@MBS MedicalBooksStore 2018 The PDF

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
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views of the individual authors and do not necessarily represent the policies and opinions of American
Psychiatric Association Publishing or the American Psychiatric Association.
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Copyright © 2018 American Psychiatric Association Publishing
ALL RIGHTS RESERVED
Sixth Edition
Manufactured in the United States of America on acid-free paper
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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
Ricardo Jorge, M.D.
Disorders
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.
14 Infectious Diseases of the Central Nervous 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.
T h e 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):
T h e 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
T h e 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
T h e 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
T h e second superior longitudinal fasciculus (SLF-II) connecting the
caudal inferior parietal lobule and posterior prefrontal cortices in the
service of spatial attention
T h e 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
T h e 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

NeuropsychiatricLimbic 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
orbitofrontal cortex disease, 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 PTSD
medial 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,
a nd 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 Right
to 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, Learning and memory
laterodorsal retrosplenial 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 Parietal sensory cortex Somatosensory function
posterolateral from body
Ventral Sensory tracts Parietal sensory cortex Facial sensation
posteromedial from 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 Striatum, cortex Activation
formation,
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.
T h e 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 No No Yes Yes Yes
syndrome
Lateral orbitofrontal Yes Yes Yes Yes No
syndrome
Anterior cingulate Yes Yes Yes Yes Yes
syndrome
Caudate disorders
Parkinson’s disease Yes No Yes No Yes
Progressive supranuclear Yes No Yes Yes Yes
palsy
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 Yes Yes Yes Yes Yes
Parkinson’s 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 Hallucinations, delusions, elation,
inattention), apathy, depression obsessive-compulsive behavior,
paraphilias
GABA Seizures, anxiety Amnesia, incoordination, sedation
Glutamate Cognitive impairment (especially amnesia), Seizures, excitotoxicity
psychosis, apathy
Norepinephrine Cognitive impairment (especially Anxiety
inattention), 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 α 1 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-HT 1, 5-HT2, 5-HT4) and to a lesser extent by
ionotropic receptors (i.e., 5-HT 3). 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 system Functional Emotion; Neuropsychiatric
limbic and basal ganglia within extrapyramidal disorders;
first few function movement
months disorders
Supralimbic- Complete Parallel; neocortex Functional in Instrumental Neurobehavioral
neocortical adulthood cognitive disorders
functions (e.g.,
language,
praxis)
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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
t he 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
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.
I n 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.
I n 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.
I n 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
Ex ce s s i v e 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

Abnormal
Primitive reflexes Examination maneuver Normal response response
Glabellar Examiner taps 10 times on the glabella Blinking in Partial or full
(area just above and between response to blinking in
eyebrows) at rate of one per second. first few taps response to
then habituation each tap
and no further
blinks
Grasp Examiner places two fingers in patient’s No grasp Patient grasps
hand and strokes across palm or along examiner’s
fingers. fingers
Self-grasp Examiner grasps patient’s arm and, with No grasp Patient grasps own
webbing between the patient’s thumb contralateral
and fingers as the point of contact, forearm
strokes the patient’s contralateral ulnar
surface.
Foot grasp Examiner places his or her hand on the No response Plantar flexion and
plantar surface of the distal part of the adduction of
patient’s foot and toes. the toes
Palmomental Examiner strokes palm from lateral aspect No movement Ipsilateral mentalis
of hypothenar eminence to thenar (chin) muscle
eminence. contracts
Rooting Examiner uses his finger to stroke No movement Patient turns head
patient’s cheek (from mouth toward toward side
temporomandibular joint). being stroked
Snout Examiner uses his or her finger to lightly No movement Lips pucker
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 gloved knuckle between No movement Sucking motion
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 behavior Arousal, apparent age, body habitus and other 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 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.
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).
T h e 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
I n 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.
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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 language Dysarthria
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)
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,
a s 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.
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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
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
( s e e 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
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.
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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
o f 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.
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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.
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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
t h i s 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.
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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
5 0 0 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 awareness Clouding of consciousness
Develops over a short period of time Disturbance of cognition, with impairment
(represents a change from baseline) of both immediate recall and recent
memory (but relatively intact remote
memory) and disorientation
Tends to fluctuate in severity over the Rapid onset and fluctuations of symptoms
course of a day over the course of the day
Secondary features Disturbance in cognition Psychomotor disturbance
Evidence that the disturbance is a direct Disturbance of sleep or the sleep-wake
physiological consequence of another cycle
medical condition or substance/toxin Evidence of an underlying cerebral or
intoxication or withdrawal, or is due to systemic disease that can be presumed
multiple etiologies to be responsible for the manifestations
Exclusions Not better explained by another preexisting Not induced by alcohol and other
or evolving neurocognitive disorder psychoactive substances
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
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.
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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?
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., glyphosate) Anxiety, irritability, tremulousness, parkinsonian
features
Carbamates (e.g., carbaryl) Headache, nausea, giddiness, blurred vision, weakness,
increased sweating, vomiting, miosis, delayed
neuropathy
Organophosphates (e.g., chlorpyrifos) Mild: Weakness, headache, 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 disturbance, forgetfulness,
(trimethyltin) 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.
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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
A n 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
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 seizure clusters >30 Common Rare
minutes
Seizures in the presence of doctors Common Unusual
Multiple unexplained physical symptoms, Common Rare
such as unexplained “chronic pain”
Multiple operations/invasive procedures Common Rare
Seizure onset at <10 years of age Uncommon Common
Distinguishing semiological
features
Slowly evolving seizure onset Common Rare
Undulating motor activity Common Very rare
Closed eyelid during seizure onset Very common Rare
Resistance to eyelid opening Common Very rare
Asynchronous limb movements Common Rare
Side-to-side head shaking Common Rare
Severe tongue biting (side) Rare Common after GTC
Stertorous breathing postictally Not present Common after GTC
Postictal nose rubbing Not present Occurs in TLE
Ictal grasping (gripping of an object with Rare Occurs in FLE and TLE
one hand or 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.
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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
t h e 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.
Lesion Location as a Risk Factor for Poststroke 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.
Lesion Location as a Risk Factor for Poststroke 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.
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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 mild ≤0.5 ≤1 ≤1 13–15 Abnormal
Moderate >0.5 to <24 >1 to <7 >1 9–12 Normal or
abnormal
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-
I D ; 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 therapeutic trial Although patients with brain injuries may be more 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 reassessment The need for continued treatment should be 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 interactions Because patients with brain injuries are often 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 intensification If target psychiatric symptoms worsen after initiation 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,
a nd 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.
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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 (hypoxic) Low P a02 Low O2 tension in High-altitude location
hypoxia inspired air Near-suffocation in
Normal blood oxygen-
binding capacity enclosed space
Normal perfusion Choking on foreign object
Normal end-tissue oxygen Tracheal collapse
extraction capacity
Diffusion impairment Inhalation of water (near
drowning)
Severe pulmonary edema
Alveolar ventilation- Pulmonary embolism
perfusion mismatch Chronic obstructive
pulmonary disease
Venous-to-arterial shunts Vessel-to-vessel or
intracardiac shunts
Anemic (hypemic) Normal P a02 Reduced hemoglobin or Bone marrow failure
hypoxia blood cells Hemorrhage
Reduced blood oxygen-
binding capacity
Normal perfusion Interference with the Methemoglobinemia due
Normal end-tissue oxygen binding of oxygen to to carbon monoxide
extraction capacity hemoglobin poisoning, including
cigarette smoking
Ischemic (stagnant) Normal or low P a02 Insufficient blood flow Severe hypotension
hypoxia Normal P a02 Focal ischemia
Normal blood oxygen-
binding capacity Global ischemia due to
Reduced perfusion near-strangulation
Normal end-tissue oxygen Low cardiac output
extraction capacity
Low P a02 Cardiopulmonary arrest
Histotoxic hypoxia Normal P a02 Blockade of Cyanide poisoning
mitochondrial
Reduced blood 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
a n d 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 conscious Present Present Present
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.
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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
t h e 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 D 2 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.
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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.
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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
t a k i ng 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
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.
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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
Neurotransmitter Nuclei Target Wake NREM REM
Monoaminesa PAG, TMN, LC, D/MR Diffuse cortex; ++ + −
TMN→VLPO
nucleus
Acetylcholine PPT, LDT Diffuse cortex ++ − ++
Orexin Lateral hypothalamus Throughout CNS; ++ − ++
ARAS; cortex
GABA, galanin VLPO nucleus TMN; lateral − ++ +
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
t he 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/m 2 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

Half-life
Medication class Medication (hr) Dose (mg) Significant adverse effects
Benzodiazepines Temazepam 8–20 15–30 Sleep architecture changes.
(BZDs) Residual sedation, amnesia,
abuse potential, automatic
behavior in sleep, falls, dizziness,
cognitive effects
Non-BZD BZD- Zaleplon 1 5–20 Sleep architecture changes.
receptor agonists 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, dizziness
agonists
Ramelteon 0.8–2 8
Sedating Trazodone 7–15 25–150 Dizziness, orthostatic hypotension,
antidepressants 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 behavior, cataplexy-like
antagonists 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-conducive Keep the room dark and quiet (white noise is OK). Sleep hygiene
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 bedtime, wake Sleep hygiene
rhythm entrainment time, eating, and activities.
Get bright light in the morning and avoid bright light at Phototherapy
night (including TV and computer screens); use a
night-light (low light) if needed at night.
Increase drive for sleep Get regular daytime exercise and avoid exercise at Stimulus control, sleep
at night night. restriction, cognitive
Consolidate sleep at night and avoid taking naps therapies
during the day.
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 insomnia Use the bed for sleep (no TV, eating, or worrying Stimulus control, sleep
allowed). restriction, cognitive
therapies
Sleep when tired.
If awake >20 minutes, get up, do something
nonstimulating, and return to bed when tired.
Relax, reduce autonomic Have a relaxing bedtime routine. Relaxation training,
arousal Make a list of problems or worries for later. hypnosis,
biofeedback,
Avoid stressful or anxiety-provoking conversations
mindfulness
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, H 1 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.
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__________________
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)
Clinical presentation Additional data needed for MS 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 lesion Await a further clinical attacka implicating a different
CNS site
1. 1 attacka Dissemination in time, demonstrated by:
2. Objective clinical evidence of ≥2 lesions Simultaneous presence of 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 lesion (clinically For DIS:
isolated syndrome)
≥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 suggestive of MS 1 year of disease progression (retrospectively or
(PPMS) 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
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
b y 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
Executive function refers to a complex set of processes that 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.
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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, VMAT2, Induces NE and DA presynaptic release;
MAO 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 agonist Increase DA release by disinhibition of
inhibitory GABAergic neurons through μ
receptors.
Cannabis CB1 receptor agonist Increases DA by disinhibition of VTA DA
neurons through CB1 receptors on
GABAergic neurons.
Hallucinogens 5-HT2A receptor agonist Hallucinogenic effects are mediated through
stimulation of 5-HT2A receptors; bind
(numerous other targets)
directly to all DA receptor subtypes;
partial agonist at DA1 and DA2
receptors.
Caffeine Adenosine A2A antagonist A2A receptor 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
ha s 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
( MA S T; 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.
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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

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. N o 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 processing Impaired directed attention Early
Poor object or person recognition Late
Spatial confusion Late
Executive function Poor planning Early
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
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. 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 auditory) Late
Mood disorders Depression Early
Anxiety Early
Agitation Nonspecific motor behaviors, including wandering Late
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.
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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 dementia) Pick’s disease
Alzheimer’s disease (particularly autosomal dominant Creutzfeldt-Jakob disease
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
Condition Executive Attention and Visuospatial and Language and
functioning concentration 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).
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, generalized Maximal in temporoparietal cortex
disease cortical atrophy evolves over time
Parkinson’s Minimal to no significant cortical or Normal or minimally abnormal
disease hippocampal atrophy
Parkinson’s Minimal to no significant cortical or Maximal in frontoparieto- occipital cortex
disease with hippocampal atrophy
dementia
Dementia with Minimal to no significant cortical or Maximal in parieto-occipital cortex
Lewy bodies hippocampal 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.
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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

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).
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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
Behavioral-variant FTD Behavioral Deficits in Right-hemispheric Motor neuron
disinhibition executive frontal and/or disease
Apathy or inertia tasks anterior (10%–15%)
Loss of sympathy Relative temporal Parkinsonism
or empathy preservation of atrophy, (20%) or
memory and particularly supranuclear
Early
perseverative, visuospatial involving the gaze
stereotyped, or function orbitofrontal, disturbance
compulsive insular, and (less
ritualistic anterior common)
behaviors cingulate
Hyperorality cortices
Nonfluent/agrammatic- Progressive Agrammatism Left posterior Right hemibody
variant primary expressive Inconsistent fronto- insular apraxia,
progressive aphasia aphasia speech sound atrophy on parkinsonism,
characterized errors and structural MRI dystonia,
by slow, distortions and Left posterior alien limb
effortful apraxia of fronto- insular Progression to
speech with speech SPECT corticobasal
decreased Impaired hypoperfusion syndrome or
output; comprehension or PET progressive
dysarthria; and of syntactically hypometabolism supranuclear
progression to complex palsy
mutism sentences
Spared single-
word
comprehension
and object
knowledge
Relative
preservation of
memory and
visuospatial
function
Semantic-variant primary Left predominant Left predominant Asymmetric left Less common
progressive aphasia Word-finding Impaired and/or right
difficulties confrontational anterior and
Comprehension naming lateral temporal
difficulties Impaired single- atrophy on
Right predominant word structural MRI
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.
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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.
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

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
o f 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.
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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.
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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

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.
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________________
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.

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The American Psychiatric Association Publishing

1 Neurobiological Bases of Cognition, Emotion, and Behavior

5 Diagnostic Neurophysiology in Neuropsychiatry

7 Autism Spectrum Disorder Throughout the Life Span

9 Poisons and Toxins

10 Epilepsy and Seizures

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

12 Traumatic Brain Injury

13 Hypoxic-Ischemic Brain Injury

14 Infectious Diseases of the Central Nervous System

19 Alcohol and Other Substance Use Disorders

21 Neurocognitive Disorders With Lewy Bodies: DEMENTIA WITH LEWY

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.

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Marie A. DeWitt, M.D.

Shreenath V. Doctor, M.D., D.D.S., Ph.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

Ali S. Gonul, M.D.

Tina Gurnani, M.D.

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

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

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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.

Robert M. Roth, Ph.D., ABPP

Rohini D. Samudralwar, M.D.

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

Mohammed Sheikh, M.D.

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