as “depressed” or “irritable” but rarely describe elevated
moods. However, affect in a mixed episode is often more labile than
in depressed patients and may be inappropriate for the situation or
stated mood.
Patients with neuropsychiatric disease often present in a manner
in which the expression and the experience of emotion appear to be
disconnected. For example, a PD patient may deny experiencing
persistent and excessive sadness or other symptoms of depression
but present with severely restricted range of emotional expression
that resembles that often associated with depression. Other
neurological patients may present with prominent affective instability,
during which their emotional experience is not proportional to the
extreme character of their emotional expression (i.e., laughing with
little or no feeling of mirth, crying with little or no feeling of sadness)
or may even be of a valence contrary to their emotional expression
(i.e., laughing while feeling sad, crying while feeling mirth). Such
episodes, when uncontrollable, stereotyped, and provoked by
sentimentally trivial stimuli, define pathological laughing and crying,
also known as pseudobulbar affect or emotional incontinence
(Arciniegas 2013). These observed dissociations between mood and
affect suggest that mood and affect are controlled by related but
distinct neural systems. For a more complete list of the idiopathic
and neuropsychiatric etiologies of manic symptoms, see Table 25–2.
TABLE 25–2. Common associations with mania in neuropsychiatric patients
Psychiatric (idiopathic)
Bipolar disorder
Cyclothymia
Pharmacological/iatrogenic
Dopaminergic agents
Corticosteroids
Substance intoxication/withdrawal
Surgical treatments, especially,
Pallidotomy
Deep brain stimulation
Antidepressant medications
Neurological
Basal ganglia disease
Huntington’s disease
Wilson’s disease
Cerebrovascular disease
Frontal cortical/subcortical stroke
Basal ganglia stroke
Multiple sclerosis
Infectious encephalitis
Neoplasm
Paraneoplastic syndrome
HIV encephalopathy
Epilepsy
Other
Cushing’s syndrome
Vitamin deficiencies (e.g., B12 or niacin)
Hyperthyroidism
Systemic infections
Uremia
Electrolyte abnormality (e.g., hypocalcemia)
Neuroanatomical studies have played an important role in

elucidating the neurobiology of emotions and emotional regulation.
Broadly speaking, it has been shown that emotional processing
occurs within neural networks that include predominantly ventral
frontal brain structures. In particular, sad mood has been correlated
with increased activity in the ventral medial frontal cortex, with
several studies implicating Brodmann area 25 of the subgenual
cingulate cortex as a critical node in this network. Changes in this
region have been associated with antidepressant treatments
(Mayberg 2003; Mayberg et al. 2005) (Figure 25–2).
FIGURE 25–2. Imaging data supporting role for Brodmann area (BA) 25 in
depression.
(top row) Decreased activity in the subgenual cingulate (BA25; Cg25) is a
consistent finding across numerous and diverse treatment studies. (bottom row)
Increased subgenual cingulate activity is associated with increased sadness, and
functional connectivity of this region during processing of emotional stimuli may be
mediated by genetics.
DBS=deep brain stimulation; ECT=electroconvulsive therapy; SERT=serotonin
transporter; SSRI=selective serotonin reuptake inhibitor; TMS=transcranial
magnetic stimulation.
Source. Adapted from Mayberg 2003.
Suppression of sadness in healthy subjects has been associated

with the DLPFC, possibly suggesting a compensatory response in
healthy subjects that may be abnormal in depressed patients (where
abnormal DLPFC activity is typically observed). Positive emotion is
associated with similar frontal, especially prefrontal, brain structures.
Temporal lobe structures, especially the amygdala, have also been
implicated in emotional processing. Further, cortical-amygdala
interactions may be involved in emotional reactivity, with variability
between persons explained in part by genetic differences (Hariri et
al. 2005). Corroborating evidence that the amygdala is implicated in
dysphoria, studies have shown that with successful depression
treatment, amygdala hyperactivity associated with depression
subsides (Sheline et al. 2001).
Some investigators have suggested the brain has lateralized
networks for emotional regulation, such that processing of positive
emotions is more strongly associated with left-side brain function and
processing of negative emotions is more associated with right-side
neural systems. Hemispheric asymmetry is associated with emotion-
processing differences in patients with depression:
electroencephalogram (EEG) studies show that those with typical
(melancholic) depression fail to show right hemispheric dominance
(which aids in processing emotionally salient visual stimuli), whereas
individuals without depression and those with atypical depression
typically have a right hemispheric dominance when processing visual
stimuli and linguistic stimuli (Miller et al. 1995). Successful selective
serotonin reuptake inhibitor treatment for depression is associated
with decreased activation of specific brain regions in response to sad
stimuli (Fu et al. 2004). Emotion regulation might also be associated
with lateralization; some EEG studies suggest that depressed
patients who respond to selective serotonin reuptake inhibitors tend
to show greater right hemispheric activation compared with
depressed nonresponders (Bruder et al. 2001).
Patients with bipolar disorder tend to be emotionally dysregulated
and hyperreactive (Townsend and Altshuler 2012) and show
correspondingly higher activity in response to both positive and
negative emotional stimuli. Their current mood state further
influences emotion regulation; investigators have found that for
bipolar patients in depressive episodes, exposure to happy faces
induced hyperactivity in the frontal lobe, striatum, and thalamus; for
those in manic episodes, exposure to sad faces induced
hyperactivity in the fusiform gyrus (Chen et al. 2006).
Disturbance of affect has been associated with dysfunction within
the basal ganglia and related structures. PD patients, for example,
may demonstrate “depressive” affect in the absence of other
depressive symptoms; further, PD patients may have greater
difficulty demonstrating and recognizing facial expressions of
emotion (Péron et al. 2012).
The neurochemical bases of mood and affect are not clear,
although the involvement of monoaminergic systems has been
suggested. Acute depletion of tryptophan (resulting in decreased
available serotonin) can lead to a recurrence of “depressive
symptoms” in vulnerable patients (Faulkner and Deakin 2014),
although it is not clear from the literature which depressive
symptoms recur. Dopamine function has been strongly associated
with positive emotional states.
Interest and Motivation

Mood episodes are commonly associated with disturbances of
interest and motivation (i.e., perceived importance of and internal
drive to engage with the external world). In fact, a major depressive
episode may be diagnosed in the absence of expressed depressed
mood if significant anhedonia is present. Individuals with depression,
especially melancholic depression, often present with severe
anhedonia such that they typically report no pleasure from even
highly positive stimuli. Conversely, patients with mania and
hypomania often demonstrate an exaggerated level of interest and
increased responsiveness to positive stimuli—clinically, this may
present as increased goal-directed activity (e.g., vigorous writing,
cleaning) or engagement in pleasurable activity regardless of risks
(e.g., promiscuity, substance abuse).
In the absence of a mood disorder, however, interest and
motivation may also be disturbed. For example, apathy without
associated depression is a common symptom associated with PD,
Alzheimer’s dementia, and some cases of traumatic brain injury
(Cipriani et al. 2014). Further, some neurological patients (often
traumatic brain injury, including stroke, patients) demonstrate
increased pleasure seeking or disinhibition without having other
symptoms associated with mania or hypomania (Starkstein et al.
2004).
Along these lines, it is important to recognize a distinction
between anhedonia and apathy. Anhedonia is defined as a
decreased ability to experience pleasure, whereas apathy is defined
as primarily a diminished drive to engage in goal-directed thought
and activity as well as diminished emotion and emotional reactivity.
Studies of interest and motivation strongly implicate function
within ventral striatal and cortical systems that are involved in
dopamine metabolism. Ventral striatal dopaminergic pathways
appear to play a critical role in motivation (Der-Avakian and Markou
2012). Although the constructs of motivation, reward-seeking
behavior, and hedonic response are inherently intertwined, studies
suggest that dopamine might be more strongly related to motivation-
seeking behavior than to hedonic response and reward (Robinson et
al. 2005). Compared with healthy control subjects, depressed
patients show decreased resting state functional connectivity
between the cingulate cortex and striatum, including the caudate
nucleus—structures critical to the reward processing system (Bluhm
et al. 2009).
In depressed patients, anhedonia has been associated with
decreased activity in ventral basal ganglia and ventral prefrontal
cortical regions (Keedwell et al. 2005), perhaps related to depressed
patients’ attenuated emotional and neural response to positive
emotional stimuli.
Studies of apathy (separate from depression and anhedonia)
have implicated similar, but somewhat more dorsal prefrontal and
subcortical, brain regions, with studies showing decreased activity in
the left anterior cingulate and orbitofrontal gyrus and the right inferior
and medial frontal gyrus. In the context of neurodegenerative
disorders, subtype of dementia influences apathy symptoms:
patients with Alzheimer’s disease tend to have apathy in conjunction
with dysphoric mood symptoms, but patients with frontotemporal
dementia do not (Chow et al. 2009).
In summary, anhedonia and apathy appear to be mediated by
overlapping brain regions that primarily include ventral cortical and
subcortical areas. These regions largely overlap those involved in
mood regulation described above (Der-Avakian and Markou 2012).
However, studies show that specific regions may be involved in
decreased interest and motivation in the absence of the full
depressive syndrome.
Sleep
Sleep is frequently abnormal in patients with mood disorders.
Depressed patients often complain of decreased sleep due to
difficulty falling asleep (early insomnia), frequent awakenings during
the sleep cycle (middle insomnia), or early morning awakening (late
insomnia). Other patients describe hypersomnia (common in atypical
depression). Manic and hypomanic patients typically report
decreased need for sleep—that is, they feel capable of functioning
“normally” on little or no sleep at all—in addition to an overall
decreased amount of sleep, a measure that correlates with symptom
severity. Sleep disturbance in bipolar disorder is common regardless
of mood state, although it worsens preceding and during episodic
periods. As with disturbances of affect, interest, and motivation,
sleep abnormalities in the absence of a mood disorder are
commonly found in neuropsychiatric patients, such as those with PD,
Huntington’s disease, and dementia (Gagnon et al. 2008).
Sleep physiology has been extensively studied in depressed
patients. Sleep EEG abnormalities in depression include prolonged
sleep latency, decreased slow-wave sleep, and reduced rapid eye
movement (REM) latency with disturbances in the relative time spent
in both REM and non-REM sleep. Reduced REM latency is the best
studied and most reproducible sleep-related EEG finding in
depressed patients, and this abnormality is reversed by most
antidepressants. Particularly for those with more variable mood
states, sleep deprivation has an effect similar to antidepressant
medication, although the rapid, dramatic improvement in depressive
symptoms is short-lived. Imaging data have suggested that
increased pretreatment activity in the ventral anterior cingulate
cortex and ventromedial prefrontal cortex may predict antidepressant
response to sleep deprivation (Wu et al. 1999).
Electroencephalographic research also suggests that the
ventromedial prefrontal cortex in depressed patients is hyperactive
during sleep; activity in this region correlates with poor response to
treatment and the likelihood of relapse (Broadway et al. 2012).
Changes in nocturnal body temperature and attenuation of the
normal fluctuations in core body temperature during sleep further
suggest a more generalized dysregulation of normal circadian
rhythms in patients with depression. To date, however, none of these
markers has proven to be specific to depressive disorders,
suggesting a neural system underlying sleep and circadian rhythms
that is involved in but not specific to mood disorder syndromes.
Interestingly, findings in depressed patients with sleep dysregulation
suggest genetic vulnerability.
The physiology of sleep disturbances in patients with mania and
bipolar depression is less well characterized. Clinically, sleep
deprivation is a common precipitant of manic episodes, again
suggesting an important biological link between sleep and affective
symptoms, with effects on REM measures and sleep continuity
similar to those implicated in unipolar depression. Patients with
bipolar depression presenting with hypersomnia, however, do not
show a consistent reduction in REM latency.
Appetite
In patients with depression, appetite may be decreased,
increased, or unchanged. The most common abnormality is a
decrease in appetite with corresponding weight loss. However, some
patients report increased appetite and weight gain during depressive
episodes. In mania, appetite change is not a specific criterion for the
disorder, although decreased appetite (or decreased intake) is
commonly observed. As with sleep, appetite abnormalities are
common in neuropsychiatric disease.
The neurobiology of appetite disturbance in patients with mood
disorder and/or neuropsychiatric disease is not well understood. As
described above, appetite and weight changes are common in these
patients. Also, medications used to treat these conditions (e.g.,
anticonvulsants, lithium, neuroleptics) have clear effects on appetite,
body weight, and metabolism. The regulation of appetite and feeding
involves brain regions, including the hypothalamus and amygdala,
and neuromodulatory systems, including leptin (a peripheral
hormone in central nervous system activity), melanocortin,
neuropeptide Y, the HPA axis, and the monoamines (especially
dopamine) (Kishi and Elmquist 2005). In particular, depression is
hypothesized to disrupt HPA function, particularly the regulation of
corticotropin-releasing hormone, which, in turn, reduces appetite.
Psychomotor Activity
Motor and psychomotor deficits in depression include changes in
motility, mental activity, and speech. Depressed patients typically
report a subjective sense of fatigue and a perceived and observed
slowing of thought processes and physical activity. Taken to the
extreme, a depressed patient may present with catatonia.
Conversely, mania is almost always associated with a dramatic
increase in psychomotor speed (often reported as “racing” thoughts
and associated with a corresponding increase in activity level [e.g.,
pressured speech, agitation]). These changes in psychomotor
activity (including speech) tend to be state related. Spontaneous
motor activity is significantly lower when patients are depressed and
not euthymic.
As with emotional state, psychomotor activity has a subjective and
objective component. Thus, a depressed patient may “feel” as if he
or she has no energy but appear agitated and demonstrate
increased physical activity—such a disconnect may be indicative of a
mixed mood episode or anxiety. Many neuropsychiatric illnesses are
associated with a slowing of thought and motor activity without other
symptoms of depression (e.g., PD). Agitation is also a common but
nonspecific symptom in neuropsychiatric patients. Although agitation
may be indicative of a manic episode or anxiety, it may also arise as
a response to pain or as a medication side effect (e.g., akathisia
from antipsychotic medications).
Psychomotor abnormalities have largely been linked to
monoaminergic neurotransmission and dorsal cortical and
subcortical brain activity. Dopamine has been clearly implicated in
the neurobiology of psychomotor activity. PD patients have
decreased psychomotor activity (in the absence of depression) that
clearly improves with dopaminergic therapies, and stimulant
medications affecting dopaminergic function are associated with
increased psychomotor activity. Decreased dopamine in the basal
ganglia has been associated with psychomotor retardation in
depressed patients. Dorsolateral prefrontal cortex activity correlates
with psychomotor activity in depressed patients, such that decreased
blood flow or metabolism in the dorsal prefrontal cortex is associated
with psychomotor retardation (Buyukdura et al. 2011).
Emotional Bias
Patients with mood disorders commonly demonstrate mood-
congruent emotional bias in cognitive processing. For example,
depressed subjects show better recall for negative words and are
faster than nondepressed individuals at identifying negative
adjectives as self-descriptive (Stuhrmann et al. 2011). In mania,
subjects can demonstrate a strong positive emotional bias that
presents as grandiosity and overfriendliness.
Neuroticism involves temperamental hypersensitivity to negative
stimuli and the tendency to experience exaggerated negative mood
states in situations of emotional instability or dissonance. High levels
of neuroticism (especially when combined with low levels of
extroversion) may indicate a predisposition to developing
depression. Using a different model of personality, Cloninger et al.
(2006) suggest that personality traits involving negative bias (such
as high “harm avoidance” and low “self-directedness”) predict
development of depression.
Emotional bias refers to the distorted processing of emotional
stimuli. Processing of positive and negative information (such as
rewards and punishments) has been linked to the ventral prefrontal
cortex, ventral striatum, amygdala, and hippocampus (Stuhrmann et
al. 2011) and to dopamine function. Depressed patients have shown
abnormal activity in ventral cortical and subcortical brain regions
associated with processing of feedback and negative emotional
stimuli (George et al. 1997).
In this review, emotional bias is treated as a separate symptom.
However, it may be better described as the cognitive processing of
emotional stimuli. As such, it is not unreasonable to expect that
emotional bias may reflect an interaction of neural systems involved
in mood and cognition. For example, older patients with depression
have shown slower performance on the emotional Stroop Test
(compared with matched control subjects) as well as slower
response to negative versus neutral/positive words (a pattern not
seen in matched control subjects) (Dudley et al. 2002). Depressed
patients, compared with healthy control subjects, show a different
functional pattern of frontal-limbic brain activity during the standard
and emotional Stroop tasks (George et al. 1997). Negative and
positive emotional processing are both implicated in depression, with
fMRI data showing that depressed participants, when compared with
control subjects, had less activation of the frontotemporal and limbic
regions in response to happy words. In response to sad words,
depressed participants showed increased activation in the inferior
parietal lobe and less activation in the superior temporal gyrus and
cerebellum (Canli et al. 2004). However, some research suggests
that patients with depression have attenuated neural responses to
almost all emotional stimuli, which might explain depressed patients’
inaccuracy in assessing subtle facial expressions and impaired
emotional functioning (Stuhrmann et al. 2011).
Suicidal ideation is a type of extreme negative emotional bias.
Postmortem brain studies of depressed people who died by suicide
report changes in a number of additional serotonin markers,
including regional transmitter and metabolite levels, neurotransmitter
receptor density, and second messenger and transcription proteins
(Arango et al. 2003).
Cognition
The cognitive abnormalities typically seen in depressed patients
include slowed thought processes and impaired attention and
concentration. Depressed patients also demonstrate impaired
executive functioning (e.g., planning, organization, short-term
memory). Manic patients show impaired memory encoding, poor
concentration and attention, and compromised executive functioning
skills in category fluency and mental manipulation and behavioral
inhibition (Robinson et al. 2006). Even in the absence of mood
disorders, neurological patients commonly show cognitive
impairment such that these symptoms may be nonspecific in
neuropsychiatric conditions. However, in contrast to deficits
associated with many structural neurological disorders, specific
impairments in language, perception, and spatial abilities are not
usually seen in patients with idiopathic mood disorders (except as a
secondary consequence of poor attention, motivation, or
organizational abilities). Cognitive deficits in mood disorders are
typically of mild to moderate severity but can become quite severe in
prolonged or intractable depression—some patients, especially
patients with late-life depression, may develop “pseudodementia”
(Raskind 1998). Finally, cognitive disturbances may be exacerbated
in neurological patients with co-occurring mood disorders.
The neurobiology of cognition has been extensively investigated.
Mood disorders primarily disturb cognitive functioning in the dorsal
frontal and subcortical brain regions. Executive function, including
information organization, strategy planning, and problem solving, as
well as executive control of other cognitive functions (e.g., attention,
working memory, declarative memory, language), is clearly linked
with dorsolateral prefrontal cortical function and tends to be impaired
in depression. Depressed patients have shown blunting of an
expected left anterior cingulate increase during performance of a
cognitive interference task (tests of the Stroop effect). These patients
have also shown a corresponding increase in function within the
DLPFC (a region not normally recruited during this task) (George et
al. 1997), suggesting altered compensatory activity.
Bipolar patients in manic episodes show poor activation in the
orbitofrontal cortex during a response inhibition task that reliably
increases orbitofrontal activity in nonbipolar control subjects
(Altshuler et al. 2005). Disinhibition, a common feature of mania and
dementia, has been associated with ventral cortical structures
(Starkstein et al. 2004).
Conclusion: A Neural Circuitry Model of Mood

Disorders
Considering mood disorders within a neuropsychiatric context
highlights that these conditions represent dysfunction within several
distinct but interconnected neural circuits (see, e.g., Figure 25–3). An
extrapolation is that phenomenological differences between patients
with mood disorders might best be explained by differential
dysfunction within these circuits. Key features of a neural circuitry
model of mood disorders are as follows: 1) network dysfunction (i.e.,
mood disturbance) may be precipitated by dysfunction at any “critical
node” within the network; 2) dysfunction at a critical node will have
“upstream” and “downstream” effects that may result in further
symptoms; 3) compensatory alterations within the network (in
response to dysfunction) may lead to further alterations throughout
the network, resulting in further symptomatic manifestation; and 4)
successful treatment of network dysfunction may occur through
modulation of function at other critical nodes, presuming
compensatory responses are intact.
FIGURE 25–3. A proposed model of mood regulation.
Different sets of brain regions are involved in different aspects of mood experience
and modulation. Numerous interconnections exist between these different regions,
and the system is recognized to be dynamic and potentially modulated at any
critical node. Different treatments for mood disorder syndromes may act primarily
at different nodes within the system with therapeutic downstream effects.
a-ins=anterior insula; amg=amygdala; aCg24b=Brodmann area 24b/dorsal-
perigenual anterior cingulate cortex; bstem=brain stem; CBT=cognitive-behavioral
therapy; cd-vst=ventral caudate–ventral striatum; DBS=deep brain stimulation of
Brodmann area 25; hc=hippocampus; hth=hypothalamus; mb-
sn=midbrain/subthalamic nuclei; mCg24c=Brodmann area 24c/dorsal anterior
cingulate cortex; MEDS=antidepressant medications; mF9/10=medial frontal
cortex; oF11=orbitofrontal cortex; Par40=dorsal parietal; pCg=posterior cingulate
gyrus; PF9/46=dorsolateral prefrontal cortex; PM6=premotor area;
rCg24a=Brodmann area 24a/perigenual-subgenual cingulate cortex;
sgCg25=Brodmann area 25/subgenual cingulate cortex; thal=thalamus.
Within this model, distinct neural systems are associated with

specific functions (and therefore associated with underlying symptom
clusters). Cognitive, psychomotor, and sensorimotor processing is
associated with dorsal prefrontal, dorsal anterior cingulate, and
parietal and posterior cingulate cortices, as well as hippocampus.
Medial frontal, orbitofrontal, and perigenual anterior cingulate
cortices are associated with overt cognitive processing of emotional
stimuli, including salience, reward value, and self-relevance. More
covert/masked cognitive-emotional processing is associated with
medial temporal and subcortical regions, including the amygdala,
ventral basal ganglia, and midbrain structures/nuclei. The brain
regions involved in homeostatic/drive processes (e.g., sleep,
appetite), as well as body state representation (i.e., the physical
aspects of emotional experience), include the subcallosal anterior
cingulate cortex, anterior insula, and hypothalamus. Brain stem
nuclei are also included in these regions, although it is recognized
that monoaminergic projections from these nuclei influence function
throughout the entire network.
Emotional-behavioral states (e.g., depression) are then
understood to be associated with alteration within several distinct but
overlapping neural circuits, with symptomatic presentation
corresponding to the direction and degree of dysfunction within each
subnetwork. The source of dysfunction may vary (e.g., between
idiopathic and neurologically related depression), but the neural
systems involved are the same. It is further hypothesized that
treatments with different primary mechanisms of action directly alter
network activity at distinct nodes. Efficacy is then determined by how
adequately the treatment site of action matches the source of
dysfunction and/or the compensatory activity of the network. For
example, certain “first-line” treatments, such as serotonergic
antidepressant medications and cognitive-behavioral therapy (CBT),
may have different primary sites of action within the network (frontal
cortex for CBT and midbrain-subcortical regions for medications) but
rely on intact connections between various regions of the circuit and
the ability of these connected regions to respond appropriately (i.e.,
changes in midbrain-subcortical regions with medications must be
able to result in downstream functional changes in frontal cortex, and
vice versa for CBT). Similarly, poor adaptive capacity within the
network may underlie lack of response to common treatments and
explain why progressively more aggressive treatments (such as
electroconvulsive therapy and surgery) are needed to ameliorate
symptoms.
References
Altshuler LL, Bookheimer SY, Townsend J, et al: Blunted activation in orbitofrontal
cortex during mania: a functional magnetic resonance imaging study. Biol
Psychiatry 58(10):763–769, 2005 16310510
1994
Arango V, Huang YY, Underwood MD, et al: Genetics of the serotonergic system in
suicidal behavior. J Psychiatr Res 37(5):375–386, 2003 12849930
Arciniegas DB: Emotion, in Behavioral Neurology and Neuropsychiatry. Edited by
Arciniegas DB, Anderson CA, Filley CM. Cambridge, UK, Cambridge University
Press, 2013, pp 266–298
Barrett J, Della-Maggiore V, Chouinard PA, et al: Mechanisms of action underlying
the effect of repetitive transcranial magnetic stimulation on mood: behavioral
and brain imaging studies. Neuropsychopharmacology 29(6):1172–1189, 2004
15029151
Bluhm R, Williamson P, Lanius R, et al: Resting state default-mode network
connectivity in early depression using a seed region-of-interest analysis:
decreased connectivity with caudate nucleus. Psychiatry Clin Neurosci
63(6):754–761, 2009 20021629
Broadway JM, Holtzheimer PE, Hilimire MR, et al: Frontal theta cordance predicts
6-month antidepressant response to subcallosal cingulate deep brain
stimulation for treatment-resistant depression: a pilot study.
Neuropsychopharmacology 37(7):1764–1772, 2012 22414813
Brody AL, Saxena S, Mandelkern MA, et al: Brain metabolic changes associated
with symptom factor improvement in major depressive disorder. Biol Psychiatry
50(3):171–178, 2001 11513815
Bruder GE, Stewart JW, Tenke CE, et al: Electroencephalographic and perceptual
asymmetry differences between responders and nonresponders to an SSRI
antidepressant. Biol Psychiatry 49(5):416–425, 2001 11274653
Buyukdura JS, McClintock SM, Croarkin PE: Psychomotor retardation in
depression: biological underpinnings, measurement, and treatment. Prog
Neuropsychopharmacol Biol Psychiatry 35(2):395–409, 2011 21044654
Caddy C, Giaroli G, White TP, et al: Ketamine as the prototype glutamatergic
antidepressant: pharmacodynamic actions, and a systematic review and meta-
analysis of efficacy. Ther Adv Psychopharmacol 4(2):75–99, 2014 24688759
Canli T, Sivers H, Thomason ME, et al: Brain activation to emotional words in
depressed vs healthy subjects. Neuroreport 15(17):2585–2588, 2004
15570157
Caspi A, Sugden K, Moffitt TE, et al: Influence of life stress on depression:
moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–
389, 2003 12869766
Chen CH, Lennox B, Jacob R, et al: Explicit and implicit facial affect recognition in
manic and depressed States of bipolar disorder: a functional magnetic
resonance imaging study. Biol Psychiatry 59(1):31–39, 2006 16112653
Chen ZQ, Du MY, Zhao YJ, et al: Voxel-wise meta-analyses of brain blood flow
and local synchrony abnormalities in medication-free patients with major
depressive disorder. J Psychiatry Neurosci 40(6):401–411, 2015 25853283
Chow TW, Binns MA, Cummings JL, et al: Apathy symptom profile and behavioral
associations in frontotemporal dementia vs dementia of Alzheimer type. Arch
Neurol 66(7):888–893, 2009 19597092
Cipriani G, Lucetti C, Danti S, et al: Apathy and dementia: nosology, assessment
and management. J Nerv Ment Dis 202(10):718–724, 2014 25265266
Cloninger CR, Svrakic DM, Przybeck TR: Can personality assessment predict
future depression? a twelve-month follow-up of 631 subjects. J Affect Disord
92(1):35–44, 2006 16442638
Conway CR, Sheline YI, Chibnall JT, et al: Brain blood-flow change with acute
vagus nerve stimulation in treatment-refractory major depressive disorder.
Brain Stimulat 5(2):163–171, 2012 22037127
Der-Avakian A, Markou A: The neurobiology of anhedonia and other reward-
related deficits. Trends Neurosci 35(1):68–77, 2012 22177980
Dichter GS, Gibbs D, Smoski MJ: A systematic review of relations between
resting-state functional-MRI and treatment response in major depressive
disorder. J Affect Disord 172:8–17, 2015 25451389
Dudley R, O’Brien J, Barnett N, et al: Distinguishing depression from dementia in
later life: a pilot study employing the Emotional Stroop task. Int J Geriatr
Psychiatry 17(1):48–53, 2002 11802230
Einat H, Manji HK: Cellular plasticity cascades: genes-to-behavior pathways in
animal models of bipolar disorder. Biol Psychiatry 59(12):1160–1171, 2006
16457783
Faulkner P, Deakin JF: The role of serotonin in reward, punishment and
behavioural inhibition in humans: insights from studies with acute tryptophan
depletion. Neurosci Biobehav Rev 46(Pt 3):365–378, 2014 25195164
Fu CH, Williams SC, Cleare AJ, et al: Attenuation of the neural response to sad
faces in major depression by antidepressant treatment: a prospective, event-
related functional magnetic resonance imaging study. Arch Gen Psychiatry
61(9):877–889, 2004 15351766
Gagnon JF, Petit D, Latreille V, et al: Neurobiology of sleep disturbances in
neurodegenerative disorders. Curr Pharm Des 14(32):3430–3445, 2008
19075719
George MS, Ketter TA, Parekh PI, et al: Blunted left cingulate activation in mood
disorder subjects during a response interference task (the Stroop). J
Greicius MD, Flores BH, Menon V, et al: Resting-state functional connectivity in
major depression: abnormally increased contributions from subgenual cingulate
cortex and thalamus. Biol Psychiatry 62(5):429–437, 2007 17210143
Hariri AR, Drabant EM, Munoz KE, et al: A susceptibility gene for affective
disorders and the response of the human amygdala. Arch Gen Psychiatry
62(2):146–152, 2005 15699291
Heim C, Binder EB: Current research trends in early life stress and depression:
review of human studies on sensitive periods, gene-environment interactions,
and epigenetics. Exp Neurol 233(1):102–111, 2012 22101006
Hilimire MR, Mayberg HS, Holtzheimer PE, et al: Effects of subcallosal cingulate
deep brain stimulation on negative self-bias in patients with treatment-resistant
depression. Brain Stimulat 8(2):185–191, 2015 25499035
Holtzheimer PE, Kelley ME, Gross RE, et al: Subcallosal cingulate deep brain
stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen
Psychiatry 69(2):150–158, 2012 22213770
Keedwell PA, Andrew C, Williams SC, et al: The neural correlates of anhedonia in
major depressive disorder. Biol Psychiatry 58(11):843–853, 2005 16043128
Kishi T, Elmquist JK: Body weight is regulated by the brain: a link between feeding
and emotion. Mol Psychiatry 10(2):132–146, 2005 15630408
Levinson DF: The genetics of depression: a review. Biol Psychiatry 60(2):84–92,
2006 16300747
Mayberg HS: Frontal lobe dysfunction in secondary depression. J Neuropsychiatry
Clin Neurosci 6(4):428–442, 1994 7841814
Mayberg HS: Modulating dysfunctional limbic-cortical circuits in depression:
towards development of brain-based algorithms for diagnosis and optimised
treatment. Br Med Bull 65:193–207, 2003 12697626
Mayberg HS, Lozano AM, Voon V, et al: Deep brain stimulation for treatment-
resistant depression. Neuron 45(5):651–660, 2005 15748841
McGuffin P, Rijsdijk F, Andrew M, et al: The heritability of bipolar affective disorder
and the genetic relationship to unipolar depression. Arch Gen Psychiatry
60(5):497–502, 2003 12742871
Miller EN, Fujioka TA, Chapman LJ, et al: Psychometrically matched tasks for
assessment of hemispheric asymmetries of function. Brain Cogn 28(1):1–13,
1995 7546665
Morilak DA, Frazer A: Antidepressants and brain monoaminergic systems: a
dimensional approach to understanding their behavioural effects in depression
and anxiety disorders. Int J Neuropsychopharmacol 7(2):193–218, 2004
15003145
Pariante CM, Lightman SL: The HPA axis in major depression: classical theories
and new developments. Trends Neurosci 31(9):464–468, 2008 18675469
Péron J, Dondaine T, Le Jeune F, et al: Emotional processing in Parkinson’s
disease: a systematic review. Mov Disord 27(2):186–199, 2012 22162004
Raichle ME, Snyder AZ: A default mode of brain function: a brief history of an
evolving idea. Neuroimage 37(4):1083–1090; discussion 1097–1089, 2007
17719799
Raskind MA: The clinical interface of depression and dementia. J Clin Psychiatry
59 (suppl 10):9–12, 1998 9720476
Robinson LJ, Thompson JM, Gallagher P, et al: A meta-analysis of cognitive
deficits in euthymic patients with bipolar disorder. J Affect Disord 93(1–3):105–
115, 2006 16677713
Robinson S, Sandstrom SM, Denenberg VH, et al: Distinguishing whether
dopamine regulates liking, wanting, and/or learning about rewards. Behav
Neurosci 119(1):5–15, 2005 15727507
Rodríguez-Cano E, Sarró S, Monté GC, et al: Evidence for structural and
functional abnormality in the subgenual anterior cingulate cortex in major
depressive disorder. Psychol Med 44(15):3263–3273, 2014 25066663
Rosenblat JD, Cha DS, Mansur RB, et al: Inflamed moods: a review of the
interactions between inflammation and mood disorders. Prog
Neuropsychopharmacol Biol Psychiatry 53:23–34, 2014 24468642
Sanacora G, Treccani G, Popoli M: Towards a glutamate hypothesis of depression:
an emerging frontier of neuropsychopharmacology for mood disorders.
Neuropharmacology 62(1):63–77, 2012 21827775
Sheline YI, Barch DM, Donnelly JM, et al: Increased amygdala response to
masked emotional faces in depressed subjects resolves with antidepressant
treatment: an fMRI study. Biol Psychiatry 50(9):651–658, 2001 11704071
Starkstein SE, Robinson RG, Price TR: Comparison of cortical and subcortical
lesions in the production of poststroke mood disorders. Brain 110(Pt 4):1045–
1059, 1987 3651794
Starkstein SE, Garau ML, Cao A: Prevalence and clinical correlates of disinhibition
in dementia. Cogn Behav Neurol 17(3):139–147, 2004 15536301
Strakowski SM, Adler CM, Almeida J, et al: The functional neuroanatomy of bipolar
disorder: a consensus model. Bipolar Disord 14(4):313–325, 2012 22631617
Stuhrmann A, Suslow T, Dannlowski U: Facial emotion processing in major
depression: a systematic review of neuroimaging findings. Biol Mood Anxiety
Disord 1(1):10, 2011 22738433
Townsend J, Altshuler LL: Emotion processing and regulation in bipolar disorder: a
review. Bipolar Disord 14(4):326–339, 2012 22631618
Wang L, Hermens DF, Hickie IB, et al: A systematic review of resting-state
functional-MRI studies in major depression. J Affect Disord 142(1–3):6–12,
2012 22858266
Wise T, Cleare AJ, Herane A, et al: Diagnostic and therapeutic utility of
neuroimaging in depression: an overview. Neuropsychiatr Dis Treat 10:1509–
1522, 2014 25187715
Wu J, Buchsbaum MS, Gillin JC, et al: Prediction of antidepressant effects of sleep
deprivation by metabolic rates in the ventral anterior cingulate and medial
prefrontal cortex. Am J Psychiatry 156(8):1149–1158, 1999 10450253
CHAPTER 26
Anxiety Disorders
Although anxiety has long held a central place in theories of

psychopathology, it has only recently been appreciated that the
anxiety disorders are the most prevalent category of mental illness in
the United States (Kessler et al. 2010) and that they account for
approximately a third of the country’s total mental health costs
(Lepine 2002). Furthermore, although it has long been recognized
that specific neurological lesions may lead to anxiety symptoms (Von
Economo 1931), only in recent decades have advances in research
allowed specific neuroanatomical hypotheses to be proposed for
each of the anxiety disorders.
DSM-III (American Psychiatric Association 1980) provided
significant impetus to research on anxiety disorders by replacing the
category of “anxiety neurosis” with several different conditions and
by providing each with operational diagnostic criteria. DSM-IV-TR
(American Psychiatric Association 2000) anxiety disorders include
panic disorder with and without agoraphobia, social phobia (social
anxiety disorder), generalized anxiety disorder (GAD), posttraumatic
stress disorder (PTSD), obsessive-compulsive disorder (OCD),
substance-induced anxiety disorder, and anxiety disorder due to a
general medical condition. The DSM-5 (American Psychiatric
Association 2013) section on anxiety disorders no longer includes
PTSD (which is found in the section on trauma- and stressor-related
disorders) or OCD (which is included within the section on
obsessive-compulsive and related disorders). For the purposes of
this volume, we use the current DSM-5 classification and also retain
inclusion of PTSD.
In each of the anxiety disorders, it is possible to discern a
component comprising anxiety symptoms and a component
comprising avoidance symptoms. In GAD, patients have anxiety
about the future, and worry may serve as an avoidance behavior. In
panic disorder, the anxiety symptoms are those of the panic attack, a
discrete period of anxiety that develops rapidly, often spontaneously.
The individual also may develop agoraphobia symptoms, or
avoidance of those stimuli that appear to promote panic attacks. In
social anxiety disorder, panic attacks develop only in the context of
performance or other social situations in which the person fears
embarrassment or humiliation. As a result of these fears, the person
may avoid these situations. In PTSD, in the aftermath of a traumatic
event, the person has intrusive experiences, hyperarousal
symptoms, negative alterations in cognition and mood, and a range
of avoidance and numbing symptoms.
In this chapter, we review these developments in our
understanding of the anxiety disorders from a neuropsychiatric
perspective. The neurochemistry and neuroanatomy of each of the
main anxiety disorders and PTSD are considered first. Neurological
disorders that may manifest with anxiety symptoms are then
discussed, and future directions in the neuropsychiatry of anxiety
disorders are considered briefly.
Primary Anxiety Disorders
In the following sections, we consider the neuropsychiatry of each
of the major primary anxiety disorders (i.e., the “idiopathic”
psychiatric disorders in which anxiety is the defining feature). Each
section begins by sketching a simple neurochemical and
neuroanatomical model of the relevant anxiety disorder. This sketch
is then used as a framework for attempting a more complex
integration of animal data, clinical biological research (e.g.,
pharmacological probe studies), and morphometric brain imaging
studies. Although much remains to be learned about the
neurobiology of the anxiety disorders, there is a growing
consolidation of different avenues of information, with increasingly
specific models now existing for each of the major anxiety disorders.
Generalized Anxiety Disorder

The term “generalized anxiety disorder” was first introduced in
DSM-III, where it represented a refinement of the earlier concept of
“anxiety neurosis.” In DSM-III, GAD was viewed as a residual
diagnosis, to be made in the absence of other disorders. More recent
editions of DSM have, however, increasingly emphasized the
cognitive symptoms of GAD and have also emphasized that GAD is
an independent entity that may be found alone or comorbid with
other anxiety and mood conditions. GAD is the least common
anxiety disorder in specialty anxiety clinics but the most common
anxiety disorder in primary care practice (Kessler 2000).
Neuroanatomical models of GAD have not been well delineated to
date. However, it may be speculated that GAD involves
abnormalities of the amygdala and its connections with various
prefrontal cortical regions, some of which may be shared across
anxiety disorders and others which may reflect core GAD symptoms
of excessive worrying and planning. In reviewing research relevant
to this speculative model, we consider first neurochemical studies
and then neuroanatomical findings.
Neurochemical Studies
Dysregulation of serotonin neurotransmitter systems is implicated
in GAD. Indeed, there is substantial evidence that serotonergic
compounds are effective in the pharmacotherapy for GAD;
buspirone, a serotonin type 1A (5-HT1A) receptor partial agonist, is
effective in some studies, and growing evidence now shows the
efficacy of the selective serotonin reuptake inhibitors (SSRIs) and
serotonin-norepinephrine reuptake inhibitors (SNRIs) in this disorder.
As a result, most current treatment guidelines recommend SSRIs
and SNRIs as first-line pharmacologic agents in GAD (Koen and
Stein 2011).
The norepinephrine sympathetic nervous system is sensitive to
stress and anxiety, and it has been implicated in GAD (Nutt 2001). In
clinical studies of GAD, increased plasma norepinephrine and 3-
methoxy-4-hydroxy-phenylglycol (MHPG) and reduced platelet α2-
adrenergic peripheral receptor binding sites have been reported,
although not all studies of static noradrenergic measures have
produced consistent findings. Administration of more dynamic
adrenergic probes has, however, indicated reduced adrenergic
receptor sensitivity in GAD, perhaps an adaptation to high levels of
circulating catecholamines (Nutt 2001). The locus coeruleus system
may well play a regulatory role in GAD, even if it is not the sole
dysfunctional neurochemical system in the disorder. Indeed, dual
SNRIs have been shown to be effective in GAD. The locus coeruleus
system projects to the amygdala and to other structures involved in
anxiety responses, so that noradrenergic involvement is not
inconsistent with the neuroanatomical model outlined earlier.
Involvement of the γ-aminobutyric acid (GABA)–benzodiazepine
receptor complex in GAD is supported by several studies, and a
review of this literature found reduced GABAA receptors in
temporocortical areas (Nikolaus et al. 2010). GABA is the brain’s
predominant inhibitory neurotransmitter, and GABAergic pathways
are widely distributed; nevertheless, the distribution of GABA and
benzodiazepine receptors is particularly dense in limbic and
paralimbic areas. Clinical studies have shown that benzodiazepines
have efficacy comparable to the SSRIs and venlafaxine in the
treatment of GAD (Koen and Stein 2011). At the same time, long-
term use of benzodiazepines can be associated with withdrawal
symptoms and rebound anxiety, such that most treatment guidelines
do not recommend them as a first-line pharmacotherapy in GAD
(Koen and Stein 2011).
Neuroanatomical Studies
Neuroimaging research on GAD remains at a relatively early
stage. Nevertheless, findings are arguably consistent with
involvement of limbic, paralimbic, and prefrontal regions. Patients
with GAD show hypoactivation of certain prefrontal regulatory
regions that are involved in spontaneous emotion regulation and
conflict adaptation, including the ventral cingulate cortex and
dorsomedial prefrontal cortex (Etkin 2010). In contrast, patients
display hyperactivation of lateral prefrontal areas, which may reflect
compensatory engagement of worrying (Etkin et al. 2010).
Functional neuroimaging studies of amygdalar activity have been
inconsistent, with some reports of amygdala hypoactivation during
processing of threatening stimuli and other reports of amygdala
hyperactivation of this region (Etkin 2010). In a recent meta-analysis
of voxel-based morphometry studies, DSM-5 anxiety disorders,
including GAD, were associated with reduced gray matter volume in
right ventral anterior cingulate cortex and left inferior frontal gyrus
(Shang et al. 2014).
Preliminary imaging data on receptor binding in GAD are also
available. In a review of receptor binding studies in anxiety disorders,
GAD was uniquely associated with reduced temporocortical GABAA
receptors, and GAD shared with all other anxiety disorders
reductions in mesencephalic and cingulate serotonin 1A (5-HT1A)
receptors, striatal dopamine type 2 (D2) receptors, and cortical
GABAA receptors (Nikolaus et al. 2010). This suggests a role for
temporolimbic regions and the GABA-benzodiazepine receptor
complex in mediating core GAD symptoms. Nevertheless,
serotonergic neurons branch widely throughout the brain, affecting
each of the main regions postulated to mediate anxiety symptoms
(Figure 26–1).
FIGURE 26–1. Neuroanatomical model of generalized anxiety disorder
(GAD).
There is evidence of hypofunction and reduced volumes of ventral anterior
cingulate cortex (vACC) and inferior frontal gyrus (IFG), and hypofunction of
dorsomedial prefrontal cortex (dmPFC). In contrast, areas of lateral prefrontal
cortex (LPFC) are hyperactive in GAD. The amygdala (AMY) has been reported to
be hypoactive or hyperactive across studies.
Panic Disorder and Agoraphobia

Panic disorder is a highly prevalent disorder, with rates fairly
similar across different social and cultural settings. It is now well
recognized that panic disorder is associated with significant
morbidity (mood, anxiety, and substance use disorders) and also
with severe impairments in occupational and social functioning.
Indeed, a growing pharmacoeconomic literature has emphasized the
personal and financial costs of panic disorder; this is a serious
disorder that has a substantial negative effect on quality of life. DSM-
5 has separated panic disorder from agoraphobia, such that each is
an independent diagnosis with its own criteria. The co-occurrence of
panic disorder and agoraphobia are now coded as two comorbid
diagnoses, eschewing the DSM-IV diagnoses of panic disorder with
agoraphobia, panic disorder without agoraphobia, and agoraphobia
without a history of panic disorder. Moreover, panic attacks can be
listed as a specifier to any and all DSM-5 disorders.
Over the past decade or two, models of panic disorder have
become increasingly sophisticated (Gorman et al. 2004). The current
neuroanatomical models of panic disorder (Figure 26–2) emphasize
the following: 1) afferents from viscerosensory pathways to thalamus
to the lateral nucleus of the amygdala, as well as from thalamus to
cortical association areas to the lateral nucleus of the amygdala; 2)
the extended amygdala, which is thought to play a central role in
conditioned fear (Ciocchi et al. 2010); 3) the hippocampus, which is
thought crucial for conditioning to the context of the fear (and so
perhaps for phobic avoidance) (Alvares et al. 2012); and 4) efferent
tracts from the amygdala to the hypothalamus and brain stem
structures, which mediate many of the symptoms of panic. Thus,
efferents of the central nucleus of the amygdala include the lateral
nucleus (autonomic arousal and sympathetic discharge) and
paraventricular nucleus (increased adrenocorticoid release) of the
hypothalamus and the locus coeruleus (increased norepinephrine
release), parabrachial nucleus (increased respiratory rate), and
periaqueductal gray (defensive behaviors and postural freezing) in
the brain stem. This kind of general outline can be used as a starting
framework for considering the range of data relevant to the
neurobiology of panic disorder.
FIGURE 26–2. Neuroanatomical model of panic disorder.
There is substantial evidence of hyperactivation of the amygdala (AMY) and
insular cortex (INS), as well as preliminary evidence of reduced activity of ventral
anterior cingulate cortex (vACC) and reduced volume of orbitofrontal gyrus (OFG)
in panic disorder.
Early animal studies found that the locus coeruleus plays a key
role in fear and anxiety, with both electrical and pharmacological
stimulation resulting in fear responses. The locus coeruleus contains
the highest concentration of noradrenergic-producing neurons in the
brain. Viscerosensory input reaches the locus coeruleus via the
nucleus tractus solitarius and the medullary nucleus
paragigantocellularis, and the locus coeruleus sends efferents to a
range of important structures, including the amygdala,
hypothalamus, and brain stem periaqueductal gray (Nutt 2001).
Several clinical studies of panic disorder provide support for the
role of the locus coeruleus; administration of yohimbine, for example,
resulted in greater increases in MHPG in panic disorder patients
than in control subjects without panic disorder. However, not all
studies have replicated such findings, and studies of noradrenergic
function in lactate-induced panic also have been inconsistent
(Gorman et al. 2004), suggesting that additional neurochemical
factors are important in the mediation of panic attacks.
Certainly, increasing evidence indicates that the serotonergic
system plays a crucial role in panic disorder. Multiple lines of
evidence support this; for example, several studies have found that
m-chlorophenylpiperazine (m-CPP) administration leads to an acute
exacerbation of panic symptoms in panic disorder patients (Klein et
al. 1991; van der Wee et al. 2004). In addition, a good deal of
evidence supports the efficacy of the SSRIs in panic disorder;
fluoxetine, paroxetine, and sertraline all have received U.S. Food
and Drug Administration (FDA) approval for use in panic disorder.
They are as effective as and better tolerated than older agents
including tricyclics and monoamine oxidase inhibitors (MAOIs) (Koen
and Stein 2011). Benzodiazepines also are effective in treating panic
disorder (Gorman et al. 2004; Koen and Stein 2011). Alprazolam,
clonazepam, diazepam, and lorazepam are FDA approved to treat
panic disorder (Koen and Stein 2011). However, their side-effect
profile makes them a less preferred option to serotonin agents.
The serotonergic system interacts at several points with
neuroanatomical structures thought to be important in panic disorder.
First, serotonergic projections from the dorsal raphe nucleus
generally inhibit the locus coeruleus, whereas projections from the
locus coeruleus stimulate dorsal raphe nucleus serotonergic neurons
and inhibit median raphe nucleus neurons. Furthermore, the dorsal
raphe nucleus sends projections to prefrontal cortex, amygdala,
hypothalamus, and periaqueductal gray among other structures.
Thus, modulation of the serotonin system has the potential to
influence the major regions of the panic disorder circuit, resulting in
decreased noradrenergic activity, diminished release of corticotropin-
releasing factor, and modification of defense and escape behaviors.
A consideration of the various afferents to the locus coeruleus and
amygdala is relevant to considering the extensive literature on
panicogenic stimuli. It has been argued that respiratory panicogens
(e.g., carbon dioxide, lactate), baroreceptor stimulation, and
circulating peptides (cholecystokinin) promote panic via a limbic
visceroreceptor pathway. In contrast, panic attacks that are
conditioned by visuospatial, auditory, or cognitive cues may be
mediated by pathways from cortical association areas to the
amygdala (Coplan and Lydiard 1998). Ultimately, it may be possible
to determine particular genetic loci that are involved in contextual
fear conditioning, allowing for an integration of the neurochemical,
genetic, and environmental data on panic disorder (Gorman et al.
2004).
Preliminary studies in nonanxious control subjects reported
activation of amygdala and periamygdaloid cortical areas during
conditioned fear acquisition and extinction (Gorman et al. 2004).
Furthermore, in patients with panic disorder, increasing evidence
suggests temporal or amygdalar-hippocampal abnormalities (Uchida
et al. 2008), as well as frontal abnormalities (Konishi et al. 2014).
Insular cortex abnormalities also appear to be central to the
pathophysiology of panic (Paulus and Stein 2006), perhaps
mediating conditioning of fear to interoceptive cues. Although
hypocapnia-induced vasoconstriction has made the results of certain
imaging studies in panic disorder difficult to interpret, it is noteworthy
that imaging data may predict response to panicogens (Kent et al.
2005).
Advances in brain imaging methods have begun to allow the
integration of neuroanatomical and neurochemical data. Thus, a
review of receptor binding studies across the anxiety disorders
concluded that panic disorder is uniquely associated with reduced
frontocortical GABA receptors and shares with other anxiety
disorders reductions in striatal dopamine and midbrain 5-HT1A
receptors (Nikolaus et al. 2010).
Social Anxiety Disorder

Social anxiety disorder (formerly social phobia) is characterized
by a fear of social situations in which the individual may be exposed
to the scrutiny of others. These fears may be divided into those that
concern social interaction situations (e.g., dating, meetings) and
performance fears (e.g., talking, eating, or writing in public). These
fears result in avoidance of social situations or endurance of these
situations with considerable distress. Growing evidence indicates
that social phobia is a chronic disorder, with substantial comorbidity
(particularly of mood and substance use disorders) and significant
morbidity. Patients with social anxiety disorder are more likely to be
unmarried, to have weaker social networks, to fail to complete high
school and college, and to be unemployed (Ballenger et al. 1998).
One of the main changes in diagnostic criteria since publication of
DSM-IV is that individuals need not recognize that their anxiety is
excessive; instead, the anxiety must be judged to be out of
proportion to the objective danger or actual threat in the situation.
Moreover, DSM-5 has added a 6-month minimum duration criterion,
which was restricted to individuals less than 18 years of age in DSM-
IV.
Detailed neuroanatomical models of social anxiety disorder are
emerging from the past two decades of research. We review below
evidence that social anxiety shares certain brain changes with other
anxiety disorders and has also been associated with brain alterations
that appear more specific to this disorder.
Multiple lines of evidence support the role of serotonergic circuits
in social anxiety disorder. Pharmacotherapy with a number of SSRIs
is effective and well tolerated by patients, and paroxetine and
sertraline are FDA-approved for treatment of this disorder. Prior to
the appearance of serotonergic agents, MAOIs and benzodiazepines
had also shown efficacy in social anxiety, although their unfavorable
risk:benefit profile makes them less attractive (Koen and Stein 2011).
There is also evidence that the dopaminergic system is involved
in social anxiety disorder (Stein et al. 2002). Timid mice have
decreased cerebrospinal fluid dopamine levels, and introverted
depressed patients also may have decreased cerebrospinal fluid
dopamine levels. Social status in monkeys may be reflected in
differences in dopamine type 2 (D2) striatal density. More
persuasively, social anxiety may develop in the context of
Parkinson’s disease or after the administration of neuroleptics.
Evidence indicating the hypothalamic-pituitarys-adrenal (HPA)
axis may be dysfunctional in social anxiety disorder is inconsistent to
date. The aggregate of findings points to hyper-responsiveness of
the adrenal cortex in patients with social anxiety, although this is
found more consistently following a stressor, while baseline HPA
function appears similar in patients and normally functioning control
subjects. In addition, there are a number of findings linking HPA axis
abnormalities to early life stress in social anxiety disorder,
suggesting that history of trauma may help parse the inconsistent
findings in the literature (Faravelli et al. 2012).
Additional neurochemical systems deserve exploration in social
anxiety disorder. Glutamate is a particularly widespread excitatory
neurotransmitter in the brain, and a number of psychotropics act to
alter glutamatergic neurotransmission. It is notable that D-
cycloserine, a partial glutamatergic agonist, is useful in the
augmentation of cognitive-behavioral therapy in social anxiety
disorder and some other anxiety disorders. Various neuropeptide
systems, including oxytocin, have also been explored in relation to
social anxiety disorder and other anxiety disorders and may
ultimately provide treatment targets.
Meta-analyses of neuroimaging studies have revealed that social
anxiety disorder is associated with hyperactivity in the limbic fear
circuitry, especially the amygdala and insular cortex, which is a
shared pathology across many anxiety disorders (Etkin and Wager
2007; Hattingh et al. 2013) (Figure 26–3). Thus, patients with social
anxiety disorder show hyperactivation of the amygdala and insula
when exposed to both socially relevant fearful stimuli and
“nonspecific” novel stimuli (Bruhl et al. 2014). Interestingly, subjects
with behavioral inhibition, when studied as adults, also have
heightened amygdala responses to novel fear-relevant stimuli
(Schwartz et al. 2003). It is noteworthy that nonphobic control
subjects with a particular variant in the serotonin transporter gene
that is associated with anxiety traits, as well as subjects with social
anxiety, have decreased volume or increased activity in amygdala or
related circuitry (Bruhl et al. 2014; Furmark et al. 2004).
FIGURE 26–3. Neuroanatomical model of social anxiety disorder.
Hyperactivity of the amygdala (AMY) and insular cortex (INS) is consistently seen
in social anxiety disorder. Thus far, more specific to social anxiety is evidence for
hyperactive medial and lateral prefrontal cortex (PFC), posterior cingulate cortex
(PCC), and areas of parietal-occipital cortex including supramarginal gyrus (SMG)
and fusiform gyrus (FFG).
There is also burgeoning evidence for involvement of prefrontal

and parietal-occipital cortices in the pathophysiology of social anxiety
disorder. In response to tasks using socially relevant stimuli, patients
with social anxiety disorder show hyperactivation of bilateral medial
and ventrolateral prefrontal cortex (Brodmann area [BA] 10), as well
as hyperactivation of the posterior cingulate cortex (BA 31),
supramarginal gyrus (BA 40), and fusiform gyrus (BA 19) (Bruhl et
al. 2014). Evidence of such widespread cortical hyperactivation,
although still fairly preliminary, appears to set social anxiety disorder
apart from other anxiety disorders where cortical hypoactivity is a
more common finding.
Several molecular imaging studies provide additional data that are
relevant to an integrated model of social anxiety disorder. Thus,
involvement of the basal ganglia is indicated by evidence that striatal
dopamine reuptake site densities are markedly lower in patients with
social anxiety than in nonphobic control subjects, although this
reduction is also seen in other anxiety disorders (Nikolaus et al.
2010). Other findings support the hypothesis that social anxiety
disorder may be associated with a dysfunction of the striatal
dopaminergic system (Schneier et al. 2000). These types of data
may be consistent with a link between social anxiety and
dysfunctional processing of positive or rewarding information (Hare
et al. 2005) and may ultimately suggest novel approaches to
pharmacotherapy for this condition.
Posttraumatic Stress Disorder

Trauma and stressor-related disorders begin, by definition, in the
aftermath of exposure to a trauma or stressor. Four sets of
subsequent symptoms characterize PTSD: reexperiencing intrusive
phenomena (such as visual flashbacks), avoidance and numbing
symptoms, alterations in arousal and reactivity, and negative
alterations in mood and cognition hyperarousal. This latter category
is new in DSM-5 and includes most of the DSM-IV numbing
symptoms as well as some new or reconceptualized symptoms,
including persistent negative emotional state. The cluster for
alterations in arousal and reactivity retains most of the DSM-IV
hyperarousal symptoms and adds irritable/aggressive behavior as
well as reckless or self-destructive behavior. Of note, the stressor
criterion has also changed, such that Criterion A (points 1–4)
delineates more specific and restrictive definitions of what qualifies
as a “traumatic” event, and Criterion A2 (subjective reaction) has
been deleted.
It should be emphasized that the prevalence of exposure to
trauma is significantly higher than the prevalence of PTSD, indicating
that most trauma does not lead to this disorder. Indeed, an important
development in the PTSD literature is a growing emphasis that this is
not a “normal” reaction to an abnormal event (Yehuda and LeDoux
2007). Rather, PTSD has been established as a serious disorder that
is associated with significant morbidity and mediated by
neurobiological and psychological dysfunctions (Etkin and Wager
2007; Rauch et al. 2006; Yehuda and LeDoux 2007).
Features of current neuroanatomical models of PTSD (Figure 26–
4) include the following: 1) Amygdalothalamic pathways are involved
in the rapid, automatic (implicit) processing of incoming information.
2) Hyperactivation of the amygdala and insular cortex, which sends
afferents to other regions involved in the anxiety response (e.g.,
hypothalamus, brain stem nuclei), occurs. 3) The hippocampus is
reduced in volume and involved in (explicitly) remembering the
context of traumatic memories. 4) Activity is decreased in certain
frontal cortical areas, consistent with decreased verbalization during
processing of trauma (e.g., deactivation of Broca’s area), failure of
fear extinction (e.g., failure to recruit medial and ventral prefrontal
areas), and an inability to override automatic amygdala processing.
FIGURE 26–4. Neuroanatomical model of posttraumatic stress disorder
(PTSD).
Hyperactivity of the amygdala (AMY) and insular cortex (INS) are consistently
seen in PTSD, as well as hypoactivity of the ventromedial prefrontal cortex
(vmPFC) and ventral anterior cingulate cortex (vACC). The hippocampus (HIPPO)
is reduced in volume.
A number of neurochemical findings in PTSD are consistent with
sensitization of various neurotransmitter systems (Charney 2004). In
particular, there is evidence of hyperactive noradrenergic function
and dopaminergic sensitization. Such sensitization is also consistent
with the role of environmental traumas in PTSD; dopamine agonists
and environmental traumas act as cross-sensitizers of each other.
Evidence indicates that the amygdala and related limbic regions may
play a particularly important role in the final common pathway of
such hyperactivation.
Also, growing evidence suggests the importance of the serotonin
system in mediating PTSD symptoms. Clinical studies of abnormal
paroxetine binding and exacerbations of symptoms in response to
administration of m-CPP are certainly consistent with a role for
serotonin in PTSD (Southwick et al. 1997). Furthermore, a number of
serotonin reuptake inhibitors and venlafaxine have been found to be
effective and safe for the treatment of PTSD (Koen and Stein 2011).
These agents may act on amygdala circuits, helping to inhibit
efferents to structures such as hypothalamus and brain stem nuclei,
which mediate fear.
A third set of neurochemical findings in PTSD has focused on the
HPA system. PTSD is characterized by increased baseline cortisol-
releasing factor (CRF) and decreased plasma levels of cortisol, and
these findings differ from those observed in other anxiety disorders
and in depression (Yehuda and LeDoux 2007). It has been
suggested that the joint occurrence of high CRF and low basal
cortisol reflect a long-term physiological adaptation of the HPA axis
to chronic stress. Moreover, there is considerable preclinical
evidence that early life stress leads to short- and long-term
alterations of HPA function. Specifically, an initial sensitization and
high cortisol levels may occur during persistent and recurrent early
traumatization, followed by a blunting of HPA axis responsivity as a
longer-term adaptation to chronic stress, along with downregulation
of CRF receptors.
One important implication of the HPA findings is the possibility that
dysfunction in this system results in neuronal damage, particularly to
the hippocampus (Rosso et al. 2017). Animal studies have
documented hippocampal damage after exposure to either
glucocorticoids or naturalistic psychosocial stressors. Parallel
neurotoxicity in human PTSD could account for some of the
cognitive impairments that are characteristic of this disorder,
although the association between hippocampus integrity and
glucocorticoid functioning has been more difficult to determine from
human brain imaging studies of PTSD (Yehuda and LeDoux 2007).
A number of structural imaging studies are, in fact, consistent with
the possibility of hippocampal dysfunction occurring in PTSD. A
meta-analysis of magnetic resonance imaging studies, for example,
emphasized the consistent finding of decreased hippocampal
volume in PTSD secondary to adult or childhood trauma (Woon et al.
2010). In some studies, decreased volume has been associated with
greater trauma exposure, increased symptom severity, or worse
neuropsychological impairment. Nevertheless, evidence also shows
that decreased hippocampal volume may precede the onset of
PTSD and thus constitutes a risk factor for the development of this
condition. In addition, there are now increasing data suggesting
decreased volume in medial and ventral prefrontal cortex (Rauch et
al. 2006).
Functional imaging studies have provided additional information in
support of a neuroanatomical model of PTSD. Several studies in
control subjects without PTSD have provided evidence for
subcortical processing of masked emotional stimuli by the amygdala.
Furthermore, a range of studies have found that PTSD patients
exposed to audiotaped traumatic and neutral scripts had increases in
neuronal activity in limbic and paralimbic areas compared with
healthy control subjects (Etkin and Wager 2007). Also, areas of
decreased activity may mediate symptoms; for example, decreased
activity in Broca’s area during exposure to trauma in PTSD is
consistent with patients’ inability to verbally process traumatic
memories (Rauch et al. 2006). Moreover, in a meta-analysis of
functional imaging studies of symptom provocation and negative
emotional processing across multiple anxiety disorders, PTSD was
associated with greater activity of the amygdala and insular cortex,
as well as hypoactivation of the anterior cingulate cortex and
ventromedial prefrontal cortex (Etkin and Wager 2007). Interestingly,
the latter finding was specific to PTSD and not seen in the other
anxiety disorders, which may be consistent with extinction deficits in
PTSD (Milad et al. 2009).
Once again, modern techniques have allowed for the integration
of neurochemical and neuroanatomical data. For example, positron
emission tomography has been used in combat veterans with PTSD
and healthy control subjects after administration of yohimbine
(Bremner et al. 1997); this noradrenergic agent resulted in a
significant increase in anxiety in the patients with PTSD, and these
subjects also had a decrease in activity in several areas, including
prefrontal, temporal, parietal, and orbitofrontal cortex.
Neurological Disorders With Anxiety Symptoms

Neurological conditions that affect a range of different
neuroanatomical structures may be associated with anxiety
symptoms or disorders (Muller et al. 2005). Given that temporolimbic
regions, striatum, and prefrontal cortex all likely play an important
role in the pathogenesis of certain anxiety disorders, we begin by
reviewing the association between lesions in these areas and
subsequent anxiety symptoms before moving on to disorders with
more widespread pathology. This literature not only is clinically
relevant but also raises valuable questions for further research.
Various lesions of the temporolimbic regions have been
associated with the subsequent development of panic disorder.
Temporal lobe seizures (Muller et al. 2005), tumors (Kellner et al.
1996–1997), and parahippocampal infarction (Maricle et al. 1991) all
have been reported to manifest with panic attacks. The association
seems particularly strong with right-side lesions. Conversely,
removal of the amygdala results in placidity toward previously feared
objects (Kluver and Bucy 1939) and deficits in fear conditioning
(Muller et al. 2005).
This literature, taken together with clinical observations that panic
disorder may be accompanied by dissociation and depersonalization
and possibly by electroencephalographic abnormalities and temporal
lobe abnormalities (see subsection “Panic Disorder and
Agoraphobia”), as well as preliminary data that show panic disorder
can respond to anticonvulsants, raises the question of whether
partially overlapping mechanisms may be at work in both temporal
lobe seizure disorder and panic disorder. Certainly, it has been
suggested that electroencephalogram and anticonvulsant trials may
be appropriate in patients with panic disorder refractory to
conventional treatment (Koen and Stein 2011).
Anxiety symptoms may be seen in striatal disorders (Muller et al.
2005). In Huntington’s disease, for example, anxiety has been
reported as a common prodromal symptom, with later development
of several different anxiety disorders (Leroi and Michalon 1998).
Anxiety symptoms and disorders are also common in Parkinson’s
disease (Muller et al. 2005) and may correlate inversely with left
striatal dopamine transporter availability (Erro et al. 2012). Such
findings arguably indicate that further attention should be paid to the
role of the dopaminergic system in anxiety disorders (Stein et al.
2002), although other neurotransmitter systems also may be
important in mediating anxiety symptoms in Parkinson’s disease.
Anxiety symptoms and disorders can also be seen in a range of
neurological disorders that affect multiple brain regions, including the
frontal cortex. In multiple sclerosis, for example, anxiety symptoms
may be found in up to 44% of subjects, and anxiety disorders are
also not uncommon (Marrie et al. 2015). Whether this anxiety
reflects a psychological reaction or reflects the deposition of
demyelinating plaques remains somewhat unclear, but treatment of
symptoms should not be ignored.
Similarly, anxiety symptoms have been noted to be common in
Alzheimer’s disease and in other dementias including vascular and
frontotemporal dementias (Regan and Varanelli 2013). The relation
between regional pathology and anxiety symptoms in these
conditions deserves further attention. Additional work on the
management of anxiety in dementia is also needed.
Although the prevalence of depression after stroke has been well
studied, fewer studies have focused on anxiety after stroke.
However, in one study of 309 admissions to a stroke unit, GAD was
present in 26.9% of the patients (Castillo et al. 1993). The authors
reported that anxiety plus depression was associated with left
cortical lesions, whereas anxiety alone was associated with right
hemisphere lesions. Also, worry was associated with anterior and
GAD with right posterior lesions. Longitudinal studies have found
that GAD can persist for several years after the stroke (Morrison et
al. 2005). Again, anxiety plus depression may be associated with left
hemisphere lesions and anxiety alone with right hemisphere lesions.
Anxiety disorders also have been reported in the aftermath of
traumatic brain injury (TBI). Anxiety symptoms are present in as
many as 70% of victims of mild TBI, and anxiety disorders can be
diagnosed in 29% of individuals across all severity levels of TBI
(Moore et al. 2006). Prevalence rates for individual anxiety disorders
vary widely across TBI studies. PTSD is the most commonly studied
anxiety disorder following traumatic injury, with anywhere from 20%
to 84% of PTSD patients have symptoms that also meet TBI criteria
across studies (Moore et al. 2006). Of particular interest is the
finding that PTSD can develop even when the patient has
neurogenic amnesia for the traumatic event; this finding may suggest
that implicit memories of trauma are sufficient for later PTSD to
emerge.
Conclusion
Several lessons emerge from a review of the neuropsychiatry of
anxiety disorders. First, the anxiety disorders are common and
disabling disorders not only in general clinical settings but also in
patients with neurological illnesses such as Alzheimer’s disease,
stroke, and traumatic brain injury. Although the link between
depression and neuropsychiatric disorders is increasingly
recognized, the importance of anxiety disorders in the context of
neurological illnesses has perhaps been relatively overlooked,
paralleling their underdiagnosis and undertreatment in primary care
settings. The anxiety disorders deserve to be carefully diagnosed,
thoroughly assessed, and rigorously treated.
Second, both animal and clinical studies increasingly indicate that
the amygdala and paralimbic structures play important roles in
conditioned fear and in anxiety disorders. Amygdala lesions are
classically associated with decreased fear responses, and
conversely, limbic hyperactivation is characteristic of several different
anxiety disorders. Paralimbic regions such as the anterior cingulate
appear to play a key role at the interface of cognition and emotion.
The apparent centrality of such systems to different anxiety disorders
may account in part for their high comorbidity. Other limbic
involvement may be specific to particular disorders (e.g., decreased
hippocampal volume in PTSD or parahippocampal asymmetry in
panic disorder).
Models of anxiety disorders increasingly integrate data from
genetics, brain imaging, and treatment studies. Thus, particular
genetic variants appear to be associated with increased activation of
specific neuronal circuits during functional imaging, and effective
pharmacotherapy and psychotherapy may act to normalize such
circuitry. Serotonin reuptake inhibitors and cognitive-behavioral
therapy are increasingly viewed as first-line treatments for anxiety
disorders. Innervation of amygdala and paralimbic structures by
serotonergic neurons may be crucial in explaining their efficacy.
Further advances in our understanding of the neurobiological bases
of fear conditioning and extinction may lead to new therapeutic
interventions.
References
Alvares LdeO, Einarsson EO, Santana F, et al: Periodically reactivated context
memory retains its precision and dependence on the hippocampus.
Hippocampus 22(5):1092–1095, 2012 22120981
Disorders, 3rd Edition. Washington, DC, American Psychiatric Association,
1980
Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric
Association, 2000
Ballenger JC, Davidson JR, Lecrubier Y, et al: Consensus statement on social
anxiety disorder from the International Consensus Group on Depression and
Anxiety. J Clin Psychiatry 59 (suppl 17):54–60, 1998 9811431
Bremner JD, Innis RB, Ng CK, et al: Positron emission tomography measurement
of cerebral metabolic correlates of yohimbine administration in combat-related
posttraumatic stress disorder. Arch Gen Psychiatry 54(3):246–254, 1997
9075465
Bruhl AB, Delsignore A, Komossa K, et al: Neuroimaging in social anxiety disorder
—a meta-analytic review resulting in a new neurofunctional model. Neurosci
Biobehav Rev 47:260–280, 2014 25124509
Castillo CS, Starkstein SE, Fedoroff JP, et al: Generalized anxiety disorder after
stroke. J Nerv Ment Dis 181(2):100–106, 1993 8426166
Charney DS: Psychobiological mechanisms of resilience and vulnerability:
implications for successful adaptation to extreme stress. Am J Psychiatry
161(2):195–216, 2004 14754765
Ciocchi S, Herry C, Grenier F, et al: Encoding of conditioned fear in central
amygdala inhibitory circuits. Nature 468(7321):277–282, 2010 21068837
Coplan JD, Lydiard RB: Brain circuits in panic disorder. Biol Psychiatry
44(12):1264–1276, 1998 9861469
Erro R, Pappatà S, Amboni M, et al: Anxiety is associated with striatal dopamine
transporter availability in newly diagnosed untreated Parkinson’s disease
patients. Parkinsonism Relat Disord 18(9):1034–1038, 2012 22789824
Etkin A: Functional neuroanatomy of anxiety: a neural circuit perspective. Curr Top
Behav Neurosci 2:251–277, 2010 21309113
Etkin A, Wager TD: Functional neuroimaging of anxiety: a meta-analysis of
emotional processing in PTSD, social anxiety disorder, and specific phobia. Am
J Psychiatry 164(10):1476–1488, 2007 17898336
Etkin A, Prater KE, Hoeft F, et al: Failure of anterior cingulate activation and
connectivity with the amygdala during implicit regulation of emotional
processing in generalized anxiety disorder. Am J Psychiatry 167(5):545–554,
2010 20123913
Faravelli C, Lo Sauro C, Godini L, et al: Childhood stressful events, HPA axis and
anxiety disorders. World J Psychiatry 2(1):13–25, 2012 24175164
Furmark T, Tillfors M, Garpenstrand H, et al: Serotonin transporter polymorphism
related to amygdala excitability and symptom severity in patients with social
phobia. Neurosci Lett 362(3):189–192, 2004 15158011
Gorman JM, Kent JM, Sullivan GM, et al: Neuroanatomical Hypothesis of Panic
Disorder, Revised. Focus 2(3):426–439, 2004
Hare TA, Tottenham N, Davidson MC, et al: Contributions of amygdala and striatal
activity in emotion regulation. Biol Psychiatry 57(6):624–632, 2005 15780849
Hattingh CJ, Ipser J, Tromp SA, et al: Functional magnetic resonance imaging
during emotion recognition in social anxiety disorder: an activation likelihood
meta-analysis. Front Hum Neurosci 6:347, 2013 23335892
Kellner M, Hirschmann M, Wiedemann K: Panic attacks caused by temporal
tumors: an exemplary new case and a review. Depress Anxiety 4(5):243–245,
1996–1997 9167792
Kent JM, Coplan JD, Mawlawi O, et al: Prediction of panic response to a
respiratory stimulant by reduced orbitofrontal cerebral blood flow in panic
disorder. Am J Psychiatry 162(7):1379–1381, 2005 15994724
Kessler RC: The epidemiology of pure and comorbid generalized anxiety disorder:
a review and evaluation of recent research. Acta Psychiatr Scand Suppl
(406):7–13, 2000 11131470
Kessler RC, Ruscio AM, Shear K, et al: Epidemiology of anxiety disorders. Curr
Top Behav Neurosci 2:21–35, 2010 21309104
Klein E, Zohar J, Graci MF, et al: Anxiogenic effects of m-CPP in patients with
panic disorder: comparison to caffeine's anxiogenic effects. Biol Psychiatry
3(10):978–984, 1991 1756202..
Kluver H, Bucy PC: Preliminary analysis of functions of the temporal lobes in
monkeys. Arch Neurol Psychiatry 42(6):979–1000, 1939
Koen N, Stein DJ: Pharmacotherapy of anxiety disorders: a critical review.
Dialogues Clin Neurosci 13(4):423–437, 2011 22275848
Konishi J, Asami T, Hayano F, et al: Multiple white matter volume reductions in
patients with panic disorder: relationships between orbitofrontal Gyrus volume
and symptom severity and social dysfunction. PLoS One 9(3):e92862, 2014
24663245
Lepine JP: The epidemiology of anxiety disorders: prevalence and societal costs. J
Clin Psychiatry 63 (suppl 14):4–8, 2002 12562112
Leroi I, Michalon M: Treatment of the psychiatric manifestations of Huntington’s
disease: a review of the literature. Can J Psychiatry 43(9):933–940, 1998
9825166
Maricle RA, Sennhauser S, Burry M: Panic disorder associated with right
parahippocampal infarction. J Nerv Ment Dis 179(6):374–375, 1991 2051154
Marrie RA, Reingold S, Cohen J, et al: The incidence and prevalence of
psychiatric disorders in multiple sclerosis: a systematic review. Mult Scler
21(3):305–317, 2015 25583845
Milad MR, Pitman RK, Ellis CB, et al: Neurobiological basis of failure to recall
extinction memory in posttraumatic stress disorder. Biol Psychiatry
66(12):1075–1082, 2009 19748076
Moore EL, Terryberry-Spohr L, Hope DA: Mild traumatic brain injury and anxiety
sequelae: a review of the literature. Brain Inj 20(2):117–132, 2006 16421060
Morrison V, Pollard B, Johnston M, et al: Anxiety and depression 3 years following
stroke: demographic, clinical, and psychological predictors. J Psychosom Res
59(4):209–213, 2005 16223623
Muller JE, Koen L, Stein DJ: Anxiety and medical disorders. Curr Psychiatry Rep
7(4):245–251, 2005 16098277
Nikolaus S, Antke C, Beu M, et al: Cortical GABA, striatal dopamine and midbrain
serotonin as the key players in compulsive and anxiety disorders—results from
in vivo imaging studies. Rev Neurosci 21(2):119–139, 2010 20614802
Nutt DJ: Neurobiological mechanisms in generalized anxiety disorder. J Clin
Psychiatry 62 (suppl 11):22–27; discussion 28, 2001 11414547
Paulus MP, Stein MB: An insular view of anxiety. Biol Psychiatry 60(4):383–387,
2006 16780813
Rauch SL, Shin LM, Phelps EA: Neurocircuitry models of posttraumatic stress
disorder and extinction: human neuroimaging research—past, present, and
future. Biol Psychiatry 60(4):376–382, 2006 16919525
Regan B, Varanelli L: Adjustment, depression, and anxiety in mild cognitive
impairment and early dementia: a systematic review of psychological
intervention studies. Int Psychogeriatr 25(12):1963–1984, 2013 24125507
Rosso IM, Crowley DJ, Silveri MM, et al: Hippocampus glutamate and N-acetyl
aspartate markers of excitotoxic neuronal compromise in posttraumatic stress
disorder. Neuropsychopharmacology. .42(8):1698–1705, 201728195577
Schneier FR, Liebowitz MR, Abi-Dargham A, et al: Low dopamine D(2) receptor
binding potential in social phobia. Am J Psychiatry 157(3):457–459, 2000
10698826
Schwartz CE, Wright CI, Shin LM, et al: Inhibited and uninhibited infants “grown
up”: adult amygdalar response to novelty. Science 300(5627):1952–1953, 2003
12817151
Shang J, Fu Y, Ren Z, et al: The common traits of the ACC and PFC in anxiety
disorders in the DSM-5: meta-analysis of voxel-based morphometry studies.
PLoS One 9(3):e93432, 2014 24676455
Southwick SM, Krystal JH, Bremner JD, et al: Noradrenergic and serotonergic
function in posttraumatic stress disorder. Arch Gen Psychiatry 54(8):749–758,
1997 9283511
Stein DJ, Westenberg HG, Liebowitz MR: Social anxiety disorder and generalized
anxiety disorder: serotonergic and dopaminergic neurocircuitry. J Clin
Psychiatry 63 (suppl 6):12–19, 2002 12027115
Uchida RR, Del-Ben CM, Busatto GF, et al: Regional gray matter abnormalities in
panic disorder: a voxel-based morphometry study. Psychiatry Res 163(1):21–
29, 2008 18417322
van der Wee NJ, Fiselier J, van Megen HJ, Westenberg HG: Behavioural effects of
rapid intravenous administration of meta-chlorophenylpiperazine in patients
with panic disorder and controls. J Clin Psychiatry 14(5):413–417, 2004
15336303
Von Economo C: Encephalitis Lethargica, Its Sequelae and Treatment. London,
Oxford University Press, 1931
Woon FL, Sood S, Hedges DW: Hippocampal volume deficits associated with
exposure to psychological trauma and posttraumatic stress disorder in adults: a
meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 34(7):1181–1188,
2010 20600466
Yehuda R, LeDoux J: Response variation following trauma: a translational
neuroscience approach to understanding PTSD. Neuron 56(1):19–32, 2007
17920012
________________
Dr. Stein is supported by the Medical Research Council of South
Africa. Dr. Rosso is supported by the National Institute of Mental
Health and the Dana Foundation. Dr. Rauch is partially supported by
the National Institute of Mental Health and the United States Army
Medical Research Acquisition Activity.
Index
Page numbers printed in boldface type refer to tables or figures.
“A” test, 72
AASM (American Academy of Sleep Medicine), 374, 380, 381, 382
Aβ. See Amyloid
Abacavir, 315
Abdominal pain
drug-induced
atomoxetine, 163
opioid maintenance treatment, 426
stimulants, 161
pheochromocytoma and, 366
Acamprosate, for alcohol dependence, 420
ACDS v1.2 (Adult ADHD Clinical Diagnostic Scale Version 1.2), 159
Acetaminophen, 281
Acetylcholine (ACh)
biosynthesis of, 33
disorders associated with deficiency of, 33, 33–34
disorders associated with excess of, 33, 34
origins and destinations of, 32, 32–34, 34
in specific conditions
aggression, 34
Alzheimer’s disease, 33, 440, 441, 496, 513
delirium, 33, 188, 195–196, 199
depression, 34
frontotemporal dementia, 496
hypoxic-ischemic brain injury, 298
Lewy body disorders, 33–34, 462, 468, 469, 515, 516
neurotoxin exposures, 210–211, 212, 213
sleep-wake disorders, 375, 375, 389
traumatic brain injury, 268, 269, 282
Acetylcholine receptors
muscarinic, 33
in Alzheimer’s disease, 513
in organophosphate toxicity, 210, 211
nicotinic, 33
nicotine actions on, 415
Acetylcholinesterase inhibitors. See also specific drugs
in Alzheimer’s disease, 496, 520
in delirium, 198
prophylaxis, 193
in frontotemporal dementia, 496–497, 498
in Huntington’s disease, 481
in hypoxic-ischemic brain injury, 298
in Lewy body disorders, 468, 469–470, 471, 472, 515, 520
in multiple sclerosis, 410
after traumatic brain injury, 280, 282
ACh. See Acetylcholine
Achenbach Child Behavior Checklist and Teacher Report Form, 158
Acquired immunodeficiency syndrome (AIDS). See Human immunodeficiency
virus disease/acquired immunodeficiency syndrome
ACRM (American Congress of Rehabilitation Medicine), 266–267, 282
ACTH. See Adrenocorticotropic hormone
Actigraphy, 380, 387
Activation likelihood estimation (ALE) studies of neuroanatomy of emotion, 18
Activities of daily living (ADLs)
agnosia and, 79
Alzheimer’s disease and, 436, 452, 456
delirium and, 190, 192
dementia with Lewy bodies and, 470
Huntington’s disease and, 480, 481
multiple sclerosis and, 404
poststroke, 257, 258, 260
substance-related neurocognitive disorders and, 419
Acute hemiconcern syndrome, 73
Acute Physiology and Chronic Health Evaluation II (APACHE-II), 192
Acyclovir, 326, 327
AD. See Alzheimer’s disease
ADC (AIDS dementia complex), 303, 305, 306
Addison’s disease, 364–365
Adenotonsillectomy, for obstructive sleep apnea, 386
ADHD. See Attention-deficit/hyperactivity disorder
ADHD Investigator Symptom Rating Scale (AISRS), 159
ADHD Rating Scale–IV (ADHD-RS-IV), 158
ADI-R (Autism Diagnostic Interview— Revised), 176
Adjustment disorder
diabetes mellitus and, 355
HIV disease and, 313
ADLs. See Activities of daily living
ADOS (Autism Diagnostic Observation Schedule), 176
Adrenal insufficiency, 364–365
α2-Adrenergic agonists. See also Clonidine; Guanfacine
for attention-deficit/hyperactivity disorder, 163–164
for opioid detoxification, 426
Adrenocorticotropic hormone (ACTH), 529
Cushing’s syndrome and, 363
deficiency of, 365
fungal exposure and, 218
mania in multiple sclerosis and, 401
regulation of release of, 364
Adrenoleukodystrophy, 504
Adult ADHD Clinical Diagnostic Scale Version 1.2 (ACDS v1.2), 159
Adult ADHD Investigator Symptom Rating Scale (AISRS), 159
Adult ADHD Self-Report Scale Version 1.1 (ASRS v 1.1) Symptom Checklist, 159
Advance-care planning, in frontotemporal dementia, 495
Advanced sleep-wake phase disorder, 379, 387
AEDs. See Antiepileptic drugs
Affective disorders, 100. See also Emotional lability; Mood disorders
attention-deficit/hyperactivity disorder and, 161
covert seizures and, 142
hypoparathyroidism and, 367, 368
hypothalamic-pituitary-thyroid axis and, 361–363
hypothyroidism and, 358
neuroanatomical correlates of, 3, 4
poststroke pathological affective display, 260–261
prion disease and, 321
pseudobulbar affect, 23, 68–69, 533
brain tumors and, 337
in frontotemporal dementia, 492
in multiple sclerosis, 396, 401, 402, 403
poststroke, 246, 260–261
after traumatic brain injury, 278–279
thyrotoxicosis and, 361
Aflatoxins, 217
Aggression. See also Violence
acetylcholine and, 33, 34
vs. agitation, 59
assessment of, 84, 141
conditions associated with
Alzheimer’s disease, 447, 448–449, 513
attention-deficit/hyperactivity disorder, 154, 155
treatment of, 160, 163, 167
autism spectrum disorder, 178
catastrophic reaction, 259
cerebrovascular disease, 261
herpes simplex virus encephalitis, 326
hyperprolactinemia, 366
manganese toxicity, 211
postictal psychosis, 236, 512
posttraumatic stress disorder, 554
seizure disorders of childhood, 142
traumatic brain injury, 271, 280
drug-induced
atomoxetine, 163
benzodiazepines, 238
stimulants, 423
electroencephalography in, 143
history taking for, 51
locus of brain injury and, 51
personality changes and, 51
serotonin and, 33, 35
Aging. See Elderly persons
Agitation, 59
vs. akathisia, 59
assessment of, 84
electroencephalography, 140
neuroimaging, 126, 129
Alzheimer’s disease, 59, 447, 448
with psychosis, 513
treatment of, 456
brain tumors, 341
delirium, 187, 188, 196
treatment of, 198
dementia with Lewy bodies, 471
epilepsy with psychosis, 236, 511
treatment of, 496, 498
HIV disease, 305
Huntington’s disease, 479
mood disorders, 538
multiple sclerosis, 402
neurotoxin exposures, 211
schizophrenia, 507
stroke, 255, 257
substance withdrawal, 418
alcohol, 420
stimulants, 423
drug-induced
benzodiazepines, 238, 470
L-dopa, 390
norepinephrine reuptake inhibitors, 253
stimulants, 253
Agnosia, 79–80, 100
assessment of, 79–80
auditory, 7
Alzheimer’s disease, 446
frontotemporal dementia, 490, 492
prion disease, 321
environmental, 7, 12, 12, 14, 23
finger, 7
hemisomatagnosia, 79
neuroanatomical correlates of, 4, 6–7, 10
phonagnosia, 14, 23
prosopagnosia, 7, 12, 12, 14, 23, 79, 446, 490, 492, 518
simultanagnosia, 79–80, 293, 297, 446
visual object, 7, 12, 12, 80
Agoraphobia
epilepsy and, 235
panic disorder and, 545, 546, 548
Agraphia, 7, 11, 12, 14
aphasia and, 74
Parkinson’s disease with dementia and, 466
Aid to Capacity Evaluation, 113
AIDS (acquired immunodeficiency syndrome). See Human immunodeficiency virus
disease/acquired immunodeficiency syndrome
AIDS dementia complex (ADC), 303, 305
AISRS (Adult ADHD Investigator Symptom Rating Scale), 159
Akathisia, 59
vs. agitation, 59
drug-induced, 59
antipsychotics, 181, 538
reboxetine, 253
sleep disruption due to, 388
stimulants, 253
tetrabenazine, 480
Akinesia, 4, 26, 59
nocturnal, 472
psychic, 259
Alcohol
attention-deficit/hyperactivity disorder and gestational use of, 158
binge drinking, 419, 420
blood alcohol concentration, 420
drug interactions with
antiretroviral agents, 315
benzodiazepine receptor agonists, 382, 427
intoxication with, 420
mechanism of action of, 415
prevalence of use, 419
receptor binding of, 36
sleep effects of, 377, 391
Alcohol use disorders, 413, 414, 419–422, 431
benzodiazepine abuse, 427
HIV disease, 314–315
laboratory testing for, 418
neuroimaging in, 119, 119, 126
neuropsychiatric syndromes and, 420–422
alcoholic cerebellar degeneration, 421
alcoholic polyneuropathy, 421–422
central pontine and extrapontine myelinolysis, 422
hepatic encephalopathy, 422
Korsakoff syndrome, 98, 420, 421
major neurocognitive disorders, 421
Wernicke’s encephalopathy, 56, 420–421
relapse prevention for, 420
as risk factor for poststroke depression, 249, 250
screening instruments for, 417
Alcohol Use Disorders Identification Test— Consumption (AUDIT-C), 417
Alcohol use history, 50
Alcohol withdrawal, 416, 420
delirium tremens and, 141, 420
electroencephalography during, 141
monitoring severity of, 420
onset of, 420
prevention of, 418
protracted, 420
seizures during, 224, 420
ALE (activation likelihood estimation) studies of neuroanatomy of emotion, 18
Alexia, 7, 12, 12, 14, 74–75
without agraphia, 12, 12, 74
Alien hand sign, 79
Alkyltin neurotoxicity, 211
Allan-Herndon-Dudley syndrome, 360
Allocortex, 5, 7
Alprazolam
abuse potential of, 427
for epilepsy with anxiety, 235
for panic disorder, 550
withdrawal from, 428
ALS (amyotrophic lateral sclerosis), 212, 389, 460, 488, 492
Aluminum neurotoxicity, 211, 211–212
Alzheimer’s disease (AD), 435–456
aluminum exposure and, 212
cognitive evaluation, 452–455
abstract thought, 455
attention, concentration, and working memory, 455
executive function, 454
language, 453–454
learning and memory, 452–453
mental status examination, 452
orientation, 453
praxis and temporoparietal function, 454
laboratory testing, 450
neuroimaging, 131–132, 132, 133, 450, 451
physical and neurological examinations, 449–450
cognitive impairment in, 50, 131, 436, 439, 440, 442–443, 442–446, 448, 449,
452–455, 456, 461
cognitive reserve and, 407
domains of, 443
executive function, 446, 454
higher visual function, 445–446, 454
language, 445, 453–454
memory, 444, 452–453
orientation, 444–445, 453
praxis, 445, 454
conditions associated with delirium, 191
diabetes mellitus, 352
olfactory abnormalities, 380
psychosis, 447, 448, 452, 504, 513–514
sleep disturbances, 389, 456
course of, 451–452
diagnostic criteria for, 436, 442, 443–444
differential diagnosis of
dementia with Lewy bodies, 132–133, 133, 461, 464
emotional and behavioral symptoms of, 447, 447–449
agitation and sundowning, 448–449
anxiety, 448
apathy, 447
depression, 448
psychosis, 448, 504
social cognition, 449
unawareness of deficits, 447–448
extrapyramidal features of, 465
mild cognitive impairment as prodrome for, 50, 131, 451
neurobiology of, 4, 435, 437–442
autopsy pathology, 437, 437–440
neurofibrillary tangles, 439, 439
senile plaques, 437–439, 438
synaptic loss, 440
cerebrospinal fluid biomarkers, 440
in vivo amyloid-PET imaging, 129, 132, 133, 438–439
in vivo tau imaging, 439
neurochemistry, 441–442, 513–514
acetylcholine, 33, 440, 441, 496, 513
dopamine, 513–514
glutamate, 441
norepinephrine, 440, 441
serotonin, 440, 441, 513
pathophysiology, 440–441
α-synuclein pathology, 459, 460
neuroimaging in, 131–132, 132, 133
amyloid PET imaging, 129, 132, 133, 438–439
vs. dementia with Lewy bodies, 132–133, 133, 461
possible, 436, 442–443
posterior cortical atrophy variant, 445
preclinical, 435
probable, 436, 442
treatment of, 455–456
Amantadine
in dementia with Lewy bodies, 470
for posthypoxic disorders, 296, 298, 299
for posttraumatic disorders, 279, 280, 281, 282
American Academy of Child and Adolescent Psychiatry
guidelines for screening for autism spectrum disorder, 176
guidelines for treatment of attentiondeficit/hyperactivity disorder, 160
American Academy of Neurology
guidelines for cognitive assessment, 83
on HIV-associated cognitive impairment, 305
practice parameter for autism spectrum disorder, 176
practice parameter for diagnosis of dementia, 450
review of quantitative electroencephalography, 146
on use of acetylcholinesterase inhibitors in Parkinson’s disease with dementia,
470
American Academy of Pediatrics
practice guidelines for screening for autism spectrum disorder, 176
practice guidelines for treatment of attention-deficit/hyperactivity disorder, 160
American Academy of Sleep Medicine (AASM), 374, 380, 381, 382
American Clinical Neurophysiology Society, 146
American Congress of Rehabilitation Medicine (ACRM), 266–267, 282
American Neuropsychiatric Association, 1, 82
American Psychological Association, 95–96
ɣ-Aminobutyric acid (GABA), 36
disorders associated with deficiency of, 33, 36
disorders associated with excess of, 33
origins and destinations of, 32, 36
in sleep physiology, 375, 375
in specific conditions, 36
delirium, 196
generalized anxiety disorder, 547, 548
substance use disorders, 415
alcohol withdrawal, 420
inhalants, 430
opiates, 424
traumatic brain injury, 268
ɣ-Aminobutyric acid (GABA) receptors, 36
in generalized anxiety disorder, 547, 548
in panic disorder, 551
types of, 36
Amitriptyline
for depression in diabetes mellitus, 357
for insomnia, 383
for migraine prophylaxis, 281
seizures induced by, 234
Amnesia. See also Memory impairment
anterograde, 4, 421, 427
for ictal events, 142, 227, 229, 235
neuroanatomical correlates of, 4, 11, 14, 16, 20, 26
posttraumatic, 50, 266, 267, 269–270, 271, 272
retrograde, 50, 266
Amoxapine, 234
Amphetamine (AMP)
abuse of, 414, 423
formulations of, 160–161
indications for
attention-deficit/hyperactivity disorder, 160–161
narcolepsy, 385
interaction with antiretroviral drugs, 315
intoxication with, 64, 423
mechanism of action of, 415, 417
psychosis induced by, 424
Amusia, 7
Amygdala, 3, 16, 17
in emotional processing, 17, 18, 534, 539
facial movements and lesions of, 57
in fear and anxiety, 558
neurological disorders with anxiety symptoms, 557
panic disorder, 548, 549, 550, 550–551
posttraumatic stress disorder, 19, 20, 554, 555, 556
social anxiety disorder, 19, 20, 552, 553
specific phobias, 19, 20
in herpes simplex virus encephalitis, 20
in Klüver-Bucy syndrome, 21, 51
in mood disorders, 528, 532, 534, 539, 541, 541
bipolar disorder, 532
depression, 530, 531, 534, 538
neuroimaging of, 131
neurotransmitter projections of, 32, 33, 34, 35
in poststroke mania, 256
relationships with thalamic nuclei, 27
in schizophrenia, 508
in substance use disorders, 416
Amyloid
β-amyloid (Aβ) in Alzheimer’s disease, 437–438, 438, 440–441, 457, 487
cerebrospinal fluid assays for, 450
cerebral amyloid angiopathy, 438
insulin dysregulation and, 353
Amyloid positron emission tomography imaging, 129, 132, 133, 438–439
Amyloid precursor protein (APP), 438, 440–441
Amyotrophic lateral sclerosis (ALS), 212, 389, 460, 488, 492
“Anarchic hand,” 79
Anhedonia
vs. apathy, 258, 536
depression and, 313, 526, 532, 535, 536
in diabetes mellitus, 356
Huntington’s disease and, 482
schizophrenia and, 37
stimulant withdrawal and, 423
Anomia, 75, 79
Alzheimer’s disease and, 443, 446
neuroanatomical correlates of, 7, 11, 12, 79
Anorexia. See Appetite changes Anorexia nervosa, 48, 51
Anosmia, 54, 124, 271, 272
Anosodiaphoria, 82
Anosognosia, 82
Alzheimer’s disease and, 447, 447–448
for visual impairment, 297
Anoxic brain injury, 289. See also Hypoxicischemic brain injury
Anterior cingulate syndrome, 30
Anti-inflammatory drugs, 197
for mood disorders, 529
for posttraumatic headache, 281, 282
Antibiotics
for Lyme disease, 321
for syphilis, 317
for Whipple’s disease, 324
Anticholinergic effects of drugs, 33
delirium, 33, 54, 192, 197, 468
paroxetine, 254
pupillary dilation, 54
tricyclic antidepressants, 252
Anticonvulsants. See Antiepileptic drugs
Antidepressants, 542. See also specific drugs and classes
adverse effects of, 357
chorea, 61
mania, 534
seizures, 233, 234
sleep effects, 390, 391
weight gain and glycemic effects, 357–358
electroencephalogram abnormalities and response to, 142, 537
indications for
anxiety disorders
in epilepsy, 235
generalized anxiety disorder, 547
panic disorder, 549
social anxiety disorder, 551–552
attention-deficit/hyperactivity disorder, 164
depression, 528, 534, 535
in brain tumor patients, 337, 339, 341, 343–344, 347
in diabetes mellitus, 356, 357–358
in epilepsy, 234
in HIV disease, 313
poststroke, 252–254, 253, 255, 278
posttraumatic, 278
frontotemporal dementia, 495–496, 498
Huntington’s disease, 483, 484
Lewy body disorders, 470
narcolepsy, 385–386
panic disorder, 549–550
pseudobulbar affect in multiple sclerosis, 402
sleep disorders, 389
hypersomnias, 385–386
insomnia, 281, 382, 383, 472
in stroke patients
depression, 252–254, 253, 255, 278
pathological affective display, 261
subictal mood disorders, 144
after traumatic brain injury
aggression, 280
depression, 278
insomnia, 281
pathological laughing and crying, 279
interactions with antiepileptic drugs, 234
thyroid hormone augmentation of, 361–362
use in epilepsy, 234
Antidepressants, tricyclic (TCAs). See also specific drugs
cardiovascular effects, 252
sedation, 390
seizures, 234
indications for
narcolepsy, 385
panic disorder, 549
parasomnias, 387
posthypoxic disorders of consciousness, 296
posttraumatic disorders of affect, 279
posttraumatic headache, 281
posttraumatic insomnia, 281
thyroid hormone augmentation of, 361
use in delirium, 197
Antidepressants, tricyclic (TCAs), indications for, depression
in diabetes mellitus, 356, 357
in HIV disease, 313
poststroke, 252–253, 253
Antiepileptic drugs (AEDs), 230–232, 427. See also specific drugs
chorea, 61
neurobehavioral disturbances, 237–238
sedation, 390
sexual effects, 51
suicidality, 234
factors affecting choice of, 231, 231
indications for
affective lability after traumatic brain injury, 279
brain tumor patients, 336, 339, 341, 341, 343
epilepsy, 230–232
combination therapy, 231–232
forced normalization after treatment with, 512
after hypoxic-ischemic brain injury, 293
with mood disorders, 233–234
with psychogenic nonepileptic seizures, 240
with psychosis, 237, 510
epileptiform discharges in psychiatric disorders, 144
in Huntington’s disease, 480, 483, 484
mania in HIV-infected persons, 314
posttraumatic aggression, 280
rapid-cycling bipolar disorder, 144
sleep-related movement disorders, 388
subictal mood disorders, 144–145
initiation of, 230
interaction with selective serotonin reuptake inhibitors, 234
narrow-spectrum and broad-spectrum drugs, 231, 231
predicting response to
electroencephalography, 143–144
magnetoencephalography, 148
receptor binding of, 36
Antihistamines, 197, 376, 456
for insomnia, 383
Anti–NMDA receptor encephalitis, 520
Antipsychotics. See also specific drugs
adverse effects of, 181, 383, 471
akathisia, 538
cardiovascular effects, 199
chorea, 61
in elderly dementia patients, 199
extrapyramidal symptoms, 198–199
metabolic effects, 181, 538
neuroleptic malignant syndrome, 464, 471
neuroleptic sensitivity in Lewy body disorders, 460, 464, 465, 466, 471, 520
in patients with brain tumors, 337, 341
in patients with frontotemporal dementia, 496
sedation, 390
seizures, 237, 337, 341
social anxiety disorder, 552
stuttering, 76
dopamine D2 receptor blockade by, 34, 366, 464, 471, 520
effects on event-related potentials, 149–150
indications for
aggression, 143, 280
posttraumatic, 280
brain tumor patients, 341
corticosteroid-induced psychiatric symptoms, 364
delirium, 195, 198–199
prophylaxis, 193
mania
in HIV disease, 314
poststroke, 256
posttraumatic, 278
poststroke depression, 252
posttraumatic insomnia, 281
psychosis, 504, 520–521
in epilepsy, 237
schizophrenia, 66, 143, 508
Antiretroviral therapy, combined (cART), 303, 304
central nervous system penetration of, 312
cytomegalovirus brain infection and, 309
drug interactions with, 313
alcohol and substances of abuse, 315
substances of abuse, 315
HIV-associated neurocognitive disorder and, 305, 310, 311–312
demographic changes from pre-cART era, 309
neuropsychiatric side effects of, 315–316
primary central nervous system lymphoma and, 307
progressive multifocal leukoencephalopathy and, 308
suicidality and, 313
Antisocial personality disorder, 143, 155
Anton’s syndrome, 81, 297, 518
Anxiety
vs. agitation, 59
vs. akathisia, 59
alleviating during neuropsychiatric assessment, 99
assessment of, 84
computerized test batteries and, 112
neuropsychological testing, 103
catastrophic reaction and, 259
cautious gait and, 59
compulsions driven by, 63
drug-induced
antiretroviral agents, 315, 316
corticosteroids, 364
tetrabenazine, 480
topiramate, 238
neuroanatomical correlates of, 18, 19, 20, 21, 22, 39, 556–557
neurotransmitters and, 19, 33, 34, 35, 441
tremor and, 61
Anxiety disorders, 545–558. See also specific disorders
cannabis effects in, 422
conditions associated with, 556–558
Alzheimer’s disease, 59, 441, 447, 448, 452, 456
autism spectrum disorder, 178, 179
brain tumors, 336, 338, 344
treatment of, 344
cardiac arrest, 298–299
Cushing’s syndrome, 363
dementia with Lewy bodies, 462, 470
treatment of, 471
depression, 538, 558
diabetes mellitus, 352, 358
epilepsy, 233, 234–235
treatment of, 235
HIV disease, 313, 324
Huntington’s disease, 479, 483, 557
hyperparathyroidism, 367
hyperthyroidism, 360, 361
hypoparathyroidism, 367, 368
hypothyroidism, 358, 359
hypoxic-ischemic brain injury, 298–299
multiple sclerosis, 399, 400, 557
neurotoxin exposure, 209, 210, 216, 218
Parkinson’s disease, 466, 470, 557
pheochromocytoma, 366
prion disease, 321
psychogenic nonepileptic seizures, 238, 240
stroke, 245, 246, 256–257, 261, 557
treatment of, 257
substance use disorders, 414, 418, 419, 431, 545
benzodiazepine withdrawal, 428
cannabis withdrawal, 422
stimulant withdrawal, 423
traumatic brain injury, 271, 275, 278, 280, 557–558
DSM classification of, 545
generalized anxiety disorder, 546–548, 549
panic disorder and agoraphobia, 548–551, 550
posttraumatic stress disorder, 553–556, 555
prevalence of, 545
social anxiety disorder, 551–553, 553
substance-induced, 545
symptoms of, 545–546
treatment of, 558
Anxiety neurosis, 546
Anxiolytics. See also Benzodiazepines; specific drugs
abuse/misuse of, 414, 427–429
hospitalization for hyperthyroidism and use of, 361
poststroke generalized anxiety disorder and, 257
use in Lewy body disorders, 470
APACHE-II (Acute Physiology and Chronic Health Evaluation II), 192
Apathy
vs. anhedonia, 536
assessment of, 84
akinetic mutism, 28, 259
Alzheimer’s disease, 33, 435, 447, 447, 456, 536
with psychosis, 513
brain tumors, 335, 340, 341, 346
delirium, 188
epilepsy, 236
treatment of, 496
lead poisoning, 211
Parkinson’s disease, 4, 536
primary central nervous system lymphoma, 307
stroke, 245, 246, 247, 258–259, 261
substance-related neurocognitive disorders, 419
traumatic brain injury, 271, 280, 282, 536
vs. depression, 248, 280, 482
neuroanatomical correlates of, 16, 20, 22, 26, 28–29, 536
neurochemisty of, 33, 33
Apathy Scale, 259
Apgar scores, 48
Aphasia, 74–75, 107. See also Mutism
anomic, 74, 107
assessment of, 73, 74–75, 79, 107
neuropsychological tests, 107
conditions associated with affective aprosodia, 77–78
agraphia, 74
apraxia, 15, 78
brain tumors, 335
epilepsy, 228
minimally conscious state, 296
Parkinson’s disease with dementia, 466
primary progressive aphasia, 76, 491–492
nonfluent/agrammatic-variant, 487, 488, 489, 491, 492
semantic-variant, 487, 488, 490, 491–492
conduction, 12, 107
expressive, 107
fluent, 8
neuroanatomical correlates of, 4, 8, 10, 12, 14, 31, 39
nonfluent, 14, 259, 445
receptive, 107
transcortical motor, 76, 77
Aphemia, 76
Apolipoprotein E genotype
delirium and, 195
APP (amyloid precursor protein), 438, 440–441
Appearance of patient, assessment of, 67, 67–68
Appetite changes. See also Eating/feeding abnormalities
assessment of, 51, 84, 100
Addison’s disease, 364
depression, 397, 525, 526, 537–538
with brain tumor, 343
in HIV disease, 313
neurobiology of, 537–538
hyperthyroidism, 360
manganese poisoning, 211
substance use disorders
barbiturate withdrawal, 428
cannabis, 422
hallucinogens, 429
drug-induced atomoxetine, 163
monoamine oxidase inhibitors, 357
stimulants, 161
tricyclic antidepressants, 357
Appetitive functions, history taking for, 50–51
Applied behavior analysis, in autism spectrum disorder, 180
Apraxia, 4, 31, 39, 78, 100, 108
assessment of, 78, 108–109
callosal, 11, 12, 78–79
aphasia, 15, 78
disconnection syndromes, 12, 12
primary progressive aphasia, 491
of eyelid opening, 56–57
of gaze, 56
ideational/conceptual, 78, 109, 297, 443, 446
ideomotor, 78, 443, 446
left hemispheric lesions and, 14, 15
limb-kinetic, 78, 443, 446
vs. minimally conscious state, 296
oculomotor, 56, 293, 297, 446
parietal, 12
of speech, 56, 74
in primary progressive aphasia, 491
Aprosodia, 10, 14, 23, 77–78
affective, 23, 77–78
executive, 14
receptive, 14
right hemisphere lesions and, 77–78
ARAS. See Ascending reticular activating system
Arcuate fasciculus, 10, 12, 400
Argyll Robertson pupils, 54, 317
Aripiprazole
in autism spectrum disorder, 181
for frontotemporal dementia, 496
hyperprolactinemia induced by, 366
for psychosis in Huntington’s disease, 483
after traumatic brain injury, 279
Armodafinil
for narcolepsy, 385
for posttraumatic fatigue, 281
Arsenic neurotoxicity, 212
Ascending reticular activating system (ARAS), 3, 24, 32
hypoxic-ischemic injury of, 290
in peduncular hallucinosis, 258
in sleep physiology, 374–376, 375
ASD. See Autism spectrum disorder
Asperger, Hans, 172
Asperger’s disorder, 172, 173. See also Autism spectrum disorder
Aspirin, 281, 317, 529
ASRS v1.1 (Adult ADHD Self-Report Scale Version 1.1) Symptom Checklist, 159
Assessment
neuroimaging, 117–136
neurophysiological testing, 139–150
neuropsychiatric, 1–2, 47–85
neuropsychological, 1, 95–114
Association cortex(ices), 5
Alzheimer’s disease and, 435
auditory, 6, 7
cortical-subcortical connections with, 25
deficits associated with lesions of, 7–8, 10
heteromodal, 5, 7, 7–8, 9, 25
parietal lobe epilepsy and, 228
psychosis and, 509
thalamocortical interactions with, 26
unimodal, 6, 7, 7, 9, 25
visual, 6, 7
in Lewy body disease, 469
Asterixis, 57, 62–63, 422
Ataxia
alcoholic cerebellar degeneration and, 421
benzodiazepine overdose and, 427
Cogan’s syndrome and, 56
cytomegalovirus encephalitis and, 309
Hashimoto’s encephalitis and, 361
HIV-associated neurocognitive disorder and, 307
multiple system atrophy and, 465
neurotoxin exposures and, 209, 218
optic, 80, 293, 297, 446
prion disease and, 321, 322
St. Louis encephalitis and, 327
subacute sclerosing panencephalitis and, 324
tabes dorsalis and, 317
Wernicke’s encephalopathy and, 421
Whipple’s disease and, 323
Athetosis, 61, 293
Atomoxetine (ATX), for attention-deficit/ hyperactivity disorder, 162–163
adverse effects of, 162, 163
with anxiety disorders, 162
with autism spectrum disorder, 181
Atropine, 211
Attention
concentration, 72
domain-specific tests, 83
neuropsychological tests, 98, 100, 101, 103, 105–106
vigilance, 72
executive control of, 80
shifting of, 72
spatial, neuroanatomical correlates of, 8, 11, 14
Attention-deficit/hyperactivity disorder (ADHD), 153–168
clinical assessment (rating scales), 158–159
neuropsychological testing, 96, 105, 156, 159
objective measures, 159
clinical presentations of, 154
conditions associated with, 155
anxiety, 155
conduct disorder, 153, 155
depression, 155
impulse-control disorders, 155
learning disorders, 154, 155, 159
oppositional defiant disorder, 153, 155, 163
Tourette syndrome, 155
default mode network in, 157
descriptive psychopathology of, 153–154
diagnosis of, 153–154
diet and, 158, 167
epidemiology of, 154–155
neuropsychological models of, 155–156
pathophysiology of, 156–158
genetic factors, 156–157
neurobiological factors, 157–158
risk factors for, 158
combined treatments, 166–167
emerging nonpharmacological therapies, 167
pharmacotherapy, 160–164, 167
α2-adrenergic agonists, 163–164
atomoxetine, 162–163
bupropion, 164
modafinil, 164
stimulants, 160–162, 167
practice guidelines for, 160
psychoeducation, 159–160
psychosocial treatments, 160, 164–166, 167–168
Attentional impairment, 72, 100, 223
Alzheimer’s disease, 455, 461
attention-deficit/hyperactivity disorder, 105, 153, 154, 155, 156
vs. absence seizures, 142
neuroanatomical correlates of, 157
cannabis use, 422
delirium, 185, 187, 188, 189, 196
disorientation, 73
memory failure, 73
multiple sclerosis, 403, 404
neglect, 72–73
nonconvulsive seizure disorders of childhood, 142
Parkinson’s disease, 461
posttraumatic fatigue, 281
psychic paralysis of gaze, 56
dopamine and, 33
neuropsychological testing for, 105–106
norepinephrine and, 33
ATX. See Atomoxetine
AUDIT-C (Alcohol Use Disorders Identification Test—Consumption), 417
Auditory cortex, 6, 7
Autism Diagnostic Interview—Revised (ADI-R), 176
Autism Diagnostic Observation Schedule (ADOS), 176
Autism spectrum disorder (ASD), 171–182
in adults, 176, 177
age at symptom onset and diagnosis of, 174, 175
behavioral features of, 171–172, 175–176
clinical presentation of, 175
anxiety, 178, 179
epilepsy, 143, 174, 178
medical disorders, 174, 177
movement abnormalities, 172, 175
sleep disorders, 177, 178, 179, 181
differential diagnosis of, 177–178
schizophrenia, 172, 178
in DSM, 172–173
etiology of, 174–175
environmental factors, 173, 174, 177, 181, 203–204, 210
genetic factors, 173, 174, 176, 177
pregnancy-prenatal factors, 174, 176
family history of, 177
head circumference and, 52
historical descriptions of, 171–172
intellectual ability and, 174
neurobiology of, 24, 175
prevalence of, 173–174
research in, 179
screening and assessment of, 176–177
electroencephalography, 143, 174, 177
seizures and, 143, 174, 177
social and communication deficits in, 15, 171, 172, 175, 177, 182
echolalia, 77
stereotypies in, 63, 172, 175, 177
treatment of, 181
support and treatment for, 179–181, 182
behavioral interventions, 179–181
medications, 181
vaccines and, 174–175
Autoimmune disorders
depression and, 527
encephalitis, 203–204, 504
anti–NMDA receptor encephalitis, 520
false-positive syphilis test in, 317
neuroimaging in, 119, 125
neurotoxin-induced, 203, 204, 208, 219
aluminum, 212
molds, 219
primary autoimmune hypothyroidism, 358, 362
psychosis and, 520
sleep disturbances and, 388
thyroiditis, 361, 362
Automatic obedience, 64
Autonomic arousal, 18, 384, 385, 548
Autonomic dysfunction
absence seizures and, 229
depression, hypothalamic-pituitaryadrenal axis and, 365, 528–529
hypoglycemia and, 354
Lewy body disorders and, 459, 460, 463–464, 465, 467
management of, 472
neuroleptic malignant syndrome and, 464
during substance withdrawal
alcohol, 420
opioids, 426
vegetative state and, 294
Autoscopy, 49, 236
Avoidant/restrictive food intake disorder, 178–179
AZT (zidovudine), 315
B-SNIP (Bipolar-Schizophrenia Network on Intermediate Phenotypes) study, 507,

508
Babinski sign, 54, 58, 65
BAC (blood alcohol concentration), 420
Baclofen, 296
Balint’s syndrome, 56, 293, 297, 446
Ballismus, 62
Bannworth syndrome, 319
Barbiturates. See also specific drugs
abuse of, 427
Barkley Current Symptoms Scale, 159
BAs (Brodmann’s areas) of brain, 5
Basal ganglia, 2, 3, 16, 38
in anxiety, 20, 21
in balance disorders, 58
in ballismus, 62
in depression, 19, 20, 527, 527, 530, 541
anhedonia, 536
in Parkinson’s disease, 535
poststroke, 252
psychomotor retardation, 538
emotional dysfunction with diseases of, 17, 18
frontal-subcortical circuits affected by diseases of, 31
GABA projections to, 32, 36
in HIV disease, 311, 312
in Huntington’s disease, 36, 132, 134, 483
hypoxic-ischemic injury affecting
cognitive impairments, 297
movement disorders, 293
imaging of, 126, 128, 132, 134
in mania, 20, 534
in obsessive-compulsive disorder, 20, 21, 31
in paraphilias, 21
in poststroke disorders
apathy, 258
depression, 252
psychosis, 257
in primary central nervous system lymphoma, 307
in prion disease, 322
in psychosis, 20, 21
poststroke, 257
schizophrenia, 507
role in executive function, 110
in St. Louis encephalitis, 327
in stereotypies, 64
in toxoplasma brain abscess, 307
in vascular neurocognitive disorders, 134
in West Nile virus encephalitis, 328
BASC-2 (Behavioral Assessment Scales for Children, 2nd Edition), 158
“Bath salts,” 423
BBB. See Blood-brain barrier
BDI-II (Beck Depression Inventory-II), 397
BDS (Behavioral Dyscontrol Scale), 81
Beck Depression Inventory, 111
Beck Depression Inventory-II (BDI-II), 397
Behavior
brain neurochemistry and, 31–38, 32–37
histological organization of cortex and, 5
neurobiological bases of cognition, emotion and, 1–39
Behavior modification, for attention-deficit/ hyperactivity disorder, 166
classroom-based, 165, 166
Behavior Rating Inventory of Executive Function, 110
Behavioral Assessment of Dysexecutive Syndrome, 110
Behavioral Assessment Scales for Children, 2nd Edition (BASC-2), 158
Behavioral disturbances. See also Aggression; Agitation; Impulsivity
Alzheimer’s disease and, 447, 447–449
autism spectrum disorder and, 171–172, 175–176
brain tumors and, 338–341, 340
epilepsy and, 255–259
frontotemporal dementia and, 487, 488, 489, 491
Huntington’s disease and, 481–484
hypoxic-ischemic brain injury and, 298–299
Lewy body disorders and, 470–471
primary central nervous system lymphoma and, 338
sickness behavior, 356
Behavioral Dyscontrol Scale (BDS), 81
Behavioral interventions. See also Cognitivebehavioral therapy
for attention-deficit/hyperactivity disorder, 160, 164–166
for autism spectrum disorder, 179–181
in epilepsy
for anxiety, 235
for depression, 234
for psychosis, 521
for sleep disorders
circadian rhythm sleep-wake disorders, 387
insomnia, 382–384, 385
parasomnias, 387
Behavioral Neurology & Neuropsychiatry (BNNP), 1–2
Behavioral parent training (BPT), for attention-deficit/hyperactivity disorder, 165–
166
Behavioral therapy (BT), for attention-deficit/ hyperactivity disorder, 160, 165, 167
Bender-Gestalt test, 80
Benzodiazepine receptor agonists (BzRAs), 427
adverse effects of, 382, 383, 427
impaired driving, 427–428
avoiding use in Lewy body disorders, 472
for insomnia, 382, 383
posttraumatic, 281
Benzodiazepines (BZDs). See also specific drugs abuse/misuse of, 427
adverse effects of, 237–238, 383, 480, 547
delirium, 192, 197
disinhibition, 238, 427
exacerbation of obstructive sleep apnea, 391
suicidality, 427
avoiding use of
in Lewy body disorders, 470, 472
chronic use of, 427, 547
neuroimaging studies of, 428
neuropsychological effects of, 428–429
flumazenil reversal of, 414
GABAA receptors for, 36, 415
indications for
epilepsy, 231, 237
with anxiety, 235
Huntington’s disease, 479–480, 483
insomnia, 383
posttraumatic, 281
panic disorder, 550
parasomnias, 387
posttraumatic aggression, 280
overdose of, 427
withdrawal from, 237, 428, 547
Bereitschaftspotential, 63
Beta-blockers
for posttraumatic aggression, 280
Binge drinking, 419, 420
Binswanger’s disease, 4
Biomarkers
for Alzheimer’s disease, 440
for Creutzfeldt-Jakob disease, 321–322
for delirium, 194, 195
for herpes simplex virus encephalitis, 325–326
for HIV-associated neurocognitive disorder, 310
for Lyme disease, 320
for substance use disorders, 418, 436
for syphilis, 317
for varicella zoster virus encephalitis, 326
for West Nile virus encephalitis, 328
Bipolar disorder, 525. See also Mania
aberrancy of interhemispheric asymmetry in, 24
assessment of, 98
bipolar I disorder, 526
with catatonia, 64
clinical features of, 526
cognitive dysfunction in, 540
epilepsy, 233
HIV disease, 314
sleep disturbances, 537
stroke, 255–256
substance use disorders, 414, 419
depressive episodes in, 144, 530, 532, 537
emotional dysregulation in, 534–535
genetic factors in, 530
neuroanatomical correlates of, 24, 530, 532
oxidative stress and, 207
Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study, 507,
508
Birth history, 48
BISQ (Brain Injury Screening Questionnaire), 271
Bladder dysfunction
Lewy body disorders and, 467, 472
Lyme disease and, 320
Blepharospasm, 56–57, 60
Blink rate, 55
Block Design test, 108, 111
Blood alcohol concentration (BAC), 420
Blood-brain barrier (BBB)
aluminum transport across, 212
contrast agent transport across, 125
damage by HIV-infected astrocytes, 304
drug transport across
histamine H1 receptor antagonists, 38
sleep-wake effects of, 390
manganese transport across, 213
organic anion-transporting polypeptide at, 362
organic mercury transport across, 214
Blurting, 77
BNNP (Behavioral Neurology & Neuropsychiatry), 1–2
Borderline personality disorder, 144, 155
Borrelia burgdorferi infection, 319–321. See also Lyme disease
Boston Diagnostic Aphasia Examination, 79, 107
Boston Naming Test, 2nd edition, 107
BPT (behavioral parent training), for attention-deficit/hyperactivity disorder, 165–
166
Bradycardia
during opioid withdrawal, 426
organophosphate poisoning and, 209
selective serotonin reuptake inhibitor–induced, 253, 254
during stimulant withdrawal, 423
Bradykinesia
in methanol intoxication, 216
in Parkinson’s disease, 465, 465, 466, 514
Brain. See also specific brain structures
behavior related to neurochemistry of, 31–38, 32–37 (See also
Neurotransmitters)
Brodmann’s areas of, 5
developmental changes in structure and function of, 2–5
hemispheric lateralization of, 4
median zone of (reticular formation), 2, 3, 3, 4, 24, 38
model of behavioral neuroanatomy, 2–5, 3
paramedian-limbic zone of, 2, 3, 3–4, 5, 15–24, 16, 38
reward circuitry of, 21, 31, 158, 414, 416, 536
supralimbic zone of (neocortex), 2, 3, 4, 5–15, 38
watershed areas of, 291
Brain abscess
chronic opiate use and, 426
toxoplasmosis and, 307
Brain biopsy
in Creutzfeldt-Jakob disease, 322
in toxoplasmosis, 307
in Whipple’s disease, 323
Brain Injury Screening Questionnaire (BISQ), 271
Brain tumors, 266, 333–348
in adults, 333–336
causes of, 335
symptoms of, 335
blood-brain barrier disruption by, 125
in childhood, 344–346
adult survivors of, 346
proposed mechanisms of neurocognitive impairment in, 346
treatment of, 346
long-term neurocognitive sequelae of, 345–346
posterior fossa syndrome and, 339, 345
functional neuroimaging for, 127
identifying patients with, 336–338
locations of, 334
neuropsychiatric disorders and, 338–344
anxiety, 336, 338, 344
treatment of, 344
depression, 336, 338, 341–344, 347, 527
etiology of, 342
frequency of, 341–342
personality and behavioral changes, 338–341, 340
treatment of, 339–341, 341
tumor location and, 20, 21, 338–339
neuropsychological testing for, 96, 113
neurotransmitter effects of, 31
olfactory abnormalities and, 54
research on neuropsychiatric aspects of, 346–348, 347
seizures and, 226, 230, 333, 335, 337, 341, 343, 344
Brief Psychiatric Rating Scale, 84
Brief Visuospatial Memory Test, 107
Broca, P.P., 15
Brodmann’s areas (BAs) of brain, 5
Bromocriptine
for depression in hyperprolactinemia, 366
after hypoxic-ischemic brain injury
cognitive impairment, 298
disorders of consciousness, 296
after traumatic brain injury
fatigue, 281
Brown Attention-Deficit Disorder Scales, 159
BT. See Behavioral therapy
Buprenorphine, 418, 424
maintenance treatment with, 426
Bupropion
in attention-deficit/hyperactivity disorder, 164
for depression, 528
in HIV disease, 313
with traumatic brain injury, 278
for excessive daytime sleepiness, 472
seizures induced by, 234, 278
Bush-Francis Catatonia Rating Scale, 64
Buspirone, 427
for generalized anxiety disorder, 547
Butorphanol, for migraine, 282
BZDs. See Benzodiazepines
BzRAs. See Benzodiazepine receptor agonists
C-reactive protein, 195

C9ORF72 (gene), 488
CAADID (Conners’ Adult ADHD Diagnostic Interview for DSM-IV), 159
CAARS (Conners’ Adult ADHD Rating Scales), 159
Caffeine, 413, 414, 431
sleep effects of, 377, 379, 385, 391
tremor induced by, 61
CAGE-D, 417
California Verbal Learning Test–II, 107
Callosal disconnection syndromes, 11–12, 12, 78–79
CAM. See Confusion Assessment Method
Canadian Psychological Association, 96
Cannabinoids, synthetic, 422
Cannabis, 414, 422–423, 429, 431
antiretroviral therapy and, 315
neurocognitive effects of chronic use of, 422–423
neuropsychiatric complications and possible benefits of, 422
withdrawal from, 416, 422
Capgras syndrome, 70, 462, 513, 514, 516, 517, 517–518, 519
Carbamate neurotoxicity, 208, 209, 210
Carbamazepine, 231, 231
for alcohol withdrawal, 419
for bipolar disorder in multiple sclerosis, 401
in epilepsy with mood disorder, 234
for REM sleep behavior disorder, 472
for schizophrenia with electroencephalography abnormalities, 143
after traumatic brain injury, 278, 279, 280
Carbidopa-levodopa, after traumatic brain injury, 281, 282
Carbohydrate-deficient transferrin (CDT), 418
Carbon disulfide neurotoxicity, 216
Carbon monoxide (CO) poisoning, 20, 30, 126, 214–215, 215
hypoxic-ischemic brain injury due to, 287, 288, 290
Cardiac arrest, hypoxic-ischemic brain injury due to, 287, 290, 291, 298–299
Cardiovascular disease
diabetes mellitus and, 353, 356
obstructive sleep apnea and, 386
poststroke depression risk and, 249, 250
sleep disorders and, 388
syphilis and, 316, 317
Cardiovascular effects of drugs
atomoxetine, 163
citalopram, 495
clonidine, 164
doxylamine, 383
guanfacine, 164
hallucinogens, 429
inhalants, 431
opioids, 426
reboxetine, 253
stimulants, 161–162, 253, 254
synthetic cannabinoids, 422
tricyclic antidepressants, 252, 253, 357
cART. See Antiretroviral therapy, combined
Catalepsy, 64, 507
Catastrophic reaction, 22, 23
Catatonia, 64, 119
assessment scales for, 64
autism spectrum disorder and, 173
depression and, 538
echolalia and, 77
herpes simplex virus encephalitis and, 326
schizophrenia and, 64, 504, 505, 507
Catechol-O-methyltransferase (COMT) gene, 156
Catechol-O-methyltransferase (COMT) inhibitors, in dementia with Lewy bodies,
470
Caudate nucleus, 16
in depression, 528, 536
disorders associated with dysfunction of, 30
frontal-subcortical circuit disorders and, 26, 28, 29, 30
in Huntington’s disease, 29, 132, 134, 478, 528
imaging of, 132, 134
in manganese poisoning, 213
in mania, 19, 29
poststroke, 255, 256
in movement disorders, 26
nonpyramidal hemimotor syndrome, 58
in obsessive-compulsive disorder, 21
in Parkinson’s disease, 468, 528
in poststroke psychosis, 518
CBF. See Cerebral blood flow studies
CBM (classroom-based behavior modification), for attention-deficit/hyperactivity
disorder, 165, 166
CBT. See Cognitive-behavioral therapy
CBT-I (cognitive-behavioral therapy for insomnia), 382, 384, 385
CD4+ T cells, in HIV disease, 304, 307, 308, 309, 310
CD8+ T cells
in progressive multifocal leukoencephalopathy, 308
CDC (Centers for Disease Control and Prevention), 210, 317, 320
Celecoxib, 529
Center for Epidemiologic Studies Depression Scale (CES-D), 247, 355, 397, 399
Centers for Disease Control and Prevention (CDC), 210, 317, 320
Central pontine and extrapontine myelinolysis, alcohol-induced, 422
Central sleep apnea, 380, 386
Cerebellar degeneration, alcoholic, 421
Cerebral amyloid angiopathy, 438
Cerebral blood flow (CBF) studies, 22, 128. See also Neuroimaging, functional
in delirium, 195
in epilepsy, 134
in HIV disease, 311
in hypoxic-ischemic brain injury, 290
in traumatic brain injury, 268, 283
Cerebral metabolic rate, regional (rCMR), 128, 129
Cerebral palsy, 65
Cerebrospinal fluid (CSF) analysis
MRI and, 122–123
Creutzfeldt-Jakob disease, 321–322
delirium, 195
HIV-associated neurocognitive disorder, 309, 310, 312
insomnia, 381
Lyme disease, 319, 320
multiple sclerosis, 396, 398–399
neurosyphilis, 316, 317
progressive multifocal leukoencephalopathy, 309
St. Louis encephalitis, 327
toxoplasmosis, 307, 308
varicella zoster virus encephalitis, 325
West Nile virus encephalitis, 328
Whipple’s disease, 322, 323
Cerebrovascular disorders, 246–261. See also Stroke patients
Certification
in behavioral neurology & neuropsychiatry, 1
in neuropsychology, 96
CES-D (Center for Epidemiologic Studies Depression Scale), 247, 355, 397, 399
Charcot’s sign, 57
Charles Bonnet syndrome, 70, 71
CHARTER (CNS HIV Antiretroviral Therapy Effects Research) study, 310
Chelation therapy
for aluminum exposure, 212
for arsenic exposure, 212
for lead exposure, 213
for manganese exposure, 213
Childhood abuse/trauma, 49
hypothalamic-pituitary-adrenal axis activity, depression and, 365, 529
posttraumatic stress disorder and, 556
Childhood brain tumors, 344–346
adult survivors of, 346
proposed mechanisms of neurocognitive impairment in, 346
treatment of, 346
long-term neurocognitive sequelae of, 345–346
posterior fossa syndrome and, 339, 345
Children and adolescents
attention-deficit/hyperactivity disorder in, 153–168
autism spectrum disorder in, 171–182, 203
blink reflex in, 55
brain development of, 2
asymmetry and physical anomalies, 52
delirium in, 187, 192
assessment scales for, 194
developmental history of, 48
diabetes mellitus in, 352
effects of right hemisphere damage in, 22
environmental factors and psychiatric disorders in, 203
carbon monoxide poisoning, 214, 215
lead poisoning, 211, 213
epilepsy in, 232, 235
event-related potential paradigms for, 150
late-life development of psychiatric symptoms usually beginning in, 337
Lyme disease in, 319
nonconvulsive seizure disorders in
absence seizures, 142
focal seizures, 142
Lennox-Gastaut syndrome, 142, 226
schizophrenia in, 505
sleep disturbances
in insomnia, 382
parasomnias, 386
periodic leg movements in sleep, 387
sleep-disordered breathing, 380, 386
stereotypies in, 63–64
traumatic brain injury in, 267, 268, 276
Chlorpromazine, 237, 364
Cholecystokinin, 551
Choline acetyltransferase, 13, 19
mercury toxicity and, 214
Cholinergic system. See Acetylcholine
Cholinesterase inhibitors. See Acetylcholinesterase inhibitors
Chorea, 61
Creutzfeldt-Jakob disease, 322
anxiety and, 483
psychosis, 61
Whipple’s disease, 323
differential diagnosis of, 61
dopamine and, 33, 34
drug-induced, 61
stimulants, 423
frontal-subcortical circuit dysfunction and, 26
Sydenham’s, 20, 30, 31, 61
vs. tardive dyskinesia, 64
Choreoathetosis, 61, 422, 423
Chronotherapy, 387
CIDI (Composite International Diagnostic Interview), 352, 355
Cingulate gyrus, 3, 7, 11, 16
anterior cingulate circuit, 28–29
deep brain stimulation of, 23
Cingulum bundle, 11
Circadian clock, 374
Circadian rhythm sleep-wake disorders (CRDs), 377, 380, 387
Citalopram
for agitation in Alzheimer’s disease, 456
for depression
in epilepsy, 234
posttraumatic, 278
for poststroke pathological affective display, 261
CIWA-Ar (Clinical Institute Withdrawal Assessment for Alcohol—Revised), 420
CJD. See Creutzfeldt-Jakob disease
Clasp-knife phenomenon, 60
Classroom-based behavior modification (CBM), for attention-deficit/hyperactivity
disorder, 165, 166
Clinical Institute Withdrawal Assessment for Alcohol—Revised (CIWA-Ar), 420
Clock Drawing Test, 80, 108
Clomipramine, 234, 484
Clonal pluralization of the self, 517
Clonazepam
for epilepsy with anxiety, 235
for REM sleep behavior disorder, 471–472
Clonidine
for attention-deficit/hyperactivity disorder, 163–164
combined with methylphenidate, 163
for opioid detoxification, 419, 426
Clozapine
in Lewy body disorders
for psychosis, 471, 520
for REM sleep behavior disorder, 472, 515
seizures induced by, 237
Cluttering, 76
CMV (cytomegalovirus) encephalitis, in HIV disease, 306, 309
CN abnormalities. See Cranial nerve abnormalities
CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study, 310
CO poisoning. See Carbon monoxide poisoning
Cocaine, 414, 423–424
history taking for use of, 50
stereotypies induced by, 64
Cogan’s syndrome, 56
Cognitive-behavioral stress management interventions, 314
Cognitive-behavioral therapy (CBT)
for anxiety, 558
in HIV disease, 314
for attention-deficit/hyperactivity disorder, 165, 166
for brain tumor patients, 341
for depression
in HIV disease, 313
neural circuitry model of mood disorders and sites of action of, 541, 542
posttraumatic, 278
for insomnia (CBT-I), 382, 384, 385
for parasomnias, 387
for psychogenic nonepileptic seizures, 240
for psychosis, 521
after traumatic brain injury, 278, 280, 281–282
Cognitive-energetic model of attentiondeficit/hyperactivity disorder, 156
Cognitive examination, 67, 71–85
components of, 71–82
attention and working memory, 71–72
communication, 73–78
blurting, 77
echolalia, 76–77
language, aphasia, and discourse, 74–75
mutism, 75–76
palilalia, 77
prosody and affective aprosodia, 77–78
speech and dysarthria, 74
stuttering and cluttering, 76
executive function and dysfunction, 80–81
insight and unawareness of deficits, 81–82
memory, 73
neglect, 72–73
orientation, 73
praxis and apraxia, 78
recognition and agnosia, 79–80
signs of callosal disconnection, 78–79
visuospatial function and dysfunction, 80
initiation of, 71
instruments for, 82–84
domain-specific measures, 83–84
Mini-Mental State Examination, 82–83
Montreal Cognitive Assessment, 82–83
Alzheimer’s disease, 452–455
HIV-associated neurocognitive disorder, 306
timing of, 71
Cognitive impairment, 50, 274, 282–283. See also Delirium; Dementia; Executive
dysfunction; Memory impairment
domain-specific measures, 83–84
functional neuroimaging, 127, 131–134, 132, 133
neuropsychological testing, 97, 98, 99
screening, 50
chronic and stable, 50
Alzheimer’s disease, 50, 131, 436, 439, 440, 442–443, 442–446, 444, 448,
449, 452–455, 456, 461
with psychosis, 513
bacterial meningitis, 324
brain tumors, 335, 338, 341
depression and, 342, 344
survivors of childhood tumors, 345–346, 347
Cushing’s syndrome, 363–364
delirium, 191, 192, 195
dementia with Lewy bodies, 459, 460, 461, 461–462, 464, 468, 510
cognitive fluctuations, 461, 463
depression, 98, 105, 539–540
diabetes mellitus, 352–354
medications and, 357
frontotemporal dementia, 489, 491, 492
herpes simplex virus encephalitis, 324–325
HIV-associated neurocognitive disorder, 304–305, 313
comorbidities contributing to, 310
neuroimaging findings in, 311
nomenclature and diagnostic criteria for, 303, 305–306
plasma and CSF biomarkers and, 310
treatment of, 309, 311–312
Huntington’s disease, 480–481
hypoparathyroidism, 367
hypothyroidism, 359
hypoxic-ischemic brain injury, 287, 295, 297, 300
delayed posthypoxic leukoencephalopathy, 299
survivors of cardiac arrest, 299
mania, 539, 540
medical conditions, 98
multiple sclerosis, 396–397, 402, 403–410
assessment of, 408
depression and, 400
neuroimaging findings in, 408–409
mycotoxin exposure, 217
neurological diseases, 98, 539
with dementia, 461, 465–466
with psychosis, 515
poststroke depression, 249, 250–251, 252, 253, 254
poststroke mania, 255
primary progressive aphasia, 489–490
prion disease, 321
psychosis, 82
interictal, 512
schizophrenia, 98, 507–508
solvent toxicity, 216
subacute sclerosing panencephalitis, 324
substance use disorders, 50, 414, 419
alcohol, 421
benzodiazepines, 428–429
inhalants, 431
methamphetamine, 425
opioids, 426–427
traumatic brain injury, 50, 273, 274, 276, 282
vascular neurocognitive disorder, 4, 50, 134
delusions and, 69
drug-related
antiparkinsonian agents, 470
antipsychotics, in patients with brain tumors, 341
in patients with traumatic brain injury, 281
efavirenz, 316
emotional disturbances and, 68, 69
mild
dementia with Lewy bodies and, 464, 510
diagnosis of, 436
dopamine and, 34
memory impairment and, 444
progression to Alzheimer’s disease, 131, 451
social cognition deficits and, 449
neurotransmitter disturbances and, 33, 34, 37
vascular cognitive impairment, no dementia, 4
Cognitive rehabilitation, 97, 282, 298
Cognitive reserve
activities to maximize, 494
delirium and, 192
Cognitive therapy
for attention-deficit/hyperactivity disorder, 166, 167
for insomnia, 384
Cogwheeling, 60
Coma, 24, 71, 192
barbiturate-induced, 427
in cerebral malaria, 324
emergence from, 294
Glasgow Coma Scale, 266, 267, 270
in hypoglycemia, 354
posthypoxic, 292, 294, 295, 300
posttraumatic, 271–272, 275
Communication abilities. See also Aphasia; Language; Speech
blurting, 77
echolalia, 76–77
language, aphasia, and discourse, 74–75, 107
mutism, 75–76
palilalia, 77
prosody and affective aprosodia, 77–78
speech and dysarthria, 74
stuttering and cluttering, 76
conditions associated with impairments of
autism spectrum disorder, 171, 172–173, 175, 177–178, 180, 182
brain tumors, 345
minimally conscious state, 296
primary progressive aphasia, 491–492, 494
thought disorder, 504
vegetative state, 294
hemispheric lateralization of, 15, 70
Community Parent Education Program, 165
Complementary and alternative medicine, in autism spectrum disorder, 181
Composite International Diagnostic Interview (CIDI), 352, 355
Comprehension
in fluent aphasia, 8
Compulsions, 63. See also Obsessive-compulsive disorder
treatment of, 495
Computed tomography (CT), 117, 118, 119–121, 125
brain lesions on, 120
compared with magnetic resonance imaging, 123, 126
contrast-enhanced, 118, 125
imaging request for, 126
interpretation of, 131
patient preparation for, 126
PET and, 130
in pregnancy, 126
quantitative electroencephalography and, 146
safety of, 126
cytomegalovirus encephalitis, 309
delirium, 198
depression, 527
progressive multifocal leukoencephalopathy, 308–309
schizophrenia, 508
toxoplasmosis, 307
technical considerations for, 119–121
Computed tomography (CT) angiography, of anterior communicating artery
aneurysm, 120
Computerized neuropsychological test batteries, 112
COMT (catechol-O-methyltransferase) gene, 156
COMT (catechol-O-methyltransferase) inhibitors, in dementia with Lewy bodies,
470
Concentration, 340
conditions associated with impairment of, 104
HIV disease, 305
hypothyroidism, 359
neurotoxin exposures, 211, 215, 216
hallucinogens, 429
drug effects on
norepinephrine and, 35
Concreteness, 69, 81, 455
Concussion. See Traumatic brain injury
Conduct disorder, 153, 155
Confabulation, 67, 98
Anton’s syndrome and, 518
Korsakoff syndrome and, 98, 421
Confusion
asterixis and, 62
delirium and, 140, 141, 141
antipsychotic exacerbation of, 464
dopamine and, 34
Ganser state and, 69
antiretroviral drug–induced, 315
myoclonus and, 62
neurosyphilis and, 318, 319
neurotoxin exposures and, 209, 211, 216
postictal, 227, 229, 235, 512
posttraumatic, 266, 271, 272
substance withdrawal and, 418
alcohol, 420, 421
varicella zoster virus infection and, 326
Wernicke’s encephalopathy and, 56, 421
West Nile virus encephalitis and, 328
Confusion Assessment Method (CAM), 190, 194
CAM-S, 194
for children, 194
Family CAM, 194
3-D CAM, 194
Confusional arousals, 386, 510, 511
Conners’ Adult ADHD Diagnostic Interview for DSM-IV (CAADID), 159
Conners’ Adult ADHD Rating Scales (CAARS), 159
Conners’ Continuous Performance Test, 105
Conners’ Parent and Teacher Rating Scales, 3rd Edition, 158
Consciousness
loss of
in Lewy body disorders, 463
sedative-hypnotic withdrawal seizures with, 428
traumatic brain injury with, 98, 266, 267, 269–270, 272
posthypoxic disorders of, 294–297, 295, 300
coma, 294
minimally conscious state, 295–296
vegetative state, 294–295
Constipation
drug-induced
norepinephrine reuptake inhibitors, 253
tricyclic antidepressants, 252, 253
treatment of, 472
Content of thought. See also Delusions; Hallucinations
Contingency management, for attentiondeficit/hyperactivity disorder, 156, 165
Continuous-performance tasks, 72, 105–106, 159
Continuous performance test (CPT), 159
Controlled Oral Word Association Test (COWAT), 406
Conversion disorder
examination for, 52
event-related potentials, 150
evoked potentials, 148–149, 150
with limb paralysis, 23
psychogenic nonepileptic seizures and, 143, 238
Coordination
assessment of, 53, 58, 65, 100
conditions associated with impairment of
brain tumors, 337
hypoglycemia, 354
lithium therapy, 401
neurotoxin exposures, 211, 216
cannabis, 422
inhalants, 430
finger, 78, 108
GABA and, 33
Cornell Assessment of Pediatric Delirium, 194
Corpus callosum, 11
agenesis of, 65
callosal disconnection syndromes, 11–12, 12, 78–79
deficits associated with lesions of, 11, 12, 15
in HIV-associated neurocognitive disorders, 311
MRI studies of, 124
in traumatic brain injury, 268
Cortical-subcortical connections, 8, 19, 25–31, 134, 531
frontal-subcortical circuits, 26–31, 28
subcortical functional anatomy, 135
thalamocortical interactions, 25–26, 27
Corticobasal degeneration, 62, 79, 489, 492
Corticospinal signs, 54
Corticosteroids
adverse effects of
obesity, 380
psychiatric effects, 339, 341, 342, 364, 365
in brain tumor patients, 339, 341, 342
delirium, 197
mania, 364, 401, 534
tremor, 61
for brain tumor patients, 336, 339, 341
effect on diagnosis of primary central nervous system lymphoma, 308
for Hashimoto’s encephalitis, 361
Corticotropin-releasing factor in Alzheimer’s disease, 441–442
Cortisol levels in Cushing’s disease, 363–364
in delirium, 196, 197, 198
melatonin regulation of, 181
in posttraumatic stress disorder, 554–555
COWAT (Controlled Oral Word Association Test), 406
CPT (continuous performance test), 159
Cranial nerve (CN) abnormalities
brain tumors and, 334, 337
chronic neuroborreliosis and, 320
examination for, 53
posttraumatic, 272
REM sleep behavior disorder and, 380
syphilitic meningitis and, 318
“Crash,” after stimulant withdrawal, 423
CRDs (circadian rhythm sleep-wake disorders), 377, 380, 387
Creutzfeldt-Jakob disease (CJD), 321–322
sporadic (sCJD), 321–322
variant (vCJD), 321–322
Cryptococcus neoformans meningitis, in HIV disease, 306, 308
CSF analysis. See Cerebrospinal fluid analysis
CT. See Computed tomography Curcumin, 529
Cushing’s disease, 352
cardinal features of, 363
psychiatric symptoms of, 363–364
cognitive impairment, 363–364
mood and anxiety disorders, 363
psychosis, 363
D-Cycloserine, 552
Cytochrome P450 (CYP) enzyme system
antidepressants and, 343–344
antiretroviral agents and, 313, 316
atomoxetine and, 163
Cytokines in Alzheimer’s disease, 441
in delirium, 195, 196
in depression
poststroke, 252
in HIV-associated neurocognitive disorders, 304
in sickness behavior, 356
in sleep disturbances in neurological disorders, 388
vomitoxin and, 217
Cytomegalovirus (CMV) encephalitis, in HIV disease, 306, 309
D-KEFS (Delis-Kaplan Executive Function System) Sorting Test, 109

DA. See Dopamine DAT. See Dopamine transporter
Datura stramonium, 429
Decisional capacity, determination of, 97, 112–113
Decubitus ulcers, 188, 199
Deep brain stimulation
for mood disorders, 541
depression, 23, 525, 527, 535
mania, 534
for posthypoxic movement disorders, 293
Default mode network (DMN)
in depression, 530–531
Defiant Children program, 165
Déjà vu, 49, 142, 226, 321, 325, 337, 517
Delayed posthypoxic leukoencephalopathy, 299–300
Delayed sleep-wake phase disorder, 387, 390
Delirium, 185–199
clinical evaluation of, 196
identification of etiologies, 196–197, 198
laboratory studies, 197
clinical features and presentation of, 187–190
course and symptom persistence, 188–189
delirium subtypes, 185, 188, 189
hallucinations and delusions, 187, 188, 191, 195
hemianopsia, 55
inattention, 185, 187, 188, 189, 196
paratonia, 60
thinking pattern, 69
tremor, 62
Alzheimer’s disease, 192, 436, 452, 453
brain tumors, 341
dementia, 186, 187, 191, 192, 193, 196
epilepsy, 142, 236
Hashimoto’s encephalitis, 361
hypothyroidism, 359
nonconvulsive status epilepticus, 140, 141
poststroke depression, 253
poststroke psychosis, 257
psychosis, 521
stroke, 187, 190, 192
alcohol withdrawal, 141, 198, 420
hallucinogens, 429
vascular dementia, 192
detection and recognition of, 193–194
barriers to, 193
DSM and ICD criteria, 185, 186, 196
electroencephalography, 140–141, 194, 195, 197
quantitative EEG, 146
neuroimaging, 119
neurophysiological testing, 141
screening and severity instruments, 188, 190, 193–194, 196
drug-induced, 197
anticholinergic agents, 33, 54, 192, 197, 468
antiepileptic drugs, 237
in elderly persons, 141, 186–187, 188
dementia and, 186
detection of, 193, 194, 196
electroencephalography monitoring for, 197
mortality associated with, 190
risk factors for, 191–192
in hospitalized patients, 186–187, 190, 192
in intensive care unit, 140, 187, 188, 191
management of, 197–199
outcomes of, 190
screening for, 194
medications, 198–199
nonpharmacological, 197–198
onset and course of, 141
outcomes of, 190–191
financial costs, 191
morbidity, 190–191
mortality, 141, 190
neuropsychiatric sequelae, 191
pathophysiology and neurobiology of, 194–196
acetylcholine, 33, 33, 188, 195–196, 199
biomarkers, 195
cerebral blood flow, 195
genetic factors, 195
melatonin, 193, 195–196
neuroimmunological hypothesis, 195–196
observations and findings, 194–195
in pediatric patients, 187, 192, 194
postoperative, 186, 187, 192
prevention of, 192
risk factors for, 191–192, 199
subsyndromal, 189–190
terminology for, 185
Delirium Index, 194
Delirium Motor Checklist (DMC), 188
Delirium Observation Screening Scale, 194
Delirium Rating Scale (DRS), 194
Delirium Rating Scale—Revised–98 (DRS-R-98), 190, 194
Delirium tremens (DTs), 141, 420
Delis-Kaplan Executive Function System (D-KEFS) Sorting Test, 109
Delusional disorder, 504
posttraumatic, 519
Delusional misidentification syndromes, 70, 516–518
Alzheimer’s disease, 447, 448–449, 513, 516
Lewy body disorders, 462, 514, 516
functional neuroimaging in, 518
neuroanatomical correlates of, 517–518
types of, 516, 517
Frégoli syndrome, 70, 514, 516, 517
Delusions, 11, 69–70, 503–504, 521. See also Psychosis
acetylcholine and, 33
assessment of, 67, 69–70, 84
vs. autism spectrum disorder, 177, 178
Alzheimer’s disease, 447, 448, 449, 452, 513–514
delirium, 187, 188, 191
dementia with Lewy bodies, 462, 471, 510, 514–516
neurosyphilis, 319
Parkinson’s disease with dementia, 466, 471, 514–516
prion disease, 321
schizophrenia, 504–505, 521
seizures, 143, 236, 510, 512
stroke, 257–258, 518
Wilson’s disease, 520
control, 506
Cotard, 506
denial of, 82
dopamine and, 33
drug-induced
anticholinergic agents, 33
NMDA receptor antagonists, 37
stimulants, 423, 424
erotomanic, 506
grandiose, 319, 506, 512, 519
of jealousy, 506, 513, 519
paranoid (persecutory), 70, 402, 424, 447, 448, 452, 462, 506, 510, 513, 514,
516, 519, 520
referential, 506, 519
religious, 512
somatic, 505, 506
of theft, 448, 449, 504, 506, 516
thought broadcasting, 506
thought insertion, 505, 506
thought withdrawal, 505, 506
treatment of, 520
types of, 506
Dementia. See also specific types
antipsychotic risks in elderly patients with, 199
assessment of, 84
electroencephalography, 141, 141–142
quantitative EEG, 146, 147
functional imaging, 127
Alzheimer’s disease, 435–456, 536
anxiety disorders, 557
apathy, 536
brain tumors, 339
delirium, 186, 187, 191, 192, 193, 196
HIV-associated neurocognitive disorders, 304–306, 329
Lewy body disorders, 459–473, 510
with psychosis, 514–516
Parkinson’s disease with dementia, 459, 465, 465–472
prion disease, 321–322
psychosis, 511, 514–519, 521
in Lewy body disorders, 514–516
misidentification syndromes, 516–518
sleep disorders, 389, 511, 537
alcohol, 421, 422
syphilis, 318, 319
differential diagnosis of, depression, 102
electroencephalography for, 141, 141–142
disinhibition and, 540
eye movement abnormalities in, 56
falls in patients with, 58
melatonin levels in, 195
mild cognitive impairment as prodrome for, 50
neurotransmitters and, 33, 33, 35, 36
paratonia in, 60
pathological affect and, 68
vascular, 50, 494
misidentification syndromes in, 516
subcortical, gait disorder of, 58
“Dementia paralytica,” 318
Dementia praecox, 64
Dementia with Lewy bodies (DLB), 460–465
acetylcholine in, 33–34, 462
clinical features of, 460–464
autonomic dysfunction, 463–464
cognitive fluctuations, 460, 463
cognitive profile, 461, 461–462
executive function, attention, and concentration, 461
language and communication, 462
memory and learning, 461–462
visuospatial function, 461
excessive daytime sleepiness, 463
extrapyramidal features, 465
motor features, 62, 462–463
neuroleptic sensitivity, 460, 464
psychosis, 504, 510, 514–516
delusions, 462, 471, 510, 514–516
hallucinations, 70, 98, 460, 462, 469, 471, 472, 510, 514–516
REM sleep behavior disorder, 389, 460, 463, 468
delay in diagnosis of, 460
diagnostic criteria for, 460–461
differential diagnosis of, 464–465
Alzheimer’s disease, 132–133, 133, 461, 464
dopamine in, 461
neuroimaging in, 461, 468–469, 469
vs. Alzheimer’s disease, 132, 132–133, 461
neuropathology of, 459, 460, 460, 467
clinicopathological correlates, 468
autonomic dysfunction, 472
behavioral pathology, 470–471
cognitive symptoms, 469–470
motor symptoms, 470
sleep disorders, 471–472
Demyelination
central pontine and extrapontine myelinolysis and, 422
deficits associated with, 11
delayed posthypoxic leukoencephalopathy and, 299
on MRI, 124
multiple sclerosis and, 395, 396, 399, 410, 557
posthypoxic movement disorders and, 293
substance-related, 431
Dennis-Robertson syndrome, 218
Depersonalization, 49, 236, 428, 429, 557
Depression, 525–542
vs. apathy, 248, 280, 482
assessment of
cognitive examination, 71
electroencephalography, 534, 537
differentiation from dementia, 141–142
neuroimaging, 527–528, 530–531
functional imaging, 527–528, 530–531
structural imaging, 365, 527, 530
neuropsychological testing, 98, 99, 102, 103, 104, 105, 110
bipolar, 144, 530, 532, 537
with psychosis, 513
anxiety disorders, 538, 558
autism spectrum disorder, 178–179
brain tumors, 336, 338, 341–344, 347
catastrophic reaction, 259, 260
catatonia, 59
cautious gait, 59
cognitive deficits, 98, 105, 539–540
delirium, 142, 191
dementia, 142, 527
diabetes mellitus, 352, 355–358
emotional bias, 538–539
epilepsy, 143, 233–234
with postictal psychosis, 236, 511
herpes simplex virus infection, 326
HIV disease, 305, 310, 312–313, 312–314
Huntington’s disease, 479, 481, 482, 484, 527
multiple sclerosis, 396–401
cognitive impairment and, 407, 408, 409
neurosyphilis, 319
Parkinson’s disease, 4, 466–467, 470, 527
with dementia, 466
with psychosis, 515
prion disease, 321
psychogenic nonepileptic seizures, 238
psychosis, 504
postictal, 236, 511
sleep disturbances, 51, 379, 389–390
speech abnormalities, 74
stroke, 245–255, 261, 527, 557 (See also Poststroke depression)
substance use disorders, 414, 415, 419, 431
alcohol, 420
hallucinogens, 429
inhalants, 431
stimulants, 423
suicidality, 539
wandering behavior, 59
default mode network in, 530–531
drug-induced
barbiturates, 238
levetiracetam, 238
tetrabenazine, 480
topiramate, 238
genetic factors and, 530, 534, 537
hypothalamic-pituitary-adrenal axis and, 365, 528–529, 531, 532, 541, 541
hypothalamic-pituitary-thyroid axis and, 361–363, 365
neuroanatomical correlates of, 4, 11, 19, 20, 22, 23, 23, 29, 30, 530–532
neurotransmitters and, 33, 34, 35, 528
pseudodementia of, 142, 149, 540
sadness and, 68, 526, 533
vegetative symptoms of, 313
Derailment, 69, 503, 504
Derealization, 49, 346, 428, 429
Desipramine, 401
Developmental coordination disorder, 178
Developmental disorders
dysmorphic features and, 54
neuropsychological evaluation of, 96, 97, 105, 113
stereotypies and, 64
Developmental factors
asymmetry and minor physical anomalies, 52, 54
Dextroamphetamine (DEX)
for attention-deficit/hyperactivity disorder, 160
for traumatic brain injury patients, 280, 281, 282
Dextromethorphan-quinidine, for pseudobulbar affect
posttraumatic, 279
Diabetes mellitus, 351–358
anxiety disorders and, 352, 358
cardinal features of, 351–352
in children, 352
cognitive disorders and, 352–354
long-term cognitive effects, 353–354
in type 1 diabetes, 352–353
in type 2 diabetes, 353
depression and, 352, 355–358
prevalence of, 355
in type 1 diabetes, 355
in type 2 diabetes, 355–356
gestational
hypoglycemia and, 354–355
incidence of, 351
poststroke depression and, 250
psychiatric symptoms in, 352
type 1 and type 2, 351–352
use of iodinated contrast agents in, 125
Diagnostic and Statistical Manual of Mental Disorders (DSM), 2, 85
anxiety disorders in, 235, 545
panic disorder and agoraphobia, 548
attention-deficit/hyperactivity disorder in, 153, 154, 155, 159
autism spectrum disorder in, 172–173
delirium in, 185, 186, 188, 189, 196
depression in, 526
brain tumors and, 342–343, 347
poststroke depression, 245–247, 248
mood disorders in, 526
neurocognitive disorders in, 50
Alzheimer’s disease, 435–456, 442–443
domains for assessment of, 83
frontotemporal dementia, 487–498
Lewy body disorders, 459–473
poststroke anxiety in, 256
poststroke depression in, 245–247, 248
poststroke mania in, 255
schizophrenia in, 504–505
sleep-wake disorders in, 377
social communication disorder in, 177
substance use disorders in, 413–414, 414, 416, 418, 419, 429
Dialectical behavior therapy, for attentiondeficit/hyperactivity disorder, 165
Diarrhea
in organophosphate poisoning, 209
Diazepam
abuse potential of, 427
Diet
attention-deficit/hyperactivity disorder and, 158, 167
for constipation, 472
frontotemporal dementia and, 488
monoamine oxidase inhibitors and, 278, 357
primary progressive aphasia and, 492
sleep-related breathing disorders and, 386
Diffusion-weighted imaging (DWI), 123, 125
Digit Span test, 72, 105, 109, 110, 455
Digit Symbol Coding test, 105
Dihydropyridines, 197
2,5-Dimethoxy-4-methylamphetamine (DOM), 429
Dimethyltryptamine (DMT), 429
Diphenhydramine, for insomnia, 383
Disability determination, 97, 110
Disconnection syndromes, callosal, 11–12, 12, 78–79
Disinhibition, 536
assessment of, 84
brain tumors, 339, 341
frontotemporal dementia, 488, 489, 490, 493
HIV infection, 305
substance use disorders and, 314
mania, 540
prion disease, 321
drug-induced
barbiturates, 238
Disorders of consciousness, posthypoxic, 294–297, 295, 300
coma, 294
Disorientation, 100, 223
Alzheimer’s disease, 442, 443, 444–445, 446, 453
delirium, 186, 187, 193, 196
Gerstmann syndrome, 7
neurosyphilis, 319
prion disease, 321
Dissociation, 69, 72, 75, 141, 144, 557
status dissociatus, 511
Dizziness
drug-induced
sedative-hypnotics, 383
selective serotonin reuptake inhibitors, 255, 257
inhalant-induced, 430
neurotoxin-induced, 209, 215, 216
posttraumatic, 271
DLB. See Dementia with Lewy bodies
DMC (Delirium Motor Checklist), 188
DMN. See Default mode network
DMT (dimethyltryptamine), 429
Doll’s eyes, 56
DOM (2,5-dimethoxy-4-methylamphetamine), 429
Donepezil, for cognitive dysfunction
for REM sleep behavior disorder, 472
in frontotemporal dementia, 496, 497
posthypoxic, 298
posttraumatic, 282
sleep effects of, 390
L-Dopa. See Levodopa
Dopamine (DA), 34
in appetite regulation, 538
asymmetries in limbic system, 19
blink rate and, 55
in emotional bias, 539
in interest and motivation, 536
origins and destinations of, 32, 34, 35
in psychomotor activity, 536
panic disorder, 551
social anxiety disorder, 552, 553
delirium, 188, 195, 196
depression, 528
fungal toxicity, 218
lead poisoning, 213
Parkinson’s disease, 34, 468, 514, 538
with psychosis, 515
neuroleptic malignant syndrome, 464
positive emotional states, 535
Dopamine receptors, 34
in Alzheimer’s disease with psychosis, 513–514
D2, 34
antipsychotic blockade of, 34, 366, 464, 471, 520
in generalized anxiety disorder, 548
in HIV-associated neurocognitive disorder, 311
in social anxiety disorder, 552
types of, 34
Dopamine transporter (DAT), 417
in attention-deficit/hyperactivity disorder, 156, 157
in depression, 528
in Parkinson’s disease with anxiety, 557
PET imaging in HIV disease, 311
SPECT imaging in neurocognitive disorders, 128, 132, 132
in stimulant mechanism of action, 415
Dopaminergic medications, 34, 388, 525
adverse effects of
hallucinations/psychosis, 71, 466, 514–515
mania, 534
sleep effects, 390
in dementia with Lewy bodies, 463, 470
for hyperprolactinemia, 366
for Parkinson’s disease, 71, 463, 470, 538
in posttraumatic stress disorder, 554
for sleep-related movement disorders, 388
Dorsolateral prefrontal syndrome, 28, 30
Down syndrome, 380, 459, 460
Doxepin, 383
Doxylamine, 383
Dravet syndrome, 226
Drawing tasks, 80
Dream enactment behavior, 379, 511. See also Rapid eye movement sleep
behavior disorder
DRS (Delirium Rating Scale), 194
DRS-R-98 (Delirium Rating Scale—Revised– 98), 190, 194
DSM. See Diagnostic and Statistical Manual of Mental Disorders
DTs (delirium tremens), 141, 420
Duloxetine, 357, 401
DWI. See Diffusion-weighted imaging
Dysarthria, 73, 74, 100. See also Speech disorders
without agrammatism, 76
bulbar (flaccid), 74
alcoholic cerebellar degeneration, 421
Pakinson’s disease with dementia, 466
posterior fossa syndrome, 345
primary progressive aphasia, 489, 491
pyramidal disorders, 74
cortical, 78
Dysbiosis, neurotoxin exposure and, 207–208, 210
Dysgraphia, 73. See also Agraphia
Dyskinesia
dopamine and, 34
oral, 62
tardive, 61, 62, 64, 81, 181, 520
Dyslexia, 24, 48. See also Reading impairment
Dysmorphic features, 54
Dysphagia, 74
Dysthymia. See Persistent depressive disorder
Dystonia, 26, 60
Creutzfeldt-Jakob disease and, 322
drug-induced
antipsychotics, 181
stimulants, 423
myoclonus and, 62
posthypoxic, 293
progressive supranuclear palsy and, 492
tardive, 62
Early Start Denver Model, for autism spectrum disorder, 180

Eating/feeding abnormalities. See also Appetite changes
aberrancy of interhemispheric asymmetry and, 24
sleep-related eating disorder, 379, 510
locus of brain injury and, 51
Echolalia, 64, 76–77
Economic costs
of delirium, 191
of mood disorders, 525
of panic disorder, 548
“Ecstasy” (methylenedioxmethamphetamine), 315, 414, 429
ECT. See Electroconvulsive therapy
EDSS (Expanded Disability Status Scale), 407
EEG. See Electroencephalography
Efavirenz, 315–316
Elderly persons
Alzheimer’s disease in, 435, 436, 437, 453
evaluation for, 98
benefits of cognitive and physical activity to reduce dementia risk in, 493–494
blurting in, 77
brain changes in, 2
reduced brain weight, 437
brain tumors in, 335, 337
cautious gait in, 58–59
Charles Bonnet syndrome in, 70
delirium in, 141, 186–187, 188
dementia and, 186
detection of, 193, 194, 196
electroencephalography monitoring for, 197
mortality associated with, 190
dementia with Lewy bodies in, 472
depression in
emotional bias and, 539
epilepsy and, 233
differentiation of depression and dementia in, 102
epilepsy in, 233, 235
eye movement abnormalities in, 55
imaging in
amyloid-PET imaging, 133, 439
functional neuroimaging, 127–128
subdural hematoma, 120
language of, 453
medication use in
antidepressants, 142
antipsychotic risks, 199, 456, 496
citalopram, 254, 495
olfactory changes in, 54
oral dyskinesia in, 62
Parkinson’s disease in, 4
Parkinson’s disease with dementia in, 472
poststroke apathy in, 258, 259
poststroke depression in, 248, 249
psychosis in, 21
right-hemisphere dysfunction in, 22
sleep disturbances in, 387, 389
sleep requirements of, 389
St. Louis encephalitis in, 327
supralimbic zone disorders in, 4
time and day orientation in, 444
traumatic brain injury due to falls in, 268
type 2 diabetes mellitus in, 354, 362
cognitive disorders and, 352
varicella-zoster virus infection in, 326
West Nile virus encephalitis in, 328
Electrocardiogram, 162, 198, 380, 381
Electroconvulsive therapy (ECT), for depression, 535, 542
posttraumatic, 278
Electroencephalography (EEG), 139, 140–146
quantitative (QEEG), 139, 140, 145–147, 150
applications of, 146, 147
sensitivity and specificity of, 146
during REM sleep, 376
aggression/violence, 143
antisocial personality disorder, 143
autism spectrum disorder, 143, 174, 177
borderline personality disorder, 144
delirium, 140–141, 194, 195, 197
differentiation from dementia, 141–142
epilepsy, 134, 140, 225, 230
frontal lobe epilepsy, 228
with psychosis, 236
epileptiform discharges in psychiatric disorders, 143–144
with seizures and myoclonus, 292
identification of covert seizures, 142–143
panic disorder, 143, 145, 557
prion disease, 322
rapid-cycling bipolar disorder, 144
schizophrenia, 143
sedative-hypnotic withdrawal seizures, 428
subictal mood disorders, 144–145
video-electroencephalography in psychogenic nonepileptic seizures, 238, 240
standard, 140–145
applications of, 140–145
evoked potentials and, 148
indications for, 140, 141
interpretation of, 140, 145
limitations of, 145
magnetoencephalography and, 147
types of abnormalities on, 140
Emotion(s). See also Mood
activation likelihood studies of, 18
in Alzheimer’s disease, 447, 447–449
assessment of emotional status, 68–69
changes preceding seizures, 49
frontal lobes in regulation of, 17, 68–69, 533–534
imaging studies of neuroanatomy of, 17–18
lateralization and valence-related hypotheses of, 17–18
limbic and paralimbic structure and function in relation to, 3, 15, 17–18
effects of lateralized brain dysfunction, 22–24, 23
mood and affect, 532–533
neurobiological bases of cognition, behavior and, 1–39
posthypoxic disturbances of, 298–299
temporal lobes in regulation of, 17, 69
Emotional bias, in mood disorders, 538–539
Emotional lability, 51, 68
assessment of, 84
delirium and, 187
neurosyphilis and, 318
neurotoxin exposure and, 211, 216
posttraumatic, 271, 278–279
stimulant-induced, 161
during withdrawal, 423
Emotionalism (pseudobulbar affect), 23, 68–69, 533
multiple sclerosis and, 396, 401, 402, 403
posttraumatic, 278–279
Emtricitabine, 315
Endocrine disorders, 351–368
Addison’s disease, 364–365
diabetes mellitus, 351–358
hyperprolactinemia, 366–367
hypoparathyroidism, 367–368
pheochromocytoma, 365–366
thyroid disorders, 358–363
hyperthyroidism, 360–361
hypothalamic-pituitary-thyroid axis and depression, 361–363
hypothyroidism, 358–360
Enkephalin, 38
Entorhinal-hippocampal complex, 15–16, 19, 27, 32, 36. See also Hippocampus
Environmental agnosia, 7, 12, 12, 14, 23
Environmental autonomy, 80, 81
Environmental-dependency reaction, echolalia as, 77
Environmental factors, 1
Alzheimer’s disease and, 446, 448, 449, 513
autism spectrum disorder and, 173, 174, 177, 181, 203–204, 210
delirium and, 193, 197–198
developmental anomalies and, 52
mood disorders and, 530
poisons and toxins, 203–219
posthypoxic myoclonus and, 292
sleep disturbances and, 378, 382, 385
substance use disorders and, 416, 419
Ephedra, 423
Epilepsy, 223–241. See also Seizures; Status epilepticus
age distribution of, 235
clinical presentation, 229–230
electroencephalography, 140, 142–143, 225, 230
magnetoencephalography, 147, 148
classification of, 224–225
anxiety disorders, 234–235
autism spectrum disorder, 143, 174, 178
brain tumors, 323, 335, 339, 341, 343, 344, 347, 347
misidentification syndromes, 516
mood disorders, 143, 233–234, 527, 534
psychogenic nonepileptic seizures, 239–240
psychosis, 21, 70, 71, 98, 235–237, 504, 509–510, 511–512
sexual dysfunction, 20, 21, 51
dacrystic, 49
definition of, 224
vs. electrical seizure, 224
etiologies of, 225
familial neonatal, 226
focal, 224–225
frontal lobe, 227–228, 239, 379
gelastic, 49
generalized, 225
genetic, 225
history taking for ictal events, 49
juvenile myoclonic, 226
limbic system dysfunction and, 20, 21
management of, 230–232, 231 (See also Antiepileptic drugs)
neurobehavioral effects of antiepileptic drugs, 237–238
treatment-refractory disease, 232
neurobehavioral manifestations of focal seizures, 225–228
frontal lobe epilepsy, 227–228
occipital lobe epilepsy, 228
parietal lobe epilepsy, 228
temporal lobe epilepsy, 226–227
neurobehavioral manifestations of generalized seizures, 228–229
absence epileptic seizures, 228–229
tonic-clonic epileptic seizures, 229
occipital lobe, 228
palilalia in, 77
parietal lobe, 228
vs. psychogenic nonepileptic seizures, 238–239, 239
psychopathology and, 223, 223
psychosocial impacts of, 232–233
extent of, 232
social interventions for, 232–233
reflex, 226
in sleep, 378, 379, 389
startle reaction in, 63
vs. stereotypies, 64
stigma of, 232
stuttering in, 76
syndromic, 225, 226
temporal lobe, 145, 226–227, 239
amnestic state in, 227
with aura, 226
emotional facial weakness in, 57
epigastric rising in, 226
glutamate and, 37
language and discourse in, 75
mesial, 37, 142
movement abnormalities in, 227
neurobehavioral manifestations of, 226–227
personality traits and, 51
preictal emotional changes in, 49
sexual function disorders and, 20, 21
with version, 227
Epileptiform discharges, identification of
electroencephalography, 143–144, 145, 230
EPs. See Evoked potentials
Epworth Sleepiness Scale, 380
Ergotamines, 282
ERPs. See Event-related potentials
Escitalopram, 255, 278
Eszopiclone, 383, 427
Ethylene oxide (EtO) poisoning, 215, 215
Euphoria
assessment of, 84
mania, 68, 533
in HIV disease, 314
multiple sclerosis, 68, 396, 401–402
neurotoxin exposure, 211, 216
drug-induced
cannabis, 422
inhalants, 430
opiates, 424, 426
sedative-hypnotics and anxiolytics, 427
stimulants, 423
secondary, right brain lesions and, 23
European Federation of Neurological Societies, 282
Event-related potentials (ERPs), 149–150
auditory N100, 149
auditory P200, 149
P300, 149
in conversion disorder, 150
in dementia, 149
in schizophrenia, 149–150
Evoked potentials (EPs), 139, 148–149
in multiple sclerosis, 396, 399
posthypoxic, 291
Excessive daytime sleepiness, 379, 384. See also Hypersomnia
assessment of
Epworth Sleepiness Scale, 380
history taking, 51, 377
Multiple Sleep Latency Test, 381, 384
caffeine and, 391
posttraumatic, 281
Excitotoxicity
glutamate in, 33, 36, 37
HIV brain infection and, 304, 312
hypoxic-ischemic brain injury and, 292
Executive dysfunction, 81, 110. See also Cognitive impairment
Alzheimer’s disease, 435, 442, 443, 446, 454, 461, 504
attention-deficit/hyperactivity disorder, 155, 156, 159
brain tumors, 340
delirium, 58
poststroke, 250
frontotemporal dementia, 110, 487, 488, 489, 491, 494
HIV-associated neurocognitive disorder, 305, 306
efavirenz and, 316
Huntington’s disease, 480–481
hypothyroidism, 359
multiple sclerosis, 400, 403, 406, 407, 408
Parkinson’s disease with dementia, 461, 465, 466
prion disease, 321
schizophrenia, 98, 508, 509
alcohol, 421
inhalants, 431
opiates, 426–427
stimulants, 424, 425, 430
traumatic brain injury, 271–272, 275, 276, 277, 282
vascular dementia, 50
falls due to, 58
neuroanatomical correlates of, 4, 5, 8, 11, 25, 26–28, 27, 110, 118, 540
thought disorder and, 69
Executive dysfunction model of attentiondeficit/hyperactivity disorder, 156
Executive function, 80–81, 109, 340
domain-specific cognitive measures, 83
neuropsychological tests, 109–110
Executive Interview (EXIT), 81
Exercise
for constipation, 472
sleep effects of, 374, 385, 386
EXIT (Executive Interview), 81
Expanded Disability Status Scale (EDSS), 407
Extrapyramidal dysfunction
antipsychotic-induced in delirium, 198–199
in HIV disease, 314
pimavanserin for reduction of, 521
apraxia of eyelid opening and, 56–57
hepatic encephalopathy and, 422
multiple system atrophy and, 465
palilalia and, 77
Parkinson’s disease and, 465, 465
levodopa for, 470
Parkinson’s disease with dementia and, 465, 467
rigidity and, 60
stuttering and, 76
Extrapyramidal function, 38, 38
Extrapyramidal release signs, 59
Eye examination, 54–57
blink rate, 55
eye movement abnormalities, 53, 55–57 (See also Nystagmus; Saccades)
posthypoxic, 295
posttraumatic, 272
in vegetative state, 295
Kayser-Fleischer rings, 54–55
pupillary abnormalities, 55, 317
visual fields, 55 (See also Visual field defects)
Ezogabine, 231
FAB (Frontal Assessment Battery), 81

Facial movement, examination of, 57
Fahr’s disease, 30, 61
Falls
alcohol intoxication and, 420
delirium and, 190
drug-associated
antipsychotics, 341
benzodiazepine receptor agonists, 383
gait disturbances and, 58
myoclonus and, 292
startle reaction and, 63
traumatic brain injury due to, 268
Family Confusion Assessment Method, 194
Family history, 47, 52. See also Genetic factors
of Alzheimer’s disease, 436, 442
of autism spectrum disorder, 177
of cardiovascular disease, 162
of epilepsy, 145
of frontotemporal dementia, 487–488
of mood disorders
antiepileptic drug treatment and, 237, 238
bipolar disorder in multiple sclerosis and, 401
poststroke depression risk and, 249, 249–250
poststroke mania risk and, 255
posttraumatic disinhibition syndrome risk and, 339
of panic disorder, 235
of psychosis, 504, 521
of sleep disturbances, 377
Fatigue
assessment of, 71, 98, 99, 102, 112
brain tumors, 343, 347
depression, 479
in multiple sclerosis, 397, 399, 400
Lyme disease, 320
multiple sclerosis, 389, 396, 397, 399, 400
molds, 217, 218
posttraumatic depression, 247, 254
traumatic brain injury, 98, 271, 280–281
selective serotonin reuptake inhibitor–induced, 255
Felbamate, 231
Finger-rolling test, 57
Finger Tapping Test, 108
FLAIR. See Fluid-attenuated inversion recovery imaging
FLE. See Frontal lobe epilepsy
Flip-flop switches and sleep, 376–377
Fludrocortisone, 472
Fluency
category, 106, 462
in depression, 539
cluttering and, 76
design, 14
primary progressive aphasia and
nonfluent-variant, 487, 488, 489, 491
semantic-variant, 491
verbal, 14
tests of, 106, 109, 406
written, 74
Fluid-attenuated inversion recovery (FLAIR) imaging, 123, 123, 124
compared with PET, 130
in HIV disease, 311
Flumazenil, 414
Fluoxetine
for depression in multiple sclerosis, 401
interaction with antiepileptic drugs, 23
for poststroke depression, 253, 254
Fluvoxamine, 234, 496
fMRI. See Magnetic resonance imaging, functional
Forced normalization, 236, 237, 512
Form of thought, assessment of, 69
Formaldehyde toxicity, 215
Fragile X syndrome, 174, 177
Frascati criteria for HIV-associated neurocognitive disorders, 305, 306, 310
Frontal Assessment Battery (FAB), 81
Frontal lobe epilepsy (FLE), 227–228
aberrant nocturnal behaviors in, 379
hyperkinetic, 228
vs. psychogenic nonepileptic seizures, 228, 239
unique features of, 227–228
Frontal lobe syndrome, 26, 69
Frontal lobes, 5, 11
in abnormal eating behaviors, 51
in aggression, 51
in alcohol-related neurocognitive disorder, 421
in “anarchic hand,” 79
anatomic asymmetries between, 12–13
in anxiety disorders
in neurological disorders, 557
panic disorder, 551
in apathy, 536
in asterixis, 63
in bipolar disorder, 534–535
in borderline personality disorder, 144
in delirium, 195
in delusions, 70
dopamine in, 32, 34
in echolalia, 77
in emotional regulation, 17, 68–69, 533–534
in executive functioning, 109, 110
in eye movement abnormalities, 56, 57
in gait abnormalities, 58, 59
in herpes simplex virus encephalitis, 324, 520
hypoxic-ischemic injury of, 293, 297
in language disturbances, 107
in memory impairment, 73
in mood disorders, 540, 541
depression, 22, 527, 527, 529, 531, 539, 540
mania, 256, 314
treatment and, 542
in mutism, 76
in neglect, 72
in neurocognitive disorders
frontotemporal dementia, 133, 487, 488, 489, 491, 519
vascular, 134
neuroimaging of, 120, 124
functional, 128, 130
in neurosyphilis, 319
mania, 256
psychosis, 258
primitive reflexes and, 65
in psychosis, 519–520
misidentification syndromes, 516–518
poststroke, 518
schizophrenia, 507–508, 509
thalamocortical connections, 27
traumatic injury of, 268, 272, 519
tumors of, 333, 334, 338–339, 342
in unawareness of deficits, 81, 101
Frontal-occipital fasciculus, 11
Frontal release signs, 59, 65
Frontal-subcortical circuits, 2, 25, 26–31, 28, 29
anterior cingulate circuit, 28–29
disorders associated with dysfunction of, 29–31, 30
dorsolateral prefrontal circuit, 27–28
lateral orbitofrontal circuit, 28
motor circuit, 26
oculomotor circuit, 26
Frontal Systems Behavior Scale, 110
Frontotemporal dementia (FTD), 487–498
vs. Alzheimer’s disease, 487
clinical features of, 488–492, 489–490
behavioral variant FTD (bvFTD), 487, 488, 489, 491
motor symptoms, 489–490, 492
nomenclature, 492
nonfluent/agrammatic variant (nfvPPA), 489, 491
semantic variant (svPPA), 490, 491–492
psychosis, 31, 36, 483, 519
family history of, 487–488
future treatment options for, 497–498
genetic factors in, 487–488, 493, 519
incidence of, 487
neuroimaging in, 489–490
neuropathology of, 487, 489–490
therapeutic approaches to, 488, 492–497
nonpharmacological, 492–495
advance care planning, 495
counseling and education, 493
safety, 494
stimulation and activity, 493–494
pharmacotherapy, 495–497
acetylcholinesterase inhibitors, 496–497
antipsychotics, 496
dopamine agonists, 496
memantine, 497
selective serotonin reuptake inhibitors, 495–496
stimulants, 496
symptomatic vs. disease-modifying therapy, 492
Frontotemporal lobar degeneration (FTLD) pathology, 487–488, 489–490, 491–
492, 493, 497–498
FTD. See Frontotemporal dementia
FTLD (frontotemporal lobar degeneration) pathology, 487–488, 489–490, 491–
492, 493, 497–498
Functional magnetic resonance imaging (fMRI). See Magnetic resonance imaging,
functional
Fungal exposure and mycotoxins, 216–219
Fused in sarcoma (FUS), in frontotemporal dementia, 487, 489, 493, 497
G proteins, 31, 417

GABA. See ɣ-Aminobutyric acid
Gabapentin, 231, 231, 388
GAD. See Generalized anxiety disorder
Gadolinium contrast agents, 125
in HIV disease, 310–311
Gait abnormalities, 58–59
assessment for, 54, 58
cautious gait, 58–59
alcohol use disorder, 421
brain tumors, 335
inhalant intoxication, 430
Lyme disease, 320
organophosphate poisoning, 209
subcortical vascular dementia, 58
frontal gait disorder, 58
gait initiation failure, 58
postural control failure, 58
stressed gait, 58
tandem gait, 54
Galanin, 375
Galantamine, for cognitive dysfunction
posthypoxic, 298
Galveston Orientation and Amnesia Test (GOAT), 271
Gambling, pathological, 155
Gamma-hydroxybutyrate (GHB), 315
Ganser state, 69
Gas exposure, 214–215, 215
GCS (Glasgow Coma Scale), 266, 267, 270
GDS (Geriatric Depression Scale), 247
Gegenhalten, 60, 64, 449
Generalized anxiety disorder (GAD), 545, 546–548
brain tumors, 344
stroke, 256–257, 557
neuroanatomical correlates of, 546, 547–548, 549
neurochemistry of, 546–547
neuroimaging in, 547
symptoms of, 546
treatment of, 547
Genetic factors, 52, 374. See also Family history; Polymorphisms
with psychosis, 514
apolipoprotein E genotype, 195, 354, 450, 514
attention-deficit/hyperactivity disorder and, 156–157
delayed sleep-wake phase disorder and, 390
autism spectrum disorder and, 173, 174, 176, 177
circadian clock and, 374
delayed posthypoxic leukoencephalopathy and, 299
delirium and, 195
depression and, 530, 534, 537
hypothalamic-pituitary-adrenal axis and, 362, 365
poststroke, 246, 247, 248–249, 249
drug effects and
atomoxetine, 163
sleep-wake effects, 390
epilepsy and, 225
frontotemporal dementia and, 487–488, 493, 519
reproductive issues and, 479
testing for, 52, 134, 478–479, 483
hypothyroidism response to T3 and, 360
narcolepsy and, 384
poststroke mania and, 255
response to neurotoxin exposures and, 219
alcohol, 420
Geriatric Depression Scale (GDS), 247
Geriatric patients. See Elderly persons
Gerstmann syndrome, 7
GGT (ɣ-glutamyltransferase), 418
Glabellar reflex, 53, 66, 272
Glasgow Coma Scale (GCS), 266, 267, 270
Glatiramer acetate, 409
Glioblastoma multiforme, 335
Gliomas, 333–336, 338, 341–342, 344. See also Brain tumors
Globus pallidus, 17, 19
in apathy, 22
poststroke, 259
frontal-subcortical circuit disorders and, 26, 28, 28–29, 30, 31
in neurotoxin exposures
carbon monoxide, 215
manganese, 213
neurotransmitter projections of, 32, 36, 38
in obsessive-compulsive disorder, 20, 21
thalamic nuclei and, 27
Glutamate, 36–37
acamprosate modulation of, 420
caffeine effects on, 415
disorders associated with deficiency of, 33
in excitotoxicity, 36, 37
in sleep physiology, 376
arsenic poisoning, 212
epilepsy, 37
lead poisoning, 213
mercury poisoning, 214
Glutamate receptor antagonists
for Alzheimer’s disease, 37, 455, 497
for dementia with Lewy bodies, 470
effect on circadian clock, 374
memantine, 37
for posttraumatic cognitive impairment, 282
Glutamate receptors, 37
NMDA, 37
in depression, 528
inhalant actions on, 415, 430
in lead toxicity, 213
ɣ-Glutamyltransferase (GGT), 418
Glycine, 38
Glyphosate neurotoxicity, 208, 209, 209–210
GOAT (Galveston Orientation and Amnesia Test), 271
Gourmand syndrome, 51
Grasp reflex, 53, 65, 66, 272
Gray matter of brain, 3, 11, 24
on CT, 119, 121
in delayed posthypoxic leukoencephalopathy, 300
in multiple sclerosis, 402, 408–409
in panic disorder, 548, 549, 550
regional cerebral blood flow and regional cerebral metabolic rate in, 128
in sleep physiology, 375, 375, 376
in substance use disorders
cannabis, 422
opiates, 426
toxoplasmosis in, 307
in varicella zoster virus encephalitis, 327
Grip strength, 108
GRN (gene), 498, 519
Grooved Pegboard Test, 108
Growth effects of stimulants, 161
Guanfacine, for attention-deficit/hyperactivity disorder, 163, 164
Gynecomastia, risperidone-induced, 181
HAD (HIV-associated dementia), 305–306

HADS (Hospital Anxiety and Depression Scale), 342, 397, 399
Halazepam, 427
Hallucinations, 70–71, 503, 504. See also Psychosis
neurophysiological testing, 141
auditory, 71, 504
conditions associated with, 70, 98
Alzheimer’s disease, 33, 98, 447, 448, 452, 513, 514
brain tumors, 337
Charles Bonnet syndrome, 70
delirium, 187, 188, 191, 195
dementia with Lewy bodies, 70, 98, 460, 462, 471, 472, 510, 514–516
Ganser state, 69
herpes simplex virus encephalitis, 325, 326, 520
neurosyphilis, 319
ocular disease, 70
Parkinson’s disease with dementia, 98, 465, 466, 514–516
treatment of, 471
prion disease, 321
schizophrenia, 37, 70, 504–507, 521
secondary psychoses, 506–507
seizures, 143, 227, 228, 235, 236, 511–512
stroke, 257–258, 518
substance withdrawal
alcohol, 420
stimulants, 423
Wilson’s disease, 520
dopamine and, 33
drug-induced
L-dopa, 390
hallucinogens, 429, 430
NMDA receptor antagonists, 37
nucleoside reverse transcriptase inhibitors, 315
orexin-receptor antagonists, 383
hypnagogic, 71, 384, 386
hypnopompic, 384
musical, 71
olfactory, 71
visual, 70–71, 504
Hallucinogens, 414, 416, 429–430
neuropsychiatric complications of, 429–430
hallucinogen persisting perception disorder, 430
Haloperidol
for delirium, 198
prophylaxis, 193
for motor symptoms of Huntington’s disease, 479–480
pimavanserin potentiation of, 521
Hamilton Anxiety Scale, 257
Hamilton Depression Rating Scale (HDRS), 247
Hammond’s disease, 61
HAND. See HIV-associated neurocognitive disorders
Handedness, 48–49
Hashimoto’s encephalitis, 361, 520
HCRT (gene), 37, 375f
HD. See Huntington’s disease
HDRS (Hamilton Depression Rating Scale), 247
HDSA (Huntington’s Disease Society of America), 478, 479
Head circumference, 52
Headache. See also Migraine
cannabis for, 420
cryptococcal meningitis and, 308
drug-induced
stimulants, 161
Lyme disease and, 319, 320
neurosyphilis and, 316, 318
neurotoxin-induced, 209, 215, 216, 218
posttraumatic, 271, 272
REM sleep and, 389
Rocky Mountain spotted fever and, 324
substance use disorders and
cocaine, 423
hallucinogens, 429
toxoplasmosis and, 307
Hearing, 7, 27, 53
Hearing loss, 73
musical hallucinations and, 71
syphilitic meningitis and, 318
Hemianopsia, 55, 78
delirium and, 55
homonymous, 12, 12, 14
Hemiconcern syndrome, 73
Hemisensory deficits, 6, 12, 14
Hemisomatagnosia, 79
Hemispatial neglect, 14, 23, 72–73, 80, 104
Hemispheric specialization, laterality, and dominance, 12–15, 14
anatomic asymmetries, 12–13
asymmetric cognitive function, 13–15, 14
asymmetric neurochemical anatomy of limbic system, 19
callosal disconnection syndromes, 11–12, 78–79
disorders associated with lateralized limbic and paralimbic disturbances, 22–24,
23
handedness, 48–49
lateralization and valence-related hypotheses of emotion, 17–18
Hemorrhage
alcohol-related falls and, 420
cerebrovascular disease with, 245
hypoxic-ischemic brain injury with, 288
neuroimaging of
CT, 120, 125, 126
MRI, 124
petechial
carbon monoxide poisoning and, 215
traumatic brain injury and, 267, 272
varicella zoster virus encephalitis and, 326
Hepatic effects of drugs
alcohol, 315, 422
atomoxetine, 163
nevirapine, 315
Herbicide exposure, 206
glyphosate, 208, 209, 209–210
Heroin, 299, 415, 418, 424
Herpes simplex virus (HSV) encephalitis, 16, 20, 21, 59, 324–326, 329
cerebrospinal fluid and plasma biomarkers for, 325
cognitive disorders and, 324–325
demographics of, 325
diagnostic criteria for, 325
neuroimaging in, 325–326
pathogenesis of, 325
psychiatric manifestations of, 326
psychosis and, 325, 326, 519–520
treatment of, 326
N-Hexane neurotoxicity, 216
Hippocampus, 3, 4, 5, 11, 17. See also Entorhinal-hippocampal complex
in Alzheimer’s disease, 131, 435, 437, 438, 440, 441, 451, 469
in anxiety
neurological disorders and, 557
panic disorder, 548, 551
posttraumatic stress disorder, 554, 555, 555, 556
childhood brain tumor treatment effects on, 346, 347
emotional bias, 532
endocrine disorders and, 365
Parkinson’s disease and, 469
poststroke, 252
in endocrine disorders
with depression, 365
in epilepsy, 226, 226, 230
in HIV disease, 312
hypoxic-ischemic injury affecting, 290, 291, 297
in mood regulation, 540, 541
arsenic, 212
lead, 213
in depression, 528
with psychosis, 515
in psychosis
schizophrenia, 508
role in emotional regulation, 18
role in memory and amnestic disorders, 7, 16, 19, 20, 73
cannabis, 422
stimulants, 424
Histamine, 38
receptors for, 38
in sleep-wake cycle, 38, 375, 375, 376
History taking, 47–52, 85
aggression, 51
alcohol and substance use, 50
appetitive functions, 50–51
birth, 48
development, 48
family history, 52
with family present, 48
handedness, 48–49
ictal events, 49
neurotoxin exposure, 205–206, 206
occupation, 51–52
personality changes, 51
HIV-associated dementia (HAD), 305–306
HIV-associated neurocognitive disorders (HAND), 304–306
assessment instruments for, 306
contributions of comorbidities to, 310
neuroimaging biomarkers for, 310–311
pathogenesis of HIV brain infection, 304–305
plasma and cerebrospinal fluid biomarkers for, 310
HIV Dementia Scale, 306
HIV encephalitis (HIVE), 305, 306
HLA. See Human leukocyte antigens Hoffmann sign, 54, 65
Homonymous hemianopsia, 12, 12, 14
Hospital Anxiety and Depression Scale (HADS), 342, 397, 399
Houston Guidelines for training neuropsychologists, 96
HPA. See Hypothalamic-pituitary-adrenal axis
HPT (hypothalamic-pituitary-thyroid) axis, in depression, 361–363, 365
HSV. See Herpes simplex virus encephalitis
5-HT. See Serotonin
Human immunodeficiency virus (HIV) disease/acquired immunodeficiency
syndrome (AIDS), 303–316
anxiety and, 314
CD4+ T cell count in, 304, 307, 308, 309, 310
combination antiretroviral therapy for, 303, 311–312
neuropsychiatric side effects of, 315–316
nonadherence to, 312
depression and, 312–314
suicide and, 313–314
treatment of, 313
history of, 303
HIV-associated neurocognitive disorders, 304–306
assessment instruments for, 306
contributions of comorbidities to, 310
neuroimaging biomarkers for, 310–311
pathogenesis of HIV brain infection, 304–305
plasma and cerebrospinal fluid biomarkers for, 310
mania and, 314
neuropsychological assessment in, 305
olfactory abnormalities in, 54
opportunistic infections and neoplasms in, 303–304, 306–309
cryptococcal meningitis, 308
primary central nervous system lymphoma, 307–308
syphilis, 316
toxoplasmosis, 306–307
psychosis and, 314
substance use disorders and, 314–315
opioids, 426
Human leukocyte antigens (HLA)
mold toxicity and, 219
narcolepsy and, 384
Humor, 5, 18
loss of sense of, 51, 75, 233
Huntington’s disease (HD), 477–484
behavioral symptoms of, 481–484
anxiety, 479, 483, 557
apathy, 481, 482
depression, 20, 30, 36, 481, 527, 527–528, 529
irritability, 482–483
mania, 20, 29, 30, 481, 534
obsessive-compulsive disorder, 20, 29, 30, 36, 484
psychosis, 20, 21, 36, 483, 519
repetitive behaviors, 483–484
sleep abnormalities, 537
suicidality, 482
cognitive symptoms of, 480–481
dementia, 36, 480, 483
SPECT imaging of, 132, 134
treatment of, 481
future treatment options for, 484
GABA deficiency in, 36
genetic factors in, 477–478
reproductive issues and, 479
testing for, 52, 134, 478–479, 483
motor symptoms of, 61, 62, 479–480
eye movement abnormalities, 55
neuroanatomical correlates of, 20, 21, 26, 29, 30
neurochemistry of, 527
neuropathology of, 478
neuropsychological assessment in, 96, 113
Huntington’s Disease Society of America (HDSA), 478, 479
Hydrocephalus, 120, 318, 345, 450
Hydrogen sulfide toxicity, 215
Hyperactivity, 100
attention-deficit/hyperactivity disorder and, 153, 154, 155, 157 (See also
Attention-deficit/hyperactivity disorder)
autism spectrum disorder and, 178, 181
benzodiazepine-induced, 238
lead poisoning and, 211
nonconvulsive seizure disorders of childhood and, 142
Hypercortisolemia. See Cortisol levels
Hyperglycemia
diabetes mellitus and, 351–354, 356, 357
traumatic brain injury and, 268
Hypergraphia, 21, 51
Hyperosmia, 54
Hyperparathyroidism, 367
Hyperphagia, 51, 488
Hyperprolactinemia, 366–367
antipsychotic-induced, 181, 366
causes of, 366
psychiatric symptoms in, 366
treatment of, 367
Hypersexuality, 20, 21
stimulant-induced, 423
Hypersomnia (hypersomnolence), 377, 379, 384–386. See also Excessive daytime
sleepiness
conditions associated with delirium, 188
in bipolar disorder, 537
Kleine-Levin syndrome, 51, 378, 384, 386
neuromuscular diseases, 389
evaluation of, 377, 378, 379, 384
idiopathic, 384
Hypertension
cerebrovascular disease and, 245
hypercortisolism and, 356
rebound, clonidine and, 164
supine, in Lewy body disorders, 472
tricyclic antidepressant–induced, 253
Hyperthyroidism, 360–361
anxiety, 361
cognitive disorders, 361
mood disorders, 361
psychosis, 361
Hypertonus, 59–60, 63, 209
Hypocretin, 37. See also Orexin
Hypoglycemia, 354–355
diabetes mellitus and, 354–355
antidepressant effects on, 356, 357
cognitive effects of, 352, 353, 354
diffusion-weighted imaging in, 125
factitious, 354–355
idiopathic postprandial, 354
insulin-induced, 354
reactive, 354
Hypomania, 533, 535, 537. See also Mania
bipolar I disorder, 526
epilepsy, 233
hypothyroidism, 359
stroke, 255
dopamine and, 34
Hyponatremia
Addison’s disease and, 364
in chronic beer drinkers, 422
Hypoparathyroidism, 367–368
Hyposexuality, 20, 21, 51
Hyposmia, 54, 272, 380
Hypotension
during barbiturate withdrawal, 428
carbon monoxide poisoning and, 290
during opioid withdrawal, 426
Hypotension, orthostatic
dementia with Lewy bodies and, 464, 471, 472
drug-induced
antidepressants, 383
trazodone, 357
antihistamines, 383
antipsychotics, 383, 464, 471
management of, 472
Shy-Drager syndrome and, 465
Hypothalamic-pituitary-adrenal (HPA) axis
in arsenic poisoning, 212
in delirium, 195
in depression and mood regulation, 365, 528–529, 531, 532, 541, 541
appetite and feeding regulation, 538
poststroke, 252
in posttraumatic stress disorder, 554–555
Hypothalamic-pituitary-thyroid (HPT) axis, in depression, 361–363, 365
Hypothalamus, 2, 3, 16, 24
in amnestic disorders, 20
in eating disorders, 51
hamartoma of, 49
in hypothyroidism, 358
in neuroendocrine regulation, 16, 24
neurotransmitter projections of, 32, 35, 37–38
in panic disorder, 548, 549, 550
in paraphilias, 20
in sexual disorders, 20, 21
in sleep-wake cycle, 374–376, 375
hypersomnolence, 389
mood disorders and, 389
Hypothyroidism, 358–360
mycotoxin exposure and, 218
overt and subclinical, 358
primary autoimmune, 362
anxiety, 359
cognitive disorders, 359
psychosis, 359
reactive hypoglycemia and, 354
Hypoventilation
opiate-induced, 426
sleep-related, 379, 380, 386
Hypoxemia, sleep-related, 386
Hypoxic-ischemic brain injury, 287–300
vs. anoxic brain injury, 289
definition of, 287–289
due to carbon monoxide poisoning, 287, 288, 290
neuroanatomy of, 290–291
neurological and neurobehavioral sequelae of, 291–300
cognitive impairments, 297–298
recovery from, 297
delayed posthypoxic leukoencephalopathy, 299–300
disorders of consciousness, 294–297, 295
coma, 294
emotional disturbances, 298–299
movement disorders, 293
patterns of weakness, 293–294
seizures and myoclonus, 292–293
outcome predictors for, 291
pathophysiology of, 289–290
vs. stroke, 290
subtypes of hypoxia in relation to, 287–289, 288
survival after, 287, 300
IADLs. See Instrumental activities of daily living
ICD. See International Classification of Diseases
ICDSC (Intensive Care Delirium Screening Checklist), 190, 194
ICSD-3 (International Classification of Sleep Disorders), 377
ICU delirium. See Intensive care unit delirium
IGF-1 (insulin-like growth factor 1), 195, 342
IL. See Interleukins
ILAE (International League Against Epilepsy), 224, 225
Illogicality, 69
Imipramine, 234, 401
Immune reconstitution syndrome, in Whipple’s disease, 324
Immunological factors. See also Autoimmune disorders; Inflammatory processes
in central nervous system infections, 303
in delirium, 195–196
in herpes simplex virus encephalitis, 324, 325
in HIV-associated neurocognitive disorders, 304, 305, 309
in neurotoxin exposures, 204, 206, 207, 208, 212, 217, 218, 219
in type 1 diabetes mellitus, 351
in varicella zoster virus infection, 326
Impulse-control disorders
poststroke, 246
Impulsivity
attention-deficit/hyperactivity disorder and, 153, 154, 155, 156, 157
treatment of, 159, 160, 162, 163, 167
blurting and, 77
catatonia and, 64
dopaminergic medication–induced, 470
HIV disease with substance use disorders and, 314
posttraumatic, 271
suicidal, 144
epilepsy and, 233
Incoherence, 69, 463, 504
The Incredible Years parenting program, 165
Infections of central nervous system, 203, 303–329
blood-brain barrier disruption in, 125
cerebral malaria, 324
chronic opioid use and, 426
diffusion-weighted imaging in, 125
herpes simplex virus, 324–326, 329, 519–520
opportunistic infections and, 303–304, 306–309
toxoplasmosis, 306–307
Lyme disease, 319–321
meningitis
bacterial, 324
viral, 324
prion disease, 321–322
psychosis and, 519–520
Rocky Mountain spotted fever, 324
seizures and, 224
sleep disturbances and, 388–389
syphilis, 316–319
varicella zoster virus, 326–327
West Nile virus, 328
Whipple’s disease, 322–324
Inflammatory processes
depression and, 529
HIV brain infection and, 304, 312
biomarkers of, 310
comorbidities and, 310
progressive multifocal leukoencephalopathy and, 308, 309
Lyme disease and, 319, 320
multiple sclerosis and, 395, 410
neurotoxin exposure and, 203, 204, 207, 208, 217, 218, 219
psychiatric disorders in diabetes mellitus and, 353, 354, 356
Information processing
evoked potentials in evaluation of, 148
neuroanatomical correlates of, 6, 7, 8–10, 25, 27
Information processing speed, 340
assessment of, 67, 83, 104, 105–106, 109
multiple sclerosis and, 400, 403, 404–405, 406–407, 408
posthypoxic, 297, 298, 299
posttraumatic, 276, 282
substance use disorders and
alcohol, 421
MDMA, 430
opiates, 426
stimulants, 424
tests of, 109, 404
Inhalants, 414, 416, 430–431
neuropsychological aspects of, 431
types of, 430
Insecticides. See Pesticide exposure
Insight, 340
during aberrant nocturnal behaviors, 379
impairment of, 81–82, 101
psychosis and, 503, 504, 505, 507, 510, 521
unawareness of deficits, 81–82
“alien hand sign,” 79
Alzheimer’s disease and, 435, 447, 447–448
Insomnia, 381–384
childhood, 382
chronic, 381
circadian rhythm sleep-wake disorders, 387
delirium, 188
HIV disease, 389
schizophrenia, 390
drug-induced
reboxetine, 253
selective serotonin reuptake inhibitors, 389
evaluation of, 377–379, 378, 382
actigraphy, 380
polysomnography, 381
rating scales, 380
limit-setting type, 382
cognitive and behavioral interventions, 382–384, 385
pharmacotherapy, 382, 383
paradoxical, 381
psychophysiological, 381–382, 390
short-term, 381
sleep maintenance, 382
sleep onset association type, 382, 388
Insomnia Severity Index, 380
Instrumental activities of daily living (IADLs)
Insula, 3, 7, 16, 18, 19, 33
in anxiety disorders, 20
posttraumatic stress disorder, 554, 555, 556
social anxiety disorder, 552, 553
brain tumors of, 339
in mood regulation, 541, 541
in psychosis, 515
Insulin, 351–355, 356
Insulin-like growth factor 1 (IGF-1), 195, 342
Insulin resistance, 353, 354, 356, 388
Insulin tolerance test, 218
Intelligence/intellectual functioning (IQ), 340
autism spectrum disorder and, 82, 173, 174, 175, 176, 177, 178, 180
crystallized, 110–111
dysmorphic features and, 54
fluid, 111
handedness and, 49
hypoparathyroidism and, 368
limbic system disorders and, 19
neurotoxin exposures and
ethylene oxide, 215
lead, 211
school performance and, 48
tests of, 103, 110–111
Intensive Care Delirium Screening Checklist (ICDSC), 190, 194
Intensive care unit (ICU) delirium, 140, 187, 188, 191
outcomes of, 190
screening for, 194
Interferon β-1a and interferon β-1b, 409
Interleukins (IL)
in delirium, 195, 196
in depression
poststroke, 252
in neurological disorders with sleep disorders, 388
Intermetamorphosis syndrome, 516, 517
International Classification of Diseases (ICD)
autism spectrum disorder in, 172
delirium in, 185, 186, 196
sleep-wake disorders in, 377
International Classification of Sleep Disorders (ICSD-3), 377
International HIV Dementia Scale, 306
International League Against Epilepsy (ILAE), 224, 225
Interpersonal therapy, for HIV-related depression, 313
Inventory of Executive Function, 110
Iodinated contrast agents, 235
IQ. See Intelligence/intellectual functioning
Iron, 207, 212, 213
periodic leg movements in sleep and, 388
synuclein pathology and, 460
Irritability, 51, 100
assessment of, 84
brain tumors, 341
delirium, 187, 188
depression
poststroke, 245
epilepsy, 233, 236
Huntington’s disease, 480, 481, 482–483
treatment of, 483
mania, 68
in HIV disease, 314
mixed mood episodes, 533
neurosyphilis, 319
neurotoxin exposures, 209, 211, 215, 218
prion disease, 321
stroke, 245, 246, 255, 261
cannabis, 422
drug-induced
atomoxetine, 163
Jacksonian march, 227

Jamais vu, 49, 142, 226
JC virus, 308–309
Jet lag, 387
Jimsonweed, 429
Judgment
executive function and, 81, 109
impairment of, 223
manganese poisoning and, 211
substance use disorders and, 314, 421, 429
“K2,” 422
Kallmann’s syndrome, 65
Kanner, Leo, 171–172
Kayser-Fleischer rings, 54–55
Ketamine, 37, 315, 429
Ketorolac, 282
Khat, 423
Kleine-Levin syndrome, 51, 378, 384, 386
Klippel-Feil syndrome, 65
Klüver-Bucy syndrome, 21, 51, 325
Kuru, 321
Laboratory testing, 99. See also Cerebrospinal fluid analysis; Neurophysiological

testing
for Addison’s disease, 364
in delirium, 197
for hyperparathyroidism, 367
for neurotoxin exposure, 205, 215, 219
in substance use disorders, 415, 417, 418
for syphilis, 316–317
Lacosamide, 231
Lamotrigine
for posthypoxic disorders of consciousness, 296
to prevent steroid-induced psychiatric disturbances, 364
for seizures, 231, 231
Language, 80, 540. See also Speech
assessment of, 67, 73, 74–75
domain-specific cognitive measures, 83
Braille or sign, 73, 74, 76
comprehension of, 107
expressive, 107
“melody” of, 77 (See also Prosody)
neuroanatomical correlates of, 4, 5, 7, 8, 11, 18, 38, 38
hemispheric lateralization, 14, 15, 75
receptive, 107
vs. speech, 73
Language disturbances, 73, 100, 223. See also Aphasia
Alzheimer’s disease and, 436, 442, 443, 445, 453–454, 461
autism spectrum disorder and, 15, 172, 173, 175, 176, 177, 178, 179, 180
bacterial meningitis and, 324
delirium and, 187
disorientation and, 73
echolalia, 77
epilepsy and, 49, 75
Parkinson’s disease with dementia and, 461, 465, 466
primary progressive aphasia, 491–492, 494
substance-induced neurocognitive disorder and, 419
Lateral orbitofrontal syndrome, 30
LDX (lisdexamfetamine), for attention-deficit/hyperactivity disorder, 161
Le geste antagoniste, 60
Lead neurotoxicity, 211, 212–213
inhalant use and, 431
“Leaky gut” syndrome, 207
Learning, 106. See also Memory
tests of, 106–107
Learning disabilities, 5, 48
Alzheimer’s disease and, 436, 442, 442, 443, 444, 452–453, 461
attention-deficit/hyperactivity disorder and, 154, 155, 159
autism spectrum disorder and, 178, 180
bacterial meningitis and, 324
dementia with Lewy bodies and, 461, 461–462
depression and, 365
epilepsy and, 232
event-related potentials in, 150
evoked potentials in, 149
hippocampal damage and, 363, 365
HIV-associated neurocognitive disorder and, 305, 306, 310
lead poisoning and, 211, 213
mercury poisoning and, 211
multiple sclerosis and, 406, 409
posttraumatic, 266, 271, 276
Korsakoff syndrome, 421
methamphetamine, 425
Lennox-Gastaut syndrome, 142, 226
Levetiracetam, 231, 234, 238, 339
Levodopa
adverse effects of
hallucinations, 466
movement disorders, 61, 64
sleep effects, 390
for dementia with Lewy bodies, 470
with REM sleep behavior disorder, 472
after hypoxic-ischemic brain injury, 296, 298, 299
for multiple system atrophy, 465
for Parkinson’s disease, 465, 470
dementia risk with declining response to, 465
effect on blink rate, 55
for pseudobulbar affect in multiple sclerosis, 402
Lewy body disorders, 459–473. See also Dementia with Lewy bodies; Parkinson’s
disease
dementia with Lewy bodies, 460–465
neuroimaging in, 468–469, 469
neuroleptic sensitivity in, 460, 464, 465, 466, 471, 520
neuropathology of, 459, 460, 467–468
Parkinson’s disease with dementia, 465–467
motor symptoms, 470
Light therapy
for circadian rhythm sleep-wake disorders, 387
in delirium, 193
Limbic system, 2, 3, 5, 15–24, 16
asymmetric neurochemical anatomy of, 19
disorders associated with disturbances of, 3–4, 5, 16–17, 19–21, 20
disorders associated with lateralized dysfunction of, 22–24, 23
structure and function in relation to emotion, 3, 15, 17–18
structures of, 3, 15–16
Line-bisection task, 72
Lisdexamfetamine (LDX), for attention-deficit/hyperactivity disorder, 161
Lithium, 530
myoclonus, 62
tremor, 61
indications for
Kleine-Levin syndrome, 386
mania
in HIV disease, 314
posttraumatic, 278
prevention of steroid-induced psychiatric disturbances, 364
tauopathies, 498
in subictal mood disorders, 144
LOC. See Loss of consciousness
Locked-in syndrome, 12, 12, 295, 296
Locus coeruleus
in Alzheimer’s disease, 439, 440, 441
in fear and anxiety, 548
in manganese toxicity, 213
norepinephrine projections from, 32, 35, 36, 441
in Parkinson’s disease with dementia, 468
in sleep-wake cycle, 374, 375
Lofexidine, for opioid detoxification, 426
Longitudinal fasciculus, 11, 12
Loose associations, 69
Lorazepam
for alcohol withdrawal, 418
Loss of consciousness (LOC)
sedative-hypnotic withdrawal seizures with, 428
traumatic brain injury with, 98, 266, 267, 269–270, 272
LSD (lysergic acid diethylamide), 315, 414, 429
Lyme disease, 319–321
diagnostic biomarkers for, 320
neuroborreliosis, 319–320
pupillary signs of, 54
sleep disturbances and, 320, 388–389
treatment of, 321
Lysergic acid diethylamide (LSD), 315, 414, 429
MACFIMS (Minimal Assessment of Cognitive Function in MS), 408

Macrocephaly, 52
Macropsia, 49
Magnetic resonance angiography (MRA), 123
Magnetic resonance imaging (MRI), 117, 121–125
brain lesions on, 123, 124
compared with computed tomography, 123, 126
contraindications to, 127
contrast-enhanced, 125–126
diffusion-weighted imaging (DWI), 123, 125
equipment for, 121, 122, 126
fluid-attenuated inversion recovery (FLAIR) imaging, 123, 123, 124
compared with PET, 130
in HIV disease, 311
history of, 121
patient monitoring during, 127
in pregnancy, 127
pulse sequences for, 122–123
safety of, 127
alcohol-related neurocognitive disorder, 421
brain tumors, 337
delirium, 198
epilepsy, 134, 230
HIV-associated neurocognitive disorder, 310–311
multiple sclerosis, 396, 398–399, 400, 401
with cognitive dysfunction, 408, 409
with psychosis, 402
prion disease, 322
schizophrenia, 508
stroke with or without mood disorders, 527
toxoplasmosis, 307
traumatic brain injury, 123, 124, 125, 134, 266–267, 267, 274
with psychosis, 519
susceptibility-weighted, 123
T1- and T2-weighted, 122–123, 123
Magnetic resonance imaging, functional (fMRI), 118
in attention-deficit/hyperactivity disorder, 157, 158
of emotional processing, 17–18
in vegetative state, 295
Magnetic resonance spectroscopy
in poststroke depression, 252
Magnetoencephalography, 118, 139, 147–148, 346
Major depressive disorder (MDD). See Depression
Making Sense of Brain Tumor program, 340
Malaria, cerebral, 324
Mammillary bodies, 16, 19, 27
in Korsakoff syndrome, 421
neuroimaging of, 126, 131
Manganese neurotoxicity, 20, 30, 31, 207, 211, 213
Mania, 526. See also Bipolar disorder; Hypomania
appetite changes in, 537
conditions associated with, 533, 534
cognitive dysfunction, 539, 540
depression with mixed features, 526
epilepsy, 236, 512
HIV disease, 314
hypothyroidism, 359
multiple sclerosis, 401, 402
neurosyphilis, 319
sleep deprivation, 384, 390, 537
stroke, 245, 246, 255–256
disinhibition in, 540
drug-induced
corticosteroids, 364, 401, 534
emotional bias in, 538
interest and motivation in, 535–536
neuroanatomical correlates of, 11, 19, 20, 22, 23, 26, 29, 30, 532, 535, 540
psychomotor activity in, 538
Mannerisms, 64, 228, 445
MAO-A (monoamine oxidase A) gene, 156
MAOIs. See Monoamine oxidase inhibitors
Maprotiline, 234
MAPT (gene), 487
Marijuana. See Cannabis
MAS (mixed amphetamine salts), 160–161
MAST (Michigan Alcoholism Screening Test), 417
Matrix Reasoning test, 111
McDonald Criteria for multiple sclerosis, 396, 398–399
MCI. See Mild cognitive impairment
MCS (minimally conscious state), 295, 295–296, 300
MDAS (Memorial Delirium Assessment Scale), 194
MDD (major depressive disorder). See Depression
MDMA (methylenedioxmethamphetamine, “ecstasy”), 315, 414, 429
Measles, 324
MECP2 (gene), 177
Median zone of brain (reticular formation), 2, 3, 3, 4, 24, 38
Meige syndrome, 60
Melatonin
for autism spectrum disorder, 181
for circadian rhythm sleep-wake disorders, 387
in delirium, 193, 195–196
for REM sleep behavior disorder, 471–472
Melatonin receptor agonist. See Ramelteon
Memantine, 37
Memorial Delirium Assessment Scale (MDAS), 194
Memory
for aberrant nocturnal events, 379
assessment of, 67, 72, 73, 106–107, 110
cognitive screening instruments, 82, 83
neuropsychological testing, 98, 100, 101, 102, 104, 105, 106–107
autobiographical, 508, 535
consolidation of, 106
encoding of, 106
episodic, 106
emotion-related, 106
explicit (declarative), 80, 83, 106, 406
figural, 73
GABA and, 33
glutamate and, 33, 528
for ictal events, 49
implicit (procedural), 106, 406
long-term, 106, 406
hemispheric lateralization, 14, 15
nonverbal, 14
recognition, 106
retrieval of, 106
semantic (fact), 106
short-term, 106
spatial, 108
stages of, 106
verbal, 14, 15, 73, 106–107
visual, 106, 107
working (See Working memory)
Memory impairment. See also Amnesia
acetylcholine and, 33, 441
attentional dysfunction and, 73
Alzheimer’s disease, 435, 436, 441, 442, 442–443, 444, 445, 451, 452–453,
455, 461, 462
brain tumors, 335, 340, 345, 346
delirium, 186, 187–188
dementia with Lewy bodies, 461, 461–462
with psychosis, 516
epilepsy, 227, 229, 235
HIV-associated neurocognitive disorder, 305, 306, 310
hypothyroidism, 359
treatment of, 298
Lyme disease, 320
mood disorders, 365, 539, 540, 541
neurosyphilis, 319
neurotoxin exposures, 203, 211, 213, 215, 216, 218
Parkinson’s disease with dementia, 461, 465, 466
prion disease, 321
Rocky Mountain spotted fever, 324
schizophrenia, 508
alcohol, 420, 421
cannabis, 422
inhalants, 431
sedative-hypnotics and anxiolytics, 427, 428–429
traumatic brain injury, 50, 266, 267, 269–270, 271, 272, 275, 276, 277, 282
drug-induced, 33
levetiracetam, 238
Memory tests, 73, 106–107
performance validity tests, 110
Meningiomas, 333, 335. See also Brain tumors
Meningitis
bacterial, 324
chronic opiate use and, 426
Cryptococcus neoformans, 306, 308
cytomegalovirus, 309
Lyme disease and, 319–320
seizures and, 230
syphilitic, 316, 318
viral, 324
herpes simplex virus, 325
West Nile virus, 328
Meningovascular neurosyphilis, 317, 318
Mental status examination, 67, 67
Meperidine, 424
Mercury neurotoxicity, 158, 211, 213–214
Mescaline, 429
Metacognitive therapy (MCT), for attentiondeficit/hyperactivity disorder, 165, 166
Metamorphopsia, 49
Metformin, 125
Methadone, 316, 418, 424, 427
maintenance treatment with, 426
Methamphetamine
for narcolepsy, 385
neurocognitive disorders induced by, 425
Methanol neurotoxicity, 216, 216
Methaqualone, 427
3-Methoxy-4-hydroxy-phenylglycol (MHPG), 547, 549
Methyl chloride neurotoxicity, 216
N-Methyl-D-aspartate receptor antagonists, 37
for Alzheimer’s disease, 37, 455
for posttraumatic cognitive impairment, 282
N-Methyl-D-aspartate receptors, 37
in depression, 528
Methylene blue, 497–498
Methylenedioxymethamphetamine (MDMA, “ecstasy”), 315, 414, 429
Methylmercury neurotoxicity, 211, 214
Methylphenidate (MPH)
vs. atomoxetine, 162
with autism spectrum disorder, 181
combined with clonidine, 163
dosage of, 161
for childhood brain tumor survivors, 346
formulations of, 160
in Huntington’s disease, 481, 482
after hypoxic-ischemic brain injury, 296, 298
for narcolepsy, 385
after traumatic brain injury, 278, 279, 280, 281, 282
MHPG (3-methoxy-4-hydroxy-phenylglycol), 547, 549
Michigan Alcoholism Screening Test (MAST), 417
Microcephaly, 52, 177
Micropsia, 49, 430
Midodrine, 472
Migraine, 281, 336
hallucinations and, 70, 98
misidentification syndromes and, 516
olfactory abnormalities and, 54
poststroke generalized anxiety disorder and, 257
posttraumatic, 281–282
prophylaxis for, 231, 240, 281
REM sleep and, 389
Mild cognitive impairment (MCI), 50
diagnosis of, 436
dopamine and, 34
memory impairment and, 444
progression to Alzheimer’s disease, 50, 131, 451
social cognition deficits and, 449
Milnacipran, 357
Mindfulness training
for patients with brain tumors, 341
Mini International Neuropsychiatric Interview (M.I.N.I. 6.0), 246
Mini-Mental State Examination (MMSE), 82–83, 84, 250, 260, 306, 408, 448, 452,
453, 454, 497
Minimal Assessment of Cognitive Function in MS (MACFIMS), 408
Minimally conscious state (MCS), 295, 295–296, 300
Minnesota Multiphasic Personality Inventory, 2nd Edition (MMPI-2), 111–112
Minocycline, 312, 529
Mirror movements, 57, 64–65
Mirror sign, 516, 517
Mirrored self-misidentification, 517
Mirtazapine
for depression, 528
in HIV disease, 313
for insomnia
with irritability in Huntington’s disease, 483
posttraumatic, 281
Misidentification syndromes, 70, 516–518
Alzheimer’s disease, 447, 448–449, 513, 516
types of, 516, 517
Mitgehen, 60
Mixed amphetamine salts (MAS), 160–161
MMPI-2 (Minnesota Multiphasic Personality Inventory, 2nd Edition), 111–112
MMSE (Mini-Mental State Examination), 82–83, 84, 250, 260, 306, 408, 448, 452,
453, 454, 497
MoCA (Montreal Cognitive Assessment), 82–83, 303
Moclobemide, 401
Modafinil
for excessive daytime sleepiness
idiopathic hypersomnia, 386
narcolepsy, 385
Stevens-Johnson syndrome and, 164
Molds and mycotoxins, 216–219
Monoamine oxidase A (MAO-A) gene, 156
Monoamine oxidase inhibitors (MAOIs), 528
in panic disorder, 549–550
Montreal Cognitive Assessment (MoCA), 82–83, 303
Mood. See also Emotion(s)
vs. affect, 532–533
drug effects on
cannabis, 422
hallucinogens, 429, 430
lability of (See Emotional lability)
Mood disorders, 68, 525–542. See also specific mood disorders
conditions associated with, 526–528, 527, 533, 534
with psychosis, 513
anxiety disorders, 538, 558
attention-deficit/hyperactivity disorder, 153, 155, 161, 164
brain tumors, 336, 338, 341–344, 347
catastrophic reaction, 259, 260
catatonia, 59
cautious gait, 59
cognitive deficits, 98, 105, 539–540
cognitive dysfunction, 539, 540
delirium, 142, 191
dementia, 142, 527
depression with mixed features, 526
diabetes mellitus, 352, 355–358
epilepsy, 49, 143, 231, 233–234, 236, 512
with postictal psychosis, 236, 511
herpes simplex virus infection, 326
HIV disease, 305, 310, 312–314
Huntington’s disease, 29, 479, 481, 482, 484, 527
hypothyroidism, 358, 359, 360
multiple sclerosis, 396–402, 410
cognitive impairment and, 407, 408, 409
neurological disorders, 527
neurosyphilis, 319
Parkinson’s disease, 4, 466–467, 470, 527
with dementia, 466
with psychosis, 515
prion disease, 321
psychosis, 504
postictal, 236, 511
sleep deprivation, 384, 390, 537
sleep disturbances, 51, 379, 389–390
speech abnormalities, 74
stroke, 245–255, 261, 527, 557 (See also Poststroke depression)
alcohol, 420
hallucinogens, 429
inhalants, 431
stimulants, 423
suicidality, 539
wandering behavior, 59
DSM-5 classification of, 526
genetic factors, 530
hypothalamic-pituitary-adrenal axis, 365, 528–529, 531, 532, 541, 541
neural circuitry model, 540–542, 541
neuroanatomical correlates, 3, 4, 19, 22, 29, 31, 39, 530–532
neurochemistry, 528–530
neurobiology of symptom domains of, 532–540
appetite changes, 537–538
cognitive deficits, 539–540
interest and motivation, 535–536
mood and affect, 532–535, 534, 535
psychomotor activity, 538
neuroimaging in, 130, 527–528, 529
obstetric complications and, 48
prevalence of, 525
cannabis, 422
Mood stabilizers. See also specific drugs
antiepileptic drugs as, 234, 237, 240
for brain tumor patients, 341
for corticosteroid-induced psychiatric symptoms, 364
for mania
poststroke, 256
for posttraumatic depression, 278
weight gain induced by, 391
Morning glory seeds, 429
Morningness-Eveningness Questionnaire, 380, 387
Morphine, 192, 415, 424, 426
Motivation, 340
conditions associated with reduction of
attention-deficit/hyperactivity disorder, 157, 158, 165
cannabis use, 422
mood disorders, 525, 535–536, 540
depression in multiple sclerosis, 400
poststroke apathy, 258, 259
psychosis, 507
Motor abilities. See also Apraxia; Movement abnormalities; Praxis
Motor circuit, 26
Motor cortex, 26
frontal lobe epilepsy and, 227
mutism and, 76
primary, 5–6, 7, 8, 25
MRI studies in HIV infection, 311
Motor neuron disease
alcoholic polyneuropathy and, 422
amyotrophic lateral sclerosis, 212, 389, 460, 488, 492
dysarthria and, 74
Movement abnormalities. See also specific types
antipsychotic-induced, 181
assessment of, 57–65, 68
agitation, 59
akathisia, 59
akinesia, 59
asterixis, 62–63
ballismus, 62
catatonia, 64
chorea and athetosis, 61
dyskinesia, 62
dystonia, 60
gait abnormalities, 58–59
hypertonus, 59–60
myoclonus, 62
startle reaction, 63
stereotypes and mannerisms, 63–64
synkinesia and mirror movements, 64–65
tics and compulsions, 63
tremor, 61
weakness, 57–58
delirium, 188
depression, 19
epileptic seizures, 227, 228, 239
hypoxic-ischemic brain injury, 292–293, 300
Lewy body disease, 459, 460, 462–463, 472, 473, 514
Rett’s disorder, 177
schizophrenia, 507
eye movements, 55–57
facial movement, 57, 76
patient’s unawareness of, 81
sleep-related, 51, 377, 378, 379, 387–388
in Parkinson’s disease, 459, 460, 463
SPECT imaging in, 128
MPH. See Methylphenidate
MRA. See Magnetic resonance angiography
MRI. See Magnetic resonance imaging
MS. See Multiple sclerosis
MS Functional Composite, 405
MSLT (Multiple Sleep Latency Test), 381, 384
MTA (Multimodal Treatment of Attention Deficit Hyperactivity) study, 161, 166–167
Multilingual Aphasia Examination, 107
Multimodal Treatment of Attention Deficit Hyperactivity (MTA) study, 161, 166–167
Multiple sclerosis (MS), 395–410
autoimmune theories of, 395
McDonald Criteria, 396, 398–399
gender and age distribution of, 395–396
neuropsychiatric disorders and, 396–410
anxiety disorders, 399, 400, 557
bipolar disorder/mania, 401, 534
cognitive dysfunction, 396–397, 403–410
assessment of, 408
attention, 404
dementia, 404
imaging studies of, 408–409
information processing speed, 404–405
language, 406
memory impairment, 405–406
nature of deficits, 403–404
prevalence of, 403
risk factors and moderating variables for, 407
visuospatial function, 407
working memory, 405
depression, 396–401, 527
assessment instruments for, 397, 399
cognitive dysfunction and, 400, 407
comorbidities with, 399–400
etiology of, 400
prevalence of, 397
suicidality and, 397
euphoria, 68, 396, 401–402
pseudobulbar affect, 401, 402, 403
psychosis, 402–403, 504
neuropsychological assessment in, 96, 100, 108, 113, 404–405, 408
primary progressive (PPMS), 396, 407
relapsing-remitting (RRMS), 395, 396, 405, 407
secondary progressive (SPMS), 396, 405, 407
symptoms of, 396
Multiple Sleep Latency Test (MSLT), 381, 384
Multiple system atrophy, 459, 460, 463, 465
Mutism, 75–76
akinetic
apathy and, 28, 259
due to anterior cingulate injury, 28
vs. minimally conscious state, 296
catatonia and, 64
in postsurgical posterior fossa syndrome, 345
in primary progressive aphasia, 76, 489, 491
selective, vs. autism spectrum disorder, 177, 178
Mycotoxins, 216–219
Myelination, 3
Myerson’s sign, 55
Myoclonus, 62
corticobasal degeneration and, 62
Creutzfeldt-Jakob disease and, 62, 322
drug-induced, 62
nocturnal, 51
posthypoxic, 300
seizures and, 292–293
startle reaction and, 63
vs. tics, 62
NAc. See Nucleus accumbens
Naloxone, 414, 424
Naltrexone
for alcohol dependence, 420
for opioid dependence, 426
Naming, 8, 15
conditions associated with deficits of
Alzheimer’s disease, 453–454
semantic-variant primary progressive aphasia, 490, 491
confrontation, 106, 107
Napping, 377, 379, 382, 385, 386
Narcissistic personality disorder, 155
Narcolepsy, 51, 376, 378, 384–385
anxiety disorders and, 390
with or without cataplexy, 378, 384, 385, 386
diagnosis of, 384
hallucinations and, 70, 71
obesity and, 379
treatment of, 164, 385–386
visual hallucinations and, 70
National Comorbidity Survey Replication, 155
National Institute on Aging-Alzheimer’s Association (NIA-AA), 436
National Survey on Drug Use and Health, 419, 422, 427
Nausea/vomiting, 420
during alcohol withdrawal, 420
during benzodiazepine withdrawal, 428
cryptococcal meningitis and, 308
drug-induced
atomoxetine, 162, 163
selective serotonin reuptake inhibitors, 253, 255, 257
MRI-induced, 127
pesticide-induced, 209
NE. See Norepinephrine
NEBA (Neuropsychiatric EEG-Based Assessment Aid), 159
NEECHAM Confusion Scale, 194
Nefiracetam, 259
Neglect, 14, 23, 72–73, 80, 104
Neocortex, 2, 4, 5–15
disorders associated with lesions of, 4
functional organization of, 5–10, 7
hemispheric specialization, laterality, and dominance, 12–15, 14
histological organization of, 5, 6
white matter connections in, 10, 10–12
NET (norepinephrine transporter), 415
Neuritic plaques, in Alzheimer’s disease, 437–439, 438, 440, 467, 487, 513
Neuroacanthocytosis, 30, 63
Neurobehavioral Rating Scale—Revised (NRS-R), 84
Neurobiology, 1–39, 118, 118
cortical-subcortical connections, 25–31
frontal-subcortical circuits, 26–31, 28
median zone (reticular formation), 2, 3, 3, 4, 24, 38
neurochemistry and behavior, 31–38, 32–37 (See also Neurotransmitters)
paramedian-limbic zone (limbic system), 2, 3, 3, 15–24, 16, 38
disorders associated with dysfunction of, 3–4, 5, 16–17, 19–21, 20, 39
of specific conditions
Alzheimer’s disease, 437–442, 438, 439
delirium, 194–196
HIV brain infection, 304–305
hypoxic-ischemic brain injury, 289–291
mood disorders, 528–532
symptom domains, 532–540
poststroke apathy, 259
poststroke depression, 251–252
poststroke mania, 256
poststroke pathological affective display, 260
poststroke psychosis, 257–258
substance use disorders, 416, 417
traumatic brain injury, 268–269
supralimbic zone (neocortex), 2, 3, 4, 5–15, 38
disorders associated with dysfunction of, 4, 38–39
Yakovlev’s model of, 2–5, 3
Neuroborreliosis, 319–321. See also Lyme disease
Neurochemistry, 31–38, 32–37. See also Neurotransmitters
Neurocognitive disorder(s). See also Cognitive impairment
Alzheimer’s disease, 435–456, 442–443
assessment of
neuroimaging, 117–136
neurophysiological testing, 139–150
neuropsychiatric, 1–2, 47–85
neuropsychological, 1, 95–114
frontotemporal dementia, 487–498
HIV-associated, 304–306
with Lewy bodies, 459–473 (See also Dementia with Lewy bodies; Parkinson’s
disease)
major, 50 (See also Dementia)
mild, 50, 404, 436 (See also Mild cognitive impairment)
substance-related, 419
alcohol, 421
vascular, 4, 50, 494
vascular cognitive impairment, no dementia (VCIND), 4
Neurodevelopmental mechanisms, 1, 2–5
Neurofeedback, in attention-deficit/hyperactivity disorder, 167
Neurofibrillary tangles (NFTs), in Alzheimer’s disease, 437, 439, 439, 487, 513
Neuroimaging, functional, 117–118, 127–131, 134, 139. See also specific imaging
modalities
indications for, 127
modalities for, 117–118
positron emission tomography, 118, 133
single-photon emission computed tomography, 117–118, 132
Alzheimer’s disease, 131–132, 132, 133, 438–439, 450, 469, 469
with misidentification syndromes, 518
with psychosis, 513
generalized anxiety disorder, 547–548
dementia with Lewy bodies, 132, 132, 469, 469, 516
depression, 527–528, 530–531, 539
epilepsy, 134
postictal psychosis, 512
Lewy body disorders, 132, 132, 468–469, 469, 516
psychosis, 515, 518, 519
schizophrenia, 507
toxoplasmosis, 307
with psychosis, 519
vascular neurocognitive disorders, 134
Neuroimaging, structural, 117, 118–127, 139. See also specific imaging modalities
contrast-enhanced, 125–126
indications for, 119, 119
modalities for, 117, 119–126
computed tomography, 117, 119–121
magnetic resonance imaging, 117, 121–125
selection of, 126
in pregnancy, 126, 127
safety of, 126–127
alcohol-related neurocognitive disorder, 421
brain tumors, 337
delirium, 198
epilepsy, 134, 230
HIV-associated neurocognitive disorder, 310–311
multiple sclerosis, 396, 398–399, 400, 401, 408–409
with cognitive dysfunction, 408, 409
with psychosis, 402
prion disease, 322
schizophrenia, 508
stroke, 119, 125, 127, 130, 136
with or without mood disorders, 527
toxoplasmosis, 307
traumatic brain injury, 119, 119, 123, 124, 125, 134, 266–267, 267, 274
with psychosis, 519
Neuroleptic malignant syndrome (NMS), 464, 471
Neuroleptic sensitivity, in Lewy body disorders, 460, 464, 465, 466, 471, 520
Neuroleptics. See Antipsychotics
Neurological Evaluation Scale, 65–66
Neurological examination, 52–65
asymmetry and minor physical anomalies, 52, 54
elements of, 53–54
eyes, 54–57
blinking, 55
eye movements, 55–57
visual fields, 55
facial movement, 57
movement abnormalities, 57–65
agitation, 59
akathisia, 59
akinesia, 59
asterixis, 62–63
catatonia, 64
chorea, athetosis, ballismus, and dyskinesia, 61–62
dystonia, 60
gait abnormality, 58–59
hypertonus, 59–60
myoclonus, 62
startle reflex, 63
stereotypies and mannerisms, 63–64
synkinesia and mirror movements, 64–65
tics and compulsions, 63
tremor, 61
weakness, 57–58
olfaction, 54
primitive reflexes, 65
Alzheimer’s disease, 435, 449–450
delirium, 198
toxoplasmosis, 307
subtle neurological signs (soft signs), 65–67
Neuromuscular disease, sleep disorders and, 380, 381, 389
Neuropathy
alcoholic, 421–422
diabetic, 351, 357
inhalant-induced, 431
Neuropeptide Y, 538
Neurophysiological testing, 1, 139–150
event-related potentials, 149–150
evoked potentials, 148–149
magnetoencephalography, 118, 139, 147–148, 346
quantitative electroencephalography, 139, 146–147
standard electroencephalography, 140–146
Neuroplasticity
glucocorticoid effects on, 364
antidepressant effects on, 254
sleep effects on, 373
Neuropsychiatric assessment, 1–2, 47–85
appearance and behavior, 67–68
cognitive examination, 71–82
content of thought, 69–71 (See also Delusions; Hallucinations)
emotional expression and regulation, 68–69
form of thought, 69
history taking, 47–52
cognitive screening instruments, 82–83
domain-specific cognitive measures, 83–84
neuropsychiatric assessments, 84
mental status examination, 67, 67
neurological examination, 52–65, 53–54
subtle neurological signs, 65–67
Neuropsychiatric EEG-Based Assessment Aid (NEBA), 159
Neuropsychiatric Inventory (NPI), 84
Neuropsychiatric Inventory—Clinician version (NPI-C), 84
Neuropsychiatric Inventory—Nursing Home version (NPI-NH), 84
Neuropsychiatric Inventory—Questionnaire (NPI-Q), 84
Neuropsychological assessment, 1, 95–114
categories of tests for, 105–112
attention and processing speed, 105–106
emotional status and personality, 111–112
executive function, 109–110
intellectual functioning, 110–111
language, 107
memory, 106–107
motor abilities and praxis, 108–109
visuospatial and visuoconstructional abilities, 107–108
computerized test batteries for, 112
to determine decisional capacity, 97, 112–113
for disability determination, 97, 110
factors affecting quality of, 104–105
indications for, 96–99, 100, 113
in inpatient settings, 96–97
interpretation of tests for, 104–105
nature of tests for, 102–104
mean, 102
normal distribution curve, 102
normative data, 102–103, 103
range of scores, 102
reliability and validity, 103
sensitivity and specificity, 103–104
standard deviation, 102
in outpatient settings, 97
process of, 101–102
qualifications for performance of, 95–96
Houston Guidelines, 96
role of referring neuropsychiatrist in, 99–101
attention-deficit/hyperactivity disorder, 96, 105, 156, 159
dementia, 98
multiple sclerosis, 96, 100, 108, 113, 404–405, 408
traumatic brain injury, 97–98, 104, 110, 113, 275–276
Neurosyphilis, 316–319. See also Syphilis
Neuroticism, 530, 538–539
Neurotoxin exposure, 203–219
assessment of, 205–206, 206, 219
gases, 214–215, 215
carbon monoxide, 214–215
ethylene oxide, 215
mechanisms of neurotoxicity, 206–208
dysbiosis, 207–208
induction of autoimmunity, 208
neuroinflammation, 207
oxidative stress, 207
metals, 211, 211–214
aluminum, 211–212
arsenic, 212
lead, 212–213
manganese, 213
mercury, 213–214
molds and mycotoxins, 216–219
neuropsychiatry and, 205
pesticides, 208–211, 209
glyphosate, 208, 209–210
organophosphate and carbamate compounds, 210–211
routes, sources, and types of, 204–205
solvents, 215–216, 216
Neurotransmitters, 31–38, 32–37. See also specific neurotransmitters
acetylcholine, 32–34, 34
asymmetric brain concentrations of, 13
in limbic system, 19
behavioral alterations associated with disturbances of, 32, 33
dopamine, 34, 35
enkephalin, 38
GABA, 36
glutamate, 36–37
glycine, 38
histamine, 38
local (intrinsic), 31
norepinephrine, 35, 36
orexin, 37–38
projection (extrinsic), 31
origins and destinations of, 32
receptor binding of, 31–32
serotonin, 35, 37
in sleep physiology, 38, 375, 375, 376
Alzheimer’s disease, 440, 441–442
with psychosis, 513
anxiety disorders, 19, 33, 34, 35, 441, 557
panic disorder, 548, 549, 550, 551
social anxiety disorder, 551–552, 553
arsenic poisoning, 212
brain tumors, 31
delirium, 188, 195, 196
dementia, 33, 33, 35, 36
depression, 33, 34, 35, 252, 527, 528, 535
poststroke, 527
epilepsy, 37
fungal toxicity, 218
lead poisoning, 213
with psychosis, 515
mercury poisoning, 214
mood disorders, 528–530
neuroleptic malignant syndrome, 464
obsessive-compulsive disorder, 33, 34, 36
positive emotional states, 535
stroke, 31
inhalants, 430
opiates, 424
suicidality, 539
thyroid disorders, 362
substance P, 38
vasoactive intestinal peptide, 38
Nevirapine, 315
NFTs (neurofibrillary tangles), in Alzheimer’s disease, 437, 439, 439, 487, 513
nfvPPA (nonfluent/agrammatic-variant primary progressive aphasia), 488, 489,
491, 492
NIA-AA (National Institute on Aging- Alzheimer’s Association), 436
Nicotine, 158, 413, 415, 431
Nightmares, 386, 389
abacavir-induced, 315
lead poisoning and, 211
Nimodipine, 312
NMDA receptors. See N-Methyl-D-aspartate receptors
NMS (neuroleptic malignant syndrome), 464, 471
Non–24-hour sleep-wake rhythm disorder, 387
Nonfluent/agrammatic-variant primary progressive aphasia (nfvPPA), 488, 489,
491, 492
Nonnucleoside reverse transcriptase inhibitors, 315–316
Nonpyramidal syndromes, 57–58
Non–rapid eye movement (NREM) sleep, 373, 374
neurotransmitters in, 375, 375, 376
oscillation between REM sleep and, 376
parasomnias during, 386, 389
stages of, 374
Nonsteroidal anti-inflammatory drugs (NSAIDs), 197, 281, 282
Norepinephrine (NE), 35
asymmetries in limbic system, 19
origins and destinations of, 32, 35, 36
receptors for, 35
depression, 528
Norepinephrine reuptake inhibitors (NRIs), for poststroke depression, 253, 254
Norepinephrine transporter (NET), 415
Nortriptyline, for poststroke disorders
anxiety, 257
depression, 252–253, 253
pathological affective display, 260–261
NPI (Neuropsychiatric Inventory), 84
NPI-C (Neuropsychiatric Inventory— Clinician version), 84
NPI-NH (Neuropsychiatric Inventory— Nursing Home version), 84
NPI-Q (Neuropsychiatric Inventory— Questionnaire), 84
NREM sleep. See Non–rapid eye movement sleep
NRIs (norepinephrine reuptake inhibitors), for poststroke depression, 253, 254
NRS-R (Neurobehavioral Rating Scale— Revised), 84
NRTIs (nucleoside reverse transcriptase inhibitors), 315
NSAIDs (nonsteroidal anti-inflammatory drugs), 197, 281, 282
Nucleoside reverse transcriptase inhibitors (NRTIs), 315
Nucleus accumbens (NAc), 16, 26, 28
in apathy, 20, 22, 29
in mood disorders, 531
in Alzheimer’s disease with psychosis, 513
in substance use disorders, 20, 22, 416, 417
Nucleus basalis of Meynert, 33, 440, 441, 468, 496
Nursing Delirium Screening Scale (NuDESC), 194
Nursing home patients
delirium in, 181, 186, 187, 189, 192
poststroke apathy in, 258
sundowning in, 389
Nystagmus, 53, 56
cytomegalovirus encephalitis and, 309
neurosyphilis and, 318
O-Log (Orientation Log), 271

Obesity
hypersomnias, 384
medication-related, 380
obesity-hypoventilation syndrome, 379, 386
obstructive sleep apnea, 379, 380, 386
Obsessions, 63, 67
Obsessive-compulsive disorder (OCD), 63, 545
vs. autism spectrum disorder, 177–178
Huntington’s disease, 20, 29, 30, 484
stuttering, 76
substance/medication-induced, 414, 419
Obstetric complications, 48. See also Pregnancy
Obstructive sleep apnea (OSA), 280, 379, 386
diagnosis of, 381
drug effects on, 390–391
epidemiology of, 386
epilepsy and, 389
medical conditions and, 386
parasomnias and, 386
pathophysiology of, 386
physical and neurological examination for, 379–380
symptoms of, 386
treatment of, 164, 380, 381, 386
Occipital lobes, 6, 7, 11, 12, 27
in Anton’s syndrome, 518
asymmetries of, 13
brain tumors in, 334
in dementia with Lewy bodies, 132, 132, 468, 469, 516
epilepsy of, 228
hallucinations in diseases of, 70, 518
in social anxiety disorder, 552, 553
Occupational history, 51–52
OCD. See Obsessive-compulsive disorder
Ochratoxins, 217, 218
Oculogyric crisis, 60
ODD (oppositional defiant disorder), 153, 155, 163
Olanzapine
for delirium prophylaxis, 193
for psychosis in Huntington’s disease, 483
Olfaction
anosmia, 54, 124, 271, 272
examination of, 54
in REM sleep behavior disorder, 380
Olfactory bulb, 16, 33
trichothecene neurotoxin effects on, 218
Olfactory reference syndrome, 71
Opioid use disorder, 413, 414, 424–427, 431
intoxication, 424
pupillary signs of, 54
neurocognitive aspects of chronic use, 426–427
neuropsychiatric complications of chronic use, 426
prescription drug abuse, 424
prevalence of, 424
treatment of, 426
detoxification, 426
opioid maintenance treatment, 424, 426
for overdose, 424
Opioid withdrawal, 416, 424–426
onset of symptoms of, 426
protracted, 426
Opioids
adverse effects of
central sleep apnea, 386
delirium, 197, 199
overuse headache, 336
indications for
migraine, 282
pain, 414
cannabis augmentation of, 422
tension headache, 281
naloxone reversal of, 414, 424
overdose of, 424, 426
tolerance to, 424–426
use in pregnancy, 424
Oppositional defiant disorder (ODD), 153, 155, 163
Orbitofrontal cortex, 3, 7, 16, 17, 28, 29
disinhibition syndrome and tumors of, 339
disorders associated with lesions of, 16, 20, 27, 28, 30
personality alterations, 20, 21
sexual disorders, 20, 21
depression, 20
mania, 29, 256, 540
Parkinson disease with depression, 528
muscarinic receptors in, in Alzheimer’s disease, 513
in obsessive-compulsive disorder, 20, 21, 31
in Parkinson disease, 528
in Parkinson disease serotonin receptors, 515
in substance use disorders, 20, 21–22
Orexin, 37–38, 375, 375–376, 389
Orexin receptor antagonists, 382, 383
Organizational skills training (OST), 165, 166
Organochlorine neurotoxicity, 208, 209, 210
Organophosphate neurotoxicity, 208, 209, 210–211
Orientation. See also Disorientation
instruments for, 271
spatial, 100, 108
Orientation Log (O-Log), 271
Orthostatic hypotension. See Hypotension, orthostatic
OSA. See Obstructive sleep apnea
OST (organizational skills training), 165, 166
Overinclusiveness, 69
Oxazepam, 427
Oxcarbazepine, 231
Oxidative stress
diabetes mellitus, cognitive impairment and, 353, 354
neurotoxin-induced, 207
lead, 212, 213
manganese, 213
mercury, 214
mycotoxins, 218
posthypoxic, 293
posttraumatic, 268
Oxycodone, 424
Oxygen therapy
for carbon monoxide poisoning, 215
for migraine, 282
Oxytocin
Paced Auditory Serial Addition Test (PASAT), 109, 405
Pacing. See also Wandering
PAD. See Pathological affective display
Palilalia, 77
Palinacousis, 71
Palinopsia, 70, 337
Panic attacks, 141, 546, 548
age at onset of, 235
MDMA intoxication, 430
electroencephalography during, 145
neurochemistry of, 549, 551
nocturnal, 390, 510
vs. seizures, 235
Panic disorder, 545, 546, 548–551, 557
conditions associated with agoraphobia, 545, 548
epilepsy, 235, 557
HIV disease, 314
nonconvulsive seizure disorders, 142
electroencephalography in, 143, 145, 557
magnetoencephalography in, 148
PANS (pediatric acute-onset neuropsychiatric syndrome), 203
PAP (positive airway pressure) therapy, for obstructive sleep apnea, 380, 386
Papez, J.W., 15, 19
Papilledema, 216, 337, 367
Paraganglioma, 366
Parahippocampal gyrus, 3, 7, 16, 17
Paralimbic cortex, 5, 7, 11, 16
Paramedian-limbic zone of brain, 2, 3, 3, 15–24, 16, 38
disorders associated with dysfunction of, 3–4, 5, 16–17, 19–21, 20, 39
Paranormal beliefs, 49
Paraphasia, 100, 491
Paraphilias, 20, 21, 33, 34
Parasomnias, 386–387, 389, 510, 511
benzodiazepine receptor agonist–induced, 427–428
classification of, 386
evaluation of, 377, 378, 379
Parathyroid disorders, 367–368
Paratonia, 53, 59, 60
posttraumatic, 272
Parenchymatous neurosyphilis, 317, 318
Parent-Child Interaction Therapy, 165
Parent Management Training, 165
Parenting
behavioral training programs for, 165–166
Paresthesias, 223
alcoholic polyneuropathy and, 421
antiretroviral agent–induced, 315
hypoparathyroidism and, 367
parietal lobe epilepsy and, 228
Parietal lobe epilepsy (PLE), 228
Parietal lobes, 6, 7, 11
brain tumors in, 334
in delirium, 195
delusions with strokes in, 518
in depression, 539
in executive functioning, 110
in HIV disease, 311
PET scan of, 130
in prosopagnosia, 518
in social anxiety disorder, 552, 553
Parkinsonism
asymmetric, mirror movements in, 65
cogwheeling in, 60
dementia with Lewy bodies and, 460, 463, 472, 514
antipsychotic exacerbation of, 464, 471
dopamine deficiency and, 33, 34
low blink rate, 55
frontal-subcortical circuit disturbances and, 26
frontotemporal dementia and, 487, 489, 494
manganese-induced, 31, 211
postencephalitic, palilalia in, 77
posthypoxic, 287, 293
speech abnormalities and, 74, 76
Parkinson’s disease (PD), 459–473, 460
clinical features of akathisia, 59
disturbances of affect, 533, 535
disturbances of interest and motivation, 536, 537
extrapyramidal symptoms, 465
hallucinations, 71, 98
myoclonus, 463
neuroleptic sensitivity, 464
postural instability and gait abnormalities, 58, 463
psychomotor activity, 538
tremor, 61
aluminum exposure, 212
anxiety disorders, 466, 470, 557
depression, 30, 526, 527, 527–528
inhalant use, 431
psychosis, 509, 514–515
REM sleep behavior disorder, 389, 463, 468
vs. dementia with Lewy bodies, 464
neuroanatomical correlates of, 3–4, 20, 21, 26, 30, 31
neurochemistry of, 34, 468, 513, 527, 538
neuroimaging in, 468–469, 469, 529
functional imaging, 132, 132, 527–528
neuropathology of, 459, 460
neuropsychological testing in, 96, 105, 108, 113
postencephalitic, 30, 31
risk factors for cognitive decline in, 465–467
cognitive fluctuations, 467
cognitive profile, 466
language, 466
memory impairment, 466
visuospatial abilities, 466
preclinical cognitive impairment, 467
psychiatric features, 466–467
motor symptoms, 470
Parkinson’s disease with dementia (PDD), 459, 460, 465–467, 472
extrapyramidal symptoms, 465
neuroleptic sensitivity, 464
misidentification syndromes and, 516
neuropathology of, 459, 460, 467–468
clinicopathological correlates, 468
prevalence of, 465
risk factors for cognitive decline in Parkinson’s disease, 465–467
Paroxetine
for poststroke anxiety, 257
for posttraumatic stress disorder, 554
for social anxiety disorder, 551
PASAT (Paced Auditory Serial Addition Test), 109, 405
Pathological affective display (PAD), poststroke, 260–261
assessment of, 260
frequency of, 260
mechanism of, 260
Pathological gambling, 155
Pathological laughing and crying. See Pseudobulbar affect
Pathological Laughter and Crying Scale (PLACS), 260
Patient Health Questionnaire (PHQ-2 and PHQ-9), 247, 397, 399
Patient Placement Criteria algorithm for substance use disorders, 417
PBA. See Pseudobulbar affect
PCNSL. See Primary central nervous system lymphoma
PCP (phencyclidine), 37, 315, 414, 416, 429
PD. See Parkinson’s disease
PDD. See Parkinson’s disease with dementia
Pediatric Anesthesia Emergence Delirium Scale, 194
Pediatric acute-onset neuropsychiatric syndrome (PANS), 203
Pedophilia, 21
Peduncular hallucinosis, 70, 257, 258, 337
Penicillin G, for syphilis, 317
Pentoxifylline, 181
Perceptual Reasoning Index (PRI), 111
Performance validity tests (PVTs), 110
Periodic leg movements in sleep (PLMS), 378, 387–388, 463
Perseveration, 77, 81, 100, 109. See also Repetitive behaviors
frontotemporal dementia and, 488, 489
varicella-zoster virus infection and, 326
Persistent depressive disorder (dysthymia), 144, 525, 526, 527
epilepsy and, 233
Personality assessment, 111–112
Personality Assessment Inventory, 111–112
Personality changes, 51, 100
neuroimaging, 119
brain tumors, 335, 338–341, 340
temporal lobe epilepsy, 51
Personality disorders. See also specific personality disorders
epilepsy and, 142
psychogenic nonepileptic seizures and, 238, 240
Pervasive developmental disorder, 172–173. See also Autism spectrum disorder
Pesticide exposure, 204, 208–211
autoimmunity induced by, 208
glyphosate, 208, 209–210
organophosphate and carbamate compounds, 210–211
oxidative stress due to, 207
PET. See Positron emission tomography
Peyote, 430
PFS (posterior fossa syndrome), 339, 345
Phantom boarder syndrome, 70, 506
Phencyclidine (PCP), 37, 315, 414, 416, 429
Phenobarbital, 231, 234, 428
Phenytoin, 231
Pheochromocytoma, 365–366
Phonagnosia, 14, 23
Phototherapy. See Light therapy
PHQ-2 and PHQ-9 (Patient Health Questionnaire), 247, 397, 399
Pick’s disease, 460, 492
Pimavanserin, 520–521
Piriform cortex, 7, 14
Pittsburgh Sleep Quality Index, 380
PLACS (Pathological Laughter and Crying Scale), 260
Plantar grasp reflex, 65, 66
Plaques
in Alzheimer’s disease, 437–439, 438, 440, 467, 487, 513
Plasmodium falciparum brain infection, 324
PLE (parietal lobe epilepsy), 228
PLMS (periodic leg movements in sleep), 378, 387–388, 463
PML (progressive multifocal leukoencephalopathy), 306, 308–309
PNES. See Psychogenic nonepileptic seizures
Poikilotonia, 60
Poisoning. See Neurotoxin exposure
Polychlorinated biphenyls, 158
Polymorphisms, genetic. See also Genetic factors
affecting drug metabolism
atomoxetine, 163
efavirenz, 316
affecting response to thyroid hormone treatment in depression, 362
in hypothyroidism, 360
in Alzheimer’s disease with psychosis, 514
in neurocognitive symptoms after cranial radiotherapy, 346
in poststroke depression, 249, 249
Polysomnography (PSG), 380–381
Positive airway pressure (PAP) therapy, for obstructive sleep apnea, 380, 386
Positron emission tomography (PET), 118, 127, 128–129, 130
advantages of, 129
amyloid PET imaging, 129, 132, 133, 438–439
equipment for, 122
interpretation of, 128, 129, 130, 131
patient preparation for, 129–130
radiotracers for, 128, 129, 130, 131, 311
safety of, 131
Alzheimer’s disease, 131–132, 133, 438–439, 450, 469
with misidentification syndromes, 518
dementia with Lewy bodies, 132, 469, 469
epilepsy, 134
psychosis, 515, 518, 519
toxoplasmosis, 307
Postconcussion syndrome, 277
Posterior fossa syndrome (PFS), 339, 345
Poststroke anxiety, 256–257
frequency of, 246, 256
lesion location and, 257
treatment of, 257
Poststroke apathy, 245, 247, 258–259, 261
lesion location and, 258–259
mechanism of, 259
treatment of, 259
Poststroke depression (PSD), 19, 20, 22, 245–255, 261, 527, 527, 528
anxiety disorders and, 256, 257, 557
apathy and, 258, 259
assessment scales for, 246, 247
effect on stroke outcomes, 251
frequency of, 246, 247–248
mechanism of, 251–252
pathological affective display and, 260
prevention of, 254–255
demographic factors, 248
genetic factors, 248–249
medical history, 250
psychiatric history, 249–250
social support, 251
stroke characteristics, 250
serotonin in, 527
effects of antidepressants on stroke recovery, 254
Poststroke mania (PSM), 255–256
frequency of, 246
mechanism of, 256
phenomenology of, 255
treatment of, 256
Poststroke psychosis, 257–258, 261
frequency of, 246
peduncular hallucinosis, 258
seizures and, 258
Posttraumatic amnesia (PTA), 50, 266, 267, 269–270, 271, 272
Posttraumatic encephalopathy, 271
Posttraumatic stress disorder (PTSD), 545, 553–556
ICU delirium, 191
traumatic brain injury, 278, 558
vs. psychosis, 519
DSM-5 criteria for, 554
HPA axis in, 554–555
startle reaction in, 63
symptoms of, 546, 553–554
Posturing, 58, 64
in epilepsy, 227, 379
in nonconvulsive status epilepticus, 62
PPA. See Primary progressive aphasia
PPMS (primary progressive multiple sclerosis), 396, 407. See also Multiple
sclerosis
Pralidoxime, 211
Pramipexole, 296, 472
Praxis, 38, 38. See also Apraxia
assessment of, 67, 78, 83, 108–109
PRE-DELIRIC tool, 192
Pregabalin, 231, 231, 344
Pregnancy
factors associated with attention-deficit/ hyperactivity disorder in offspring, 158
factors associated with autism spectrum disorder in offspring, 174
folic acid supplementation during, 174
history of maternal illness in, 48
hyperprolactinemia and, 366
neuroimaging in
computed tomography, 126
magnetic resonance imaging, 127
SPECT or PET, 131
opioid use in, 424
restless legs syndrome in, 388
syphilis in, 316, 317
Premenstrual symptoms, 144
Premotor cortex, 25, 27, 58
Prescription drug abuse/misuse, 162, 424
PRI (Perceptual Reasoning Index), 111
Primary central nervous system lymphoma (PCNSL)
behavioral changes and, 338
HIV disease and, 306, 307–308
vs. toxoplasma brain abscess, 307
Primary progressive aphasia (PPA), 488, 490, 491–492. See also Frontotemporal
dementia
neuropathology of, 491
nonfluent/agrammatic-variant (nfvPPA), 488, 489, 491, 492
semantic-variant (svPPA), 488, 490, 491–492
therapeutic approaches to, 492–497
Primary progressive multiple sclerosis (PPMS), 396, 407. See also Multiple
sclerosis
Primidone, 231
Primitive reflexes, 53, 65, 66, 272
Prion disease, 321–322
diagnostic biomarkers for, 321–322
management of, 321
neuropsychiatric manifestations of, 321
Processing speed. See Information processing
Processing Speed Index (PSI), 105
Progranulin, in frontotemporal dementia, 487–488, 519
as treatment target, 498
Progressive multifocal leukoencephalopathy (PML), 306, 308–309
Progressive supranuclear palsy, 30
blurting in, 77
eye movement abnormalities in, 55, 56, 57
frontal-subcortical circuit disorders and, 26, 30, 31
neurofibrillary tangles in, 439
palilalia in, 77
primary progressive aphasia and, 489, 492
sleep disturbances in, 389
treatment of, 497
Pronator drift, 57
Propranolol, 279, 341
Prosody. See also Aprosodia
affective, 18, 23, 78
assessment of, 67, 77–78, 107
cluttering and, 76
Prosopagnosia, 7, 12, 12, 14, 23, 79, 446, 490, 492, 518
Protease inhibitors, 315
PSD. See Poststroke depression
Pseudobulbar affect (PBA) (pathological laughing and crying), 23, 68–69, 533
in multiple sclerosis, 396, 401, 402, 403
Pseudodementia, 142, 149, 540
Pseudotumor cerebri, 320
PSG (polysomnography), 380–381
PSI (Processing Speed Index), 105
Psilocybin, 429
PSM. See Poststroke mania
Psychogenic disorders, 58, 143
stuttering, 76
Psychogenic nonepileptic seizures (PNES), 49, 224, 238–240, 241
with coexisting epilepsy, 239–240
developmental, 238
differentiation from epileptic seizures, 239, 239
hyperkinetic frontal lobe epilepsy, 228
management of, 240
posttraumatic, 238
prevalence of, 238
stuttering and, 76
Psychomotor performance
conditions associated with alterations of agitation, 59
akinesia, 59
delirium, 186, 196
euphoria, 402
insomnia, 382
Lewy body disorders, 464, 470
alcohol, 420, 422
inhalants, 431
sedative-hypnotics, 427–428
toxoplasmosis, 307
topiramate effects on, 238
Psychosis, 503–521. See also Delusions; Hallucinations
Alzheimer’s disease, 447, 448, 452, 504, 513–514
brain tumors, 337
catatonia, 64
chorea, 61
dementia with Lewy bodies, 471, 510, 514–516
epilepsy, 21, 70, 71, 98, 235–237, 504, 509–510, 511–512
herpes simplex virus encephalitis, 325, 326, 519–520
Huntington’s disease, 21, 36, 483, 519
hypothyroidism, 359
metabolic diseases, 520
misidentification syndromes, 516–518, 517
multiple sclerosis, 402–403, 504
neurosyphilis, 319
nonconvulsive seizure disorders of childhood, 142
Parkinson’s disease, 466, 470, 471, 514–516
prion disease, 321
sleep disorders, 510–511, 515, 521
stroke, 21, 70, 98, 257–258, 261, 504, 511, 518
cannabis, 422
inhalants, 431
definition of, 503
vs. delirium, 141
dementia symptoms secondary to, 142
dopamine and, 34
drug-induced
stimulants, 161
GABA and, 36
glutamate and, 33
intensive care unit, 140
lack of insight in, 82
personality changes and, 51
primary, 504
schizophrenia, 504–509
secondary, 504, 509–520
hallucinations in, 504, 506–507
seizures and, 258
thought disorder in, 69, 503–504
treatment of, 504, 520–521 (See also Anti-psychotics)
Psychosocial interventions
for Alzheimer’s disease, 455, 456
for attention-deficit/hyperactivity disorder, 160, 164–166, 167–168
for epilepsy, 232–233
for frontotemporal dementia, 493–494
Psychotherapy. See also specific psychotherapies
for anxiety disorders, 558
for depression
in brain tumor patients, 344
in HIV disease, 313
in epilepsy, 237
to improve antiepileptic drug compliance, 234
after hypoxic-ischemic brain injury, 299
for poststroke depression, 252
prevention, 255
for psychogenic nonepileptic seizures, 240
PTA (posttraumatic amnesia), 50, 266, 267, 269–270, 271, 272
PTSD. See Posttraumatic stress disorder
Pulvinar sign, 322
Punding, 64
Pupillary signs, 54, 317
Purdue Pegboard Test, 108
Pure word deafness, 7
Putamen
frontal-subcortical circuits and, 26, 28
in HIV disease, 311
in Parkinson’s disease with psychosis, 515
PVTs (performance validity tests), 110
Quantitative electroencephalography (QEEG), 139, 140, 145–147, 150
applications of, 146, 147
sensitivity and specificity of, 146
Quetiapine
for insomnia, 383
in Lewy body disorders
psychosis, 471, 515
REM sleep behavior disorder, 472
Quotient ADHD System, 159
Ramelteon, 427
for delirium, 193
Rapid eye movement (REM) sleep, 373, 374
aberrant behaviors during, 379
in depression, 537
epilepsy during, 379
in medical disorders, 388
in narcolepsy, 384
neurotransmitters in, 38, 375, 375, 376
oscillation between NREM sleep and, 376
parasomnias during, 386
in psychiatric disorders, 389–390
REM sleep behavior disorder, 379–380, 385, 386, 389
in Lewy body disorders, 463, 465, 468, 471–472, 511
serotonin and visual hallucinations in, 515
Rapid eye movement sleep behavior disorder (RBD), 379–380, 386, 389, 463
diagnosis of, 386
idiopathic, 389
Lewy body disorders and, 389, 460, 463, 465, 468, 471–472, 511
narcolepsy and, 385
Rapid plasma reagin (RPR) test, 317
Rapid serial processing tests, 404–405
RBD. See Rapid eye movement sleep behavior disorder
rCMR (regional cerebral metabolic rate), 128, 129
Reaction time tests, in multiple sclerosis, 404, 405
Reactive attachment disorder, 177
Reading impairment, 7, 12, 12, 14, 24, 48, 74–75
Reboxetine, 253
Receptors
acetylcholine
muscarinic, 33
nicotinic, 33
nicotine actions on, 415
α-adrenergic, 35
β-adrenergic, 35
ɣ-aminobutyric acid, 36
types of, 36
autoreceptors, 31
dopamine, 34
in Alzheimer’s disease with psychosis, 513–514
D2, 34
antipsychotic blockade of, 34, 44, 366
neuroleptic blockade of, 34
types of, 34
glutamate, 37
NMDA, 37
in depression, 528
heteroreceptors, 31
histamine H1, 38
ionotropic, 31, 33, 35, 36, 37
metabotropic, 31, 33, 34, 35, 36, 37
neurotransmitter binding to, 31–32
presynaptic and postsynaptic, 31
serotonin, 35
pimavanserin affinity for, 471
Reduplicative paramnesia, 516–517, 517, 519
Reflex testing, 53, 65
Regional cerebral metabolic rate (rCMR), 128, 129
Relapsing-remitting multiple sclerosis (RRMS), 395, 396, 405, 407. See also
Multiple sclerosis
Relaxation training
Religiosity, 21, 51, 142, 512
REM sleep. See Rapid eye movement sleep
REM sleep behavior disorder. See Rapid eye movement sleep behavior disorder
Repetition, 8, 15
echolalia, 76–77
palilalia, 77
in semantic-variant primary progressive aphasia, 490, 491
stuttering and, 76
Repetitive behaviors
agitation and, 59
autism spectrum disorder and, 171, 172–173, 175, 177–178
treatment of, 181
catatonia and, 64
compulsions and, 63
dystonia and, 60
treatment of, 495
treatment of, 484
stereotypies, 63–64 (See also Stereotypies)
tardive dyskinesia, 64
Restless legs syndrome (RLS), 378, 379, 380, 387–388
aging and, 389
antidepressant-induced, 389
epilepsy and, 389
treatment of, 388
Reticular formation, 24, 27
in REM sleep behavior disorder, 468
Rett’s disorder, 63, 173, 177
Reward circuitry of brain, 21, 31, 158, 414, 416, 536
Reward sensitivity model of attentiondeficit/hyperactivity disorder, 156
Rey 15-Item Test, 110
Rey Complex Figure Test, 107
Rigidity, 59, 60
in hepatic encephalopathy, 422
methanol-induced, 216
in multiple system atrophy, 465
Risperidone
for brain tumor–associated agitation, 341
for delirium, 199
prophylaxis, 193
pimavanserin potentiation of, 521
Rivastigmine, for cognitive dysfunction
in dementia with Lewy bodies, 469–470
in frontotemporal dementia, 496–497
posthypoxic, 298
posttraumatic, 282
RLS. See Restless legs syndrome Rocky Mountain spotted fever, 324
Rossolimo sign, 65
RPR (rapid plasma reagin) test, 317
RRMS (relapsing-remitting multiple sclerosis), 395, 396, 405, 407. See also
Multiple sclerosis
Rufinamide, 231
Saccades, 53, 55–56

Sadness, 68, 340, 533
apathy and
poststroke, 258
depression and, 68, 526, 533
in HIV disease, 313
lack of response to, 533
speech and, 78
Sadomasochism, 21
Safety concerns, 96
aggressive behavior and, 280
for neuroimaging
functional imaging, 131
structural imaging, 126–127
Salvia divinorum, 429
Sarcoidosis, 54
Schizoaffective disorder, 487, 504, 508
Schizophrenia, 504–509, 521
aberrancy of interhemispheric asymmetry in, 24
vs. autism spectrum disorder, 172, 178
clinical features of, 504–507
behavior, 507
catatonia, 64, 504, 505, 507
cognitive impairment, 98, 105
delusions, 504–505, 521
eye movement disturbances, 55
hallucinations, 37, 70, 504–507, 521
impaired prefrontal lobe function, 507–508
movement abnormalities, 507
genetic factors and, 509
head circumference and, 54
obstetric complications and, 48
prevalence of, 504
subtle neurological signs in, 66
Schizophrenia spectrum disorders, 55, 61, 64, 66, 70, 504, 505, 507, 509
Schizophreniform disorder, 504
Schizotypal personality disorder, 49, 504
SCID (Structured Clinical Interview for DSM Disorders), 397, 399
SCID-5-RV (Structured Clinical Interview for DSM-5 Disorders, Research Version),
246
SCN (suprachiasmatic nuclei), 374, 376, 389
Scopolamine, 33
SDMT (Symbol Digit Modalities Test), 405, 409
SE. See Status epilepticus Second messenger systems, 31, 364, 415, 529, 539
Secondary progressive multiple sclerosis (SPMS), 396, 405, 407. See also
Multiple sclerosis
β-Secretase, 440
ɣ-Secretase, 440
Sedation
drug-induced, 390, 480
antihistamines, 383
antipsychotics, 390
atomoxetine, 162, 163
in Huntington disease, 480
clonidine, 164
cognitive impairment and, 357
guanfacine, 164
histamine H1 receptor antagonists, 38
tetrabenazine, 480
trazodone, 281
GABA and, 33
Sedative-hypnotics
abuse/misuse of, 413, 414, 427–429
alcohol use disorder and, 427
intoxication and overdose due to, 427–428
neuropsychiatric complications of, 428
neuropsychological effects of, 428–429
avoiding in frontotemporal dementia, 498
for imaging procedures, 126, 129–130
as risk factor for delirium, 192, 197, 199
withdrawal from, 413, 416, 428
Seizures, 223–241. See also Epilepsy; Status epilepticus
absence (petit mal), 142, 228–229, 231
antidepressant-induced, 234
electroencephalography, 140–145, 230
history taking, 49, 229–230
magnetoencephalography, 147–148
neuroimaging, 230
neuropsychological evaluation, 96, 113
quantitative electroencephalography, 145–147
atonic, 229
clonic, 229
autism spectrum disorder, 143, 174, 177, 178
brain tumors, 226, 230, 333, 335, 337, 341, 343, 344
cerebral malaria, 324
delirium, 141
depression, 143
epilepsy with psychosis, 511–512
hypoglycemia, 354
hypoxic-ischemic brain injury, 287, 292–293, 300
neurosyphilis, 319
secondary psychosis, 258
sleep deprivation, 384
alcohol withdrawal, 224, 420
opiates, 424
sedative-hypnotic and anxiolytic withdrawal, 428
stimulants, 423
toxoplasmosis, 307
covert, identification of, 142–143
crying (dacrystic), 49
definition of, 224
electrical, 224
electroconvulsive therapy–induced, 253
febrile, 48, 224, 230
focal epileptic, 224–225
GABA and, 33
generalized epileptic, 225
glutamate and, 33, 37
laughing (gelastic), 49
management of, 230–232, 231 (See also Antiepileptic drugs)
myoclonic, 229
vs. panic attack, 235
psychogenic nonepileptic, 49, 224, 238–240, 241
recurrence risk for, 230
tonic, 229
tonic-clonic (grand mal), 229
unprovoked, 224
Selective serotonin reuptake inhibitors (SSRIs). See also specific drugs
adverse effects of, 253–254, 255, 257
sexual dysfunction, 253, 253, 357
sleep effects, 389
tremor, 255
event-related potentials and resistance to, 149
indications for
anxiety disorders
in epilepsy, 235
panic disorder, 549
poststroke, 257
social anxiety disorder, 551–552
in epilepsy, 234
in HIV disease, 313
poststroke, 253, 253–254, 255, 278
posttraumatic, 278
poststroke anxiety, 257
poststroke depression, 253, 253–254, 255, 278
poststroke pathological affective display, 261
interaction with antiepileptic drugs, 234
thyroid hormone augmentation of, 361–362
Selegiline
for posttraumatic apathy, 280
Self-grasp reflex, 53, 66
Semantic-variant primary progressive aphasia (svPPA), 488, 490, 491–492
Senile plaques, in Alzheimer’s disease, 437–439, 438, 440, 467, 487, 513
Sensory cortex
parietal, 25
primary, 5, 6, 7, 8, 8
MRI studies in HIV infection, 311
Sensory examination, 53
Serotonin (5-HT), 35
origins and destinations of, 32, 35, 37, 38
in sleep physiology, 375, 389, 515
with psychosis, 513
delirium, 196
poststroke, 252
Lewy body disorders with psychosis, 515
MDMA intoxication, 430
suicidality, 539
thyroid disorders, 362
Serotonin-norepinephrine reuptake inhibitors (SNRIs). See also specific drugs
in Alzheimer’s disease, 455–456
for depression in diabetes mellitus, 356, 357
for HIV-related depression, 313
Serotonin receptors, 35
pimavanserin affinity for, 471
Serotonin transporter (SERT)
in cocaine mechanism of action, 415
Sertraline
for depression
in epilepsy, 234
poststroke, 253, 254, 255, 278
posttraumatic, 278
for social anxiety disorder, 552
tremor induced by, 255
Sexual function and behavior, 50–51
changes in sexual preference, 51
drug effects on
selective serotonin reuptake inhibitors, 253, 253, 357
epilepsy and, 20, 21, 51
Parkinson’s disease and, 466, 467
substance use disorders and, 414, 419
stimulants, 423
Shift work sleep disorder, 164, 387
Shingles, 326
Shy-Drager syndrome, 465
Sickness behavior, 356
Simultanagnosia, 79–80, 293, 297, 446
Single-photon emission computed tomography (SPECT), 117–118, 127, 128
advantages of, 129
dopamine transporter imaging, 128, 132, 132
medications and, 129
patient preparation for, 129–130
radiotracers for, 128, 129–130, 131
safety of, 131
dementia with Lewy bodies, 132, 132, 469, 469, 516
epilepsy, 134
postictal psychosis, 512
toxoplasmosis, 307
technical considerations for, 128
SLE (St. Louis encephalitis), 327
Sleep, 50, 373–377
drug effects on, 388, 390–391
alcohol, 391
caffeine, 391
efavirenz, 316
sedative-hypnotics and anxiolytics, 427–428
headache upon awakening from, 336
napping, 377, 379, 382, 385, 386
non–rapid eye movement (NREM), 373, 374
oscillation between REM sleep and, 376
parasomnias during, 386, 389
stages of, 374
rapid eye movement (REM), 373, 374
aberrant behaviors during, 379
in depression, 537
epilepsy during, 379
in medical disorders, 388
in narcolepsy, 384
neurotransmitters in, 38, 375, 375, 376
oscillation between NREM sleep and, 376
parasomnias during, 386
in psychiatric disorders, 389–390
REM sleep behavior disorder, 379–380, 385, 386, 389
in Lewy body disorders, 463, 465, 468, 471–472, 511
serotonin and visual hallucinations in, 515
tics during, 63
Sleep apnea, 51
central, 380, 386
obstructive, 280, 379, 386
diagnosis of, 381
drug effects on, 390–391
epilepsy and, 389
modafinil for, 164
Sleep attacks, 51, 390
Sleep deprivation, 378
delirium due to, 141
for depression, 389–390, 537
electroencephalography and, 145
hypersomnolence and, 379
mania due to, 384, 390, 537
medical disorders and, 388
psychosis and, 510
seizures due to, 384, 389
Sleep diary, 380
Sleep disorders, 377–391. See also specific sleep disorders
aberrant nocturnal behaviors, 379
actigraphy, 380
history taking, 50–51, 377
instruments for, 380
neurological examination, 380
physical examination, 379–380
polysomnography, 380–381
sleep diaries, 380
circadian rhythm sleep-wake disorders, 377, 380, 387
autism spectrum disorder, 177, 178, 179, 181
delirium, 186, 187, 193, 195–196, 198
REM sleep behavior disorder, 460, 460, 463, 468, 471–472, 511
depression, 313, 389–390, 526, 536–537
in bipolar disorder, 537
poststroke, 246
epilepsy, 389
HIV disease, 389
hospitalization, 388
hypoglycemia, 354
hypothalamic injury, 24
Lyme disease, 320, 388–389
mania, 389–390, 537
poststroke, 255
medical disorders, 388
neuroborreliosis, 320
neurological disorders, 388–389
neuromuscular diseases, 380, 381, 389
panic disorder, 390
posthypoxic disorders of consciousness, 294, 296
psychosis, 510–511, 515, 521
schizophrenia, 390
stroke, 386, 388, 511
substance use disorders, 377, 414, 418, 419
hallucinogens, 429
opioids, 424
stimulants, 430
traumatic brain injury, 271, 272, 280–281
in elderly persons, 389
hypersomnias, 384–386
hypersomnolence, 379
insomnia, 377–379, 381–384
parasomnias, 377, 378, 379, 386–387, 389, 510, 511
sleep-related breathing disorders, 386
sleep-related movement disorders, 387–388
Sleep hygiene, 281, 378, 379, 380, 384, 385, 387, 456, 472
Sleep logs, 387
Sleep physiology, 374–377
circadian clock, 374
in depression, 537
flip-flop switches, 376–377
neurotransmitters and, 375, 375
orexin, 37–38, 375–376
waking state, 374–376
Sleep-related breathing disorders (SRBDs), 377, 380, 386. See also Sleep apnea
alcohol use and, 391
diagnosis of, 380, 381
neurological diseases and, 389
Sleep-related eating disorder, 379, 510
Sleep-related hypoventilation syndromes, 379, 380, 386
Sleep-related hypoxemia disorder, 386
Sleep-related movement disorders, 51, 377, 387–388
evaluation of, 378, 379
Sleep restriction therapy, 384
Sleep state misperception, 381
Sleep terrors, 379, 386, 511
Sleepwalking, 379, 386
benzodiazepine receptor agonist–induced, 427–428
SNAP and SNAP-IV (Swanson, Nolan, and Pelham) Parent and Teacher Rating
Scales, 158
Snout reflex, 53, 66, 272
SNRIs. See Serotonin-norepinephrine reuptake inhibitors
Social anxiety disorder, 545, 551–553
DSM criteria for, 551
HPA axis in, 552
neuroanatomical correlates of, 19, 20, 552–553, 553
neuroleptic-induced, 552
panic attacks in, 546
Social cognition
substance-related neurocognitive disorders and, 419, 421
Social skills training, 165, 180
Social support
poststroke depression and, 246, 249, 251
traumatic brain injury and, 269, 280
Society for Behavioral and Cognitive Neurology, 1
Sodium oxybate, 385
Solvent neurotoxicity, 215–216, 216
Somatoform disorders, 148, 238, 240
Somatoparaphrenia, 82
Somatosensory cortex, 6, 26
Somatostatin, 441
Somnolence. See also Hypersomnia
drug-induced
antipsychotics, 471
clonidine, 164
neurotoxin-induced, 211, 216
after stroke involving bifurcation of basilar artery, 511
Spasticity, 58, 59–60, 294, 396, 465
SPECT. See Single-photon emission computed tomography
Speech, 100. See also Language
apraxia of, 56, 74
assessment of, 67, 73–78, 101, 107
blurting, 77
cluttering, 76
disorganized, 503, 504, 505
echolalia, 76–77
examining motor aspects of, 74, 75
festinant, 76, 77
hypophonic, 4, 74, 218
incoherent, 69, 463, 504
vs. language, 73
palilalia, 77
perseveration of, 100
poverty of, 69
pressured, 69, 245, 255, 402, 538
prosody and, 77–78
rhythm of, 76
scanning, 74
Speech disorders. See also Dysarthria
poststroke, 245
frontal lobe epilepsy and, 228
mutism, 75–76
neurotoxin exposures and, 211, 216
Parkinson’s disease and, 4, 74, 76
poststroke mania and, 255
primary progressive aphasia and, 489, 490, 491, 494
schizophrenia and, 503, 504–505
stuttering, 76
substance intoxication and
inhalants, 430, 431
stimulants, 423
Speech-language pathologists, 298
“Spice,” 422
SPMS (secondary progressive multiple sclerosis), 396, 405, 407. See also Multiple
sclerosis
SQ (Symptom Questionnaire), 367
SRBDs. See Sleep-related breathing disorders
SSRIs. See Selective serotonin reuptake inhibitors
St. Louis encephalitis (SLE), 327
Stammering, 76
Startle reaction, 63, 77, 180
Status dissociatus, 511
Status epilepticus (SE), 510
nonconvulsive, 62
psychosis and, 236
posthypoxic, 292–293
psychosis and, 236, 510, 511
during sedative-hypnotic withdrawal, 428
Stereotypies, 63–64, 141. See also Repetitive behaviors
autism spectrum disorder and, 63, 172, 175, 177
treatment of, 181
blurting, 77
catatonia and, 64
nocturnal epilepsy and, 379
pathological affect and, 68, 260, 533
Stimulant-related disorders, 162, 413, 414, 423–424, 431
intoxication, 423
neurocognitive deficits and, 424, 425
prevalence of, 423
withdrawal, 416, 423
Stimulants. See also specific drugs
indications for
attention-deficit/hyperactivity disorder, 160–162, 167
adverse effects of, 161–162
clonidine and, 163
dosing of, 161
depression
in HIV disease, 313
excessive daytime sleepiness, 385
posttraumatic apathy, 280
posttraumatic fatigue, 281
sleep effects of, 385, 390
STOP-BANG Questionnaire, 380
Stretch reflexes, 53
Stroke patients, 11, 245–261
acute hemiconcern syndrome in, 73
anxiety in, 20, 21, 256–257, 261, 557
frequency of, 256
treatment of, 257
apathy in, 20, 258–259
lesion location and, 258–259
mechanism of, 259
treatment of, 259
assessment of
electroencephalography, 140, 141
neuroimaging, 119, 125, 127, 130, 136
catastrophic reaction in, 259–260
delirium in, 187, 190, 192
dementia in, 22
depression in, 19, 20, 22, 245–255, 527, 527, 528
assessment scales for, 246, 247
effect on stroke outcomes, 251
frequency of, 246, 247–248
mechanism of, 251–252
prevention of, 254–255
with diabetes mellitus, 351, 353, 358
disinhibition in, 536
hemiplegia in, 60
with HIV disease, 310, 311
hypertonia in, 60
hypoxic-ischemic brain injury in, 290
limbic system dysfunction in, 4, 16, 20, 22
with Lyme disease, 320
mania in, 20, 255–256, 534
mechanism of, 256
phenomenology of, 255
treatment of, 256
with neurosyphilis, 316, 320
neurotransmitter disruptions in, 31
pathological affective display in, 260–261
assessment of, 260
frequency of, 260
mechanism of, 260
prevalence of neuropsychiatric disorders in, 245, 246
psychosis in, 21, 70, 98, 257–258, 261, 504, 511, 518
seizures in, 224, 226, 230
sleep disturbances in, 386, 388
psychosis and, 511
stereotypies in, 64
stuttering in, 76
with substance use disorders, 50
opiates, 426
Stroop Color-Word Interference Test, 109
Stroop Test, 539
Structured Clinical Interview for DSM Disorders (SCID), 397, 399
Structured Clinical Interview for DSM-5 Disorders, Research Version (SCID-5-RV),
246
Stuttering, 76
Subacute sclerosing panencephalitis, 324
Subjective doubles, syndrome of, 517
Subspecialty of Behavioral Neurology & Neuropsychiatry, 1
Substance Abuse and Mental Health Services Administration, 423
Substance P, 38
Substance use disorders (SUDs), 413–431. See also specific substances of abuse
clinical diagnosis of, 417–419
laboratory tests, 417
screening instruments, 417
severity assessments, 417
urine toxicology testing, 417
panic disorder, 548
attention-deficit/hyperactivity disorder, 153, 154, 155, 158, 164, 167
delirium, 186
HIV disease, 306, 310, 313, 314–315
efavirenz therapy and, 315, 316
mood disorders, 527, 534, 536
neurocognitive disorders, 50, 414, 419
sleep disturbances, 377, 378, 381, 390–391
definition of terms, 413–416
craving, 416, 419
dependence, 413–414
tolerance, 414–415
withdrawal, 416
DSM-5 classification of, 414, 419
history taking for, 47, 50
brain reward circuitry, 416
dopamine, 415, 416, 417, 424, 431
neuropsychiatric syndromes by drug class, 419–431
alcohol, 419–422
cannabis, 422–423
hallucinogens, 429–430
inhalants, 430–431
opioids, 424–427
sedative-hypnotics and anxiolytics, 427–429
stimulants, 423–424, 425
during pregnancy, 48
attention-deficit/hyperactivity disorder in offspring and, 158
pupillary abnormalities and, 54
substance mechanisms of action, 415
treatment of
Patient Placement Criteria algorithm for, 418
for withdrawal symptoms, 417–418
Substantia nigra
Alzheimer’s disease with neurofibrillary tangles in, 439
frontal-subcortical circuits and, 26, 28, 28
manganese, 213
neurotransmitter projections of, 32, 34, 35, 36, 38
in Parkinson’s disease with dementia, 468, 514
Subthalamic nuclei, 28
in ballismus, 62
deep brain stimulation of, for depression, 527
glutamate projections from, 32, 36
in mood regulation, 541
Subtle neurological signs (soft signs), 65–67
Suck reflex, 53, 66, 272
SUDs. See Substance use disorders Suicidal ideation or behavior, 526
brain tumors, 342
depression, 539
epilepsy, 233, 234, 238
drug-related antiepileptic drugs, 234
atomoxetine, 163
barbiturates, 238
inhalants, 431
stimulants, 423
tetrabenazine, 480
electroencephalography for, 144
genetic factors and, 530
postmortem brain studies of, 539
serotonin and, 33, 35, 539
Sundowning, 140, 389, 447, 448
Supportive psychotherapy
for HIV-related adjustment disorder, 313
Suprachiasmatic nuclei (SCN), 374, 376, 389
Supralimbic zone of brain (neocortex), 2, 3, 4, 5–15, 38
disorders associated with dysfunction of, 4, 38–39
Susceptibility-weighted imaging, 123
Suvorexant, 382, 383
svPPA (semantic-variant primary progressive aphasia), 488, 490, 491–492
Swanson, Nolan, and Pelham (SNAP and SNAP-IV) Parent and Teacher Rating
Scales, 158
Sydenham’s chorea, 20, 30, 31, 61
Symbol Digit Modalities Test (SDMT), 405, 409
Symbol Search test, 105
Symptom Questionnaire (SQ), 367
Syncope, convulsive, 224
Syndrome of subjective doubles, 517
Synkinesia, 56, 64–65
α-Synuclein pathology, 459, 460
Syphilis, 316–319
Argyll Robertson pupils and, 54, 317
chronic opioid use and, 426
clinical presentation of, 316–317
forms of neurosyphilis, 318–319
meningovascular neurosyphilis, 317, 318
parenchymatous neurosyphilis, 317, 318
syphilitic meningitis, 318
gummatous, 317
latent, 317
otosyphilis, 317
palilalia and, 77
primary, 316
psychosis due to, 520
secondary, 316–317
tertiary, 317
testing for, 450
Systemic lupus erythematosus, 61, 317, 520
T3 (triiodothyronine), 359–362
T4 (thyroxine), 359, 362
Tabes dorsalis, 317
Tachycardia
drug-induced
antipsychotics, 383
doxylamine, 383
hallucinogens, 429
reboxetine, 253
stimulants, 253
hyperthyroidism and, 360
Tangentiality, 69, 452
Tardive dyskinesia, 61, 62, 64, 81, 181, 520
Tardive dystonia, 62
Tasimelteon, 387
Tau imaging, 439
Tau protein
in Alzheimer’s disease, 440, 450, 467, 498
in frontotemporal dementia, 487–488, 489, 493
as treatment target, 497–498
TBI. See Traumatic brain injury
TCAs. See Antidepressants, tricyclic
TDP-43 (transactive response DNA-binding protein 43), 487–488, 489–490, 492,
493, 497–498, 519
Temazepam, 383, 428
Temperament, 48
neuroticism and, 538
Temporal lobe epilepsy (TLE), 145, 226–227, 239
amnestic state in, 227
with aura, 226
emotional facial weakness in, 57
epigastric rising in, 226
glutamate and, 37
language and discourse in, 75
mesial, 37, 142
movement abnormalities in, 227
personality traits and, 51
preictal emotional changes in, 49
sexual function disorders and, 20, 21
with version, 227
Temporal lobes, 6, 7, 8, 16
in anorexia nervosa, 51
in anxiety, 20, 21, 551, 556, 557
asymmetries between
anatomic, 12–13
neurochemical, 19
in borderline personality disorder, 144
in delirium, 195
dopamine in, 32, 34
in echolalia, 77
in emotional regulation, 17, 69
evoked potentials in, 148
in executive functioning, 110
in hallucinations, 71
in herpes simplex virus encephalitis, 324, 325, 519–520
in HIV disease, 311
in language disturbances, 107
in mood disorders, 531, 532, 534, 539, 541
in multiple sclerosis, 400, 402–403, 409
in neurocognitive disorders, 131, 133
frontotemporal dementia, 487, 488, 489, 519
primary progressive aphasia, 490, 491–492
neuroimaging of
MRI, 121, 124
PET, 529
in personality alterations, 20, 51
in psychosis, 20, 21, 235, 505–506, 510, 519–520
in anti–NMDA receptor encephalitis, 520
in epilepsy, 511, 512
in herpes simplex virus encephalitis, 519–520
with misidentification syndromes, 517, 518
in multiple sclerosis, 402–403
poststroke, 518
in sexual dysfunction, 20, 21
thalamocortical connections, 27
traumatic injury of, 268, 519
tumors of, 333, 334, 339
in visual field defects, 55
in visuospatial processing, 108
white matter connections in, 10–11
Tenofovir, 315
Test of Memory Malingering, 110
Test of Nonverbal Intelligence, 111
Tetrabenazine, 479–480, 484
Tetrahydrocannabinol (THC). See also Cannabis
Texas Functional Living Scale, 113
Thalamic nuclei, 3, 4, 16
asymmetric neurochemical anatomy of, 19
reticular nucleus, 24, 27
Thalamus, 2, 3, 5, 10
in alcoholism, 421, 422
in apathy, 20, 22
in balance disorders, 58
in brain infections
prion disease, 322
toxoplasma brain abscess, 307
cortical projectionis from, 25, 25
emotional activation of, 18
in facial movement disorders, 57
frontal-subcortical circuits and, 28, 29
imaging of, 126, 128, 133
depression, 20
mania, 19, 20, 29, 30, 255, 256
in movement disorders, 293
asterixis, 63
in palilalia, 77
mania, 255, 256
psychosis, 257
THC (tetrahydrocannabinol). See also Cannabis
Thiamine, for alcohol withdrawal, 420, 421
Thought blocking, 503
Thought broadcasting, 506
Thought content, 67, 69–71. See also Delusions; Hallucinations
Thought disorder, 69, 503–504, 505
poststroke psychosis and, 257
Thought insertion, 505, 506
Thought process, 67, 69
Thought withdrawal, 505, 506
“Three words–three shapes” test, 73, 80
Thyroid disorders, 358–363
hyperthyroidism, 360–361
hypothalamic-pituitary-thyroid axis and depression, 361–363
hypothyroidism, 358–360
Thyroid hormone transporter, 360, 362
Thyroid-stimulating hormone (TSH), 197, 358, 359, 362
Thyroiditis, 360
Thyrotoxicosis. See Hyperthyroidism
Thyroxine (T4), 359, 362
Tics, 63
attention-deficit/hyperactivity disorder and
α2-adrenergic agonists for, 163
guanfacine for, 164
stimulant effects on, 161
vs. compulsions, 63
dopamine and, 33, 34
vs. myoclonus, 62
vs. repetitive complex movements in autism, 64
in Tourette syndrome, 52, 63, 77, 155
TLE. See Temporal lobe epilepsy
TMN (tuberomammillary nucleus), 38, 375, 375, 376
TMS. See Transcranial magnetic stimulation, repetitive
TMT (Trail Making Test), 106, 109
Tobacco use disorder, 413, 414, 415, 416
“Top of the basilar artery” syndrome, 511
Topiramate
“Torque test” of drawing circles, 49
Torticollis, 60
Tourette syndrome (TS), 52, 63, 77, 155. See also Tics
Tower of London task, 109
Toxins. See Neurotoxin exposure
Toxoplasma gondii encephalitis, 306–307
Trail Making Test (TMT), 106
Tramadol, 282
Transactive response DNA-binding protein 43 (TDP-43), 487–488, 489–490, 492,
493, 497–498, 519
Transcranial magnetic stimulation, repetitive (rTMS)
for depression, 531–532, 535
for schizophrenia, 506, 521
Transient ischemic attack, 192
Transvestism, 21
Tranylcypromine, 401
Traumatic brain injury (TBI), 204, 265–283
in children and adolescents, 267, 268, 276
combat-related, 204
akathisia, 59
anxiety disorders, 271, 275, 278, 280, 557–558
apathy, 536
depression, 271, 275, 278, 280, 282, 527
language disturbances, 75, 76, 77
olfactory abnormalities, 54, 271, 272
posttraumatic stress disorder, 278, 558
psychosis, 504, 519
definition of, 265–267
disinhibition and, 536
due to falls in elderly persons, 268
evaluation of, 269–276
history taking, 50, 269–271
mental status examination, 272–274
neuroimaging, 119, 119, 123, 124, 125, 274–275
neuropsychological testing, 96, 97–98, 104, 113, 275–276
physical examination, 272
symptoms and course of illness, 271–272, 273
with loss of consciousness, 98, 266, 267, 269–270, 272
management of neuropsychiatric sequelae of, 277–283
affective disorders, 278–279
aggression, 280
apathy, 280
headache, 281–282
mood disorders, 278
posthypoxic disorders of consciousness, 296
principles of pharmacotherapy, 279
seizure prophylaxis, 293
sleep disorders and fatigue, 280–281
mild, 265, 266, 276–277
ACRM criteria for, 266–267
course of, 272, 273
multiple, 277
single, uncomplicated, 276–277
neuropathophysiology of, 268–269
penetrating vs. nonpenetrating, 266
posttraumatic amnesia and, 50, 266, 267, 269–270, 271, 272
preinjury, injury, and postinjury factors related to psychiatric effects of, 269, 270
severity of, 265, 266, 272, 273
Glasgow Coma Scale score, 266, 267, 270
synuclein pathology in, 460
vegetative state due to, 294, 295
Trazodone
for insomnia, 383
posttraumatic, 281
Tremor, 61
akathisia and, 59
akinesia and, 59
delirium, 62
hypoglycemia, 354
neurosyphilis, 319
substance withdrawal
alcohol, 420
barbiturates, 428
drug-induced
hallucinogens, 429
inhalants, 431
sertraline, 255
examination for, 57, 61
imaging studies of, 126
intention (kinetic), 61
vs. myoclonus, 62
postural, 60, 61
rest, 61
rubral (midbrain), 61
Treponema pallidum infection, 316–319. See also Syphilis
antibody tests for, 317
Trichloroethylene exposure, 216, 216
Trichothecene toxins, 217, 218
Tricyclic antidepressants (TCAs). See Antidepressants, tricyclic
Triiodothyronine (T3), 359–362
Triple P—Positive Parent Program, 165
Triptans, for migraine, 282
Tropheryma whipplei infection, 322–324. See also Whipple’s disease
TS (Tourette syndrome), 52, 63, 77, 155. See also Tics
TSH (thyroid-stimulating hormone), 197, 358, 359, 362
Tuberomammillary nucleus (TMN), 38, 375, 375, 376
Tuberous sclerosis, 174, 177, 516
Tumor necrosis factor α, 195, 400, 441, 529
Twin studies
of autism spectrum disorder, 174
of schizophrenia, 509
Unawareness of deficits, 81–82. See also Anosognosia

“alien hand sign,” 79
Uncinate fasciculus, 10, 256
Urine toxicology testing, 417
U.S. Huntington’s Disease Genetic Testing Group, 478
Utilization behavior, 63
Vaccines, 212
autism spectrum disorder and, 174–175
Valacyclovir, 327
Valproate
for mania in multiple sclerosis, 401
obesity induced by, 380
prenatal exposure to, 174
for tauopathies, 498
after traumatic brain injury, 278, 279, 280, 281
Vanderbilt ADHD Diagnostic Rating Scales (parent and teacher), 158
Varicella zoster virus (VZV) encephalitis, 326–327
cerebrospinal fluid and plasma biomarkers for, 326
cognitive disorders and, 326
demographics of, 326
pathogenesis of, 326
shingles and, 326
treatment of, 327
Vascular neurocognitive disorder, 4, 50, 494
vascular cognitive impairment, no dementia (VCIND), 4
VCI (Verbal Comprehension Index), 111
VCIND (vascular cognitive impairment, no dementia), 4
VDRL test for syphilis, 317
Vegetative state (VS), 294–295, 295, 300
Venlafaxine
for narcolepsy, 386
for posttraumatic stress disorder, 554
Ventral tegmental area (VTA)
dopamine projections from, 32, 34, 35
in substance use disorders, 415, 416, 417
Verbal Comprehension Index (VCI), 111
Vigilance
assessment of, 72
impairment of, 72
due to solvent exposure, 216
Violence, 51. See also Aggression
electroencephalography in persons with, 143
postictal, 142, 512
during sleep, 510
thoughts of, 67
Visual agnosia, 7
Visual cortex, 6, 7
in HIV disease, 311
in occipital lobe epilepsy, 228
PET imaging of, 132
Visual field defects, 14, 26, 100
in callosal disconnection syndromes, 78
in simultanagnosia, 446
testing for, 53, 55
Visual grasping, 56
Visual neglect, 108, 336–337
Visual Puzzles test, 111
Visuospatial deficits, 80
Alzheimer’s disease and, 436, 445–446, 449, 461, 462
delirium and, 187
dementia with Lewy bodies and, 461, 461, 462, 464
multiple sclerosis and, 404, 405, 406, 407, 408
Parkinson’s disease with dementia and, 461, 465, 466, 467
posthypoxic, 297
signs and symptoms of, 100
Visuospatial function, 340
intelligence tests, 111
neuropsychological tests, 80, 104, 107–108
in frontotemporal dementia, 487, 488, 489, 490, 491
hemispheric lateralization of, 14, 15, 108
Vocabulary test, 106
Voluminous mental state, 49
Vomitoxin, 217
Vorbeireden (vorbeigehen), 69
VS (vegetative state), 294–295, 295, 300
VTA. See Ventral tegmental area
VZV. See Varicella zoster virus encephalitis
WAIS-IV. See Wechsler Adult Intelligence Scale–IV

Waking state, 374–376
Waldrop scale, 52
Wandering
Alzheimer’s disease and, 59, 447, 448, 449
treatment of, 471
Watershed areas of brain, 291
Waxy flexibility, 64, 507
WCST (Wisconsin Card Sorting Test), 109, 507
Weakness, 100
brain tumors, 335
hypoxic-ischemic brain injury, 293–294, 300
neurotoxin exposure, 209, 215, 218
alcohol, 421
inhalants, 430
Wechsler Adult Intelligence Scale–IV (WAIS-IV), 105, 106, 110–111
Block Design subtest, 108, 111
Digit Span subtest, 72, 105, 109, 110, 455
Digit Symbol Coding subtest, 105
Information subtest, 106
Matrix Reasoning subtest, 111
normative data for, 103
Perceptual Reasoning Index, 111
Processing Speed Index, 105
Symbol Search subtest, 105
Verbal Comprehension Index, 111
Visual Puzzles subtest, 111
Vocabulary subtest, 106
Working Memory Index, 105
Wechsler Memory Scale, 107, 405
Weight changes
depression and, 537–538
drug-induced, 538
antidepressants
monoamine oxidase inhibitors, 357
trazodone, 357, 383
atomoxetine, 163
stimulants, 161
hyperthyroidism and, 360
pesticide-induced, 209
Wender-Reimherr Adult Attention Deficit Disorder Scale, 159
Wernicke’s area, 6, 7, 8, 13
Wernicke’s encephalopathy, 56, 420–421
West Nile virus (WNV) encephalitis, 328
Whipple’s disease, 322–324
clinical presentation of, 322–323
neuropsychiatric manifestations of, 323
treatment of, 324
White matter of brain, 4, 5
brain tumors and, 337, 346, 347
connections of, 10–12
on CT, 119, 120, 121, 123
deficits associated with dysfunction of, 11
visual field defects, 55
hypoxic-ischemic injury of, 291, 293, 297
MDMA effects on, 430
on MRI, 122, 124
in poststroke psychosis, 258, 518
regional cerebral blood flow and regional cerebral metabolic rate in, 128
toxoplasmosis in, 307
in traumatic brain injury, 268, 274
in vascular neurocognitive disorders, 134
WHO Collaborating Centre Task Force on Mild Traumatic Brain Injury, 276
Wilson’s disease, 30, 54, 520, 527, 534
Wisconsin Card Sorting Test (WCST), 109, 507
WMI (Working Memory Index), 105, 111
WNV (West Nile virus encephalitis), 328
Word Memory Test, 110
Working memory
neuropsychological tests, 105, 109
executive control of, 80, 109
orofacial, 11
brain tumors, 345
depression, 540
HIV disease, 305
schizophrenia, 508
hallucinogens, 430
inhalants, 431
stimulants, 424
viral meningitis, 324
white matter connections and, 11
Working Memory Index (WMI), 105, 111
Writer’s cramp, 60
Writing, 4, 14
assessment of, 107
fluency in, 74
handedness and, 49
impairment of, 73, 100 (See also Agraphia)
to reduce dementia risk, 494
Yakovlev, Paul, 2–3, 3

Yohimbine, 549, 556
Zaleplon, 383, 427

Zidovudine (AZT), 315
Zolpidem, 427
avoiding in Lewy body disorders, 472
for insomnia, 383
Zonisamide, 231
Zopiclone, 427
PLATE (Figure 1–1) Updated version of Yakovlev’s model of the nervous
system demonstrating the median zone (yellow), paramedian-limbic zone
(blue), and supralimbic zone (red).
Source. Based on Yakovlev and Lecours 1967.
PLATE 2. (Figure 1–2) Histological structure of six-layered neocortex in a 5-
year-old male (NeuN immunostain).
Roman numerals along each band correspond to the following layers: I–plexiform
(molecular); II–external granular; III–pyramidal; IV–internal granular; V–ganglionic;
VI–multiform (polymorphous).
Source. Micrograph courtesy of Bette K. Kleinschmidt-DeMasters, M.D., University
of Colorado School of Medicine.
PLATE 3. (Figure 1–3) Primary motor (green) and sensory (blue) cortex.
PLATE 4. (Figure 1–4) Unimodal association cortex (red).
PLATE 5. (Figure 1–5) Heteromodal association cortex (pink).
PLATE 6. (Figure 1–6) Brain dissection shows short corticocortical
connections and intrahemispheric connections.
PLATE 7. (Figure 1–7) Limbic and paralimbic cortex (purple).
PLATE 8. (Figure 1–8) Cortical projections from the thalamus (blue).
PLATE 9. (Figure 1–9) Organization of the prefrontal-subcortical circuits.
The prefrontal cortical regions (dorsolateral prefrontal, lateral orbitofrontal, and
anterior cingulate) project to specific striatal regions (green) that in turn project to
globus pallidus and substantia nigra (blue). These structures project to the
thalamic nuclei (in blue, projections from globus pallidus interna to thalamus and
from globus pallidus externa to subthalamic nucleus; (in green, from subthalamic
nucleus to globus pallidus interna) that subsequently connect to the frontal lobe
(green), completing the circuit.
PLATE 10. (Figure 1–10) Prefrontal cortical origins of the dorsolateral (blue),
anterior cingulate (pink), and lateral orbitofrontal (green) circuits.
PLATE 11. (Figure 1–11) Cholinergic projections from the nucleus basalis
(red).
PLATE 12. (Figure 1–12) Nigrostriatal and mesocortical dopaminergic
projections arising from the substantia nigra and ventral tegmental area,
respectively (green).
PLATE 13. (Figure 1–13) Noradrenergic projections from the locus
coeruleus (pink).
PLATE 14. (Figure 1–14) Serotonergic projections (blue).
PLATE 15. (Figure 4–1) Circuits.
There are three areas within the prefrontal cortex (PFC) that govern important
aspects of behavior via reciprocal connections with subcortical structures, thus
forming cortico-subcortical circuits. The dorsolateral PFC circuit (pink) mediates
executive functions such as organization, planning, and allocation of attention. The
orbitofrontal PFC circuit (blue) mediates socially appropriate behavior, impulse
control, and empathy. The anterior cingulate PFC circuit (green) contributes to
motivation by balancing the inhibitory input of the supplemental motor areas with
its own stimulus that supports wakefulness and arousal. Evidence supports the
participation of the cerebellum, although its functions still need further study. The
anterior cingulate PFC also participates in emotional and memory-related functions
as part of the circuit of Papez (gold). nuc=nucleus.
PLATE 16. (Figure 4–2) Computed tomography (CT) cases.
Intensity (brightness) in CT images is a function of tissue density. Dense tissues
such as bone and blood will appear white, indicating an almost complete
absorption of the X-rays (high attenuation). Brain tissues have intermediate
densities and so are shades of gray. CT provides excellent visualization of some
conditions, such as hemorrhage, and is the preferred imaging method for acute
head injury. CT is also useful when magnetic resonance imaging (MRI) is
contraindicated. (A) Middle-aged male with hyperdense subarachnoid
hemorrhage. (B) Middle-aged male with hyperdense subdural hematoma. (Case
contributed by David M. Keadle, M.D.) (C) Elderly male with isodense subdural
hematoma. (D) Bifrontal encephalomalacia in young adult male with retained
shrapnel (MRI contraindicated) and metallic artifact after exposure to improvised
explosive device. (E) Early-middle-aged male with significant generalized atrophy.
(F) Middle-aged male with old right frontal infarct, white matter ischemia, and
lacunar infarct (not well visualized on this slice). (G) and (H) Late-middle-aged
male with dilated ventricles/hydrocephalus. (I) Late-middleaged male (CT
angiogram, coronal) with anterior communicating artery aneurysm and dilated
ventricles. (Case contributed by Daniel C. Barr, M.D.)
PLATE 17. (Figure 4–3) Neuroimaging equipment.
Several aspects of neuroimaging equipment can be challenging for some patients
to tolerate. The patient’s head is commonly restrained to minimize movement, and
the patient must remain still once placed into the rather narrow bore of the
scanner. MRI=magnetic resonance imaging; PET=positron emission tomography.
PLATE 18. (Figure 4–4) Computed tomography (CT) versus magnetic
resonance imaging (MRI).
MRI provides better visualization of anatomy and usually of pathology than CT, as
illustrated by a clinical case of a late-middle-aged female with a history of two mild
traumatic brain injuries (TBIs). The only abnormality noted on the CT was mild
hypoattentuation in the periventricular white matter. Gliotic foci that are likely
residual from the TBIs are clearly visualized on T2W and fluid-attenuated inversion
recovery (FLAIR) MRI (yellow circles) but not on T1W or diffusion-weighted
imaging (DWI) MRI. Magnetic resonance angiography (MRA) indicated that the
vasculature was patent.
PLATE 19. (Figure 4–5) Magnetic resonance imaging (MRI) cases.
(A)–(C) Young adult male with multiple demyelinating lesions of the cortical and
subcortical white matter and corpus callosum that did not enhance on contrast
imaging. (Case contributed by Tammy Smith, Pharm.D.) (D) and (E) Middle-aged
male with significant encephalomalacia (arrow) and gliosis (arrowhead) of both
frontal lobes and the right temporal lobe (not pictured) from an assault a decade
prior. Patient now has anosmia and significant orbitofrontal function deficits. Note
that these two types of pathology are more easily distinguishable on (E) fluid-
attenuated inversion recovery (FLAIR) MRI than (D) T2W MRI. (F) Adult male with
encephalomalacia (arrow) and gliosis (arrowhead) in the midline frontal cortex due
to being hit on the occiput decades earlier. (G)FLAIR and (H) T1W postcontrast of
young adult male with 13.5-mm lesion in the medial right cerebellum, without
edema, hemorrhage, mass effect, or enhancement on contrast. Differential
includes low-grade astrocytoma or early oligodendroglioma. (I) Early-middle-aged
male with multiple areas of increased signal in the cortical white matter on FLAIR
MRI, consistent with diffuse axonal injury from multiple exposures to explosions.
PLATE 20. (Figure 4–6) An 18-fluoro-2-deoxyglucose positron emission
tomography ([18F]-FDG, FDG-PET) case.
Late-middle-aged male with cognitive and mood disorders after a frontoparietal
cerebrovascular accident. Note that the affected area in the high right frontal and
parietal lobes near the vertex is more fully visualized on axial FDG-PET
(decreased metabolism indicated by lighter area on grayscale and dark blue-
purple on pseudo color scale) than fluid-attenuated inversion recovery magnetic
resonance imaging (FLAIR MRI). Visualization on PET is improved by application
of a pseudo color scale and fusion with companion computed tomography. Three-
dimensional (3D) reconstructions can also improve visualization.
PLATE 21. (Figure 4–7) Single-photon emission computed tomography
(SPECT) cases.
Functional neuroimaging can provide insight into the etiology of cognitive decline,
illustrated here with SPECT imaging of (A–D) blood flow and (E and F) dopamine
transporter binding (DAT). (A and B) In neurocognitive disorder due to Alzheimer’s
disease, perfusion deficits are commonly symmetrical and focal in (A) early stage
with widespread progression in (B) late stage. (C) Abnormalities are more likely to
be asymmetrical and to involve occipital and subcortical areas in neurocognitive
disorder with Lewy bodies. (D) A characteristic finding early in neurocognitive
disorder due to Huntington’s disease is decreased perfusion in the basal ganglia,
particularly caudate. (E) In Parkinson’s disease, striatal DAT binding is reduced
(pseudo color scale) compared with (F) a healthy individual (grayscale). (DAT
cases contributed by Akiva Mintz, M.D., Ph.D., Wake Forest School of Medicine.)
PLATE 22. (Figure 4–8) Positron emission tomography (PET) cases.
Functional neuroimaging may provide insight into the etiology of cognitive decline,
illustrated here with axial PET imaging of glucose metabolism (18-fluoro-2-
deoxyglucose [18F]-FDG, FDG-PET) and of amyloid binding (amyloid PET). (A
and B) Early-middle-aged male with progressive deficits in activities of daily living
and inability to continue working because of cognitive decline. FDG-PET indicates
mildly decreased metabolic activity involving only bilateral parietotemporal
association cortices. (Case contributed by Djenaba Bradford-Kennedy, M.D.) Note
the normal uptake in other cortices, striatum, thalamus, and cerebellum. This
activity pattern is common in early-stage Alzheimer’s disease (AD). (C) Elderly
woman with multiple areas of high amyloid binding (orange-red) throughout cortex
on amyloid PET. This supports a diagnosis of AD. (D) In contrast, little amyloid
binding is present in this middle-aged male with temporal variant frontotemporal
dementia. (Amyloid PET cases contributed by Tiffany Chow, M.D.)
PLATE 23. (Figure 4–9) Brief guide to subcortical functional anatomy.
The approximate positions and configurations of the major subcortical structures
are color-coded onto simplified renditions of axial brain sections and a sagittal
rendition of the cerebrum and brain stem. The sagittal image is also a key to the
locations for the axial sections. Additional teaching cases and functional anatomy
reference materials can be found at www.mirecc.va.gov/visn6/Tools-Tips.asp.
PLATE 24. (Figure 12–1) Model of the interactions of preinjury factors, injury
factors and postinjury factors in relation to posttraumatic neuropsychiatric
disturbances. Source. Figure by David B. Arciniegas, M.D. © 2017. Used with
permission of the author.
PLATE 25. (Figure 15–1) Locations of benign and malignant brain tumors in
adults.
In adults, benign brain tumors dominate the meninges and pituitary region, but
most malignant tumors are located in the frontal and temporal lobes. Figures are
percentages and do not add up to 100 because of rounding. “Other” includes
tumors in the spinal cord, ventricles, pineal gland, olfactory mucosa, cerebrum,
and other unspecified or unclassified locations. Pituitary region=pituitary gland and
craniopharyngeal duct.
Source. Adapted from Ostrom et al. 2016.
PLATE 26. (Figure 18–1) Eroded brain images (radiological convention)

denoting semiautomatic brain region extraction with significantly greater
lesion loads in pseudobulbar affect compared with control multiple sclerosis
subjects.
Color legend: yellow=brain stem (bilateral) hypointense lesions; green=inferior
parietal (bilateral) hyperintense lesions; red=medial inferior frontal (bilateral)
hyperintense lesions; blue=superior frontal region (right) hyperintense lesions.
PLATE 27. (Figure 20–1) Gross pathology of Alzheimer’s disease.
Coronal pathological section of a patient with confirmed Alzheimer disease. The
section demonstrates hippocampal complex atrophy and dilatation of the temporal
horn of the lateral ventricle.
PLATE 28. (Figure 20–2) Amyloid plaques in the cerebral cortex of a patient
with Alzheimer’s disease.
The section is immunostained for β-amyloid, which appears as dark extracellular
granular material. The plaques are large compared with surrounding cellular
nuclei.
PLATE 29. (Figure 20–3) Neurofibrillary tangles (Bielschowsky silver stain)
in the cerebral cortex of a patient with Alzheimer disease.
Tangles (arrows) are intraneuronal and consist of collapsed cytoskeletal elements,
including characteristic paired helical filaments. Tangle development interferes with
normal neuronal function through loss of axonal transport and other vital
homeostatic mechanisms.
PLATE 30. (Figure 25–1) Common glucose metabolic positron emission
tomography findings in neurological and idiopathic depression.
Decreased prefrontal, dorsal cingulate, and temporal cortical metabolism is a
common finding across different depressive syndromes, including patients with
Parkinson’s disease, Huntington’s disease, and idiopathic unipolar depression.
PLATE 31. (Figure 25–2) Imaging data supporting role for Brodmann area
(BA) 25 in depression.
(top row) Decreased activity in the subgenual cingulate (BA25; Cg25) is a
consistent finding across numerous and diverse treatment studies. (bottom row)
Increased subgenual cingulate activity is associated with increased sadness, and
functional connectivity of this region during processing of emotional stimuli may be
mediated by genetics.
DBS=deep brain stimulation; ECT=electroconvulsive therapy; SERT=serotonin
transporter; SSRI=selective serotonin reuptake inhibitor; TMS=transcranial
magnetic stimulation.
Source. Adapted from Mayberg 2003.
PLATE 32. (Figure 25–3) A proposed model of mood regulation.
Different sets of brain regions are involved in different aspects of mood experience
and modulation. Numerous interconnections exist between these different regions,
and the system is recognized to be dynamic and potentially modulated at any
critical node. Different treatments for mood disorder syndromes may act primarily
at different nodes within the system with therapeutic downstream effects.
a-ins=anterior insula; amg=amygdala; aCg24b=Brodmann area 24b/dorsal-
perigenual anterior cingulate cortex; bstem=brain stem; CBT=cognitive-behavioral
therapy; cd-vst=ventral caudate–ventral striatum; DBS=deep brain stimulation of
Brodmann area 25; hc=hippocampus; hth=hypothalamus; mb-
sn=midbrain/subthalamic nuclei; mCg24c=Brodmann area 24c/dorsal anterior
cingulate cortex; MEDS=antidepressant medications; mF9/10=medial frontal
cortex; oF11=orbitofrontal cortex; Par40=dorsal parietal; pCg=posterior cingulate
gyrus; PF9/46=dorsolateral prefrontal cortex; PM6=premotor area;
rCg24a=Brodmann area 24a/perigenual-subgenual cingulate cortex;
sgCg25=Brodmann area 25/subgenual cingulate cortex; thal=thalamus.
PLATE 33. (Figure 26–1) Neuroanatomical model of generalized anxiety
disorder (GAD).
There is evidence of hypofunction and reduced volumes of ventral anterior
cingulate cortex (vACC) and inferior frontal gyrus (IFG), and hypofunction
dorsomedial prefrontal cortex (dmPFC). In contrast, areas of lateral prefrontal
cortex (LPFC) are hyperactive in GAD. The amygdala (AMY) has been reported to
be hypoactive or hyperactive across studies.
PLATE 34. (Figure 26–2) Neuroanatomical model of panic disorder.
There is substantial evidence of hyperactivation of the amygdala (AMY) and
insular cortex (INS), as well as preliminary evidence of reduced activity of ventral
anterior cingulate cortex (vACC) and reduced volume of orbitofrontal gyrus (OFG)
in panic disorder.
PLATE 35. (Figure 26–3) Neuroanatomical model of social anxiety disorder.
Hyperactivity of the amygdala (AMY) and insular cortex (INS) is consistently seen
in social anxiety disorder. Thus, far more specific to social anxiety is evidence for
hyperactive medial and lateral prefrontal cortex (PFC), posterior cingulate cortex
(PCC), and areas of parietal-occipital cortex including supramarginal gyrus (SMG)
and fusiform gyrus (FFG).
PLATE 36. (Figure 26–4) Neuroanatomical model of posttraumatic stress
disorder (PTSD).
Hyperactivity of the amygdala (AMY) and insular cortex (INS) are consistently
seen in PTSD, as well as hypoactivity of the ventromedial prefrontal cortex
(vmPFC) and ventral anterior cingulate cortex (vACC). The hippocampus (HIPPO)
is reduced in volume.

David B Arciniegas - The American Psychiatric Association Publishing Textbook of Neuropsychiatry and Clinical Neurosciences-American Psychiatric Association Publishing (2018)

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

David B Arciniegas - The American Psychiatric Association Publishing Textbook of Neuropsychiatry and Clinical Neurosciences-American Psychiatric Association Publishing (2018)

Uploaded by

Copyright:

Available Formats

The American Psychiatric Association Publishing

1 Neurobiological Bases of Cognition, Emotion,

5 Diagnostic Neurophysiology in Neuropsychiatry

7 Autism Spectrum Disorder Throughout the Life

9 Poisons and Toxins

10 Epilepsy and Seizures

12 Traumatic Brain Injury

13 Hypoxic-Ischemic Brain Injury

17 Sleep and Sleep-Wake Disorders

19 Alcohol and Other Substance Use Disorders

Karen E. Anderson, M.D.

David B. Arciniegas, M.D.

David L. Bachman, M.D.

Nash N. Boutros, M.D.

Lisa A. Brenner, Ph.D.

Anil Chacko, Ph.D.

David K. Chen, M.D.

C. Edward Coffey, M.D.

Kerry L. Coburn, Ph.D.

Jeffrey L. Cummings, M.D., Sc.D.

Richard De La Garza II, Ph.D.

Marie A. DeWitt, M.D.

Sarah E. Dreyer-Oren, B.A.

Christopher M. Filley, M.D.

Laura A. Flashman, Ph.D., ABPP

James E. Galvin, M.D., M.P.H.

David S. Geldmacher, M.D.

Omar Ghaffar, M.D., M.Sc., FRCPC

Tina Gurnani, M.D.

Colin N. Haile, M.D., Ph.D.

Robert E. Hales, M.D., M.B.A.

Paul E. Holtzheimer III, M.D., M.S.

Robin A. Hurley, M.D., FANPA

Ricardo Jorge, M.D.

Joseph S. Kass, M.D., J.D.

Geoffrey A. Kerchner, M.D., Ph.D.

Cynthia Y. King, M.D.

Thomas R. Kosten, M.D.

W. Curt LaFrance Jr., M.D., M.P.H.

Marissa C. Natelson Love, M.D.

Nicholas J. Milano, M.D.

Larry D. Mitnaul Jr., M.D., M.P.H., M.S.

Charles B. Nemeroff, M.D., Ph.D.

Jeffrey H. Newcorn, M.D.

Thomas F. Newton, M.D.

Fred Ovsiew, M.D.

Alicia S. Parker, M.D.

Shiv S. Patel, M.D.

Scott L. Rauch, M.D.

Alya Reeve, M.D., M.P.H.

Joshua J. Rodgers, M.D.

Alasdair G. Rooney, M.B.Ch.B., M.D.

Michael H. Rosenbloom, M.D.

Isabelle M. Rosso, Ph.D.

Maria Rueda-Lara, M.D.

Rohini D. Samudralwar, M.D.

Melanie Selvadurai, B.H.Sc., M.B.A.

Mohammed Sheikh, M.D.

Samuel D. Shillcutt, Pharm.D., Ph.D.

Jonathan M. Silver, M.D.

Jeremy D. Slater, M.D.

Sergio Starkstein, M.D., Ph.D.

Dan J. Stein, M.D., Ph.D.

Katherine Taber, Ph.D., FANPA