The American Psychiatric Association Publishing Textbook of Neuropsychiatry and Clinical Neurosciences [6 ed.] 2018012379, 2018012739, 9781615371877, 9781585624874

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The American Psychiatric Association Publishing

TEXTBOOK OF NEUROPSYCHIATRY and CLINICAL NEUROSCIENCES

SIXTH EDITION

The American Psychiatric Association Publishing

TEXTBOOK OF NEUROPSYCHIATRY and CLINICAL NEUROSCIENCES SIXTH EDITION

EDITED BY David B. Arciniegas, M.D. Stuart C. Yudofsky, M.D. Robert E. Hales, M.D., M.B.A.

Note: The authors have worked to ensure that all information in this book is accurate at the time of publication and consistent with general psychiatric and medical standards, and that information concerning drug dosages, schedules, and routes of administration is accurate at the time of publication and consistent with standards set by the U.S. Food and Drug Administration and the general medical community. As medical research and practice continue to advance, however, therapeutic standards may change. Moreover, specific situations may require a specific therapeutic response not included in this book. For these reasons and because human and mechanical errors sometimes occur, we recommend that readers follow the advice of physicians directly involved in their care or the care of a member of their family. Books published by American Psychiatric Association Publishing represent the findings, conclusions, and views of the individual authors and do not necessarily represent the policies and opinions of American Psychiatric Association Publishing or the American Psychiatric Association. If you wish to buy 50 or more copies of the same title, please go to www.appi.org/specialdiscounts for more information. Copyright © 2018 American Psychiatric Association Publishing ALL RIGHTS RESERVED Sixth Edition Manufactured in the United States of America on acid-free paper 22 21 20 19 18  5 4 3 2 1 American Psychiatric Association Publishing 800 Maine Ave. SW Suite 900 Washington, DC 20024-2812 www.appi.org Library of Congress Cataloging-in-Publication Data Names: Arciniegas, David B. (David Brian), 1967- editor. | Yudofsky, Stuart C., editor. | Hales, Robert E., editor. | American Psychiatric Association Publishing, publisher. Title: The American Psychiatric Association Publishing textbook of neuropsychiatry and clinical neurosciences / edited by David B. Arciniegas, Stuart C. Yudofsky, Robert E. Hales. Other titles: American Psychiatric Publishing textbook of neuropsychiatry and behavioral neurosciences. | Textbook of neuropsychiatry and clinical neurosciences | Neuropsychiatry and clinical neurosciences Description: Sixth edition. | Washington, DC : American Psychiatric Association Publishing, [2018] | Preceded by The American Psychiatric Publishing textbook of neuropsychiatry and behavioral neurosciences / edited by Stuart C. Yudofsky, Robert E. Hales. 5th ed. c2008. | Includes bibliographical references and index.

Identifiers: LCCN 2018012379 (print) | LCCN 2018012739 (ebook) | ISBN 9781615371877 (ebook) | ISBN 9781585624874 (hc : alk. paper) Subjects: | MESH: Mental Disorders | Nervous System Diseases—psychology |Diagnostic Techniques, Neurological | Neuropsychiatry—methods Classification: LCC RC341 (ebook) | LCC RC341 (print) | NLM WM 140 | DDC 616.8—dc23 LC record available at https://lccn.loc.gov/2018012379 British Library Cataloguing in Publication Data A CIP record is available from the British Library.

Contents Contributors Preface

1

Neurobiological Bases of Cognition, Emotion, and Behavior David B. Arciniegas, M.D. C. Edward Coffey, M.D. Jeffrey L. Cummings, M.D., Sc.D.

2

Neuropsychiatric Assessment Fred Ovsiew, M.D. David B. Arciniegas, 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 10

Poisons and Toxins Shreenath V. Doctor, M.D., D.D.S., Ph.D.

Epilepsy and Seizures David K. Chen, M.D. W. Curt LaFrance Jr., M.D., M.P.H.

11

Cerebrovascular Disorders Ricardo Jorge, M.D. Sergio Starkstein, M.D., Ph.D.

12

Traumatic Brain Injury Hal S. Wortzel, M.D. Lisa A. Brenner, Ph.D. Jonathan M. Silver, M.D.

13

Hypoxic-Ischemic Brain Injury C. Alan Anderson, M.D. David B. Arciniegas, 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

16

Endocrine Disorders

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

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

23

Frontotemporal Dementia

Karen E. Anderson, M.D.

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 C. Alan Anderson, M.D. 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 Karen E. Anderson, M.D. Associate Professor, Psychiatry University, Washington, D.C.

and

Neurology,

Georgetown

David B. Arciniegas, M.D. 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 David L. Bachman, M.D. Professor Emeritus, Department of Neurology, Medical University of South Carolina, Charleston Nash N. Boutros, M.D. Professor and Chairman, Department of Psychiatry, University of Missouri, Kansas City, Missouri Lisa A. Brenner, Ph.D. 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 C. Edward Coffey, M.D. Professor of Psychiatry and Neurology, Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas Kerry L. Coburn, Ph.D. Professor of Psychiatry and Neurology, Department of Psychiatry and Behavioral Sciences, Mercer University School of Medicine, Macon, Georgia Jeffrey L. Cummings, M.D., Sc.D. Director, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, Nevada Richard De La Garza II, Ph.D. Professor, Department of Psychiatry, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, Texas Marie A. DeWitt, M.D. Program Director, Geriatric Psychiatry Fellowship Program; Assistant Clinical Professor, Wayne State University School of Medicine; Staff Psychiatrist, John Dingell VA Medical Center, Detroit, Michigan

Shreenath V. Doctor, M.D., D.D.S., Ph.D. Private Practice of Neuropsychiatry, Bellaire, Texas Sarah E. Dreyer-Oren, B.A. Graduate Student, Department of Psychology, Miami University, Oxford, Ohio Christopher M. Filley, M.D. 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 Laura A. Flashman, Ph.D., ABPP Professor of Psychiatry, Neuropsychology Program, Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire James E. Galvin, M.D., M.P.H. 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 David S. Geldmacher, M.D. Warren Family Endowed Chair in Neurology and Director, Division of Memory Disorders and Behavioral Neurology, Department of Neurology, University of Alabama at Birmingham Omar Ghaffar, M.D., M.Sc., FRCPC 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 Colin N. Haile, M.D., Ph.D. 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 Robert E. Hales, M.D., M.B.A. Distinguished Professor of Clinical California, Davis School of Medicine

Psychiatry,

University

of

Paul E. Holtzheimer III, M.D., M.S. Associate Professor of Psychiatry and Surgery and Director of Mood Disorders Service, Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire Robin A. Hurley, M.D., FANPA 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 Joseph S. Kass, M.D., J.D. 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 Geoffrey A. Kerchner, M.D., Ph.D. Adjunct Clinical Associate Professor of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California Cynthia Y. King, M.D. Associate Professor of Psychiatry, University of New Mexico, Albuquerque Thomas R. Kosten, M.D. J.H. Waggoner Professor, Department of Psychiatry, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, Texas W. Curt LaFrance Jr., M.D., M.P.H. 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 Marissa C. Natelson Love, M.D. Assistant Professor, Department of Neurology, University of Alabama at Birmingham Nicholas J. Milano, M.D.

Assistant Professor, Department of Neurology, Medical University of South Carolina, Charleston Larry D. Mitnaul Jr., M.D., M.P.H., M.S. 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 Charles B. Nemeroff, M.D., Ph.D. 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 Jeffrey H. Newcorn, M.D. Associate Professor of Psychiatry and Pediatrics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York Thomas F. Newton, M.D. Professor, Department of Psychiatry, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, Texas Fred Ovsiew, M.D. Professor of Clinical Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois Alicia S. Parker, M.D. 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 Scott L. Rauch, M.D. 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 Alya Reeve, M.D., M.P.H. Emeritus Professor of Psychiatry, University of New Mexico, Albuquerque; Medical Director, United Counseling Service, Bennington, Vermont Joshua J. Rodgers, M.D. Assistant Professor of Psychiatry and Behavioral Sciences, Baylor College of Medicine; Staff Psychiatrist, The Menninger Clinic, Houston, Texas Alasdair G. Rooney, M.B.Ch.B., M.D. ST6 in General Adult Psychiatry, NHS Lothian; Honorary Fellow, University of Edinburgh, Edinburgh, Scotland Michael H. Rosenbloom, M.D. Clinical Director, HealthPartners Center for Memory and Aging and Chair HealthPartners, Department of Neurology; Assistant Professor of Neurology, University of Minnesota, Saint Paul Isabelle M. Rosso, Ph.D. Director, Anxiety and Traumatic Stress Disorders Laboratory, McLean Hospital, Belmont, Massachusetts

Robert M. Roth, Ph.D., ABPP Associate Professor of Psychiatry, Neuropsychology Program, Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire Maria Rueda-Lara, M.D. Assistant Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Leonard M. Miller School of Medicine, University of Miami, Florida Rohini D. Samudralwar, M.D. Fellow, Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine in St. Louis, St. Louis, Missouri Melanie Selvadurai, B.H.Sc., M.B.A. 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 Mohammed Sheikh, M.D. Clinical Trials Coordinator, Center for Cognitive Neurology, NYU Langone Medical Center, New York Samuel D. Shillcutt, Pharm.D., Ph.D. Professsor, Department of Psychiatry and Behavioral Sciences, Mercer University School of Medicine, Macon, Georgia Jonathan M. Silver, M.D. Clinical Professor of Psychiatry, New York University School of Medicine, New York Jeremy D. Slater, M.D.

Professor, Department of Neurology and Kraft W. Eidman Development Board Professor in the Medical Sciences, University of Texas Houston Medical School, Houston, Texas Sergio Starkstein, M.D., Ph.D. Professor of Psychiatry and Clinical Neurosciences, The University of Western Australia, Crawley, Western Australia, Australia Dan J. Stein, M.D., Ph.D. Professor and Chair, Department of Psychiatry, University of Cape Town, Cape Town, South Africa Katherine Taber, Ph.D., FANPA 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 Sudha Tallavajhula, M.D. 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 Fadi M. Tayim, Ph.D. Postdoctoral Fellow in Neuropsychology, Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire Larry E. Tune, M.D., M.A.S. Professor, Department of Psychiatry and Behavioral Sciences and Department of Neurology, Emory University School of Medicine, Atlanta, Georgia

Steven Paul Woods, Psy.D. Professor, Department of Psychiatry, Michael E. DeBakey VAMC and Baylor College of Medicine, Houston, Texas Hal S. Wortzel, M.D. 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 Stuart C. Yudofsky, M.D. 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, doubleblind, placebo-controlled multicenter study of two potential diseasemodifying 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, parallelgroup, Bayesian adaptive randomization design and dose regimenfinding 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: Evidencebased 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: David B. Arciniegas, M.D. David L. Bachman, M.D. Lisa A. Brenner, Ph.D. Anil Chacko, Ph.D. David K. Chen, M.D. Kerry L. Coburn, Ph.D. Marie A. DeWitt, M.D. Richard De La Garza II, Ph.D. Shreenath V. Doctor, M.D., D.D.S., Ph.D. Christopher M. Filley, M.D. James E. Galvin, M.D., M.P.H. Omar Ghaffar, M.D., M.Sc., FRCPC Tina Gurnani, M.D. Colin N. Haile, M.D., Ph.D. Robert E. Hales, M.D., M.B.A. Ricardo Jorge, M.D. Joseph S. Kass, M.D., J.D. Geoffrey A. Kerchner, M.D., Ph.D. Cynthia Y. King, M.D. Thomas R. Kosten, M.D.

Nicholas J. Milano, M.D. Larry D. Mitnaul Jr., M.D., M.P.H., M.S. Alicia S. Parker, M.D. Alya Reeve, M.D., M.P.H. Joshua J. Rodgers, M.D. Alasdair G. Rooney, M.B.Ch.B., M.D. Isabelle M. Rosso, Ph.D. Maria Rueda-Lara, M.D. Rohini D. Samudralwar, M.D. Melanie Selvadurai, B.H.Sc., M.B.A. Mohammed Sheikh, M.D. Jeremy D. Slater, M.D. Sergio Starkstein, M.D., Ph.D. Sudha Tallavajhula, M.D. Larry E. Tune, M.D., M.A.S. Stuart C. Yudofsky, 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 Robert E. Hales, M.D., M.B.A.

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 David B. Arciniegas, M.D. C. Edward Coffey, M.D. Jeffrey L. Cummings, M.D., Sc.D.

That brain and behavior are inseparable and that mental events are brain events are the physicalist philosophical foundations of neuropsychiatry (Arciniegas et al. 2006). Biological, social, and environmental factors, as well as their reciprocal interactions, are appreciated as influences on brain function in health and disease, and neuropsychiatrists recognize all of these factors as necessary elements of any account of mental (i.e., neuropsychiatric) function. Their influences on cognition, emotion, and behavior and the combined mechanisms by which they engender neuropsychiatric disorders, however, are understood and described in terms of their effects on brain structure and function. The Joint Advisory Committee on Subspecialty Certification of the American Neuropsychiatric Association and the Society for Behavioral and Cognitive Neurology (Arciniegas et al. 2006) directs subspecialists in Behavioral Neurology & Neuropsychiatry (BNNP) to elicit and construct comprehensive patient histories that emphasize neurodevelopmental and environmental influences on cognition, emotion, behavior, and elementary neurological function. Clinical assessment of these neuropsychiatric functions requires that practitioners understand brain-behavior relationships and possess the assessment skills needed to apply that understanding in clinical practice. The clinical assessment in BNNP employs, and is made systematic by, the use and interpretation of standardized, validated, and reliable metrics of neuropsychiatric function. Neuropsychological testing, neuroimaging, and electrophysiological and other laboratory measures that clarify the structural and functional neuroanatomy of illness, refine differential diagnostic considerations, and inform prognosis, treatment selection, and treatment response expectations are also employed, where appropriate (see Chapters 2 through 5). Interpreting clinical signs, symptoms, and syndromes in relation to structural and functional neuroanatomy (i.e., the neurobiological bases of behavior) therefore supersedes conventional (i.e., Diagnostic and Statistical Manual of Mental Disorders [DSM]–based) psychiatric diagnoses. This neuropsychiatric approach to clinical assessment and treatment is designed to avoid the practice of “mindless neurology” and “brainless psychiatry” that was pervasive during much of the twentieth century (Abraham 1999). It also eschews the historical dichotomization of clinical conditions into strict “psychiatric” or “neurological” types in favor of a more integrative approach. A comprehensive account of neuropsychiatric health and disease therefore demands a detailed understanding of the neurobiological bases of cognition, emotion, and behavior. A life span, or neurodevelopmental, perspective adds another dimension to understanding behavior: brain structure and function change dramatically with age—from fetal development through

infancy, childhood, adolescence, adulthood, and old age. Physiological functions vary more widely in elderly people than in young people, tolerance of injury and potential for recovery are diminished in elderly patients, and the neurobehavioral consequences of brain dysfunction often differ as a function of the age of the patient. This chapter is intended to introduce readers of this volume to the neuroanatomical and neurochemical bases of cognition, emotion, and behavior. First, we present a synoptic model of behavioral neuroanatomy as a framework for the remaining discussion. The model divides the nervous system into three behaviorally relevant zones: an inner zone surrounding the ventricular system, a middle zone encompassing the basal ganglia and limbic system, and an outer zone composed primarily of the neocortex. We present the anatomy of each zone and describe the behavioral consequences of injury to each. Next, we describe two distributed systems; these cross the three zones to allow information to enter the brain (thalamocortical system) and allow impulses mediating action to exit the brain (frontal-subcortical circuits). We also present neuropsychiatric syndromes associated with abnormalities of these systems. Finally, we integrate the biochemical bases of neuropsychiatric function with structural and functional neuroanatomy. Readers seeking complementary and comprehensive syntheses of this information intended specifically for subspecialists in BNNP are referred to recent reviews (Arciniegas et al. 2013; Hart 2016).

A Model of Behavioral Neuroanatomy Paul Yakovlev developed a comprehensive model of the nervous system in terms relevant to behavior (Yakovlev 1948, 1968; Yakovlev and Lecours 1967). He adopted an evolutionary perspective and noted that the brain consists of three general regions: a median zone surrounding the ventricular system, containing the hypothalamus and related structures; a paramedian-limbic zone consisting primarily of limbic system structures, basal ganglia, and parts of the thalamus; and a supralimbic zone containing the neocortex. In this chapter, we present the Yakovlev approach—updated with information from more recent anatomical studies (Benarroch 1997; Filley 2012; Hart 2016; Mesulam 2000)—as a foundation for understanding brain-behavior relationships (Figure 1–1). The median zone is immediately adjacent to the central canal, is poorly myelinated, and has neurons with short axons that synapse on nearby cells, as well as on cells with longer axons that project to more distant nuclei. The median zone contains the hypothalamus, medial thalamus, and periventricular gray matter of the brain stem as well as functionally related areas of the amygdala and insular cortex. The system mediates energy metabolism, homeostasis, peristalsis, respiration, and circulation. The median zone contains the reticular activating system and the thalamocortical projections that maintain consciousness and arousal in the awake state and that participate in sleep initiation and maintenance. No lateralization of function is evident in the median zone. This system is fully functional at birth and is responsible for the early survival of the infant.

FIGURE 1–1. Updated version of Yakovlev’s model of the nervous system demonstrating the median zone (yellow), paramedian-limbic zone (blue), and supralimbic zone (red). See Plate 1 to view this image in color. Source. Based on Yakovlev and Lecours 1967.

The paramedian-limbic zone contains neurons that are more fully myelinated than those of the median zone. Neurons here are grouped in nuclear structures that are connected in series. Many of the thalamic nuclei, the basal ganglia, cingulate gyrus, insula, orbitofrontal region, hippocampus, and parahippocampal gyri are included in this zone. The paramedian-limbic zone includes the structures composing the limbic system (Papez 1937). Structures of this zone mediate posture, are essential for generation and expression of emotion, and contribute to emotional experience. There is little lateral specialization of the paramedian structures. Phylogenetically, this level of brain development is present in reptiles (MacLean 1990). The paramedian-limbic zone is partially functional at birth, and its emerging integrity becomes evident in smiling and crawling. Disorders of motivation, mood, and affect are associated with paramedian-limbic dysfunction, and this zone is the anatomic site of structures involved in many neuropsychiatric disorders. Parkinson’s disease, with its depression, apathy, akinesia, masked facies, hypophonic voice, and marked postural changes, is an example of a common disease of elderly people affecting the paramedian-limbic zone.

The supralimbic zone is outermost in the brain and includes the neocortex and the lateral thalamic nuclei. The neurons of this zone have long, well-myelinated axons that project via white matter tracts to more distant targets. The supralimbic neocortex contains the neurons mediating higher cortical (association) functions, as well as the pyramidal neurons that project to limbs, lips, and tongue. It mediates highly skilled, fine-motor movements evident in human speech and hand control. Ontogenetically, this zone first finds expression in the pincer grasp and articulate speech. Phylogenetically, the supralimbic zone first appears in mammals and is most well developed in humans (MacLean 1990). The supralimbic zone is expressed in human cultural achievements, including art, manufacture, speech, writing, and science. The supralimbic zone exhibits lateralized specialization of structure and function, with marked differences between the functions supported by each cerebral hemisphere. The supralimbic zone is vulnerable to some of the most common neurological disorders associated with aging, including stroke and Alzheimer’s disease. For example, the expansion of the neocortex has been at the expense of a secure vasculature. The enlarged association areas have created border zones between the territories of the major intracranial blood vessels that are at risk of stroke because of limited interconnections and poor collateral flow; reduced cerebral perfusion with carotid artery disease or cardiopulmonary arrest regularly results in border zone infarctions at the margins between these vascular territories. In addition, penetrating branches form arterial end zones that have no collateral supply as they project through the white matter to the borders of the ventricles. This vascular anatomy creates an area of vulnerability to ischemia at the margins of the lateral ventricles. Periventricular brain injury has been associated with depression (Smagula and Aizenstein 2016; Sneed et al. 2008), “vascular cognitive impairment, no dementia” (VCIND; Stephan et al. 2009; see also Duncombe et al. 2017), vascular neurocognitive disorder (Kirshner 2009; Tomimoto 2015), and Binswanger’s disease (Filley 2012). Along with the hippocampus, the supralimbic zone is the major site of pathological changes in Alzheimer’s disease (Savioz et al. 2009). Focal lesions of the neocortex also result in neurobehavioral domain–restricted deficits such as aphasia (language), apraxia (skilled purposeful movements, i.e., praxis), and agnosia (recognition). This model of behavioral neuroanatomy provides an ontogenetic life span perspective showing the emerging function of these structures in early life and their disease-related vulnerability in later life. The model reflects an evolutionary perspective of the brain, emphasizing its development through time and its increasing complexity in response to evolutionary pressures. From a clinical point of view, the median zone is responsible for basic life-sustaining functions; accordingly, disturbances in this zone are reflected in disorders of consciousness and abnormalities of metabolism, respiration, and circulation. By contrast, most neuropsychological deficit syndromes, such as disorders of language, prosody, praxis, recognition, visuospatial function, calculation, and executive function, are associated with disturbances of the structure and/or function the supralimbic neocortex. Disorders of emotion (i.e., mood disorders, disorders of affect), anterograde amnesia (impairments in new learning), disorders of motivation, and personality alterations are more likely to occur with abnormalities in the paramedian-limbic zone or disturbed interactions between this zone and the median and supralimbic zones (Arciniegas 2013a; Gardini et al. 2009; Javitt 2007; Mayberg 2003). Thus, neuropsychiatric disturbances occur in characteristic patterns that correspond to brain evolution, development, structure, and function.

Neocortex (Supralimbic Zone) Histological Organization of the Cortex and Behavior Brodmann’s maps remain the classic guide to the histological organization of the cerebral mantle. Within Brodmann’s areas (abbreviated BA followed by the number of the area), three types of cortex

relevant to understanding behavior have been identified: a three-layered allocortex, a six-layered neocortex, and an intermediate paralimbic cortex. The limbic system cortex (e.g., the hippocampus) has a three-layered allocortical structure, whereas the sensory, motor, and association cortices of the hemispheres have a six-layered structure (Mesulam 2000). In the neocortex, layer I is outermost and consists primarily of axons connecting local cortical areas; layers II and III have a predominance of small pyramidal cells and serve to connect one region of cortex with another; layer IV has mostly nonpyramidal cells, receives most of the cortical input from the thalamus, and is greatly expanded in primary sensory cortex; layer V is most prominent in motor cortex and has large pyramidal cells that have long axons descending to subcortical structures, brain stem, and spinal cord; and layer VI is adjacent to the hemispheric white matter and contains pyramidal cells, many of which project to the thalamus (Mesulam 2000) (Figure 1–2). Layers II and IV have the greatest cell density and the smallest cells; conversely, layers III and V have the lowest density and the largest cells. Cell size correlates with the extent of dendritic ramification, implying that cells of layers III and V projecting to other cortical regions have the largest dendritic domains (Schade and van Groenigen 1961).

FIGURE 1–2. Histological structure of six-layered neocortex in a 5-year-old male (NeuN immunostain). See Plate 2 to view this image in color. 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 (parietal)

Vision, hearing, somatic sensation

Macropyramidal cortex

6

Primary motor cortex (motor cortex)

Movement

Unimodal association cortex

6

Secondary association (parietal, temporal, occipital cortex)

Modality-specific processing of vision, hearing, and somatic sensation

Heteromodal association cortex

6

Multimodal association (inferior parietal lobule, prefrontal cortex)

Higher-order association

Archicortex

3

Hippocampus

Memory

Paleocortex

3

Piriform cortex

Olfaction

Orbitofrontal cortex, insula, temporal pole, parahippocampal gyrus, cingulate gyrus

Emotional behavior

Allocortex

Paralimbic cortex (mesocortex)

4, 5

FIGURE 1–3. Primary motor (green) and sensory (blue) cortex. See Plate 3 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

FIGURE 1–4. Unimodal association cortex (red). See Plate 4 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

FIGURE 1–5. Heteromodal association cortex (pink). See Plate 5 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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 corticosubcortical 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. See Plate 6 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

The main long association tracts are the following (Schmahmann et al. 2007): The uncinate fasciculus connecting the orbital and medial prefrontal region with the rostral temporal region, enabling interactions between emotion and cognition, self-regulation, and visual learning The arcuate fasciculus and also the extreme capsule, which project between superior temporal areas and the superior and dorsal prefrontal cortex and which are involved in linking posterior and anterior language areas as well as integrating sound localization with spatial attention The first superior longitudinal fasciculus (SLF-I) linking the superior parietal lobule, which is involved in appreciating limb and trunk location in space, with premotor areas engaged in higher aspects of motor behavior and the supplementary motor area for intention and initiation of motor activity The second superior longitudinal fasciculus (SLF-II) connecting the caudal inferior parietal lobule and posterior prefrontal cortices in the service of spatial attention The third superior longitudinal fasciculus (SLF-III) linking the rostral inferior parietal lobule with the supramarginal gyrus, ventral premotor area, and ventral prefrontal areas, which, collectively, support gestural aspects of language as well as orofacial working memory The frontal-occipital fasciculus, which supports visuospatial processing

The middle longitudinal fasciculus, which courses rostrocaudally in the white matter of the superior temporal gyrus and which links associative and paralimbic cortices in the parietal, cingulate, parahippocampal, and prefrontal regions with the heteromodal cortices of the superior temporal region The inferior longitudinal fasciculus connecting the occipital and temporal lobes, which supports object recognition, discrimination, and memory, as well as face recognition The cingulum bundle, linking the caudal cingulate gyrus with the hippocampus and parahippocampus (for memory) as well as with the dorsolateral prefrontal cortices (BA9 and BA46) for executive function and working memory and the rostral (anterior) cingulate gyrus for motivation and drive The commissural fibers are situated in the massive corpus callosum interconnecting all lobes of one hemisphere with areas of the contralateral hemisphere and in the more diminutive anterior commissure interconnecting the olfactory regions and the middle and inferior temporal gyri of the hemispheres. Intact cerebral function depends on the integrity of the axons of the white matter, as well as on the activity of the neurons of the gray matter. White matter diseases with diffuse or multifocal demyelination produce memory abnormalities, dementia, depression, mania, delusions, and personality alterations. Focal lesions of white matter tracts produce a number of disconnection syndromes that arise when critical neuronal areas are uncoupled by an intervening injury (Geschwind 1965; Kirshner 1986; Schmahmann et al. 2007, 2008). Table 1–2 summarizes the principal disconnection syndromes. TABLE 1–2. Fiber tracts and related disconnection syndromes of the cerebral hemispheres Fiber type

Tract

Symptoms

Commissural

Corpus callosum

Left-hand tactile anomia, left-hand agraphia, lefthand apraxia, inability to match hand postures or tactile stimuli of the two hands, reduced constructional skills in the right hand

Splenium

Alexia without agraphia (this syndrome occurs when there is a left occipital injury and right homonymous hemianopsia in addition to the splenial lesion)

Arcuate fasciculus

Conduction aphasia

Arcuate fasciculus

Parietal apraxia

Inferior longitudinal fasciculus (right)

Prosopagnosia, environmental agnosia

Inferior longitudinal fasciculus (bilateral)

Visual object agnosia

Corticospinal tract

Locked-in syndrome

Association

Projection

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 Executive prosody Receptive prosody

Aprosodia Executive aprosodia 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 righthanded 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 entorhinalhippocampal 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). See Plate 7 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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 evidencebased 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 metaanalysis 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 valencegeneral limbic and paralimbic brain regions. Kirby and Robinson (2017) used activation likelihood estimation (ALE) to quantify convergence of neuroimaging-demonstrated neural activations across studies within seven categories of emotion: anger, anxiety, disgust, fear, happiness, humor, and sadness. The ALE maps demonstrated consistent cross-hemispheric limbic-paralimbic, cortical, and cerebellar activations for all categories of emotion. Within the median and paramedian-limbic zones, structures activated across emotions included the insula, reflecting its role in autonomic arousal associated with emotions and emotional judgment, as well as the amygdala, hippocampus, basal ganglia, and thalamus. Within the supralimbic zone, all emotion categories were associated with dorsolateral prefrontal cortex (BA9/46, BA44/45, and BA47) activation. Activation within BA9 and BA46 may reflect engagement of cortical areas involved in processing emotion and emotion- and reward-related decision making, whereas activation of BA44/45 (Broca’s area) may reflect engagement of structures connecting with language and affective prosody. The involvement of BA47 across multiple emotions may also implicate a role in affective components of language processing as well as emotion-related episodic memory. Convergence of emotional processing in prefrontal areas may reflect interactions between limbic-paralimbic (i.e., emotion generating) and higher cognitive (i.e., emotion integration and regulation) functions, with the prefrontal areas serving as a network hub for such integrative interactions. Collectively, these findings reinforce the modern view that emotion engages bihemispherically distributed networks, the specific elements of which vary somewhat between emotions but do not fully lateralize specific emotions, or emotions more generally, to either cerebral hemisphere. With regard to the experiential aspects of emotion, Damasio and colleagues (2000), using 15O PET, studied the neural correlates of happiness, sadness, fear, and anger using a personal life–episodes recall paradigm in 41 healthy individuals. Although there were individual variations in the specific brain regions activated during subjects’ experiences of these emotions, all involved activation of bilateral structures in limbic, paralimbic, somatosensory, prefrontal, brain stem, and cerebellar areas. Taken together with the aforementioned meta-analytic and ALE studies, these observations suggest that both the expressed and experiential aspects of emotion are mediated by complex, typically bilateral, limbic-cortical and limbic–brain stem systems.

Asymmetric Neurochemical Anatomy of the Limbic System Although emotion is bihemispherically represented and modulated neurochemically in both hemispheres, neurotransmitter asymmetries may underlie the differential occurrence of mood disorders and anxiety, with lesions of the left and right hemispheres. Asymmetries of subcortical structures are less marked than are asymmetries of cortical regions, but the left globus pallidus, right medial geniculate nucleus of the thalamus, and left lateral posterior nucleus of the thalamus have been found to be larger than the corresponding nuclei of the contralateral hemisphere (Eidelberg and Galaburda 1982; Kooistra and Heilman 1988). Asymmetries of neurotransmitter concentrations in limbic system structures have been identified. The content of dopamine and choline acetyltransferase (a marker of cholinergic function) is increased in the left globus pallidus compared with their content in the right (Glick et al. 1982); norepinephrine concentrations are greater in the left pulvinar and in the right somatosensory nuclei of the thalamus (Oke et al. 1978); and choline acetyltransferase activity is greater in the left than in the right temporal lobe (Amaducci et al. 1981).

Neuropsychiatric Disorders Associated With Limbic and Paralimbic Disturbances The limbic system serves no single unifying function, but disorders involving the limbic system frequently involve some manner of altered emotional or social function. Disorders involving limbic and paralimbic structures therefore produce a wide range of disturbance in thought, emotion, and behavior (Cummings 1985; Doane 1986) (Table 1–4). Importantly, conditions with isolated involvement of the “traditional” limbic system described by Papez (1937) tend to produce little intellectual impairment except for impairments in declarative new learning associated with lesions to or degeneration of the entorhinal-hippocampal-forniceal-mammillo-thalamic pathway. Instead, these conditions are often, although not invariably, associated with “productive” disorders of emotional function with the new appearance of positive neuropsychiatric symptoms.

TABLE 1–4. Neuropsychiatric disorders with evidence of limbic system dysfunction Neuropsychiatric Limbic and paralimbic structures disorder implicated

Diseases affecting structure

Amnesia

Hippocampus, hypothalamus

Stroke, anoxia, trauma, tumors, herpes encephalitis

Psychosis

Temporal cortex

Epilepsy, stroke, tumors, herpes encephalitis, Alzheimer’s disease

Striatum

Huntington’s disease, idiopathic basal ganglia calcification, lacunar state, schizophrenia

Depression

Striatum, thalamus, insula, medial orbitofrontal cortex

Stroke, Huntington’s disease, Parkinson’s disease, idiopathic basal ganglia calcification, idiopathic depression

Mania

Striatum

Huntington’s disease, idiopathic basal ganglia calcification

Thalamus

Stroke

Right basotemporal cortex

Stroke, trauma

Lateral orbitofrontal cortex, nucleus accumbens, basal ganglia, thalamus

Idiopathic OCD

Striatum, globus pallidus

Huntington’s disease, Sydenham’s chorea, PEPD, manganese intoxication, carbon monoxide intoxication

Orbitofrontal cortex

Trauma, tumors, degenerative disorders

Temporal cortex

Epilepsy

Amygdala

Herpes encephalitis, trauma

Amygdala

PTSD, social phobia, specific phobia

Insula

Idiopathic anxiety

Rostral anterior cingulate, ventral medial prefrontal cortex

PTSD

Temporal cortex, basal ganglia

Alzheimer’s disease, Parkinson’s disease, stroke, trauma

Apathy

Anterior cingulate, ventral striatum, nucleus accumbens, thalamus

Stroke, trauma, tumors, degenerative disorders

Hyposexuality

Temporal cortex

Epilepsy (interictal)

Hypothalamus

Trauma (surgical)

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, orbitofrontal cortex, nucleus accumbens, hypothalamus

Idiopathic addictive behavior

OCD

Personality alterations

Anxiety

Hypersexuality

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 obsessivecompulsive disorder (Baxter et al. 1987; Huey et al. 2008) and that focal lesions and neurological disorders producing obsessive-compulsive behavior frequently involve the caudate nucleus or globus pallidus (Cummings and Cunningham 1992). A variety of personality alterations have been correlated with limbic system lesions. Orbitofrontal or orbitofrontal-subcortical circuit lesions produce disinhibited, impulsive, and tactless behavior; temporolimbic epilepsy has been associated with a rigid, viscous demeanor with hypergraphia, circumstantiality, hyposexuality, and hyperreligiosity (Brandt et al. 1985); and bilateral amygdala lesions produce behavioral placidity as part of the Klüver-Bucy syndrome (Lilly et al. 1983). Disorders of sexual function also may reflect limbic system disturbances. Diminished libido has been associated with hypothalamic injury and with the interictal state of patients with temporal lobe seizure foci. Hypersexuality, including new-onset pedophilic hypersexual behavior, has been observed in patients with orbitofrontal injury (Burns and Swerdlow 2003) or trauma to the septal region and also as an ictal manifestation in the course of temporal lobe seizures (Gorman and Cummings 1992). Paraphilic behavior, including pedophilia, transvestism, sadomasochistic behavior, and exhibitionism, has been observed in patients with temporal lobe injury and epilepsy, basal ganglia disorders, and brain tumors involving limbic (including orbitofrontal) structures (Burns and Swerdlow 2003; Cummings 1985; Mendez et al. 2000; Miller et al. 1986). Drug addictions appear to be mediated in part by alterations of reward circuitry, including anterior cingulate and orbitofrontal interactions with the nucleus accumbens (Kalivas and Volkow 2005). In contrast to the tendency for limbic system disorders to generate “productive” symptoms and syndromes (i.e., excesses of normal function), apathy—a disorder of diminished motivation—is a deficit syndrome associated with damage to or degeneration of key limbic-paralimbic-subcortical

network structures. The core features of the syndrome of apathy are reductions in goal-directed cognition, emotion, and behavior (Marin 1991). This syndrome varies in severity from mild loss of interest and reduced involvement in previous affairs (i.e., diminished motivation) to an akinetic mute state with markedly reduced movement, speech, and intellectual content (Marin and Wilkosz 2005). The syndrome most commonly results from lesions of the anterior cingulate cortex or related structures of the cingulate-subcortical circuit, including nucleus accumbens, globus pallidus, and thalamus (Cummings 1993; Lavretsky et al. 2007).

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

Predominant laterality of associated lesion

Disorders of personal relevance Unilateral hemispatial neglect

Right

Prosopagnosia (inability to recognize familiar faces)

Right

Environmental agnosia (inability to recognize familiar places)

Right

Phonagnosia (inability to recognize familiar voices)

Right

Affective aprosodia (inability to inflect one’s language to communicate emotion or to comprehend the emotion communicated in the inflections of others)

Right

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 metaanalysis 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 limbiccortical 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 singlecase 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). See Plate 8 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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 laterodorsal

Mammillary body

Posterior cingulate, retrosplenial area, entorhinal-hippocampal complex

Learning and memory

Ventroanterior

Globus pallidus

Frontal cortex

Modulation of motor function

Ventrolateral

Cerebellum

Frontal cortex

Modulation, coordination, and learning of movement

Ventral posterolateral

Sensory tracts from body

Parietal sensory cortex

Somatosensory function

Ventral posteromedial

Sensory tracts from face

Parietal sensory cortex

Facial sensation

Cortical gustatory area and anterior insula

Taste

Motor nuclei

Sensory nuclei

Solitary tract Lateral geniculate

Optic tracts

Occipital cortex

Vision

Medial geniculate

Inferior colliculi

Temporal cortex

Hearing

Medial dorsal

Globus pallidus, amygdala, temporal and frontal cortex

Prefrontal cortex

Executive function, memory, social cognition, emotion

Lateral nuclear group (pulvinar)

Frontal, parietal, temporal, and occipital cortex

Frontal, parietal, temporal, and occipital cortex

Coordinates intra- and crossmodal cortical information processing

Midline

Hypothalamus

Amygdala, cingulate, hypothalamus

Visceral function

Intralaminar

Reticular formation, precentral and premotor cortex

Striatum, cortex

Activation

Reticular

Thalamic nucleus and cortex

Dorsal thalamic nuclei

Samples, gates, and focuses thalamocortical output

Association nuclei

Nonspecific nuclei

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 rightsided 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. See Plate 9 to view this image in color. 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. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

The motor circuit originates from neurons in the supplementary motor area, premotor cortex, motor cortex, and somatosensory cortex (Alexander and Crutcher 1990; Alexander et al. 1986; Arciniegas 2013b; Lichter and Cummings 2001). Throughout the circuit, the discrete somatotopic organization of movement-related neurons is maintained. Distinct types of motor disturbances are associated with lesions at different sites in the motor circuit. Motor initiation abnormalities (akinesia) are associated with supplementary motor area lesions; parkinsonism and dystonia are observed with putaminal dysfunction; and choreiform movements occur with caudate and subthalamic nucleus damage. The oculomotor circuit originates in the frontal eye fields, as well as in the prefrontal and posterior parietal cortex. Acute lesions of the cortical eye fields produce ipsilateral eye deviation, whereas more chronic lesions produce ipsilateral gaze impersistence. Lesions in other areas of the circuit produce supranuclear gaze palsies such as those seen in Parkinson’s disease, progressive supranuclear palsy, and Huntington’s disease. Three distinct frontal lobe neurobehavioral syndromes are recognized, and each corresponds to a region of origin of one of the three prefrontal-subcortical circuits: the dorsolateral prefrontal circuit, the lateral orbitofrontal circuit, and the anterior cingulate circuit (Figure 1–10) (Arciniegas 2013b; Cummings 1993; Lichter and Cummings 2001). Dysfunction of any of the member structures of the circuits results in similar circuit-specific behavioral complexes, and these frontal-subcortical circuits compose major anatomic axes governing behavior. The dorsolateral prefrontal circuit originates in the convexity of the frontal lobe and projects primarily to the dorsolateral head of the caudate nucleus. This caudate region connects to globus pallidus and substantia nigra, and pallidal and nigral neurons of the circuit project to the medial dorsal thalamic nuclei that in turn project back to the dorsolateral prefrontal region. The dorsolateral prefrontal syndrome is characterized primarily by executive function deficits. Abnormalities include developing poor strategies for solving visuospatial problems or learning new information and reduced ability to shift sets. Such behavioral changes are observed in patients with dorsolateral prefrontal lesions, as well as in those with caudate, globus pallidus, and thalamic dysfunction.

FIGURE 1–10. Prefrontal cortical origins of the dorsolateral (blue), anterior cingulate (pink), and lateral orbitofrontal (green) circuits. See Plate 10 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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 Disease

Personality change

Mania

Depression

Obsessivecompulsive disorder

Neuropsychological impairment

Prefrontal cortical disorders Dorsolateral prefrontal syndrome

No

No

Yes

Yes

Yes

Lateral orbitofrontal syndrome

Yes

Yes

Yes

Yes

No

Anterior cingulate syndrome

Yes

Yes

Yes

Yes

Yes

Parkinson’s disease

Yes

No

Yes

No

Yes

Progressive supranuclear palsy

Yes

No

Yes

Yes

Yes

Huntington’s disease

Yes

Yes

Yes

Yes

Yes

Sydenham’s chorea

Yes

No

No

Yes

Yes

Wilson’s disease

Yes

Yes

Yes

No

Yes

Neuroacanthocytosis

Yes

Yes

Yes

Yes

Yes

Fahr’s disease

UD

Yes

Yes

No

Yes

Infarction

Yes

No

Yes

Yes

Yes

Postencephalitic Parkinson’s disease

Yes

Yes

Yes

Yes

Yes

Manganese toxicity

Yes

UD

UD

Yes

Yes

Carbon monoxide toxicity

Yes

No

No

Yes

Yes

Infarction

Yes

UD

UD

No

Yes

Infarction

Yes

Yes

No

No

Yes

Degeneration

Yes

UD

UD

UD

Yes

Caudate disorders

Globus pallidus disorders

Thalamic disorders

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 diagonal band of Broca

Neocortex, hippocampus, hypothalamus, and amygdala

Reticular system

Reticular formation

Thalamus

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

Dopamine

Glutamate

Caudate and putamen

Globus pallidus and substantia nigra

Globus pallidus and substantia nigra

Thalamus

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 Acetylcholine

Reduced function

Increased function

Memory impairment, apathy, delirium, delusions

Depression, aggression

 Motor function

Parkinsonism

Chorea, tics

 Behavior

Cognitive impairment (especially inattention), apathy, depression

Hallucinations, delusions, elation, obsessivecompulsive behavior, paraphilias

GABA

Seizures, anxiety

Amnesia, incoordination, sedation

Glutamate

Cognitive impairment (especially amnesia), psychosis, apathy

Seizures, excitotoxicity

Norepinephrine

Cognitive impairment (especially inattention), depression, dementia

Anxiety

Serotonin

Depression, anxiety, suicide, aggression

Confusion, hypomania, agitation, myoclonus

Dopamine

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). See Plate 11 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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). See Plate 12 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

Dopaminergic function is mediated by metabotropic receptors that can be classified pharmacologically as D1-like (stimulate cyclic adenosine monophosphate [cAMP]) or D2-like (inhibit cAMP). These receptors have different distributions throughout the brain. The D2 receptors are blocked by neuroleptics, and it is possible that subtypes of the D2 receptor differentially mediate the motor and mental effects of dopaminergic drugs. Dopamine plays a key role in motoric functions and behavior. Dopamine deficiency or blockade leads to parkinsonism; dopamine excess produces chorea, dyskinesia, or tics. Behaviorally, dopamine deficiency causes at least mild cognitive impairment and may contribute to the depression that commonly accompanies Parkinson’s disease and other parkinsonian syndromes. Dopamine excess leads to psychosis, elation or hypomania, and confusion. Dopamine hyperactivity may contribute to the pathophysiology of schizophrenia, obsessive-compulsive behavior, anxiety, and some paraphilic behaviors (Cummings 1985, 1991). The locus coeruleus and adjacent nuclei constitute the origin of the noradrenergic projection system. A dorsal noradrenergic bundle courses in the dorsal brain stem to the septum, thalamus, amygdala, basal forebrain, hippocampus, and neocortex (Nieuwenhuys 1985) (Figure 1–13). A ventral noradrenergic bundle projects to the hypothalamus and midbrain reticular formation. Adrenergic function is mediated by metabotropic receptors that can be classified pharmacologically as α (inhibit cAMP) or β (stimulate cAMP) receptors. α-Adrenergic receptors can be further subtyped as α1 or α2; the former are located postsynaptically and the latter presynaptically and postsynaptically. These receptors have different distributions throughout the brain. Effective treatment for depression is associated with decreased numbers (downregulation) of β-adrenergic receptors. Noradrenergic hypofunction has been linked to depression, dementia, and diminished alertness and concentration (Agid et al. 1987). Increased noradrenergic activity has been linked to anxiety (Lechin et al. 1989).

FIGURE 1–13. Noradrenergic projections from the locus coeruleus (pink). See Plate 13 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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., 5HT1, 5-HT2, 5-HT4) and to a lesser extent by ionotropic receptors (i.e., 5-HT3). These receptors have different distributions throughout the brain. Serotonin deficiency has been hypothesized to play a major role in suicide, depression, anxiety, and aggression (Agid et al. 1987), and excesses of cerebral serotonin may produce confusion, hypomania, agitation, and myoclonus (Isbister and Buckley 2005). 5-HT2A receptors are implicated in the pathophysiology of psychosis.

FIGURE 1–14. Serotonergic projections (blue). See Plate 14 to view this image in color. Source. Image courtesy of M. Mega and the UCLA Laboratory of Neuroimaging.

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 Zone

Myelination

Neuronal connectivity/anatomyOntogeny

Function

Behavioral syndromes

Median

Poor

Feltwork; reticular

Functional at birth

Arousal

Disturbances of arousal, neuroendocrine control, respiration, circulation

Paramedianlimbic

Intermediate

Series; limbic system and basal ganglia

Functional within first few months

Emotion; extrapyramidal function

Neuropsychiatric disorders; movement disorders

Supralimbicneocortical

Complete

Parallel; neocortex

Functional in adulthood

Instrumental cognitive functions (e.g., language, praxis)

Neurobehavioral disorders

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CHAPTER 2

Neuropsychiatric Assessment Fred Ovsiew, M.D. David B. Arciniegas, 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 preinjury psychiatric and/or behavioral issues were contributing factors should be learned.

Alcohol and Substance Use A substance use history is taken from all patients. Questions about vocational, family, and medical impairment attributable to abuse; shame and guilt over abuse and efforts to control it; morning or secret drinking; blackouts; and other familiar issues help the clinician identify pathological behavior in this sphere. Cocaine and alcohol abuse in particular are associated with a variety of neuropsychiatric consequences, including cognitive impairment, movement disorders, seizures, and stroke (Marshall 1999).

Cognitive Impairment

Screening for cognitive complaints, their character, and their course is a routine element of the neuropsychiatric assessment. While these may be the presented complaint for some patients and be overt elements of the clinical presentation, the character and course of such problems in other cases are relatively subtle. Many patients with mild cognitive disturbance do not meet criteria for a diagnosis of dementia (or major neurocognitive disorder, as it is described in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]; American Psychiatric Association 2013), and are, instead, better described as having mild cognitive impairment (MCI), or mild neurocognitive disorder (American Psychiatric Association 2013). Familiarity with the criteria for these conditions, the domains of cognition that they typically affect (addressed in the “Mental Status Examination” subsections of this chapter), and the differences in the functional import of cognitive problems associated with mild versus major neurocognitive disorders is necessary to frame accurately additional history taking and cognitive examination. The clinician must also remain mindful that cognitive impairment is not necessarily a progressive problem: unlike those whose MCI is a prodromal stage of dementia—for example, the amnestic prodome of Alzheimer’s disease or the dysexecutive prodrome of vascular dementia—some patients present with mild cognitive impairments that are chronic and stable; traumatic brain injury, particularly when moderate or severe, commonly produces this state (Dikmen et al. 2009).

Appetitive Functions Appetitive functions include sleeping, eating, and sexual interest and performance. Disturbed sleep is common in patients with psychiatric disorders of any origin and in the general population as well. The clinician inquires about the pattern of disturbance: early waking in depressive illness, nighttime wakings related to pain or nocturnal myoclonus, excessive daytime sleepiness in narcolepsy

and sleep apnea, sleep attacks in narcolepsy, and periodic excessive somnolence in Kleine-Levin syndrome and related disorders. Simple observation of a hospitalized patient by night nursing staff, or at home by family members, can identify snoring, apneas, or abnormal movements. Sexual interest, sexual performance, and reproductive health are commonly disturbed in brain disease. A change in a person’s habitual sexual interests, either quantitative or qualitative, occurring de novo in adult life, suggests neurological disease (Cummings 1999). Hyposexuality is reportedly a feature of epilepsy, and either antiepileptic drugs or epilepsy itself may disturb sex hormones, in a fashion that may depend on the laterality of the seizure focus. Patterns of abnormal eating behavior in neuropsychiatric disorders include the hyperphagia of medial hypothalamic disease, in which food exerts an irresistible attraction, or reduced eating with lateral hypothalamic lesions; the gourmand syndrome of right anterior brain injury; the mouthing and eating of nonfood objects in bilateral amygdalar disease (part of the Klüver-Bucy syndrome); and the impulsive stuffing of food into the mouth irrespective of hunger in frontal disease. While diminished appetite is a common feature in many neurological, medical, and psychiatric conditions, the full syndromal picture of anorexia nervosa results rarely from neurological disease, usually involving right frontal and temporal regions (Uher and Treasure 2005).

Aggression Patterns of aggressive behavior in brain disease relate to the locus of injury. Commonly, the injury or degeneration is of the anterior and ventrolateral frontal regions and the networks in which they participate. Features of aggressive behavior such as its onset and cessation; the patient’s mental state and especially clarity of consciousness during the violent period; the patient’s capacity for

planned, coordinated, and well-organized action as shown in the act; the patient’s regret, or otherwise, afterward; and any associated symptoms may yield clues about the contribution of cerebral dysfunction to the behavior.

Personality Change Changes in sexual preference with onset in adult life have already been mentioned as pointers to organic mental disorder. Persisting alterations in or exaggerations of other personality traits, if not related to an abnormal mood state or psychosis, may be important indicators of the development of cerebral disease. Lability and shallowness of emotion, irritability, aggressiveness, loss of sense of humor, and coarsening of the sensibilities are often mentioned. A set of personality traits said to be distinctive for temporal lobe epilepsy includes hypergraphia, mystical or religious interests, “humorless sobriety,” tendency toward rage, interpersonal stickiness or “viscosity,” and hyposexuality. Whether these traits are related to epilepsy, to the temporal lobe injury underlying epilepsy, or merely to psychopathology remains controversial (Blumer 1999; Devinsky and Najjar 1999).

Occupation Exposures to heavy metals or volatile hydrocarbons and repeated blows to the head in boxers are examples of occupational causes of neuropsychiatric illness. Apart from gathering etiological information, the clinician needs to know about the patient’s work to gauge premorbid capacities and to assess disability.

Family History Genetic contributions to many neuropsychiatric illnesses are well delineated (e.g., Huntington’s disease); in other illnesses, the contribution is probable but its nature less clear (e.g., Tourette

syndrome). Inquiry about the family history of neuropsychiatric illness is most rewarding when pursued relative by relative, while constructing a family tree.

Neurological Examination The usual elements of the neurological examination are outlined in Table 2–1. The sensitivity and specificity of many neurological examination findings are unknown, even for signs that are routine or traditional in the clinical examination. Too often, the clinical examination proceeds by ritual. The clinician who asks the patient with right hemisphere stroke to interpret proverbs but not to copy figures, or asks him or her to remember three words but not three shapes, is bowing to tradition and ignoring the physiology of the brain disease. Moreover, the tasks may lack discernible relation to cognitive or anatomical systems: What underlies the ability to recall the names of the last four presidents? Probes of mental function should be chosen with reference to the structure of the mind, as best understood.

TABLE 2–1. The neurological examination Section Cranial nerves

Elements I: Olfaction (use items such as coffee, mint, vanilla, cinnamon) II: Visual fields, visual acuity, and pupillary responses, and fundus (i.e., retina, disc, macula) III, IV, VI: Pupillary responses to light and accommodation and extraocular movements (up, down, lateral, and convergent gaze, smooth pursuit eye movements and saccades, and observation for nystagmus) V: Facial sensation and masseter strength VII: Facial motor function VIII: Hearing and vestibular function IX, X: Palatal elevation XI: Sternocleidomastoid and trapezius strength XII: Tongue protrusion

Motor – Part I

Resistance to passive manipulation, including assessment of intrinsic tone and assessment for paratonia Observation of muscle bulk and symmetry as well as for abnormal involuntary movements

Reflexes

Stretch reflexes, including those at biceps, triceps, brachioradialis, patellar, and Achilles tendons; responses graded as 0 (absent), 1+ (diminished, may require evocation maneuvers), 2+ (active), 3+ (brisk, often with spread to other groups), and 4+ (very brisk, with spread and clonus) When clinically appropriate, additional brain stem reflexes (e.g., corneal, oculovestibular, gag) not already evaluated in the cranial nerve examination, other stretch reflexes, and cutaneous reflexes assessed

Section

Elements Assessment for primitive reflexes, including glabellar, snout, suck, palmomental, and finger grasp; among persons with more severe neurological conditions, foot grasp, self-grasp, and rooting responses assessed as well.

Motor – Part II

Strength testing of bilateral upper and lower extremities proximally and distally; responses graded as 0 (no muscle movement), 1 (visible or palpable muscle contraction), 2 (full range of motion with gravity eliminated but not against gravity), 3 (movement against gravity but not added resistance), 4 (movement against resistance but subnormal), and 5 (normal strength)

Sensory

Pain (pin prick), temperature Light touch Vibration, proprioception (including finger-to-nose with eyes closed and Romberg tests)

Coordination

Finger-nose-finger, fine finger movements, fingerthumb 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 (PierrotDeseilligny et al. 1997). Psychic paralysis of gaze, Balint’s original term, is a more accurate designation (Moreaud 2003). The dysfunction relates to a disorder of spatial attention; classically, although not necessarily, the patients show bilateral posterior parietal lesions. In so-called apraxia of eyelid opening, patients have difficulty in initiating lid elevation. This disorder occurs in extrapyramidal disease —notably, progressive supranuclear palsy (Grandas and Esteban 1994)—and as an isolated finding (Defazio et al. 1998). Eye closure and reflex eye opening are normal. In apraxia of lid opening, as distinct from blepharospasm, the orbicularis oculi are not excessively contracted; in blepharospasm, the brows are lowered below the superior orbital margins (Charcot’s sign) (Esteban et al. 2004). Sensory tricks may be effective in initiating eye opening (Defazio et al. 1998), probably an indicator of extrapyramidal dysfunction in the disorder (thus making the term apraxia incorrect). Some (e.g., Esteban et al. 2004) but not all authors distinguish the phenomenon

from ptosis of cerebral origin, which occurs with frontal lesions, especially right hemisphere infarction. Supranuclear disorders of eyelid closure may occur with bilateral frontal lesions, either structural or functional, as in the case of progressive supranuclear palsy (Grandas and Esteban 1994). Spontaneous blinking is intact, and other bulbar musculature often is involved.

Facial Movement A double dissociation in the realm of facial movement shows that emotional movements and volitional movements are separately organized. A paresis seen in movements in response to a command (“show me your teeth”) is sometimes overcome in spontaneous smiling; this indicates disease in pyramidal pathways. A severe impairment of voluntary control of the bulbar musculature with preservation of automatic movements is seen in bilateral opercular lesions, the anterior opercular or Foix-Chavany-Marie syndrome (Bakar et al. 1998). The inverse phenomenon—normal movement in response to a command but asymmetry of spontaneous emotional movements—is seen with disease in the supplementary motor area, anterior thalamus, amygdala, striatum and internal capsule, and brain stem. Emotional facial weakness is contralateral to the seizure focus in temporal lobe epilepsy (Jacob et al. 2003).

Abnormalities of Movement Weakness A complete review of the findings associated with lesions of the pyramidal tracts, spinal cord, peripheral nerves, and muscles is beyond the scope of the present work. However, there are several simple maneuvers that facilitate recognition of the motor effects of cerebral lesions that merit description here (Teitelbaum et al. 2002).

Pronator drift is assessed by asking the patient to keep the arms outstretched and supinated, with the fingers together and then with the fingers apart. Abduction of the fingers in the first portion of the test and pronation, elbow flexion, or lateral and downward drift in the second portion indicate pyramidal disease. Testing should last at least 30 seconds. Upward drift indicates a parietal lesion. (By asking the patient to hold the arms pronated, the examiner can conveniently observe for asterixis and tremor at this point in the examination.) In the finger-rolling test, the patient is asked to rotate each index finger around the other for 5 seconds in each direction. The tendency for one finger to orbit the other indicates a subtle pyramidal lesion on the stationary side. Fine finger movements are assessed by asking the patient, with the hands supinated in the lap, to touch the thumb to each of the other four fingers in turn, one hand at a time. Mirror movements (discussed in the subsection “Synkinesia and Mirror Movements” later in this chapter) are conveniently observed incidentally at this point in the examination. Greater awareness of the findings in nonpyramidal syndromes may help the clinician identify neurobehavioral syndromes associated with cerebral disease outside the primary motor regions. Caplan et al. (1990) described the features of a “nonpyramidal hemimotor” syndrome with caudate nucleus lesions. Patients show clumsiness and decreased spontaneous use of the affected limbs; associated movements are decreased as well. What appears at first glance to be paresis proves to be a slow development of full strength; if coaxed and given time, the patient shows mild weakness at worst. Freund and Hummelsheim (1985) explored the motor consequences of lesions of the premotor cortex. They observed a decrease in spontaneous use of the arm and attributed it to a failure of postural fixation; when supported, the arm showed at worst mild slowing of finger movements. The defect in elevation and abduction of the arm was best demonstrated by asking the patient to swing the

arms in a windmill movement, both arms rotating forward or backward; the same defect can be found in cycling movements of the legs, especially backward cycling (Freund 1992). Movement rapidly decomposed when such coordination was required. Pyramidal signs—increased tendon jerks, Babinski’s sign, and spasticity—may be absent in patients with these findings. In acute parietal lesions, “motor helplessness” due to loss of sensory input is sometimes seen.

Abnormality of Gait Assessment of gait is a central feature of the neuropsychiatric physical examination. Alterations in gait are common in subcortical vascular disease, for example, and may provide crucial diagnostic information. The examiner must scrutinize the patient’s rising from a chair, standing posture, postural reflexes, initiation of gait, stride length and base, and turning. Failures of gait ignition (initiation), locomotion, and postural control should be identified as such, whether alone or in combination. In mild gait ignition failure, start hesitation and occasional freezing are seen. In mild locomotion failure, slow and short strides on a widened base are present, with mild unsteadiness. In postural control failure, falling is seen in conjunction with turning impairment, ultimately leading to an inability to stand unsupported. Stressed gait (e.g., walking heel to toe or on the outer aspects of the feet) may reveal asymmetric posturing of the upper extremity in patients without other signs. Frontal gait disorder is characterized by short, shuffling steps on either a wide or a narrow base, with hesitation at starts and turns. Postural equilibrium is impaired, although not as much as in Parkinson’s disease, and the trunk is held upright on stiff, straight legs. Festination is not a feature, and the upper extremities are unimpaired or far less affected. This is the gait disorder of subcortical vascular dementia, and it must be distinguished from that of Parkinson’s disease (FitzGerald and Jankovic 1989). A widened

base strongly points away from idiopathic Parkinson’s disease and toward subcortical vascular disease or a parkinsonian-plus syndrome. Thalamic, basal ganglia, and cortical lesions can produce balance disorders with falling and unfamiliar derangements of station and gait, easily mistaken for psychogenic disorders. Falls also occur in patients with dementia or delirious patients whose executive dysfunction leads to carelessness with regard to walking rather than specific gait impairment. Contrariwise, cautious gait occurs in healthy people in treacherous footing (e.g., on ice) or in the frail and anxious elderly. Features of cautious gait include short stride length at a slow pace, a widened base, excessive knee flexion, and decreased arm swing. Such patients are often anxious and depressed and evince an excess of extrapyramidal and frontal release signs—but not pyramidal or cerebellar signs—as well as a reduction in muscle strength (Giladi et al. 2005). Although anxiety may play an important role in the genesis of the gait pattern, the organic factors must not be ignored, even though the gait disorder is not a classically localizable one.

Akinesia Akinesia has several aspects: delay in the initiation of movement, slowness in the execution of movement, and special difficulty with complex movements. The disturbance is established by requiring the patient to perform a repeated action, such as tapping thumb to forefinger, or two actions at once. A decrement in amplitude or freezing in the midst of the act is observed. When established, akinesia is unmistakable in the patient’s visage and demeanor and in the way he or she sits motionlessly and has trouble arising from the chair. A distinction between parkinsonian akinesia and depressive psychomotor retardation is not easy to make, but the associated

features of tremor, rigidity, and postural instability are generally absent in depressive illness (Rogers et al. 1987).

Agitation The term agitation is often misused to refer to the behavior of aggression or the affect of anxiety. “The preferred definition of psychomotor agitation is of a disorder of motor activity associated with mental distress which is characterized by a restricted range of repetitive, nonprogressive (‘to-and-fro’), non-goal directed activity” (Day 1999, p. 95). In distinction from akathisia, the excessive movement characteristically involves the upper extremities. Agitation in the verbal sphere is manifested in repetitive questioning or complaining, screaming, or attention seeking. In some patients with Alzheimer’s disease, wandering is associated with depressive and anxiety symptoms and may represent agitation in this cognitively impaired population. Roaming, differentiated from wandering by being purposeful and exploratory, is characteristic of frontotemporal dementia.

Akathisia Motor restlessness accompanied by an urge to move is referred to as akathisia. Although akathisia is most familiar as a side effect of psychotropic drugs, the phenomenon occurs often in idiopathic Parkinson’s disease, occasionally in traumatic brain injury, herpes simplex encephalitis, restricted basal ganglion lesions (even occurring unilaterally with a contralateral lesion), after withdrawal from dopamine-blocking drugs, or as a tardive movement disorder (Sachdev 1995). Eliciting the account of subjective restlessness from a psychotic patient may be difficult. Complaints specifically referable to the legs are more characteristic of akathisia than of anxiety. Although by derivation the term refers to an inability to sit, its objective manifestations are most prominent when the patient attempts to

stand still. The patient “marches in place,” shifting weight from foot to foot. Seated, the patient may shuffle or tap his or her feet or repeatedly cross his or her legs. When the disorder is severe, the recumbent patient may show myoclonic jerks or a coarse tremor of the legs.

Hypertonus Three alterations of motor tone (or apparent motor tone) concern the neuropsychiatrist: spasticity, rigidity, and paratonia. In spasticity, tone is increased in flexors in the upper extremity and extensors in the lower but not in the antagonists. The hypertonus shows an increase in resistance followed by an immediate decrease (the clasp-knife phenomenon) and depends on the velocity of the passive movement. This is the typical hemiplegic pattern of hemisphere stroke, universally called pyramidal, which indicates a lesion actually not in the pyramidal tract but in the corticoreticulospinal tract. However, clinicians should be aware that striking variability in muscle tone (poikilotonia) can occur in the acute phase of parietal stroke. In rigidity, tone is increased in both agonists and antagonists throughout the range of motion. Hypertonus of this type is not dependent upon the velocity with which the affected muscle (usually a limb muscle) is moved. This is the characteristic hypertonus of extrapyramidal disease. In paratonia (including mitgehen [“go with”] and gegenhalten [“stop going”]), resistance to passive manipulation is erratic and depends on the intensity of the imposed movement. This pattern of hypertonus is usually related to frontosubcortical dysfunction (Schneck 2013). The erratic quality is related to the presence of both oppositional and facilitatory aspects of the patient’s motor performance. Beversdorf and Heilman (1998) described a test for facilatory paratonia: the patient’s arm is repeatedly flexed to 90° and extended to 180° at the elbow, then the examiner’s hand is

withdrawn at the point of arm extension. In the abnormal response, the patient lifts or even continues to flex and extend the arm. A cogwheel feel to increased muscle tone is not intrinsic to the hypertonus; the cogwheeling in parkinsonism is imparted by postural (not rest) tremor superimposed on rigidity. In delirium and dementia, the paratonia of diffuse brain dysfunction can be mistaken for extrapyramidal rigidity when the examiner feels cogwheeling, which actually indicates the additional presence of the common tremor of metabolic encephalopathy or postural tremor of some other etiology.

Dystonia Dystonia refers to sustained involuntary muscle contractions that produce twisting and repetitive movements or abnormal postures. The contractions may be generalized or focal. Typically, the dystonic arm hyperpronates, with a flexed wrist and extended fingers; the dystonic lower extremity shows an inverted foot with plantar flexion. Several syndromes of focal dystonia are well recognized, such as torticollis, writer’s cramp, and blepharospasm with jaw and mouth movements (Meige syndrome). A dystonic pattern of particular interest is oculogyric crisis, in which forced thinking or other psychological disturbance accompanies forced deviation of the eyes. Dystonic movements characteristically worsen with voluntary action and may be evoked only by very specific action patterns. Dystonic movements, especially in an early stage or mild form of the illness, can produce apparently bizarre symptoms, such as a patient who cannot walk because of twisting feet and legs but who is able to run or a patient who can do everything with his or her hands except write. Adding to the oddness is the frequent capacity of the patient to reduce the involuntary movement by using “sensory tricks” (le geste antagoniste); in torticollis, for example, the neck contractions that are forceful enough to break restraining devices may yield to the patient’s simply touching the chin with his or her own finger. Eliciting

a history of such tricks or observing the patient’s use of them is diagnostic.

Tremor Tremors are rhythmic, regular, oscillating movements. The major forms of tremor are rest tremor, postural tremor, intention (or kinetic) tremor, and rubral (or midbrain) tremor. In rest tremor, the movement is present distally when the limb is supported and relaxed; action reduces the intensity of the tremor. The frequency is usually low, about 4–8 cycles per second. This is the well-known tremor of Parkinson’s disease. Because the amplitude of the tremor diminishes with action, rest tremor is usually less disabling than it might appear. In postural tremor, the outstretched limb oscillates. At times, this can be better visualized by placing a piece of paper over the outstretched hand. Postural tremor is produced by anxiety, by certain drugs (e.g., caffeine, lithium, steroids, adrenergic agonists), and by hereditary essential tremor. A coarse, irregular, postural tremor is frequently seen in metabolic encephalopathy. In intention tremor (also called kinetic tremor), the active limb oscillates more prominently as the limb approaches its target during goal-directed movements, but the tremor is present throughout the movement. Rubral, or midbrain, tremor is a lowfrequency, 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 CreutzfeldtJakob disease (in which cortical myoclonus may be elicited by auditory stimuli), dementia with Lewy bodies, and corticobasal degeneration. Myoclonus can accompany dystonia, including tardive dystonia, and tardive myoclonus without dystonia is also recognized.

Myoclonus occurring in a confused patient is usually a feature of toxic-metabolic encephalopathy, but it should raise the question of nonconvulsive status epilepticus, an easily overlooked condition (Kaplan 2002). Gaze deviation, lateralized dystonic posturing, and automatisms should be red flags for the latter condition.

Asterixis Asterixis is the repeated momentary loss of postural tone that produces a flapping movement of the outstretched hands, originally described in the setting of liver failure but subsequently recognized in many or all states of metabolic encephalopathy and in all muscle groups. It may be elicited by asking the patient to dorsiflex the index fingers for 30 seconds while the hands and arms are outstretched, with the patient watching to ensure maximum voluntary contraction. Physiologically, asterixis is the inverse of multifocal myoclonus, with brief electromyographic silences amidst otherwise sustained activity. The coarse tremor of delirium is a slower version of asterixis. Bilateral asterixis is a valuable sign because it points reliably to a toxic-metabolic confusional state. Asterixis, to our knowledge, has never been described in the idiopathic psychoses and is thus pathognomonic for an encephalopathy. Occasionally, asterixis is unilateral and reflects a lesion of the contralateral thalamic, parietal, or medial frontal structures (usually thalamic); rarely, bilateral asterixis is of structural origin.

Startle The normal reaction to an unexpected auditory stimulus invariably includes an eye blink and then predominantly flexor muscle jerks that are most intense cranially, tapering caudally. A rare, usually familial, disorder in which this reflex is disturbed is called hyperexplexia. It features hyperreflexia, hypertonus, and abnormal gait in infancy; myoclonus; and exaggerated startle, frequently causing falls. Abnormal startle reactions are also seen in posttraumatic stress

disorder, Tourette syndrome, some epilepsies, certain culture-bound syndromes such as latah and the “jumping Frenchmen of Maine,” brain stem encephalitis, postanoxic encephalopathy, and hexosaminidase A deficiency.

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

deliberate responses to an urge (like scratching because of an itch) or be given a post hoc meaning by the patient, so the distinction between “voluntary” and “involuntary” movements and actions may be obscured.

Stereotypy and Mannerism Stereotypies are rhythmic, repetitive, fixed, predictable, but purposeless movements, sometimes performed in lieu of other motor activity and for long periods of time. Stereotypies include movements such as crossing and uncrossing the legs, clasping and unclasping the hands, picking at clothes or at the nails or skin, head banging, and rocking. Stereotyped movements are seen in schizophrenia, autism, mental retardation, Rett syndrome, Tourette syndrome, neuroacanthocytosis, congenital blindness, and numerous other psychopathological states. They are particularly characteristic of frontotemporal dementia (Mendez et al. 2005). Nonautistic children may show repetitive complex movements. These are phenomenologically distinct from tics in that they are more rhythmic, patterned, and prolonged; lack premonitory urges or internal tension; are easily abolished by distraction but are not disturbing to the child and thus are not intentionally controlled; and start earlier, often before age 2 years (Mahone et al. 2004). They may persist into adulthood and may be associated with obsessive and compulsive symptoms (Niehaus et al. 2000). At times, especially in those with intellectual and developmental disabilities, a distinction of stereotypies from epileptic events may be difficult. Many of the abnormal movements of tardive dyskinesia (e.g., chewing movements, pelvic rocking) are patterned and repetitive, not random as is chorea, and they are best described as stereotypies. Amphetamine intoxication is a well-recognized cause of stereotypy, known in this setting as punding, a Swedish word introduced during a Scandinavian epidemic of amphetamine abuse (Rylander 1972). Similarly, cocaine and levodopa can cause stereotyped movements

(Evans et al. 2004). Stereotypies occur occasionally ipsilateral or contralateral to a motor deficit during the acute phase of stroke (Ghika-Schmid et al. 1997) and rarely with other focal lesions affecting motor control systems (especially the basal ganglia). Mannerisms are purposeful movements carried out in a peculiar way. Mannerisms are typically evinced in task performance and tend to be unique to the individual performing them. Although observed among persons with neuropsychiatric disorders, they are common in the general population as well.

Catatonia Catatonia, the syndrome described by Kahlbaum in the nineteenth century and absorbed into the concept of dementia praecox by Kraepelin, occurs in a wide variety of neurological and medical conditions as well as in the classic idiopathic psychoses (Taylor and Fink 2003). Catatonia comprises a large number of motor and behavioral abnormalities. Among these are motor signs such as catalepsy, posturing, or waxy flexibility; signs of psychosocial withdrawal and/or excitement such as mutism and negativism; and bizarre or repetitive movements such as grimacing, stereotypies, mannerisms, command automatism, echopraxia/echolalia, verbigeration, and impulsiveness. Taylor and Fink (2003) proposed formal criteria for the catatonia syndrome: 1) immobility, mutism, or stupor of at least an hour’s duration accompanied by catalepsy, automatic obedience, or posturing observed on two occasions or 2) two or more observations of two or more of the following motor features: stereotypy, echophenomena, catalepsy, automatic obedience, posturing, negativism, gegenhalten, or ambitendency. Such signs are common in severe mental disorders, including schizophrenia spectrum disorders, bipolar disorder, and major depressive disorder, as well as a large number of neurological and medical conditions (van der Heijden et al. 2005). Many of the signs are seen with frontosubcortical lesions (Northoff 2002), and

cataleptic postures can occur with contralateral parietal lesions (Ghika et al. 1998). Several assessment scales have been devised and validated; the most commonly used of these is the Bush-Francis Catatonia Rating Scale (Bush et al. 1996).

Synkinesia and Mirror Movements Excessive synkinesia—automatic movement accompanying intended voluntary movement—occurs in a variety of neuropsychiatric conditions. Obligatory, congenital bimanual synkinesia (“mirror movements”) persisting into adulthood occurs with cerebral palsy due to a lesion predating 24 weeks of gestation, cervical spine disease (such as Klippel-Feil syndrome), agenesis of the corpus callosum, and Kallmann’s syndrome. To observe the phenomenon, the examiner asks the patient to touch, repeatedly and in turn, the fingers of the right hand to the right thumb, and then the left fingers to the left thumb, as the hands rest supine in front of the patient; in addition to watching the active hand for fine motor coordination, the examiner watches the contralateral hand for mirror movements. The pathophysiology involves abnormal ipsilateral motor pathways or diminished transcallosal inhibition (Ueki et al. 2005). Asymmetric parkinsonism also gives rise to mirror movements (Espay et al. 2005). However, it is not uncommon that no definite malformation, injury, or degenerative condition can be identified in association with such movements (Rasmussen 1993).

Primitive Reflexes The various signs collectively referred to as primitive reflexes differ in their sensitivity and specificity for brain disease, and, in most instances, the presence of a single primitive reflex may not be clinically significant (Schneck 2013). By contrast, the presence of multiple primitive reflexes that fail to habituate on repeated stimulation more reliably suggests pathology (Di Legge et al. 2001; Owen and Mulley 2002). Thus, the examiner should place little

weight on a single primitive reflex, especially if it fatigues on repeated stimulation. The exception is the grasp reflex, which in the two studies just cited was present in no healthy subject and in only rare patients with vascular disease but not dementia—and which thus reliably indicates disease when present. The received wisdom is that the primitive reflexes listed in Table 2–2 are brought about by cortical disease, especially frontal injury or degeneration, which disinhibits primitive movement patterns. In light of that received wisdom, these signs are often described as “frontal release signs.” However, the localizing value of these signs is variable, and, with rare exception, their presence localizes to frontosubcortico-thalamo-ponto-cerebellar networks rather than to the frontal lobe alone (Schneck 2013). A possible exception to this rule is the grasp reflex, which appears to be a genuine frontal sign: in a study of 491 patients, grasping was never associated with a postcentral lesion (De Renzi and Barbieri 1992). A similar response may be elicited in the sole of the foot, but the plantar grasp is present only when the palmar grasp is present, so its diagnostic utility is limited. Awareness of the plantar grasp reflex, however, may keep the examiner from missing an extensor plantar response when this is masked by the plantar grasp.

TABLE 2–2. Primitive reflexes, their examination, and interpretation of findings Primitive reflexes

Examination maneuver

Normal response

Abnormal response

Glabellar

Examiner taps 10 times on the glabella (area just above and between eyebrows) at rate of one per second.

Blinking in response to first few taps then habituation and no further blinks

Partial or full blinking in response to each tap

Grasp

Examiner places two fingers in patient’s hand and strokes across palm or along fingers.

No grasp

Patient grasps examiner’s fingers

Self-grasp

Examiner grasps patient’s arm and, with webbing between the patient’s thumb and fingers as the point of contact, strokes the patient’s contralateral ulnar surface.

No grasp

Patient grasps own contralateral forearm

Foot grasp

Examiner places his or her hand on the plantar surface of the distal part of the patient’s foot and toes.

No response

Plantar flexion and adduction of the toes

Palmomental

Examiner strokes palm from lateral aspect of hypothenar eminence to thenar eminence.

No movement

Ipsilateral mentalis (chin) muscle contracts

Primitive reflexes

Examination maneuver

Normal response

Abnormal response

Rooting

Examiner uses his finger to stroke patient’s cheek (from mouth toward temporomandibular joint).

No movement

Patient turns head toward side being stroked

Snout

Examiner uses his or her finger to lightly tap on patient’s lips (finger oriented perpendicular to lips); alternatively, and to determine the presence of any asymmetry of response, examiner taps above the upper lip just lateral to the philtrum on each side.

No movement

Lips pucker

Suck

Examiner places gloved knuckle between patient’s lips; alternatively, a cotton tip applicator is placed simultaneously across the patient’s tongue and lower lip.

No movement

Sucking motion

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). The Charles Bonnet syndrome—visual hallucinations without other psychopathology, usually in the presence of ocular disease with visual loss—is common, especially in the elderly. The hallucinations are usually vivid images of animals or human beings or of faces, and the patient is aware of their unreality. The visual experience exceeds veridical perception in clarity. Characteristically, patients with these symptoms do not report them spontaneously. Visual hallucinations in a hemifield blind from cerebral disease (release hallucinations) occur with occipital strokes or occasionally other posterior lesions. Because the pathogenesis of hallucinations in ocular disease may differ from that in occipital disease, the eponym probably is best reserved for hallucinations associated with peripheral visual impairment. Vivid, elaborate, and well-formed visual hallucinations may occur with disease in the upper brain stem or thalamus (peduncular hallucinosis). Such hallucinations often worsen in the evening (crepuscular) or when the patient is sleepy, and again the patient is generally aware of their unreality. A dreamlike state may accompany the hallucinosis. Similar hallucinations occur as hypnagogic phenomena in narcolepsy and in response to dopaminergic drugs in Parkinson’s disease, and the brain stem mechanism may be related. Auditory hallucinations are characteristic of idiopathic psychiatric disorders but occur in association with a broad range of neurological disorders as well. Similarly to peduncular visual hallucinations, auditory hallucinations may arise from pontine lesions as well as from lesions in the temporal lobes (Braun et al. 2003). Although musical hallucinations may develop in patients with idiopathic psychiatric disorders, they characteristically are associated with progressive hearing impairment (analogous to Bonnet hallucinations), including unilateral hearing impairment (in which they

are ipsilateral to the deaf, or more deaf, ear). Analogous to pallinopsia, palinacousis refers to persisting or recurrent auditory “images” after the stimulus they echo is gone and is associated with temporal lobe lesions. Olfactory hallucinations, often taken to imply epilepsy or temporal lobe disease, are common in idiopathic psychiatric disorders. Rarely, the olfactory reference syndrome—a patient’s belief that he or she emits an aversive odor, with accompanying social withdrawal—may develop as a consequence of neurological disorders, perhaps especially right hemisphere lesions (Lochner and Stein 2003).

Cognitive Examination At what point in the interview should the cognitive examination be done? If the initial few minutes of history taking give reason to suspect substantial cognitive difficulty, one may wish to do at least some of the testing promptly. Not all of the cognitive examination needs to be done at once. Fatigue is an important factor in the cognitive performance of many patients, and long examinations may not elicit their best performance. For this reason, short periods of probing may yield new perspectives on a patient’s capacities. Shorter periods of questioning also may help prevent adverse emotional and behavioral reactions when a patient’s capacities are exceeded. When such reactions occur, the patient is often unable to engage effectively in tasks that would otherwise be within his or her capacities, yielding data collected at such times that, at best, are of limited value. A common difficulty for beginners is how to introduce the formal cognitive inquiry. All too often, one hears the examiner apologize for the “silly but routine” questions he or she is about to ask. (One never hears a cardiologist apologize for the silly but routine instrument being applied to the patient’s precordium.) This is rarely the best way to gain the patient’s full cooperation and best effort. Most of the time,

patients report symptoms that can lead naturally (i.e., naturally from the patient’s point of view) to a cognitive examination. For example, a patient with depressive symptoms may report trouble concentrating. If the examiner then says, “Let me ask you some questions to check your concentration,” the patient is more likely to collaborate and less likely to be offended. Nearly any tasks can then be introduced.

Attention and Working Memory Full alertness with normal attention lies at one end of a continuum, the other end of which is coma. Where the patient is on this continuum can be assessed by observing the reaction to a graded series of probes: entering the room, speaking the patient’s name, touching the patient without speaking, shouting, and so on through painful stimulation. The proper recording of the response is by specific notation of the probe and the reaction (e.g., “makes no response to examiner’s entrance but orients to examiner’s voice; speaks only when shaken by the shoulder”). Deficits occur in the capacity to maintain attention to external stimuli (vigilance), the capacity to attend consistently to internal stimuli (concentration), and the capacity to shift attention from one stimulus to another. Vigilance can be assessed by the patient’s capacity to carry out a continuous-performance task; such tasks have been extensively used in the psychological laboratory. In a bedside adaptation, the “A test,” the patient is presented with a string of letters, one per second, and is required to signal at each occurrence of the letter A. A single error of omission or of commission is considered an abnormal response. Concentration can be assessed by the patient’s capacity to recite the numbers from 20 to 1 or to give the days of the week or the months of the year in reverse order. A pathognomonic error is the intrusion of the ordinary forward order: “20, 19, 18, 17, 18, 19,...”

This amounts to a failure to inhibit the intrusion of the more familiar “set.” Digit span is a classic psychological test of working memory, easily performed at the bedside. The examiner recites strings of numbers, slowly, clearly, and without phrasing into chunks. The patient is required to repeat them immediately. Subsequently, the patient can be asked to repeat strings of digits after reversing them in his or her head. The normal forward digit span is usually considered to be a minimum of five. The backward digit span is a variation of this task that employs executive control of working memory (i.e., reverse ordering of information held in working memory). A related task of working memory is asking the patient to alphabetize the letters of the word world (Leopold and Borson 1997).

Neglect Hemispatial inattention, or neglect, describes a patient who is densely inattentive to the nondominant hemispace, typically the left side of his or her body—one of the most dramatic clinical phenomena in neuropsychiatry. The bedside clinician can readily identify the patient who leaves his or her left arm out of the sleeve of a gown, leaves the left side of breakfast uneaten, and so on. Neglect can be recognized further during a line-bisection task (the patient must place an X at the midpoint of a line drawn by the examiner) or a cancellation task (in which the patient crosses out letters or other items for which he or she must search in an array). However, careful attention to neglect in behavior—grooming, dressing, moving about, acknowledgment of left limbs—is even more sensitive than paperand-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 frontalsubcortical 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 domainspecific dissociations in naming ability (category-specific anomia); for example, the ability to name vegetables may be intact while the ability to name animals is devastated (Gainotti 2000). Patients who do not have elementary disorders of language, nonetheless, may have macrolinguistic deficits. When words and sentences—lexicon and syntax —are normal, paragraphs and discourse may not be. Patients with right hemisphere disease, despite the adequacy of their lexical-semantic and syntactical performance, have deficits in the capacity to tell a story or recognize the point of a joke (Brownell and Martino 1998; Paradis 1998). These patients rarely give “I don’t know” responses; rather, they contrive some answer even if implausible; they fail to draw appropriate inferences, especially from emotional data, so that incongruity is not recognized; and their sense of humor is impaired. Temporal lobe epilepsy and traumatic brain injury are associated with deficits in planning, producing, and monitoring discourse; patients’ narratives may be verbose and inefficient or contain insufficient or irrelevant information, requiring the listener to expend extra effort to understand them (Biddle et al. 1996; Field et al. 2000). These findings emphasize the value of open-ended inquiries (e.g., “What brings you to the hospital?”), with attention to the patient’s discourse taken as a whole as a sign of cerebral function. Disorders at the level of discourse are well recognized phenomenologically in psychiatry. Patients who experienced attachment disorganization in childhood show disturbances of the form of thought when discussing emotionally powerful material; this may relate to the characteristic vagueness and inconsistency of the medical accounts provided by hysterical patients (Ovsiew 2006).

Mutism The term mutism should be reserved for the situation in which a person does not speak and does not make any attempt at spoken communication despite preservation of an adequate level of consciousness. The first order of business in assessing an alert patient who does not speak is to examine phonation, articulation, and nonspeech movements of the relevant musculature (e.g., swallowing, coughing) to determine whether the disorder is due to elementary sensorimotor abnormalities involving the apparatus of speech. A restricted disturbance of verbal communication also must be distinguished from a more global disorder of the initiation of activity. At its extreme, the latter is the state of akinetic mutism. If an elementary disorder is not at fault, the examination proceeds to a search for specific disturbances of verbal communication. Does the patient make any spontaneous attempt at communication through means other than speech? Does the patient gesture? Can the patient write, or, if hemiplegic, can he or she write with the nondominant hand? Can he or she arrange cut-out paper letters or letters from a child’s set of spelling toys? Or, if familiar with sign language, can he or she sign? Some patients with acute vascular lesions restricted to the lower primary motor cortex and the adjacent frontal operculum have transient mutism and then recover through severe dysarthria without agrammatism, a disorder known as aphemia (Fox et al. 2001). The same syndrome can arise from right hemisphere disease, testifying to its nature as an articulatory rather than a language disorder (Mendez 2004; Vitali et al. 2004). Transcortical motor aphasia features a prominent disturbance of spontaneous speech, occasionally beginning as mutism. Mutism also commonly develops in patients with frontotemporal dementia or primary progressive aphasia (Snowden et al. 1992).

Stuttering and Cluttering

Common developmental stuttering, or stammering, is familiar to everyone’s ear. Rhythm of speech is disturbed by repetition, prolongation, or arrest of sounds. In developmental but not acquired stuttering, involuntary movements of the face and head resembling those of cranial dystonia—such as excessive blinking, forced eye closure, clonic jaw movements, and head tilt—are characteristically seen. Alternatively, such movements can be interpreted as being akin to tics; this view is supported by an increased prevalence of obsessive-compulsive behaviors in persons with developmental stuttering (Abwender et al. 1998). Rarely, developmental stuttering that had been overcome returns after brain injury, or developmental stuttering disappears after brain injury (Helm-Estabrooks et al. 1986). Acquired stuttering, subtly different from the developmental variety (Van Borsel and Taillieu 2001), is unusual but can be caused by stroke, traumatic brain injury, extrapyramidal disease, and antipsychotic medications. Although ictal or postictal stuttering occurs rarely in epilepsy, the more common occurrence is in psychogenic nonepileptic seizures (Chung et al. 2004; Vossler et al. 2004). Psychogenic stuttering—marked by dramatic response to psychological treatment, atypical or “bizarre” speech features, multiple concurrent pseudoneurological complaints, and variability or situation specificity in presentation—may occur with or without concomitant structural neurological disease (Duffy and Baumgartner 1997). Cluttering is a disorder of fluency in which discourse, rather than purely articulation, is disturbed by a range of deficits in speech pragmatics, motor control, and attention (Daly and Burnett 1999). Speech output is abnormal because of rapid rate, disturbed prosody, sound transpositions or slips of the tongue, poor narrative skills, and impaired management of the social interaction encompassing speech. Thoughts may be expressed in fragments; words or phrases may be repeated. In sharp contrast to developmental stuttering,

patients with cluttering are characteristically unconcerned about their impairment. Stuttering may be mistakenly diagnosed or occur in association with cluttering. Some features of the disorder are replicated by festinant speech in parkinsonism (Lebrun 1996), and rare instances of acquired cluttering have been reported (Thacker and De Nil 1996).

Echolalia In echolalia, the patient repeats the speech of another person automatically, without communicative intent or effect. Often, the speech repeated is that of the examiner, and the phenomenon is immediately apparent without being specifically elicited. At times, other verbalizations in the environment are repeated. Sometimes the patient repeats only the last portion of what he or she hears, beginning with a natural break in the utterance. Sometimes grammatical corrections are made when the examiner deliberately utters an ungrammatical sentence. The patient may reverse pronouns (e.g., “I” for “you”) in the interlocutor’s utterance, altering the sentence in a grammatically appropriate way. These corrections and alterations evince intactness of the patient’s syntactic capabilities. Speaking to the patient in a foreign language may elicit obviously automatic echolalic speech. Echolalia is a normal phenomenon in the learning of language in infancy. Echolalia in transcortical aphasia marks the intactness of primary language areas in the frontal and temporal lobes, with syntax thus unimpaired but disconnected from control by other language functions. Other neuropsychiatric disorders in which echolalia may occur include autism, Tourette syndrome, dementia of the frontal type and other degenerative disorders, catatonia, and startle-reaction disorders (McPherson et al. 1994). In all these situations, it may represent an environmental-dependency reaction, in which verbal responding is tightly stimulus bound, echolalia

representing the converse of failure of normal initiation of speech much as perseveration represents the converse of impersistence.

Palilalia Palilalia is the patient’s automatic repetition of his or her own word or phrase. Commonly, the volume of the patient’s voice trails off and the rate of speech is festinant; less frequently, in palilalie atonique, repetitions of the utterance without acceleration alternate with silence. Despite claims to the contrary, repetition need not be confined to elements at the end of the utterance (Van Borsel et al. 2001). Palilalia occurs most commonly among patients with extrapyramidal diseases, including progressive supranuclear palsy, postencephalitic parkinsonism, and idiopathic parkinsonism, but it may be observed in association with Tourette syndrome, epilepsy, traumatic brain injury, thalamic lesions, and neurosyphilis as well.

Blurting The speech of some patients is marked by impulsive utterances of stereotyped or simple responses with no aphasic or echolalic features—blurting. For example, an elderly woman had the clinical features of progressive supranuclear palsy with no elementary cognitive abnormality. When questioned, she often replied “yes, yes” or “no, no” even before the questioner finished speaking and regardless of her intended answer to the question. She could then correct herself and give the reply she wished to give and was unable to explain the behavior. This phenomenon (also described as “echoing approval” and “yes-no reversals”) seems to be related to echolalia and palilalia as well as to the environment-driven, impulsive (but not stereotyped) utterances of patients with disorders involving the frontostriatal circuitry (Ovsiew 2003).

Prosody and Affective Aprosodia

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

Praxis and Apraxia Praxis refers to the ability to perform skilled purposeful movements on demand. Inability to do so in the absence of elementary sensory or motor dysfunction that explain that inability or language comprehension problems that preclude understanding of the requested act is known as apraxia. Limb-kinetic apraxia amounts to cortical clumsiness, especially of finger coordination. Ideomotor apraxia refers to impaired ability to perform skilled transitive movements (i.e., action on an imagined object). A screening examination should use several tasks that differ with respect to their transitive versus intransitive, meaningful versus nonmeaningful,

outward-directed versus self-directed, single versus repetitive, or novel versus overlearned character, as well as their focus on oromotor, limb, or axial movement. Disorders of performing pantomimed transitive movements predominantly occur in patients with left hemisphere lesions and commonly co-occur with aphasias. As with other tasks in the cognitive examination, errors in performing skilled movements are more telling than simple failures, and the patient who shows how to hammer with a flat palm is unequivocally apraxic. For some forms of apraxia, patients do not complain of apraxic deficits and are not disabled by them because the deficits do not appear in a natural context. However, this may not always be so, and exploration of the motor performance deficit across contexts is appropriate (Hanna-Pladdy et al. 2003). The phenomenon of ideational apraxia is the incapacity to carry out a sequential or ordered set of actions toward a unitary goal in the presence of the necessary objects.

Signs of Callosal Disconnection Simple maneuvers suffice to elicit many of the crucial elements of the callosal disconnection syndromes. On examination, the patient with callosal lesions shows an inability to name odors presented to the right nostril. In visual field testing, a hemianopsia appears to be present in each hemifield alternately, opposite to the hand the patient uses to point to stimuli. Thus, when the patient is using the right hand, he or she responds only to stimuli in the right hemifield, but when the patient is using the left hand, he or she responds only to stimuli in the left hemifield. Callosal apraxia, which typically involves apraxia of only the left hand in a left hemisphere–dominant individual, can be shown by the usual testing maneuvers. This problem arises as a result of impaired transfer of motor engrams that guide praxic actions from the left hemisphere to the right hemisphere (which controls the left hand) by a callosal lesion. Similarly, writing with the left hand is impossible.

For reciprocal reasons, the right hand shows a visuo-constructional disorder. The patient has an anomia for unseen objects felt with the left hand. If the examiner places one of the patient’s hands (again unseen) into a given posture, the patient is unable to match the posture with the other hand. Similarly, the patient cannot touch with the left thumb the finger of the left hand that corresponds to the finger of the right hand touched by the examiner, and vice versa. No doubt the most dramatic feature of callosal disconnection is behavioral conflict between the hands or the patient’s sense that the left hand behaves in an “alien” fashion. Brion and Jedynak (1972) described “le signe de la main étrangère,” translated in the English summary of the article as the “strange hand sign” but subsequently (and better) as the “alien hand sign.” The original description clearly conveyed a sensory phenomenon, akin to neglect and one which Brion and Jedynak considered a hemisomatagnosia specific for touch. The authors emphasized the unawareness specifically of ownership of the hand, that is, the sense of “strangeness” or alienation and the association of this phenomenon with posterior callosal lesions. Many subsequent patients with intermanual conflict have had lesions in various positions in the callosum. However, not all patients with the alien hand phenomenon have callosal disconnection. The phenomenon of directed though unwilled behavior by the hand—the “anarchic hand”—is associated with frontal lobe pathology. Other patients without callosal lesions may have the alien hand syndrome through a combination of deficits involving praxis and proprioception (MacGowan et al. 1997). The alien hand seen in corticobasal degeneration (Fisher 2000) may fit this pattern in some instances; in others, it may be more closely akin to the levitation of the upper extremity seen with contralateral parietal lesions (Gondim et al. 2005).

Recognition and Agnosia

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

Visuospatial Function and Dysfunction

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

Executive Function and Dysfunction

Executive function refers to a complex set of processes that manage and control other, relatively basic, cognitive functions and that support purposeful goal-directed behaviors (Arciniegas 2013b). Executive function includes information retrieval and generation, set shifting, inhibitory control, environmental autonomy, planning and organization, pattern recognition, categorization, problem solving, and abstraction (i.e., intrinsic executive functions) as well as the management and control of “basic” aspects of cognition (i.e., executive control of attention, working memory, declarative memory, language, praxis, visuospatial information). Executive function provides for conscious decision making and purposive action; the initiation, maintenance, and cessation of behaviors that increase the likelihood of achieving a desired end; self-monitoring and outcome monitoring, including evaluating success of a previously decided behavior sequence in relation to the goal of that behavior; “mental flexibility,” including the ability to see beyond the concrete aspects of a thing or situation, to integrate new information into such schemas, to consider alternate schemas or actions, and to shift set; and reasoning, including the capacity to assess the current situation and potential future action options and to assign outcome probabilities to those options and pursue the one that best fits the short- and longterm 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 educationadjusted 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 domainspecific 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 wellknown 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 Laura A. Flashman, Ph.D., ABPP Fadi M. Tayim, Ph.D. Robert M. Roth, Ph.D., ABPP

Clinical

neuropsychologists are trained in the science of brainbehavior 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 brainbehavior 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 decisionmaking 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 (MannWrobel 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 Speech and language

Symptoms and signs 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)

Functional class Emotions

Symptoms and signs 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 tradeoff 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 intraindividual 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 WAISIV 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 goaldirected behavior (Roth et al. 2005; Stuss and Alexander 2000). Executive function includes the ability to independently initiate behaviors, inhibit impulses, select relevant task goals, plan and organize a means to solve problems (especially when novel or complex), think flexibly in response to changing circumstances, regulate emotions, monitor and evaluate one’s behavior, and hold information actively “online” (i.e., working memory) so that the information may be manipulated and utilized in the service of planning and guiding cognition and behavior. Accordingly, executive function is essential for the highest levels of cognition such as judgment, decision making, and self-awareness. There are numerous tests designed to assess executive function, and these vary widely in terms of the specific abilities required. Working memory is most commonly assessed using span tasks such as Digit Span Backward from the WAIS-IV, involving repeating digits in reverse order. The Paced Auditory Serial Addition Test places greater demand on working memory and processing speed, lasting several minutes and requiring an individual to add consecutive pairs of numbers presented at a fixed rate (e.g., a 3-second interval), with increased difficulty achieved by presenting numbers at an increased rate (e.g., a 2-second interval) (Gronwall 1977). The standard Stroop Color-Word Interference Test (Golden 1978) presents color words in

incongruent colors (e.g., the word red written in blue ink) and requires the individual to suppress the habitual tendency to read words rather than say colors. Verbal fluency tests (described in the subsection “Language”) may be used to measure initiation of concepts, task persistence, and ability to think flexibly. Patients with frontal lobe or diffuse brain injuries often have difficulty with relatively open-ended tests that permit them to decide how to perform the task, all the while receiving minimal instruction or feedback. Tests such as the Wisconsin Card Sorting Test (WCST; Heaton et al. 1993) and the Delis-Kaplan Executive Function System (D-KEFS) Sorting Test (Delis et al. 2001) require several abilities, including concept formation, hypothesis testing, problem solving, flexibility of thinking, and working memory. For example, the WCST requires the patient to deduce the principles by which to sort a deck of cards (i.e., to generate an understanding of the pattern/category), but without warning the patient, the examiner changes the correct principle as the test proceeds. Therefore, the patient must figure out independently that a shift in principles has occurred and change his or her behavior accordingly (i.e., to avoid perseverating on the prior pattern/category). As noted in the subsection “Attention and Processing Speed,” Part B of the TMT is also commonly used to assess a patient’s ability to think flexibly. Tests of planning and foresight, such as the Tower of London (e.g., Shallice 1982), require the person to move disks from stack to stack to match the examiner’s configuration of disks but following certain rules (e.g., no larger disk placed on top of a smaller disk, move only disk at a time). Most performance-based tests of executive function are limited, however, as they do not tap the integrated, multidimensional, relativistic, priority-based decision making that is often demanded in real-world situations (Goldberg and Podell 2000). Thus, some patients reported to have executive dysfunction in their everyday lives may perform well on tests because the examiner provides the structure, organization, and monitoring necessary for an individual’s

optimal performance (Kaplan 1988). This has led to the development of tests that try to enhance ecological validity by using real-world scenarios and problems, such as the Behavioral Assessment of the Dysexecutive Syndrome (Wilson et al. 1996), and standardized rating scales of executive function as manifested in everyday life, such as the Behavior Rating Inventory of Executive Function (Roth et al. 2005) and the Frontal Systems Behavior Scale (Grace and Malloy 2002). Executive dysfunction has been reported in patients with a wide variety of neurological and neuropsychiatric disorders, and executive dysfunction contributes to difficulties maintaining socially appropriate conduct, as well as successful academic and occupational functioning. The presence of executive dysfunction can be helpful in differential diagnosis in some situations, such as differentiating mild Alzheimer’s disease from frontotemporal dementia; the latter is generally associated with more prominent impairment. It should be noted, however, that whereas executive function has historically been most closely associated with the frontal lobes, there is a plethora of evidence indicating involvement of wide neural networks, including both cortical (frontal, parietal, and temporal lobes) and subcortical (e.g., basal ganglia, cerebellum) regions. Indeed, patients with focal lesions in nonfrontal brain regions may also present with executive dysfunction, and thus poor performance on measures of executive function does not necessarily imply frontal lobe damage.

Performance Validity Tests As noted in the section “Interpretation: Principles and Cautions,” inclusion of stand-alone and/or embedded measures of test-taking effort, also called performance validity tests (PVTs), has become a standard of practice in neuropsychological evaluations, especially when issues such as litigation and disability claims are involved (Bush et al. 2005). The basic premise of most PVTs is that they are designed to appear cognitively challenging, but in actuality, PVTs

pose little difficulty for healthy individuals as well as the vast majority of patients with clinical conditions such as TBI, depression, or mild dementia. Stand-alone PVTs most commonly involve a memory testing format such as the Test of Memory Malingering (Tombaugh 1997), the Word Memory Test (Green 2003), and the Rey 15-Item Test (Goldberg and Miller 1986). Embedded performance validity measures have been identified for numerous tests, such as reliable digit span using the WAIS-IV Digit Span subtest, allowing the examiner to gauge effort without adding additional time to the test session. A combination of stand-alone and embedded PVTs is generally preferred.

Intellectual Functioning Intellectual functioning, often expressed as the intelligence quotient (IQ), provides a context in which neuropsychological results may be interpreted. The most commonly used measure of intellectual ability in adults is the WAIS-IV (Wechsler 2008). It is composed of tests of crystallized intelligence (e.g., academic-based knowledge that is characteristically stable) as assessed through the Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI), as well as tests of fluid intelligence (e.g., constructs that can vary across time, day, and situation), as measured by the WMI and the PSI. The individual tests within each index were designed to assess relatively distinct areas of cognition, such as mental arithmetic, nonverbal abstract reasoning, and visuospatial organization, and thus are differentially sensitive to identifying dysfunction within various areas of the brain. Specific information regarding the WAIS-IV indices, including the subtests that compose them, can be found in the WAIS-IV manual (Wechsler 2008). Each index of the WAIS-IV is composed of subtest scores (e.g., the PRI contains the Block Design, Matrix Reasoning,

and Visual Puzzles subtests), and each of these subtest scores contributes to the overall index score. Significant differences among the subtest scores within an index (i.e., differences greater than 1.5 standard deviations) may result in IQ scores and/or ability levels that may not accurately represent overall ability. For example, a patient with a visuospatial deficit may have difficulty performing only the Block Design test, which is averaged with the other PRI subtests, and may produce a PRI score that does not reflect his or her true overall perceptual reasoning abilities. Therefore, neuropsychologists give consideration to both the index score and the individual subtest scores. The overall index scores, as well as the subtests that make up each index, provide a wealth of information regarding cognitive and intellectual strengths and weaknesses, in addition to potential neuroanatomical implications of dysfunction. For example, discrepancies between overall VCI and PRI scores can indicate whether an individual has a particular proficiency for verbal or perceptual reasoning abilities (i.e., greater left or right hemisphere functioning, respectively). It is important to note that many intellectual assessments, such as the WAIS-IV, require intact auditory and verbal functioning. Nonverbal measures of intellectual functioning are available for those with primary difficulties in these areas (e.g., Test of Nonverbal Intelligence; Brown et al. 2010).

Emotional Status and Personality Formal assessment of emotional status is usually included in neuropsychological batteries, as mood can impact an individual’s actual and/or perceived cognitive abilities. In addition to information obtained via the clinical interview, patients are asked to complete standardized self-report mood rating scales. For example, the Beck Depression Inventory (Beck et al. 1996) is a commonly used self-

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

functioning and thereby contribute to differential diagnosis and treatment planning.

Special Assessment Tools Computerized Test Batteries The use of computerized neuropsychological test batteries has been gradually increasing, although considerably more in research than in clinical contexts. There are numerous computerized test batteries available, which vary widely with respect to the specific domains of functioning assessed and measures employed, how the measures are implemented (e.g., instructions, stimuli, response requirements), and their psychometric properties (e.g., Cook et al. 2009). Advantages of computerized testing include test data obtained under highly standardized conditions, ease of acquiring precise data on accuracy and speed of responses, and minimal time expenditure by the examiner. On the other hand, limitations exist that render computerized testing problematic for regular clinical use. In particular, failure to acquire important information about the way an individual approaches a cognitive task or why performance is impaired (e.g., motivation, fatigue, frustration tolerance, use of strategy to complete a task), which is only possible if the examiner observes test performance, can impact the validity of the test results and thus limit interpretability. Furthermore, although people of all ages are increasingly exposed to computers, research indicates that computer-related anxiety and a negative attitude toward computers can affect test performance on computerized neuropsychological measures (Browndyke et al. 2002; Fazeli et al. 2013).

Decisional Capacity Neuropsychiatrists and physicians are at times faced with patients whose capacity to independently make personal decisions (e.g.,

legal, financial, medical) is called into question. Because neuropsychologists have extensive training in standardized assessment and interpretation, they can contribute objective data to the determination of decisional capacity. Such evaluations typically include neuropsychological measures used in standard evaluations, but it is recognized that the relationship between individual neuropsychological test scores and decision making is modest at best (Wood and O’Bryan 2011). Thus, neuropsychological evaluations conducted to help inform competency also usually employ one or more additional measures of functional abilities. Questionnaire measures pertaining to basic (e.g., hygiene, feeding) and instrumental (e.g., managing medications and finances, driving, cooking, cleaning) activities of daily living, completed by the patient and ideally also by a knowledgeable informant, can be informative. There are also semistructured interviews that facilitate acquiring information that is more specific to the nature of the suspected compromised decision-making ability. One example is the Aid to Capacity Evaluation (Etchells et al. 1999), which can help determine the extent to which a patient understands the relevant information and the potential consequences with regard to a specific medical treatment decision. The use of performance-based measures of functional abilities is also recommended for capacity evaluations. For example, the Texas Functional Living Scale (Cullum et al. 2001) has tasks in which the examinee is asked to make change, remember to take medications, tell time, look up and input a telephone number, and use a calendar.

Conclusion With advances in neuroimaging and other neurodiagnostics, there has been a shift in the focus of neuropsychological assessment from the diagnosis of possible brain damage to a better understanding of specific brain-behavior relations and the psychosocial consequences

of brain damage. Patients are referred for neuropsychological assessment for a variety of reasons. In some instances, the patient will have a known brain disorder (e.g., cerebrovascular disorder, developmental disorder, traumatic brain injury, Alzheimer’s disease or related dementing disorder, Parkinson’s disease, multiple sclerosis, Huntington’s disease, tumor, seizures, and psychiatric disorder associated with brain dysfunction). Other times, the referred individual may have a known risk factor for brain disorder; concerns related to potential changes in cognition or behavior might be the result of such a disorder. Furthermore, brain disorder or dysfunction may be suspected when a person’s behavior or personality changes without an identifiable cause. An explanation is sought because behavior patterns and personality are relatively stable characteristics of adults, and these changes require an explanation. Neuropsychology is a specialty practice focused on the assessment of brain function and brain-behavior relationships. It can be useful in defining the nature and severity of cognitive difficulties, as well as providing information about a patient’s personality characteristics, social behavior, emotional status, and adaptation to their conditions. The potential for independent living and productive activity can also be inferred from these data. Information garnered in the assessment provides a foundation for treatment planning, vocational training, competency determination, and counseling for both patients and their families. Clinical neuropsychologists serve as invaluable clinical experts who integrate information from a person’s history, behavioral observations, and test data to provide a snapshot of current cognitive functioning, help identify factors contributing to dysfunction, and guide treatment and recommendations; they are an integral and unique contributor to the patient’s clinical team.

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CHAPTER 4

Neuroimaging in Neuropsychiatry Robin A. Hurley, M.D., FANPA Shiv S. Patel, M.D. Katherine Taber, Ph.D., FANPA

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. 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). Opendesign magnets are now available that help the patient feel less confined (Bangard et al. 2007; Enders et al. 2013).

FIGURE 4–3. Neuroimaging equipment. See Plate 17 to view this figure in color. 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). See Plate 18 to view this figure in color. 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. See Plate 19 to view this figure in color. (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) fluidattenuated inversion recovery (FLAIR) MRI than (D) T2W MRI. (F) Adult male with encephalomalacia (arrow) and gliosis (arrowhead) in the midline frontal cortex due to being hit on the occiput decades earlier. (G) FLAIR and (H) T1W postcontrast of young adult male with 13.5-mm lesion in the medial right cerebellum, without edema, hemorrhage, mass effect, or enhancement on contrast. Differential includes low-grade astrocytoma or early oligodendroglioma. (I) Early-middle-aged male with multiple areas of increased signal in the cortical white matter on FLAIR MRI, consistent with diffuse axonal injury from multiple exposures to explosions.

The gradient echo sequence is also commonly used. This technique is very sensitive to anything in the tissue causing magnetic field inhomogeneity, such as blood (or its breakdown products) or calcium. These images are sometimes called susceptibility weighted because differences in magnetic susceptibility between tissues cause localized magnetic field inhomogeneity and signal loss. As a result, gradient echo images have artifacts at the interfaces between tissues with very different magnetic susceptibility, such as bone and brain. The artifacts at the skull base are sometimes severe. Another method that is clinically useful is diffusion-weighted imaging (DWI). DWI is sensitive to the speed of water diffusion and provides visualization of ischemic stroke in the critical first few hours after onset (Grignon et al. 2012; Lerner et al. 2014). DWI is also informative in other conditions, including metabolic encephalopathies (e.g., hypoglycemic, hyperammonemic, osmotic), infection, neurodegenerative conditions, and TBI (Figure 4–4) (Bathla and Hegde 2013; Keogh and Henson 2012; Le and Gean 2009). Diffusion tensor imaging, a more complex version of DWI, is presently used primarily for clinical research (Grignon et al. 2012; Lerner et al. 2014).

Contrast-Enhanced Imaging Contrast agents travel in the vascular system and normally do not cross into the brain parenchyma, because they cannot pass through

the blood-brain barrier (BBB). The BBB is formed by tight junctions in the capillaries that serve as a structural barrier, and they function like a plasma membrane. In some disease processes, the BBB becomes permeable. As a result, contrast agents can diffuse into brain tissue. Pathologic processes in which the BBB is disrupted include autoimmune diseases, infections, and tumors. Contrast enhancement can also be useful in the case of vascular abnormalities (such as arteriovenous malformations and aneurysms), although the contrast agent remains intravascular.

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

Magnetic Resonance Imaging Contrast Agents To manufacture an MRI contrast agent, a paramagnetic metal ion is attached to a very strong ligand that prevents any interaction with surrounding tissue and allows the complex to be excreted intact by the kidneys (Kanal et al. 2014). All seven currently approved contrast

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

Practical Considerations Guiding Structural Neuroimaging in Clinical Practice Selecting the Neuroimaging Type The clinical context determines the choice of imaging modality. There are a few brain-based conditions best viewed with CT, including calcification, acute hemorrhage, and skull fracture (Figure 4–2) (Thomas et al. 2010). Otherwise, MRI is the preferred modality in clinical neuropsychiatry unless it is contraindicated, because visualization of both neuroanatomy and pathology is much better (Figures 4–4 and 4–5). In addition, MRI does not produce bonerelated 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 MRIcompatible 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 obsessivecompulsive 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 fluorine18) 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-6phosphate. 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 betaamyloid 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. See Plate 20 to view this figure in color. 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 bluepurple 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. Threedimensional (3D) reconstructions can also improve visualization.

Practical Considerations Guiding Functional Neuroimaging in Clinical Practice Selecting the Neuroimaging Type PET has the advantages of higher spatial resolution and true attenuation correction (nearly eliminating attenuation artifacts). SPECT has the advantages of being more widely available and less expensive.

Imaging Request As discussed previously for ordering structural neuroimaging, it is essential to provide an accurate and complete history when ordering a functional imaging examination (“rule out pathology” or “new-onset mental status changes” are unacceptable). If a lesion is suspected in a particular location, this should be noted. The imaging physician and nuclear medicine team also need information on the patient’s current mental status (e.g., delirious, psychotic, easily agitated, paranoid). Having this information may eliminate difficulties with patient management during radiotracer administration or scanning.

Patient Preparation The clinician ordering the examination should always explain the procedure to the patient and be mindful to mention the requirement for absolute immobility during the approximately 30 minutes of scanning. During imaging, the head is generally held still with support from a cradle attached to the imaging table, sometimes with additional support from light taping (see Figure 4–3). Nuclear

cameras are not as confining as magnetic resonance scanners and, consequently, induce claustrophobic reactions much less frequently. Nonetheless, the scanning table is hard and can be uncomfortable for some patients. If the clinician ordering the examination suspects that the patient may become agitated or be unable to remain still for the length of the examination, then light sedation may be required. Many medications alter cerebral activity and blood flow; therefore, antianxiety and other sedative medications are best administered after the tracer distribution in the brain has become fixed, which is less than 10 minutes after injection for SPECT and 20–30 minutes after injection for PET. A sedative may be critical to achieving a successful scan in selected patients. The patient may be requested to abstain from certain activities or foods prior to scanning. Furthermore, he or she may be required to rest in a dark room immediately prior to and during tracer uptake.

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

Use of Neuroimaging Results in Clinical Practice The clinician ordering the neuroimaging exam should always review the images and radiology report with the patient and/or family.

In some cases, prior consultation with the radiologist may be informative. It is helpful for the clinician to have some desk reference materials on brain anatomy and circuit function available during the consultation. If the images and reports were brought by the patient and/or family, the clinician should verify that, indeed, he or she is reviewing the correct patient’s exams and reports. Common questions from patients when discussing positive findings include the following: What does this mean in terms of my symptoms? Will this get worse? Will I become demented? How will this affect me in the future? The clinician should allot sufficient time with patients and their families when presenting neuroimaging results. Neuroimaging exams are displayed according to imaging department protocols and as needed for the detection of specific pathology. Typically, noncontrast head CT examinations are displayed in axial cross section and, in most centers, in “radiologic” rather than “anatomic” view (i.e., the patient’s left is on the right side of the image and vice versa). Advanced CT imaging techniques, SPECT, PET, and MRI examinations are interpreted utilizing multiple planes (axial, coronal, and sagittal). Most anatomical landmarks are easily recognized on the axial plane, although coronal planes may be preferred for identifying some structures (i.e., amygdala, mammillary bodies).

Neurocognitive Disorders Cognitive decline is a common clinical reason for requesting neuroimaging (Bhogal et al. 2013; Nasrallah and Wolk 2014; Valkanova and Ebmeier 2014). For neurocognitive disorders due to Alzheimer’s disease (AD), neuroimaging findings vary with the stage of illness (Figures 4–7 and 4–8). Early-stage atrophy (structural neuroimaging) in the mesial temporal area, which contains the hippocampus and associated cortices, may be predictive for progression from mild cognitive impairment to AD. In later stages, MRI demonstrates generalized atrophy. SPECT/PET (functional

neuroimaging) is more specific, with a classic pattern of bilateral, symmetrical, decreased perfusion or metabolism in the medial temporal and lateral temporoparietal areas.

FIGURE 4–7. Single-photon emission computed tomography (SPECT) cases. See Plate 21 to view this figure in color. 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. See Plate 22 to view this figure in color. Functional neuroimaging may provide insight into the etiology of cognitive decline, illustrated here with axial PET imaging of glucose metabolism (18-fluoro-2deoxyglucose [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.

Traumatic Brain Injury

Neuroimaging can be of value in patients with neuropsychiatric symptoms in later stages (subacute, chronic) following TBI (Raji et al. 2014). MRI may localize larger areas of injury (see Figures 4–4 and 4–5), but diffuse axonal injury is not usually well visualized. Functional imaging is often abnormal in symptomatic patients—even when structural imaging is negative or does not explain manifesting symptoms. It must always be borne in mind, however, that many healthy individuals have some limited areas of mildly reduced perfusion. Although they are not commonly used in clinical practice, several longitudinal studies have indicated that a negative (normal) brain SPECT in the acute phase predicts good long-term neurological outcome (Jacobs et al. 1994, 1996).

Conclusion The subspecialty of neuropsychiatry/behavioral neurology, like other areas in medicine, has been deeply influenced by advancing technology. Structural and functional neuroimaging modalities have progressed to the point that they now can contribute to multiple aspects of clinical care. Thought, memory, and emotion are believed to occur by way of complicated circuits or networks (Figure 4–1) that include interconnected cortical and subcortical (Figure 4–9) areas of brain (Bonelli and Cummings 2007; Filley 2010, 2011; Haber and Rauch 2010). Additional functional anatomy reference materials can be found at www.mirecc.va.gov/visn6/Tools-Tips.asp. Optimal utilization of the rich information that neuroimaging potentially provides requires that clinicians not only be able to identify clinical conditions that warrant neuroimaging investigation (e.g., TBI, stroke, poison/toxin exposure) but also have a basic understanding of brain anatomy and circuit function.

FIGURE 4–9. Brief guide to subcortical functional anatomy. See Plate 23 to view this figure in color. 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 Kerry L. Coburn, Ph.D. Nash N. Boutros, M.D. Samuel D. Shillcutt, Pharm.D., Ph.D. 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 (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 higherorder 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, errorrelated 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 evidencebased 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 Jeffrey H. Newcorn, M.D. 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 hyperactivityimpulsivity 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. Hyperactivityimpulsivity 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 metaanalysis (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, medicationnaive 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 ganglioparieto-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 taskirrelevant 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 EEGBased 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 FDAapproved 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 immediaterelease 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 immediaterelease 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 CLONIR. 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 placebocontrolled 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 wakepromoting 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 wellsupported 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 evidencebased 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 selfregulatory or other compensatory strategies. These interventions help manage problems with task engagement, completion, and organization and minimize secondary problems related to selfesteem, 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, parentchild 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 Alya Reeve, M.D., M.P.H. Cynthia Y. King, M.D.

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 selfstimulatory behaviors become more evident at this age. A small proportion of individuals with ASD have behavioral deterioration during adolescence. In adults, symptoms of ASD often present with characteristics of having difficulty in getting along with others, rigid adherence to specific rules or habits, and narrow fields of interest or hobbies. Frequently, the diagnosis has been overlooked because of attributing behavioral characteristics to intellectual disability (diagnostic overshadowing). In circumstances of normal and high intelligence, ASD may be perceived (or tolerated) as personality quirks and idiosyncratic behavior. For example, individuals may be comfortable wearing only certain types of clothing, be sensitive to specific fabrics or touch, insist on placement of objects in specific locations, or follow specific routines. When these routines are disrupted, then prolonged dysphoria, anger, or emotional or behavioral shutdown may occur.

Assessment

Specific practice recommendations have been published by the American Academy of Neurology (Filipek et al. 2000), the American Academy of Pediatrics (Johnson et al. 2007), and the American Academy of Child and Adolescent Psychiatry (Volkmar et al. 2014). These practice parameters recommend two levels of screening/evaluation. Level I screening involves routine developmental surveillance by primary care physicians for young children. Routine early screening at ages 18 and 24 months has been recommended by the American Academy of Pediatrics (Johnson et al. 2007). Level II evaluation involves a diagnostic assessment performed by experienced clinicians. This involves obtaining a developmental history from the parents; conducting a review of available records, including medical, school, and interventions; and directly observing and interacting with the child. Second-hand reporting is not sufficient. Assessment of intellectual functioning, language, and adaptive functioning is expected. Extensive evaluations may include neuropsychological testing, tests of motor function, evaluation of psychiatric and behavioral comorbidities, and medical examination for physical anomalies, disorders of organ system functioning, and genetic screening. The current best practices standard diagnostic tool for gathering information concerning symptoms of autism from parents is the Autism Diagnostic Interview—Revised (ADI-R; Rutter 2003). The current best practices standard diagnostic tool for an observational and direct assessment of symptoms of autism is the Autism Diagnostic Observation Schedule (ADOS; Lord et al. 2001), which involves a semistructured interview specifically formatted in various modules that are developmentally appropriate for persons from infancy to adulthood and across a wide range of language and functioning levels.

Medical assessment is needed to identify potential etiological and comorbid factors, to determine the necessity for additional individual and family assessment, and to guide treatment decisions. A careful medical history, including prenatal, perinatal, postnatal, and early childhood, is important to assess risk factors associated with ASD, including maternal illness (e.g., gestational diabetes, infectious illness, exposure to teratogens), low birth weight or prematurity, and serious illness. Sleep disturbances and gastrointestinal symptoms are important to inquire about, both as treatable causes of disruptive behavior and as concomitant medical comorbidities. Family history helps identify other family members with developmental, educational, and social difficulties, as well as psychiatric disorders. Direct physical and neurological examination should seek to identify physical evidence of genetic syndromes highly associated with ASD, such as fragile X syndrome or tuberous sclerosis; abnormal neurological findings suggestive of central nervous system insult; and/or sensory impairment such as hearing loss or visual impairment. Growth parameters, including head circumference, should be assessed. Referral for specific hearing or vision assessment (more than bedside examination) is indicated if any concerns are raised through the history or examination. Blood testing for lead or other toxin exposure is appropriate if environmental risk factors persist, especially if children persist in mouthing objects. Chromosomal microarray is recommended as a standard of care for all individuals diagnosed with ASD and or developmental delay (Miller et al. 2010). Targeted genetic testing, such as fragile X DNA or methyl–CpG-binding protein 2 gene (MECP2) mutations in females with a clinical presentation consistent with Rett’s disorder (acquired microcephaly, neurological regression, and stereotypical hand movements), is recommended. Routine magnetic resonance imaging and electroencephalography are not recommended unless a person has clinically relevant symptoms such as focal neurological signs, an examination suggestive of

tuberous sclerosis, or a history that is indicative of seizures (Johnson et al. 2007).

Differential Diagnosis ASD should be differentiated from other specific developmental disorders (including language disorders), intellectual disability, reactive attachment disorder, obsessive-compulsive disorder, selective mutism, and childhood-onset schizophrenia. In adults, a similar differential is in order, as well as concerns for obsessivecompulsive 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. Obsessivecompulsive 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 egodystonic. 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 highpitched 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 ASDspecific 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 Marie A. DeWitt, M.D. Larry E. Tune, M.D., M.A.S.

Delirium has been recognized for thousands of years. The origins of the word trace back to the Latin delirare, literally meaning to “go off the furrow” (de “off, away from”+lira “earth thrown up between two furrows”) and metaphorically referring to a state of deviation or derangement. As early as 500 B.C., the terms phrenitis and delirium were used to denote mental changes associated with fever, head trauma, or poisoning. Hippocrates’ writings reference phrenitis and lethargus to distinguish between what are now recognized as the two major subtypes of delirium, hyperactive and hypoactive, respectively. Formalized diagnostic criteria were eventually established and published in DSM-III (American Psychiatric Association 1980). The essential feature of delirium, inattention, has remained consistent over the years; however, the secondary features have changed as the conceptualization of delirium has evolved. At the present time, the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD) provide generally accepted criteria for the diagnosis of delirium. Although the two systems are similar in their established diagnostic

criteria, DSM-5 (American Psychiatric Association 2013) tends to be more inclusive than ICD-10 (World Health Organization 1992), which can complicate the comparison of epidemiological data (Neufeld and Thomas 2013). Criticism of these classification systems includes the dichotomous nature of diagnosis, lack of minimum thresholds for presence of symptoms, and lack of clarity regarding the duration of symptoms (Davis et al. 2013). Table 8–1 compares these two classification systems and organizes the diagnostic criteria into primary features, secondary features, and exclusionary criteria.

TABLE 8–1. Comparison of DSM-5 and ICD-10 diagnostic criteria for delirium DSM-5 Core features

Secondary features

Exclusions

ICD-10

Disturbance in attention and awareness

Clouding of consciousness

Develops over a short period of time (represents a change from baseline)

Disturbance of cognition, with impairment of both immediate recall and recent memory (but relatively intact remote memory) and disorientation

Tends to fluctuate in severity over the course of a day

Rapid onset and fluctuations of symptoms over the course of the day

Disturbance in cognition

Psychomotor disturbance

Evidence that the disturbance is a direct physiological consequence of another medical condition or substance/toxin intoxication or withdrawal, or is due to multiple etiologies

Disturbance of sleep or the sleep-wake cycle

Not better explained by another preexisting or evolving neurocognitive disorder

Not induced by alcohol and other psychoactive substances

Evidence of an underlying cerebral or systemic disease that can be presumed to be responsible for the manifestations

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. Sleepwake 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 inhospital 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 twothirds of cases (O’Regan et al. 2014; Siddiqi et al. 2006). Patients with dementia or hypoactive delirium are more likely to have their delirium unrecognized or misattributed to dementia or depression (Teodorczuk et al. 2012). Among consults received by psychiatric consultation services, nearly half of delirium diagnoses were unrecognized by the referring team, with detection rates poorest in patients who were older, had dementia, or had the hypoactive subtype of delirium (O’Regan et al. 2014). Barriers to delirium recognition likely exist at both the individual and organizational levels and include failure to recognize the benefit of treating delirium and the low priority given to the diagnosis (Teodorczuk et al. 2012).

Screening and Severity Instruments Detection of delirium is best accomplished with the use of a reliable and valid screening instrument (Neufeld and Thomas 2013). Delirium screening in high-risk patients, including but not limited to hospitalized older adults and ICU patients, is recommended (Teodorczuk et al. 2012). Instruments, however, vary in their intended purpose (e.g., screening, diagnostic, symptom severity), threshold for detection, reliability, and validity among specific populations (Adamis et al. 2010; Davis et al. 2013; Wong et al. 2010). For example, some instruments developed for use in the ICU have been shown to be inadequate for use outside of the ICU setting (Neufeld and Thomas 2013). Furthermore, awareness of instrument bias is important because many screening instruments poorly detect the hypoactive subtype of delirium. No consensus exists regarding preferred delirium scales (Davis et al. 2013). A comprehensive review of delirium scales indicated that there were substantial psychometric and validation data to support the use of the CAM, Delirium Rating Scale (DRS), DRS-R-98, Memorial Delirium Assessment Scale (MDAS), and NEECHAM Confusion Scale (Adamis et al. 2010). The Nursing Delirium Screening Scale (NuDESC) has since been validated repeatedly. It offers a rapid screening instrument designed for use by nurses that takes less than a minute to complete (Wong et al. 2010). The NEECHAM Confusion Scale is considered a screening tool and allows for classification into categories, including “at risk” (Adamis et al. 2010). The DRS, DRS-R-98, and MDAS were identified as being good at measuring symptom severity (Adamis et al. 2010). The DRS-R-98 is a 16-item clinician-rated scale comprising 3 diagnostic and 13 severity items, whereas the MDAS contains 10 items that include symptom and examination findings with ratings based on severity (Adamis et al. 2010; Wong et al. 2010). The CAM, with its accompanying algorithm, is the most widely utilized screening and

diagnostic instrument (Inouye et al. 2014). Although it is widely used in studies, the CAM requires interviewer training and formal cognitive testing, making it less clinically useful. The 3D-CAM, however, operationalizes the CAM into a structured 3-minute diagnostic assessment, creating an instrument that is more clinically convenient (Inouye 2016). There are several additional instruments used both clinically and in research. Among these are screening tools such as the ICDSC and the Delirium Observation Screening Scale, as well as severity instruments such as the Delirium Index and CAM-S (Adamis et al. 2010; Inouye 2016). For the child and adolescent population, the Pediatric Anesthesia Emergence Delirium Scale and the Cornell Assessment of Pediatric Delirium are both designed for use in the pediatric ICU (Hatherill and Flisher 2010; Traube et al. 2014). Additionally, the CAM has been modified for use with children, while the Family CAM provides a family assessment of delirium (Inouye 2016).

Pathophysiology and Neurobiology Observations and Findings The exact pathophysiology of delirium is unknown. In their hallmark studies, Engel and Romano theorized that delirium was the result of widespread cerebral metabolic insufficiency (Williams 2013). Although the specific pathophysiology is unknown, numerous abnormalities are associated with delirium, including alterations in electroencephalography, vascular integrity, neurotransmitter systems, and biomarkers. These associations are not necessarily causal; any etiological connections, however, remain theoretical. Electroencephalographic changes during delirium were identified decades ago. The typical electroencephalographic pattern associated with delirium is global slowing with complete loss of

posterior background rhythm and intermittent rhythmic delta activity (Neufeld and Thomas 2013). In addition to these electrical disturbances, vascular disturbances have also been noted. Diffuse cerebral hypoperfusion has been observed on imaging in the frontal, parietal, and temporal lobes (Williams 2013). It is hypothesized that this decrease in cerebral blood flow, sometimes by as much as 40%, during an episode of delirium may result in cell damage and death, thereby yielding the chronic cognitive impairments that persist after an episode of delirium (Yokota et al. 2003). Several biomarkers and neurotransmitter abnormalities are associated with delirium, but their relationship to delirium remains unclear. In general, elevated markers of inflammation and coagulation (e.g., tumor necrosis factor α, interleukin [IL]–1RA, IL-6, IL-8, IL-10, C-reactive protein) and low anti-inflammatory markers (e.g., insulin-like growth factor 1 [IGF-1]) are associated with increased risk and more severe course of delirium (Maldonado 2013). Levels of cerebrospinal fluid S100B, a marker of central nervous system damage, are increased in acutely ill patients with delirium compared with levels seen in acutely ill patients without delirium (Kamholz and Blazer 2013). Genetic factors such as risk associated with the presence of the apolipoprotein E4 genotype continue to be investigated.

Neuroendoimmunological Hypothesis It is hypothesized that the various precipitants of delirium act through several different pathways, ultimately implicating a common endpoint that clinically manifests as delirium. Current evidence supports significant involvement of the cholinergic, melatonergic, and hypothalamic-pituitary-adrenal axis (HPA) inflammatory systems in the pathophysiology of delirium. These three systems interact and influence each other in a maladaptive response that creates the clinical signs and symptoms of delirium. The core pathology of delirium centers on the cholinergic system. There is a direct relationship between exposure to anticholinergic

agents and precipitation of delirium, with higher levels of anticholinergic activity associated with increased delirium severity (Han et al. 2001). Additional evidence supports the idea that endogenous serum anticholinergic activity is increased in states of delirium (Maldonado 2013; Williams 2013). Attention, the impairment of which is the core symptom of delirium, is modulated in part by the cholinergic system. Visual hallucinations, a common symptom of delirium, are associated with cholinergic dysfunction in both the frontal cortex and the ventral visual system (Meagher et al. 2010), and the cholinergic system is intimately connected with the dopaminergic system, allowing downstream influence on other neurotransmitter systems, providing a plausible explanation for any possible therapeutic role of antipsychotic medications. Cholinergic activity and circadian mechanisms have a complex relationship. Melatonin is critical in the maintenance of a healthy circadian rhythm, and abnormalities can cause sleep disturbance, a nearly ubiquitous symptom of delirium. Melatonin levels decrease with age and dementia, both of which are significant risk factors for delirium. Melatonin induces acetylcholine release at the nucleus accumbens, and cholinergic projections from the brain stem to the thalamus and midbrain have a significant role in the regulation of the sleep-wake cycle (Fitzgerald et al. 2013). Melatonin secretion may be disrupted by infections, inflammatory response, and medications. There are also connections between the circadian system and dopaminergic mechanisms, tryptophan, serotonin, γ-aminobutyric acid (GABA)–ergic mechanisms, and the HPA axis, which may contribute to the various perturbations in the dopamine, serotonin, and GABA neurotransmitter systems observed during delirium (Fitzgerald et al. 2013; Williams 2013). Cortisol, which is released in response to physical and psychological stress, aids in triggering an inflammatory cascade. A linear relationship has been described between cortisol levels and serum anticholinergic activity, suggesting that endogenous factors

such as stress states may contribute to serum anticholinergic activity (Plaschke et al. 2010). Elevated cortisol may be the result of infection, medical disease, or underlying psychological stressors. Cortisol leads to a release of various chemokines and interleukins, accounting for perturbations in levels of IL-6, IL-8, and IGF-1 in delirium. It is suspected that cortisol elevation, even when within the expected stress range, is likely of relevance to the development of delirium, especially in vulnerable individuals (Pearson et al. 2010).

Clinical Evaluation and Management Clinical Evaluation Although screening instruments can be helpful in identifying individuals at risk of or needing further evaluation for delirium, the diagnosis of delirium is clinical and based on the diagnostic criteria as listed in DSM-5 or ICD-10. Use of screening instruments alone or as a verification of a bedside evaluation can lead to overdiagnosis or underdiagnosis (O’Regan et al. 2014). The clinical examination should focus on assessing attention as well as noting other cognitive or perceptual disturbances. Methods for assessing attention vary, because there is no generally accepted means. The most accurate bedside assessments of attention may vary by population. One study found that listing the months of the year backwards (MOTYB) was the most accurate for assessment in older patients, whereas a combination of spatial span forward (SSF) and either MOTYB or reports of confusion was best in younger adults (O’Regan et al. 2014). Obtaining collateral information through chart review or discussion with staff and family is essential for establishing the acuity of symptoms, determining the existence of fluctuation in symptoms, and obtaining information regarding additional symptoms that may not be observed at the time of examination of the patient.

Known or suspected comorbid dementia can complicate the evaluation for possible delirium. The core feature of delirium is impairment in attention, regardless of the presence of dementia. Inattention, disorientation, and noncognitive symptoms are more severe in individuals with delirium superimposed on dementia than in those with dementia alone (Meagher et al. 2010). When compared with persons with delirium alone, individuals with delirium superimposed on dementia manifest more psychomotor agitation, disorganized thinking, and disorientation (Cole et al. 2002).

Identification of Etiologies Once the diagnosis of delirium has been made, a thorough medical evaluation is necessary to identify all potential causes of delirium. Updated vital signs, physical examination, and basic laboratory studies, including a complete blood count, comprehensive metabolic panel, and urinalysis, are appropriate. Additional aspects of the initial evaluation should be tailored to the specific risk factors and exposures of the patient. The medication list review is recommended, because medications, including many commonly used medications possessing anticholinergic properties, frequently contribute to the development of delirium (Han et al. 2001). Specifically, avoidance of new prescriptions of benzodiazepines, opioids, dihydropyridines, and histamine1 antagonists is recommended in those at risk of delirium, and caution is recommended with histamine2 antagonists, tricyclic antidepressants, antiparkinsonian medications, steroids, nonsteroidal antiinflammatory 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 analgesiafirst 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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Neufeld KJ, Thomas C: Delirium: definition, epidemiology, and diagnosis. J Clin Neurophysiol 30(5):438–442, 2013 24084176 Oldenbeuving AW, de Kort PL, Jansen BP, et al: Delirium in the acute phase after stroke: incidence, risk factors, and outcome. Neurology 76(11):993–999, 2011 21307355 O’Malley G, Leonard M, Meagher D, et al: The delirium experience: a review. J Psychosom Res 65(3):223–228, 2008 18707944 O’Regan NA, Ryan DJ, Boland E, et al: Attention! A good bedside test for delirium? J Neurol Neurosurg Psychiatry 85(10):1122–1131, 2014 24569688 Pandharipande PP, Girard TD, Jackson JC, et al; BRAIN-ICU Study Investigators: Long-term cognitive impairment after critical illness. N Engl J Med 369(14):1306–1316, 2013 24088092 Pearson A, de Vries A, Middleton SD, et al: Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls. BMC Res Notes 3:33, 2010 20181121 Plaschke K, Kopitz J, Mattern J, et al: Increased cortisol levels and anticholinergic activity in cognitively unimpaired patients. J Neuropsychiatry Clin Neurosci 22(4):433–441, 2010 21037129 Robinson TN, Raeburn CD, Tran ZV, et al: Motor subtypes of postoperative delirium in older adults. Arch Surg 146(3):295–300, 2011 21422360 Salluh JI, Soares M, Teles JM, et al; Delirium Epidemiology in Critical Care Study Group: Delirium epidemiology in critical care (DECCA): an international study. Crit Care 14(6):R210, 2010 21092264 Samuel M, Inouye SK, Robinson T, et al; American Geriatrics Society Expert Panel on Postoperative Delirium in Older Adults: American Geriatrics Society abstracted clinical practice guideline for postoperative delirium in older adults. J Am Geriatr Soc 63(1):142–150, 2015 25495432 Siddiqi N, House AO, Holmes JD: Occurrence and outcome of delirium in medical in-patients: a systematic literature review. Age Ageing 35(4):350–364, 2006 16648149 Teodorczuk A, Reynish E, Milisen K: Improving recognition of delirium in clinical practice: a call for action. BMC Geriatr 12:55, 2012 22974329 Traube C, Silver G, Kearney J, et al: Cornell Assessment of Pediatric Delirium: a valid, rapid, observational tool for screening delirium in the PICU*. Crit Care Med 42(3):656–663, 2014 24145848 van den Boogaard M, Pickkers P, Slooter AJ, et al: Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study. BMJ 344:e420, 2012 22323509

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CHAPTER 9

Poisons and Toxins Shreenath V. Doctor, M.D., D.D.S., Ph.D.

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 rulesbased 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 Home

Questions How old is your home? Do your symptoms get either worse or better at home? Do you feel better when you are away from home for any significant length of time? Has your home had any recent or previous water damage? Have you had roof or plumbing leaks? Any flooding? Have you noticed any musty odors? Is your home near any industrial facilities that give off chemical odors? Is home near a hazardous waste site, a chemical or power plant, a smelter? Do you smell chemical odors in the air? Does your drinking water come from a private well, city water supply, or grocery store? Are pesticides or herbicides used in your home or garden or on pets? Do you have a fireplace? Do you notice if you feel worse after using your fireplace? Have you had any problems with your air conditioning or heating systems?

Work

What kind of work do you do? Do your symptoms get either worse or better at work? Are you in contact with any chemicals? Have you noticed others at work having health issues? Describe your workplace air quality. Do you notice any odors in your workplace? Do you wear protective equipment at work? Has your workplace undergone any environmental testing?

School

Do your symptoms get either worse or better at school? Has there been any environmental testing/evaluations for mold or other substances, either airborne or surface, conducted in the classrooms at the school?

Site

Questions Has there been any damage sustained in past or present breaches of the outer building envelope, leakage into the inner building, and the need for replacement of waterdamaged 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 (trimethyltin)

Depression, rage, loss of libido and motivation, sleep disturbance, forgetfulness, personality deterioration

Aluminum

Personality change, fatigue, impaired memory and attention and executive motor functions

Arsenic

Impaired verbal memory, agitation, drowsiness, confusion, emotional lability, stupor, delirium, psychosis resembling paranoid schizophrenia

Lead Inorganic Children

Lethargy; hyperactivity; impaired intellect, reaction time, perceptual motor performance, memory, reading, spelling, auditory processing, and attention

Adults

Depression; apathy; confusion; fatigue; tension; restlessness; anger; decreases in visual intelligence, general intelligence, memory, psychomotor speed, rate of learning, attention, and visuoconstruction

Organic

Euphoria; psychosis; hallucinations; restlessness; nightmares; delirium; impaired concentration, memory, and abstract reasoning

Manganese

Somnolence, asthenia, anorexia, impaired speech, insomnia, hallucinations, excitement, aggression, mania, dementia, frontal lobe dysfunction, emotional lability, Parkinson-like symptoms, impaired judgment and memory

Mercury Inorganic

Irritability; avoidance; shyness; depression; lassitude; fatigue; agitation; decreases in visual memory, reaction time, motor speech, and learning

Organic

Incoordination, mood lability, dementia

(methylmercury)

Source. Adapted from Bleecker 1994; Bolla and Roca 1994.

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 Nmethyl-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

Source. Adapted from Bleecker 1994; Bolla and Roca 1994.

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 longterm 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 heatsensitive 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 waterdamaged 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 waterdamaged 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. W. Curt LaFrance Jr., M.D., M.P.H.

For more than a century, clinicians have observed a strong link between epilepsy and psychiatry as evidenced by frequent psychopathologies, psychosocial disturbances, and cognitive deficits among people with epilepsy. In many countries, until recently, epilepsy was conceptualized as a mental health disorder. Epilepsy can be associated not only with episodic behavioral disorders ictally and during the peri-ictal period but also with chronic behavioral disturbances interictally. Indeed, even when optimal seizure control is achieved and cognitive impairment is absent, epidemiological studies have shown greater vulnerability of people with epilepsy toward psychosocial distress (Sillanpää et al. 1998). A wide variety of etiologies affecting the central nervous system (CNS) can involve very similar behavioral signs and symptoms (Table 10– 1).

TABLE 10–1. Primary signs and symptoms of central nervous system disturbances Cognitive Affective dysregulation Communication/language dysfunction Intellectual impairment Impaired judgment Dysmnesia/inattention Disorientation Behavioral Anxiety Alteration in arousal Mood (elevation, depression, apathy) Motor (hyperkinetic, hypokinetic, or akinetic) Personality traits/changes Dyspraxia Perceptions Auditory Gustatory Kinesthetic pain/paresthesias/anesthesia Olfactory Visual Source. Adapted from Tucker 2002, p. 674.

In this chapter, we first provide an overview of the evaluation and management of epilepsy, focusing on the diverse neurobehavioral manifestations of seizures as influenced by seizure origin and extent of electrical propagation. In subsequent sections, we review the evaluation and management of the more common neuropsychiatric complications and comorbidities of the epilepsies and seizures.

Classification and Neurobehavioral Manifestations of Seizures and Epilepsy Electrical Seizure Versus Epilepsy An electrical seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. As implied in this definition, electrical seizure describes a broad spectrum of clinical manifestations (signs/symptoms) rather than a specific disease entity. Several disease entities can cause electrical seizures, including epileptic seizures, febrile seizures, and physiologic nonepileptic events, for example, alcohol/sedative withdrawal states, significant electrolyte disturbances, and oxygen deprivation from cardiac arrhythmia. Epilepsy, more specifically, is defined as a family of disorders of the brain characterized by an enduring predisposition to generate unprovoked electrical seizures (i.e., without obvious systemic disturbances known to trigger seizures). Historically, the diagnosis of epilepsy is established after a patient has experienced two or more unprovoked seizures, with the first two seizures being greater than 24 hours apart (Fisher et al. 2014). An International League Against Epilepsy (ILAE) task force recommended broadening the definition of epilepsy to address special circumstances when seizure propensity is substantial, despite the patient having had only one unprovoked seizure. The ILAE task force advised that epilepsy can be diagnosed after a single unprovoked seizure, should the probability of further seizures be similar to the general recurrence risk (~60%) after two unprovoked seizures, occurring over the next 10 years (Fisher et al. 2014). Some clinical circumstances associated with heightened probability of future seizures include the presence of remote brain insults, such as a stroke, CNS infection, or trauma (Hesdorffer et al. 2009).

The term seizure, as noted in the ILAE consensus, refers to sudden onset of symptoms that take hold of the patient, hence preventing normal function in some ways. Electrical or epileptic activity is frequently but not inherently invested in the word seizure, as this term has been used to describe other nonepileptic phenomena, such as psychogenic nonepileptic seizures (PNES) or physiologic nonepileptic events (e.g., convulsive syncope). When referring specifically to seizures of electrical origin, this term is frequently modified by the preceding descriptive term “epileptic” or “electrical.”

Classification of Seizures and Epilepsies The terminology and concepts for organization of seizures and epilepsies are constantly evolving, particularly consequent to recent advances in neuroimaging, genomic technologies, and molecular biology. Seizures are classified, by mode of seizure onset, as focal or generalized seizures. Focal seizures are conceptualized as seizures that originate from epileptogenic networks (a system of neurons) that are limited to one hemisphere. A focal epileptogenic network gives rise to seizures that demonstrate fairly stereotyped clinical manifestations. The old terminology added the descriptive term complex to denote seizures involving impairment of consciousness or awareness, while the term simple describes seizures without such impairment. However, the extent of ictal sensorium can frequently be difficult to define precisely. The new 2010 ILAE terminology recommends that focal seizures should be described according to their clinical manifestations (e.g., dyscognitive, focal motor), without trying to fit them into “complex” or “simple” categories that sometimes cannot be precisely distinguished (Berg et al. 2010). Generalized epileptic seizures are conceptualized as seizures that rapidly engage bilaterally distributed epileptogenic networks. Such

bilateral epileptogenic networks do not necessarily have to involve the entire cerebral cortex in a “generalized” sense. In most instances, limited bilateral cortical and subcortical structures are involved in the inception of generalized seizures. Under the 2010 ILAE classification, some epilepsies that involve exclusively either focal or generalized seizures can be classified as focal (localization-related) or generalized epilepsies, respectively. However, the task force recognizes that many epilepsies can include both seizure types and hence discourages the universal use of overarching categories for classifying epilepsies across all cases. The consideration of epilepsy etiologies is fundamental to the understanding of this family of disorders. The new classification for epilepsies also includes revisions of the descriptors of etiology (Berg et al. 2010). Instead of the old terms “idiopathic,” “symptomatic,” and “cryptogenic,” the following three new descriptors of etiology are recommended: 1.

The term genetic describes epilepsy as the direct result of known/presumed genetic defect(s) of which seizures are the primary sequelae.

2.

The terms structural and metabolic refer to the presence of distinct structural or metabolic conditions or diseases with demonstrated propensity toward epileptogenesis.

3.

The term unknown indicates that the underlying cause is not yet identified.

Finally, the ILAE task force recognizes that the degree of specificity to which the patients’ epilepsies are aligned within particular “syndromes” (e.g., seizure types, electroencephalogram [EEG] characteristics, age at onset) can portend significant prognostic and therapeutic implications. Such syndromic diagnosis would notably influence how patients are managed clinically or investigated in research studies. Ordered from the most specific

(top) to the least specific (bottom), the syndromic categories are listed in Table 10–2. TABLE 10–2. Epilepsy syndromes and epilepsies, as characterized by the International League Against Epilepsy Commission on Classification and Terminology (2010) based on specificity of diagnosis I.

Electroclinical syndromes (arranged by age at seizure onset) Neonatal period Example: benign familial neonatal epilepsy Infancy Example: Dravet syndrome Childhood Example: Lennox-Gastaut syndrome Adolescence–Adult Example: juvenile myoclonic epilepsy Less specific age relationship Example: reflex epilepsies

II.

Distinctive constellations Example: mesial temporal lobe epilepsy with hippocampal sclerosis

III.

Epilepsies attributed to and organized by structural-metabolic causes Examples: tumor, trauma, stroke

IV.

Epilepsies of unknown cause

Note. Diagnoses ordered from the most specific (top) to the least specific (bottom). Source. Adapted from Berg et al. 2010.

Neurobehavioral Manifestations of Focal Epileptic Seizures The semiology of seizures results from activation of specific and eloquent cortical areas by the ictal discharges and can help lateralize and/or localize the seizure focus. Knowledge of cortical

representation as well as corresponding ictal symptomatology is particularly important in the presurgical evaluation of epilepsy surgery candidates. In addition, such recognition can help distinguish neurobehavioral manifestations typical of epileptic seizures from atypical presentations warranting alternative etiological considerations. Each of the seizure types is described briefly below, with acknowledgment that clinical manifestations can vary across a wide spectrum, ranging from the full constellation of symptoms occurring in the sequence described to relatively fleeting or isolated subjective symptoms during which consciousness is intact.

Temporal Lobe Epilepsy Temporal lobe epilepsy (TLE) represents the most common type of focal epilepsy, accounting for approximately two-thirds (66%) of focal epilepsies (Semah et al. 1998), implicating the inherent vulnerability of the temporal lobe to epileptogenesis. In TLE, an overwhelming majority (~90%) of seizures arise from the mesial temporal region, frequently involving the hippocampus or perihippocampal structures (Schramm et al. 2001). A focal epileptic seizure emanating from these mesial temporal structures can manifest at first with fairly isolated affective, psychic, visceral, or special sensory symptoms such as fear, déjà vu, déjà entendu, jamais vu, jamais entendu, epigastric rising, and gustatory/olfactory perceptions, sometimes described as an aura. The most common presentation of such focal seizures is epigastric rising, in which the patient describes having fluttering sensations (“butterflies in stomach”) starting at the lower abdomen and then spreading upward. This epigastric sensation is frequently followed by spontaneous, unprovoked perception of fear; bystanders may observe expressions of distress in facial expression or verbalizations (e.g., “Help me” or “Oh no”) as the correlates of these experiences.

When the electrical activity spreads beyond the mesial temporal structures, the patient usually becomes amnestic and unconscious, in conjunction with relative neurobehavioral arrest. Also commonly occurring during this amnestic state are orogestural automatisms, which can entail chewing/lip smacking movements of the mouth, as well as semipurposeful fumbling or picking movements of the hands. These automotor hand movements usually occur ipsilaterally to the side of seizure onset. Meanwhile, the contralateral arm may assume a tonically flexed posture or other forms of dystonic limb posturing. Should the electrical activity continue to propagate outside of the temporal lobe to involve widespread bilateral structures, then the patient can demonstrate generalized convulsive activity, as described below. Such convulsive activity is heralded by version, or forced head turning, contralateral to the side of seizure onset. Subsequently, the patient enters the tonic phase, whereupon all four limbs demonstrate heightened tonicity. At times, the patient can assume asymmetric tonic limb posturing, whereupon the elbow contralateral to the side of seizure onset displays an extended position, while the opposite arm flexes over the chest (i.e., figure-4 sign). Lateral temporal epileptic seizures are classically heralded by simple auditory hallucinations, such as buzzing or ringing sounds (as opposed to the predominant affective, psychic, and visceral symptoms of mesial temporal seizures). At times, more complicated auditory hallucinations, such as human voices or organized music, can occur. Compared with mesial temporal seizures, lateral temporal seizures usually manifest with earlier dystonic motor involvement (rather than early oral automatisms), earlier widespread propagation (secondary generalization), and briefer overall seizure duration (Maillard et al. 2004).

Frontal Lobe Epilepsy Frontal lobe epilepsy (FLE) represents approximately one-fourth (24%) of all focal epilepsies, making FLE the second most common

type of focal epilepsy (Semah et al. 1998). Compared with other epilepsies, seizures of frontal lobe origin frequently manifest several unique features, including tendencies to have brief duration (30 minutes

Common

Rare

Seizures in the presence of doctors

Common

Unusual

Multiple unexplained physical symptoms, such as unexplained “chronic pain”

Common

Rare

Multiple operations/invasive procedures

Common

Rare

Seizure onset at 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 sportsand/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 recreationrelated concussion. Approximately 20% of U.S. service personnel serving in recent military conflicts have sustained a TBI, with 76.75% being mild TBI (Centers for Disease Control and Prevention et al. 2013). Nearly 3.2 million Americans are living with long-term neuropsychiatric consequences from TBI (Zaloshnja et al. 2008),

with most of those with long-term disability having experienced a TBI requiring hospitalization. Falls are the most common cause of injury, accounting for nearly 40% of TBI, resulting in U.S. emergency room visits, hospitalizations, or deaths between the years 2006 and 2010. Both the very young and old are particularly at risk for such injuries; 55% of TBI sustained by children less than a year up to 14 years and 81% of TBI in those age 65 and older were the consequence of falls. The second leading cause of TBI is unintentional blunt trauma, which accounts for approximately 15% of injuries. Motor vehicle accidents are the mechanism associated with nearly 14% of injuries, although motor vehicle accidents are second in terms of TBI-related deaths, accounting for 26% of fatalities. Assaults are the cause of nearly 10% of TBI and disproportionately affect young adults; 75% of assault-related TBI occurred in young adults between the ages of 15 and 44 (Centers for Disease Control and Prevention 2016). While sports-related TBI has received increasing attention both in the medical literature and popular press, many individuals with such injuries may not present for evaluation or emergency care, and thus these injuries are likely underrepresented in the above figures.

Neuropathophysiology of TBI TBI involves a combination of contact and inertial forces that mechanically induce disruption of cellular and metabolic processes. Although every TBI involves a unique set of forces acting upon a unique brain, the frontal and temporal lobes are particularly vulnerable to the deleterious effects of biomechanical trauma. Shearing and straining forces impact white matter, especially at the brain stem, cerebral parasagittal white matter, corpus callosum, and gray-white junctions of the cerebral cortex (Bigler 2007; Lipton et al. 2009; Meythaler et al. 2001; Povlishock and Katz 2005). This combination of neuroanatomical vulnerabilities explains the

frequency with which clinically significant early and late posttraumatic disturbances in cognition, emotion, and behavior follow TBI. Regional susceptibility to injury and related neuropsychiatric consequences are reviewed by Arciniegas (2011a). Biomechanically induced neuronal injury precipitates a complex and potentially injurious cascade of metabolic events, including dysregulation of calcium, magnesium, and potassium across injured cell membranes; biomechanically triggered action potentials; release of neurotransmitters and excitatory amino acids; calcium-regulated protein activation and mitochondrial dysfunction; alterations of cellular metabolism with free radical release and oxidative stress; activation of proteolytic enzymes; and in more severe cases, activation of programmed cell death (apoptosis). An ensuing “energy crisis” has been described, wherein increased energy demands to restore cellular homeostasis cause hyperglycolysis in the setting of normal or reduced cerebral blood flow. The resulting state is one of mismatch, with uncoupling between energy supply and energy demand (Giza and Hovda 2014). Biomechanically induced release of neurotransmitters involves a number of systems including glutamate, acetylcholine, dopamine, norepinephrine, serotonin, and γ-aminobutyric acid (GABA). This results in an early excess of neurotransmitters after injury, a state sometimes referred to as a “neurotransmitter storm.” This state usually resolves within days to several weeks in cases of severe TBI. Although neurotransmitter excess features in the early postinjury period, injury to efferent projections may eventually result in insufficient levels of various neurotransmitters. For example, early cholinergic and catecholaminergic excess is often followed by cortical cholinergic and/or catecholaminergic deficits that may contribute to the chronic neuropsychiatric impairments frequently encountered in the wake of TBI, with implications for pharmacological management (Arciniegas 2011b; Bales et al. 2009; McAllister 2009).

Evaluation of Persons With TBI Evaluation of persons with TBI entails a thorough neuropsychiatric examination based on the principles of assessment delineated in Chapter 2 (“Neuropsychiatric Assessment”). Importantly, for those with a history of TBI it is essential to remain mindful that this history is only one aspect of a much larger developmental, medical, neuropsychiatric, and psychosocial history and that these other historical elements must be given due consideration during the evaluation. Comprehensive assessment of persons with TBI therefore necessitates identifying any and all potential contributions to the individual’s presenting neuropsychiatric status, including preinjury, injury (e.g., TBI severity, concomitant injuries), and postinjury factors. Relevant preinjury factors may include age; gender; neurogenetics; neurodevelopment; premorbid intellectual function; medical, neurological, and psychiatric conditions; history of previous trauma (physical and emotional); substance use conditions; personality and coping styles; sociocultural background; and economic status. Such factors are likely to contribute to vulnerability or resilience during recovery from TBI. All postinjury factors, such as the presence or absence of appropriate medical care, concomitant physical injuries and/or medical complications, medications, education and expectations regarding TBI recovery, presence or absence of social support systems, postinjury coping styles, psychological issues, disability and role changes, and medicolegal entanglements, may influence the course of recovery and/or emergence of various neuropsychiatric symptoms (Arciniegas and Silver 2013). Silver (2012) has described a number of factors that may influence symptom manifestation, including stereotype threat, loss aversion, and feelings of anger and injustice that produce a unique differential diagnosis when compensation and/or litigation complicates clinical presentations. Importantly, these various factors will co-occur and mutually influence one another. Hence, any given

neuropsychiatric presentation will inevitably be the consequence of a complicated interplay between injury, preinjury, and postinjury factors, as illustrated in Figure 12–1 (Arciniegas and Silver 2013).

FIGURE 12–1. Model of the interactions of preinjury factors, injury factors, and postinjury factors in relation to posttraumatic neuropsychiatric disturbances. Source. Figure by David B. Arciniegas, M.D. © 2017. Used with permission of the author.

Clinical Interview to Establish the Historic Injury Event Obtaining information regarding the acute injury event is essential. Clinicians are encouraged to anchor their clinical interviews to accepted TBI definitions, such as those described in the section

“Defining TBI.” Specific questions should be asked to determine whether an alteration of consciousness, LOC, or PTA associated with an injury event occurred. Of course, if an individual experienced LOC or PTA, self-reporting of injury-related events and symptoms must be regarded with skepticism (i.e., one cannot self-report on occurrences for which one was unconscious or is amnestic). In such circumstances, the interview about the injury event will rely on what the individual has been told about the event by others at the scene or by medical providers. For example, the evaluator might also ask, “What is the last thing you remember before getting hit, and what is the first thing you remember afterward?" The ability to provide a detailed narrative of the injury event, capturing the moments just prior to impact and immediately afterward, represents a valuable data point in itself. While it may be difficult to precisely determine the duration of LOC or PTA, such inquiries will generally facilitate an initial determination as to whether an injury event meets or exceeds criteria for mild TBI. As noted above, patients may be unable to provide accurate details and may even inadvertently provide inaccurate histories. For example, an individual may presume that he or she was unconscious based upon a gap in memory, when in reality he or she was awake and alert but amnestic. For these reasons, it is generally useful to obtain collateral information when available. Collateral information (e.g., emergency room records, in which LOC and GCS scores are often documented), like the clinical interview itself, should be used to identify requisite criteria surrounding diagnosis and injury severity. Explicit documentation regarding more subtle alterations in consciousness is frequently lacking in such records. Emergency room records have been reported to miss approximately half of the cases of TBI (Powell et al. 2008). Hospital and/or rehabilitation records will sometimes include specific PTA assessments, such as the Galveston Orientation and Amnesia Test (GOAT; Levin et al. 1979) or the Orientation Log (O-

Log; Jackson et al. 1998); their presence in the medical record facilitates determination of the duration of PTA. Often, injury events are witnessed by friends or family (especially injury events occurring in the context of sports/recreation) and sometimes even captured on video. Such data may help to precisely determine the occurrence and severity of a TBI event. Although a clinical history anchored to requisite criteria for injury severity may be sufficient for establishing the occurrence of an injury event, use of psychometrically sound structured clinical instruments may also be useful for this purpose. The Ohio State University TBI Identification Method (OSU TBI-ID; Corrigan and Bogner 2007) is designed to elicit self-reports or proxy reports of a TBI occurring over a person’s lifetime. The Brain Injury Screening Questionnaire (BISQ) is another structured self-report instrument designed to elicit lifetime history of TBI (Dams-O’Connor et al. 2014). TBI remains a clinical diagnosis, and, as such, the possibility of inaccurately attributing symptoms to an injury event exists. Many factors other than TBI may cause or contribute to event-related disturbances of consciousness and/or sensory motor abilities (e.g., intoxication, cerebrovascular compromise, hypoxia-ischemia, subdural or epidural hematomas without overt brain injury, seizure, head and neck injury). Consideration of such factors prior to attributing disruptions in consciousness and/or sensorimotor abilities to TBI is recommended (Arciniegas 2013).

Symptoms and Course of Illness After TBI A broad array of neuropsychiatric symptoms may follow TBI of all severities. Common physical symptoms include headache, fatigue, sleep disturbance, vertigo or dizziness, sensitivity to light and/or sound, and anosmia. Cognitive disturbances potentially range from level of arousal and attention through higher-order executive functions and social intelligence. Problems with complex attention,

executive functioning, learning, memory, and speed of processing are common. Emotional disturbances often include irritability, depression, anxiety, affective lability, and decreased frustration tolerance. Behavioral disturbances or personality changes may involve aggression, disinhibition, impulsivity, and apathy. Although every individual and TBI should be conceptualized as being unique, there remain reasonably predictable aspects regarding the course and resolution of symptoms that are predicated on the well-established natural history of TBI (see Figure 12–2; Arciniegas et al. 2013).

FIGURE 12–2. Stages of posttraumatic encephalopathy. Source. Reprinted from Arciniegas DB, Frey KL, McAllister TW: “Cognitive impairments,” in Management of Adults With Traumatic Brain Injury. Edited by Arciniegas DB, Zasler ND, Vanderploeg RD, et al. Washington, DC, American Psychiatric Publishing, 2013, p. 141. Copyright © 2013. Used with permission.

Arciniegas et al. (2013) recommend describing the immediate neuropsychiatric consequences of TBI as an acute posttraumatic

encephalopathy. The term encephalopathy denotes the broad range of neurotrauma-induced clinical signs and symptoms that may follow an injury, with the modifier acute posttraumatic establishing a temporal relationship whereby the encephalopathy onsets immediately following the injury event. Recovery should also follow a reasonably predictable course involving the following five stages of posttraumatic encephalopathy: posttraumatic coma; posttraumatic confusional state; posttraumatic amnesia; posttraumatic dysexecutive syndrome; and recovery. Although these stages are named in accordance with the most salient cognitive feature associated with each, additional areas of impairment are often present. Some mild injuries never involve coma, confusional state, or amnesia, with recovery starting at the dysexecutive syndrome stage. Figure 12–2 illustrates a number of additional important principles relating to the natural history of TBI. Across all severities of TBI, symptoms and impairment are most pronounced immediately following injury (absent some contributing or emerging complication, such as intracranial hemorrhage), with subsequent improvement being the norm. Late-emerging symptoms and/or downward trajectories are atypical of TBI, across all levels of severity, and such manifestations suggest the presence of additional factors in need of consideration. Recognizing atypical trajectories following mild TBI is particularly important in light of the highly nonspecific nature of common postconcussive symptoms. Research comparing persons with mild TBI with individuals with orthopedic injury reveals that postconcussive symptoms, pain, and mental health are similar across all acute injuries, whether or not there is brain involvement. Hence, it is vital that clinicians attend to not only the nature of postinjury symptoms but also their temporal evolution and their trajectories (Cassidy et al. 2014). Figure 12–2 also illustrates an important point regarding the modifiers used to describe TBI severity. The terms mild, moderate, and severe refer to parameters surrounding the acute injury event

(e.g., duration of LOC, PTA). These terms are not intended to denote outcomes; a severe TBI is not necessarily associated with severe neuropsychiatric impairment in the late recovery phase. It is generally the case that more severe injuries feature a much broader spectrum of potential outcomes. Severe TBI features the broadest of spectrums, all the way from death or devastating neuropsychiatric impairment to remarkable recovery that approximates the individual’s baseline status. Mild TBI, on the other hand, generally features a far narrower spectrum of plausible outcomes relating to the direct effects of neurotrauma (see section “Mild TBI”).

Physical, Neurological, and Mental Status Examination A general physical examination should be performed on all patients, with attention to findings suggesting other physical injuries that potentially cause or contribute to symptoms commonly encountered subsequent to TBI (i.e., cervical injury causing headaches, painful musculoskeletal injury interfering with sleep). The most common cranial nerve abnormality after TBI is of the olfactory nerve. The relative frequency of anosmia and hyposmia subsequent to TBI makes this a potentially high-yield aspect of neurological examination. Eye movement disturbances are also relatively common in the setting of TBI; these disturbances may be a consequence of intracranial and/or extracranial injuries. Similarly, problems with balance may result from injury to the brain, visual or vestibular systems, and/or extracranial structures (such as the propioceptive system in the deep neck muscles). Damage to frontal subcortical circuits may result in disturbances of volitional motor inhibition, or paratonia. Primitive reflexes, including glabellar, snout, suck, palmomental, and grasp, may also feature and again suggest disturbances of frontal subcortical circuits (Arciniegas 2013).

The choice of any specific psychometrically sound instruments utilized to assess mood and/or cognition may need to be titrated to the individual’s functional status, which will be influenced by the severity of TBI, temporal proximity to the injury event, and concomitant injuries to other organ systems. Assessment of cognition is usefully anchored to measures with associated age- and education-based normative data. Careful consideration of preinjury cognitive abilities as well as psychological functioning is necessary to identify any acute or persisting changes from baseline. Importantly, the identification of any changes must be followed by consideration of functional relevance. While cognitive impairment may contribute to functional limitations, the degree to which an individual’s functional status is accounted for by cognitive deficits remains highly variable (Royall et al. 2007).

Neuroimaging Neuroimaging can play an important role in the evaluation of acute TBI. CT is particularly useful and appropriate in the setting of potential skull fracture or intracranial bleeding and may help to identify trauma-induced intracranial pathology necessitating neurosurgical intervention. As previously discussed, early structural neuroimaging with either CT or MRI helps to distinguish between complicated and uncomplicated mild TBI. Identifying complicated mild TBI is important because the prognosis associated with such injuries may be more akin to moderate TBI (Iverson et al. 2012; Williams et al. 1990). Neuroimaging’s role during the subacute or late postinjury period of recovery remains less well established. However, standard MRI sequences (typically involving T1- and T2weighted, 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 betablockers 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 antiinflammatories (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. Cognitivebehavioral 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. Comprehensiveholistic neuropsychological rehabilitation is recommended during the postacute rehabilitation phase for individuals with moderate to severe TBI. Pharmacotherapy for posttraumatic cognitive impairment spans strategies involving uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonism, augmentation of cerebral catecholaminergic function, augmentation of cerebral cholinergic function, and combinations thereof. Treatment with uncompetitive NMDA receptor antagonists, amantadine in particular, during the immediate postinjury period may decrease the duration of unconsciousness and improve arousal. For more enduring or chronic cognitive impairment, the selection of treatment strategy is usually guided by the nature of the persisting cognitive deficits. Problems involving declarative memory may respond to strategies involving cholinergic augmentation, such as donepezil or rivastigmine. Catecholaminergic augmentation may facilitate improvement in arousal, processing speed, attention, and executive function and may also offer benefits in terms of posttraumatic depression and apathy. Options include methylphenidate, dextroamphetamine, amantadine, bromocriptine, and carbidopa-levodopa (Arciniegas et al. 2013). Preliminary evidence suggests that controlled aerobic exercise may improve cognition, and concussive symptoms more generally, while restoring normal cerebral blood flow regulation (Leddy et al. 2013).

Conclusion Neuropsychiatric presentations after TBI are as unique and diverse as the individuals sustaining such injuries. Assessment thus requires a broad-based skill set that facilitates the identification of neuronal injury and its related deficits, as well as the identification of the full gamut of comorbid conditions and psychosocial circumstances that potentially contribute to symptoms and

impairment. Only by identifying the totality of factors driving neuropsychiatric impairment may we offer interventions to mitigate the diffuse circumstances contributing to the individual’s experience in the wake of injury. Such an approach will afford substantial improvement for the vast majority of persons with a history of TBI, improving function and/or quality of life for patients and their families.

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CHAPTER 13

Hypoxic-Ischemic Brain Injury C. Alan Anderson, M.D. David B. Arciniegas, M.D. Christopher M. Filley, M.D.

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 oxygenbinding 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 Hypotonic (hypoxic) hypoxia

Characteristics Contexts Low Pa02 Normal blood oxygenbinding capacity

Examples

Low O2 tension High-altitude location in inspired air Near-suffocation in enclosed space Choking on foreign object Tracheal collapse

Normal perfusion Normal endtissue oxygen extraction capacity Diffusion impairment

Inhalation of water (near drowning) Severe pulmonary edema

Alveolar ventilation- Pulmonary embolism perfusion Chronic obstructive mismatch pulmonary disease Venous-to-arterial shunts Anemic (hypemic) hypoxia

Normal Pa02 Reduced hemoglobin or Reduced blood blood cells oxygenbinding capacity Normal perfusion Normal endtissue oxygen extraction capacity

Interference with the binding of oxygen to hemoglobin

Vessel-to-vessel or intracardiac shunts Bone marrow failure Hemorrhage

Methemoglobinemia due to carbon monoxide poisoning, including cigarette smoking

Injury type

Characteristics Contexts

Ischemic Normal or (stagnant) low Pa02 hypoxia Normal blood oxygenbinding capacity

Insufficient blood flow Normal Pa02

Examples Severe hypotension Focal ischemia Global ischemia due to near-strangulation Low cardiac output

Reduced perfusion Normal endtissue oxygen extraction capacity Low Pa02 Histotoxic hypoxia

Normal Pa02 Reduced blood oxygenbinding capacity

Blockade of mitochondrial metabolism

Cardiopulmonary arrest Cyanide poisoning

Normal perfusion Reduced endtissue 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 longterm 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 hypoxicischemic 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 hypoxicischemic 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 hypoxicischemic 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 hypoxicischemic 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 hypoxicischemic 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 hypoxicischemic brain injury is similar to that used in other settings. Response to treatment can vary significantly, with some patients showing dramatic response to medications. In general, however, these conditions appear less responsive to pharmacologic treatment and interventional therapies (i.e., deep brain stimulation) than primary parkinsonism (i.e., Parkinson’s disease) and idiopathic dystonia, perhaps reflecting hypoxic-ischemic-induced damage and/or destruction of the neurons in these structures that ordinarily are the targets of these pharmacotherapies (Lu-Emerson and Khot 2010; Venkatesan and Frucht 2006).

Characteristic Patterns of Weakness As noted earlier, watershed areas are particularly vulnerable to the effects of reduced perfusion. When the injury occurs in anterior frontal white matter and involves the zone between the anterior and

middle cerebral artery territories, patients may present with bilateral arm weakness (brachial diplegia) and relatively preserved lower extremity function. This condition is commonly referred to in neurological practices as the “man-in-the-barrel syndrome.” Involvement of parieto-occipital structures in the watershed zone between the vascular territories of the middle cerebral and posterior cerebral arteries is associated with the development of cortical blindness or, more rarely, Balint’s syndrome (i.e., optic ataxia, oculomotor apraxia, and simultanagnosia). Pharmacotherapeutic and rehabilitative interventions for these problems and their complications (e.g., spasticity, contractures, gait and mobility impairments) are modeled on those applied for similar motor impairments due to other acquired brain injuries. The effectiveness of these motor-specific rehabilitative interventions in this population is not well established, but common clinical experience and several rehabilitation outcome studies suggest that these interventions may improve the functional status of persons with hypoxic-ischemic brain injuries (Burke et al. 2005; Shah et al. 2004, 2007).

Disorders of Consciousness Following initial resuscitation efforts, abnormalities of wakefulness and awareness of self and environment are common (Table 13–2). The duration of these disturbances varies with the degree and duration of hypoxia and/or ischemic hypoxia. Patients typically progress from coma through the states of diminished arousal and awareness—i.e., the disorders of consciousness, including vegetative state (VS, also known as the unresponsive wakefulness syndrome) and minimally conscious state (MCS)—albeit to varying endpoints (Giacino and Kalmar 2005; Giacino et al. 2002; van Erp et al. 2015; Whyte et al. 2009).

TABLE 13–2. Defining features of the disorders of consciousness and brain death Brain stem function

Wakefulness

Awareness

Minimally conscious state

Present

Present

Present

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 lifesustaining 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 offlabel. 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 hypoxicischemic 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 hypoxicischemic 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 recommendation.

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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 ageassociated 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 hypoxicischemic 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 Joseph S. Kass, M.D., J.D. Alicia S. Parker, M.D. Rohini D. Samudralwar, M.D.

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 HIVassociated 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 treatmentnaive 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 selfreport, 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. Singlephoton 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 HIVinfected 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 personyears 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 T1weighted 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 HIVinfected 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 T2weighted 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 (precART 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 HIVinfected patients are also associated with worse neurocognitive impairment (Sattler et al. 2015). Additionally, HIV increases the risk of stroke, an event that may have long-lasting neuropsychiatric sequelae.

Plasma and CSF Biomarkers HAND may be preventable with early virologic control and prevention of CD4+ T cell nadir below 200 cells/mm3. Because CD4+ T cell count and plasma viral load do not correlate with the risk of cognitive impairment for patients receiving cART, researchers have sought plasma, CSF, and neuroimaging biomarkers for HAND. Plasma biomarkers have included markers of activated monocytes and macrophages (e.g., increased plasma-soluble CD14 linked to impairment in attention and learning), and CSF biomarkers have focused on markers of inflammation (e.g., increased CSF neopterin, MCP-1), neuronal injury (e.g., increased neurofilament), CSF viral escape (presence of virus in CSF despite systemic viral suppression), and viral genomics (Clifford and Ances 2013).

Neuroimaging Biomarkers

Gadolinium-enhanced structural MRI of the brain is an important part of the workup of cognitive impairment in HIV-infected patients, most importantly to exclude secondary causes of dysfunction such as opportunistic processes, cerebrovascular disease, and non-HIVrelated pathologies. MRI is preferred to head CT. Brain MRIs in HAND patients vary considerably in the pathological changes they display, ranging from mild cortical and white matter atrophy to periventricular hyperintensities on a T2 fluid-attenuated inversion recovery (FLAIR) sequence that do not enhance with gadolinium on the T1 sequence. Volumetric studies have found atrophy throughout the cerebral cortex, particularly in the anterior cingulate cortex, lateral temporal lobe, primary motor and sensory cortices, and frontal and parietal lobes. Furthermore, cognitive and motor impairment is associated with reduced basal ganglia volumes and nigrostriatal and frontostriatal circuit atrophy (Steinbrink et al. 2013). Magnetic resonance spectroscopy studies consistently demonstrate reductions in N-acetylaspartate, a signature of neuronal injury, along with an increase in myoinositol and choline levels, indicative of glial proliferation, especially in the frontal white matter and basal ganglia. Diffusion tensor imaging has demonstrated reduced white matter integrity of the corpus callosum and alterations in the caudate nucleus. Cognitive impairment has also been associated with a reduction in the integrity of cortical white matter, the corpus callosum, and the corona radiate (Clifford and Ances 2013). Blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) studies have demonstrated both increased and decreased activation in various brain regions depending on the type of tasks subjects were asked to perform. fMRI may even demonstrate dysfunction before neuropsychological testing. Compared with control subjects, patients with HIV demonstrated a greater magnitude of brain activation in the lateral prefrontal cortex with normal performance during fMRI and on a battery of neuropsychological tests. HIV-

infected patients also showed increased activated brain volume in the lateral prefrontal cortex, independent of task difficulty (Clifford and Ances 2013). Resting state functional connectivity MRI changes in the salience and default networks in HIV-infected patients are similar to those that occur in normal aging (Clifford and Ances 2013). Fluorodeoxyglucose (18F) PET (FDG-PET) studies have also demonstrated both cortical hypometabolism and basal ganglia hypermetabolism (Davison et al. 2011). A PET study utilizing tracers that bind to dopamine transporters (DATs) or D2 receptors observed decreased DAT binding in the putamen and ventral striatum but no difference in D2 receptor binding in HAND patients relative to control subjects. Decreases in DAT binding were associated with increasing HAND severity (Wang et al. 2004). Even early HIV infection leaves a neuroimaging mark on the brain. The brain volumes of 15 acutely HIV-infected individuals (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 T2weighted 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 Alasdair G. Rooney, M.B.Ch.B., M.D.

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 highergrade (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 selfinduced 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 wellrehearsed 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 frontaltype 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 voxelbased 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/patientsupport/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 solutionfocused 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 highquality 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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Stimulus control, sleep restriction, cognitive therapies

Goal Relax, reduce autonomic arousal

Sleep hygiene and other behavioral interventions Have a relaxing bedtime routine.

Make a list of problems or worries for later.

CBT-I interventions Relaxation training, hypnosis, biofeedback, mindfulness

Avoid stressful or anxiety-provoking conversations and media (e.g., books, movies, news) before bed. Note. CBT-I=cognitive-behavioral therapy for insomnia.

In sleep restriction therapy, homeostatic and circadian forces are leveraged by first establishing a fixed wake time and a fixed sleep opportunity—limited initially to a sleep diary–derived average of time spent sleeping—and then progressively advancing the scheduled bed time while maximizing sleep efficiency. (Because sleep deprivation may precipitate mania or seizures, sleep restriction therapy is contraindicated for patients with these conditions.) Cognitive therapy consists of psychoeducation and guided identification and restructuring of maladaptive thoughts through learning and practicing specific skills, including paradoxical intention, attention bias, and imagery rehearsal. Relaxation training aims to reduce the physiological arousal associated with insomnia and may include progressive muscle relaxation, diaphragmatic breathing, biofeedback, hypnosis, and mindfulness. A great deal of practice in session and during waking hours is required to learn these skills for them to be readily used and effective at bedtime and not to be quickly abandoned or contribute to the already conditioned insomnia response. Phototherapy also may be helpful in insomnia or jet lag. This therapy involves the use of bright light in the morning or evening depending on whether there is a phase delay or phase advance component, respectively.

Hypersomnias The central theme of these disorders is an increased need for sleep. The main subtypes include narcolepsy (type I and type II), idiopathic hypersomnia, Kleine-Levin syndrome, and hypersomnias secondary to

medical or psychiatric conditions and medications. The MSLT is the gold standard test for defining daytime sleepiness. The clinical manifestations of narcolepsy include excessive daytime sleepiness as the cardinal symptom, and a mean sleep latency of less than 8 minutes and two or more sleeponset 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, sleeprelated 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 MorningnessEveningness 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 sleepwake 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 halflife, patient genetic factors, comorbid conditions, and drug-drug interactions. Through skillful psychopharmacology, medication effects can be harnessed for the benefit of the patient, but failing to pay heed to these effects can lead to harm, patient dissatisfaction, and noncompliance. In general, medications that interfere with receptor-neurotransmitter systems involved in wakefulness promotion (i.e., Ach, NE, DA, 5-HT, H1 or H2, alpha1), such as most antipsychotics, tricyclic antidepressants, and antiepileptic medications, are more likely to cause sedation, whereas stimulators of these systems, such as procholinergic (e.g., donepezil) or dopaminergic (e.g., L-dopa) agents, if dosed in the evening, may disrupt sleep and cause disturbing dreams and, in the case of L-dopa, hallucinations, agitation, and sleep attacks (see Table 17–1). Taking advantage of this effect, use of donepezil in patients with Alzheimer’s disease and OSA can stimulate respiratory drive and reduce apneic events (Sukys-Claudino et al. 2012). Secondary effects of medications can disrupt sleep-wake dynamics—for example, exacerbation of OSA secondarily by the muscle-relaxing effects of benzodiazepines or by increased neck circumference due to weight gain from atypical antipsychotics, mood stabilizers, and some antidepressants.

The use of substances to induce sleep or promote wakefulness in our modern society is pervasive and can be problematic. Alcohol is commonly used to induce sleep but, unfortunately, results in a net decrease in total sleep time with decreased sleep efficiency in the second half of the night, reduced restorative (SWS) sleep, and early awakening, and alcohol is associated with precipitating or worsening SRBD and PLMS (Conroy et al. 2010). Caffeine, as an adenosine receptor antagonist, is thought to promote wakefulness by interfering with the homeostatic drive for sleep, and both evening use and regular daily use are associated with disrupted sleep and daytime sleepiness (Roehrs and Roth 2008).

Conclusion Sleep is an indispensable physiological phenomenon with far-reaching implications for the physical and mental well-being of an individual. Evaluating and addressing sleep-wake disorders should be integral to health care delivery in all specialties of medicine. There is robust evidence of improvement in outcomes in many comorbid illnesses when sleep-wake disorders are managed well. Referral to a specialist trained in the management of sleep-wake disorders should also be considered in the overall treatment paradigm.

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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 Melanie Selvadurai, B.H.Sc., M.B.A. Omar Ghaffar, M.D., M.Sc., FRCPC

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 myelinoligodendrocyte 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). Immunemediated 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 1. ≥2 attacksa

Additional data needed for MS diagnosis 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 MStypical 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 gadoliniumenhancing lesions and nonenhancing lesions at any time; or A new T2 and/or gadoliniumenhancing 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 isolated syndrome)

For DIS:

Clinical presentation

Additional data needed for MS diagnosis ≥1 T2 lesion in at least 2 of 4 MStypical 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 gadoliniumenhancing and nonenhancing lesions at any time; or A new T2 and/or gadoliniumenhancing 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 (PPMS)

1 year of disease progression (retrospectively or prospectively determined), plus 2 of 3 of the following criteriad: 1. Evidence for DIS in the brain based on ≥1 T2 lesions in the MScharacteristic (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 CESD 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; obsessivecompulsive 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 normalappearing 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 wellbeing in the presence of significant neurological disability, was for many years considered the hallmark of abnormal mental status in MS (Cottrell and Wilson 1926). In their seminal 1926 work, Cottrell and Wilson delineated four states that affected two-thirds of their sample: euphoria sclerotic (i.e., persistently cheerful mood); eutonia sclerotic (i.e., lack of concern over physical disability); pes sclerotic (i.e., optimism for the future irrespective of obvious physical decline); and emotional lability, now considered to include the separate entity of pseudobulbar affect (described in the next section). Subsequent estimates of the prevalence of euphoria have declined, likely because of the introduction of structured interviews, more precise definitions, and improved sample selection. Rabins (1990) estimated a 25% median rate of euphoria in MS. Euphoria is considered a manifestation of advanced disease with extensive cerebral damage, progressive disease course, greater physical disability, and more cognitive impairment. It is important to distinguish euphoria, a fixed state, from mania and hypomania with features such as psychomotor agitation, pressured speech, decreased need for sleep, and increased energy that fluctuate over days to weeks. Reduced gray matter volume, ventriculomegaly, more frontal lesions, and greater overall lesion load have been associated with euphoria in MS (Feinstein 2007). There is no specific treatment, but caregiver psychoeducation may be helpful.

Pseudobulbar Affect

Pseudobulbar affect (PBA), also referred to as pathological laughing and crying, emotionalism, emotional incontinence, involuntary emotional expression disorder, and a host of other descriptors, denotes a syndrome of laughter without mirth and/or tears without sadness. Poeck (1969) defined four constituents of PBA: laughing or crying response to nonspecific stimuli, absence of voluntary control of facial expression, lack of association between subjective emotional state (mood) and the observed expression (affect), and absence in corresponding change in mood exceeding the period of laughing and/or crying. The four aspects of the syndrome often co-occur to varying degrees along a spectrum of severity. Approximately 10% of MS patients are affected by PBA (Feinstein et al. 1997). The precise etiology of PBA remains elusive. However, lesions involving a widely dispersed neural network that includes frontal, parietal, and brain stem regions were implicated in MS patients with PBA versus an age-, gender-, disease duration–, physical disability– matched group of MS patients without pathological affect (Figure 18– 1) (Ghaffar et al. 2008). Antidepressants and L-dopa have been traditionally used to treat PBA. A double-blind, randomized, placebocontrolled study of dextromethorphan/quinidine showed efficacy in improving PBA, quality of life, and quality of relationships in MS patients with PBA (Panitch et al. 2006).

FIGURE 18–1. Eroded brain images (radiological convention) denoting semiautomatic brain region extraction with significantly greater lesion loads (shaded) in pseudobulbar affect compared with control multiple sclerosis subjects.

Psychosis The long-held belief that psychosis is not increased in MS was challenged by Patten et al. (2005), who reported rates of psychosis of 2%–3% in MS patients compared with 0.5%–1% in the general population. Individuals within the youngest cohort, 15–24 years of age, had a greater comorbidity of psychosis and MS, and this cooccurrence 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 communityversus 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 healthrelated 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, goaldirected 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 90min 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 voxelbased 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 diseasemodifying 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, placebocontrolled 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 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.

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 methylenedioxymethamphetamine.

diethylamide;

MDMA=3,4-

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, MAO

Induces NE and DA presynaptic release; reverses transporters.

Tobacco/nicotine

nAChR agonist

Increases firing of VTA DA neurons through nicotinic β2 receptors; disinhibits DA neurons via α4β2 receptors on VTA GABAergic neurons.

Opioids (morphine, heroin)

μ receptor 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.

Drug Hallucinogens

Target 5-HT2A receptor agonist (numerous other targets)

Primary action Hallucinogenic effects are mediated through stimulation of 5HT2A receptors; bind 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=γaminobutyric acid; 5-HT=serotonin; MAO=monoamine oxidase; nAChR=nicotinic

acetylcholine receptor; NE=norepinephrine; NET=norepinephrine transporter; NMDA=N-methyl-D-aspartate; SERT=serotonin transporter; VMAT2=vesicular monoamine transporter 2; VTA=ventral tegmental area.

In this chapter, we define SUD-relevant terms and provide an overview of the neurobiology of SUDs. We then discuss making a clinical diagnosis, providing in-depth information specific to each drug class except for caffeine and tobacco, which rarely are associated with development of NPDs. Because many patients who develop significant NPDs also need attention to medically managed withdrawal from alcohol, sedatives, and opiates, we cover their management as well.

Definition of Terms In DSM-IV (American Psychiatric Association 1994), substance “abuse” was considered a mild form of addictive illness, whereas “dependence” was viewed as a more severe form, but in DSM-5 (American Psychiatric Association 2013) these terms are no longer used, and each “use disorder” simply has degrees of severity based on how many of 11 possible symptoms are endorsed. Dependence in DSM-5 includes pharmacological tolerance and withdrawal, and the severity specifier ranges from mild (two symptoms) to severe (more than five symptoms). Physical dependence typically leads to a withdrawal syndrome when the drug is discontinued abruptly. Dependence is not a diagnosis and can reflect a normal tolerance response, such as the need for higher doses of opioids in pain management as the treatment duration increases. Upon cessation of the substance, most individuals do not experience a withdrawal syndrome or drug craving. However, withdrawal can be precipitated for some drugs with the use of antagonists such as naloxone for opiates or flumazenil for benzodiazepines. “Addiction” or “addictive disease” is not part of DSM-5, although it may be defined as a

specific abnormality of the reward system of the brain producing repetitive use despite negative consequences. Tolerance is a pharmacological term meaning that increased amounts of the drug are needed to achieve the desired effect or that diminished effects occur with continued use of the same amount of the drug. Tolerance to respiratory depression and tolerance to sedating and motor coordination effects may develop at different rates, depending on the substance and the individual. Laboratory tests may be helpful for determining tolerance. For example, high blood levels of the substance with little evidence of intoxication indicate tolerance. Tolerance may be metabolic, cellular and functional, or behavioral. Metabolic tolerance means that the drug is more rapidly changed into inactive substances, most often by the liver. Cellular and functional tolerance is often put in terms of brain receptor desensitization to or uncoupling of the receptor from its second messenger system, such as cyclic adenosine monophosphate. Behavioral tolerance is individual compensation for drug effects through adjustments in behavior that are not directly related to drug metabolism or changes in the cellular response to the drug. Withdrawal symptoms vary greatly across the classes of substances, with marked and generally easily measured physiological signs of withdrawal with alcohol, opioids, sedatives, hypnotics, and anxiolytics. Withdrawal is often less apparent with stimulants, tobacco, and cannabis. Significant withdrawal has not been documented in humans after repeated use of phencyclidine, other hallucinogens, and inhalants. Craving, a feature newly introduced in DSM-5 as one of the 11 criteria symptoms for the diagnosis of an SUD, is a subjective experience and a drug-acquisitive state that motivates drug use. Real-time assessments of craving indicate that craving vacillates substantially even within the course of a day and that reports of

craving obtained at different times have different meanings and predictive power.

Neurobiology Chronic substance use can produce structural and functional brain abnormalities in overlapping brain circuits and be associated with intense drug craving and compulsive use. Many abnormalities that are associated with physical dependence resolve within days or weeks after the substance use stops. The abnormalities that produce drug craving, compulsive use, and neurocognitive dysfunction, however, are more wide-ranging, complex, and potentially longlasting brain structural changes. These brain changes may be amplified by environmental effects interacting with genetically aberrant brain pathways and neurotransmitter sensitivities. Druginduced changes combined with genetic vulnerabilities can produce craving that leads to relapse months or years after acute withdrawal resolves. The reinforcing effects of substances increase dopamine (DA) to supraphysiological levels within several brain reward circuits, particularly the ventral tegmental area (VTA) to the nucleus accumbens (NAc) (Volkow et al. 2010). The postsynaptic binding of DA activates the NAc, whereas presynaptic binding to the VTA neurons can lead to feedback inhibition of further DA release from the VTA (Figure 19–1). Other brain areas, such as the hippocampus and amygdala, create a lasting memory called conditioned association that links these good feelings and later craving with the circumstances and environment in which they occur. These cravings occur when the drug user reencounters those persons, places, or things that were associated with their drug use. Finally, the action decisions that lead to substance users making poor decisions and seeking out more drugs in spite of many obstacles and adverse health consequences involve a reduction in prefrontal cortex activity

that otherwise inhibits drug craving leading to relapse (Goldstein and Volkow 2011). Thus, medication development to address abnormalities in the neurocircuitry for various substance use disorders is of primary importance.

FIGURE 19–1. Hypothetical representation of a dopamine (DA) neuron projection from the ventral tegmental area (VTA) and its target neuron located in the nucleus accumbens (NAc). DA released by the presynaptic neuron may bind a number of DA receptor subtypes (D1–D5) identified initially by the way in which they modulate the conversion of adenosine triphosphate (ATP) to cyclic adenosine 3′,5′monophosphate (cAMP) and later confirmed through genetic cloning. DA is inactivated by reuptake of DA through the dopamine transporter (DAT) back into the presynaptic cell for recycling and repackaging into synaptic vesicles. Intraneuronal DA is sequestered into the vesicles by the vesicular monoamine transporter (VMAT). Cocaine blocks the DAT, increasing synaptic levels of DA (1). High levels of DA then activate its respective receptors. Cocaine-induced enhancement of dopamine activation of D1/D5 receptors increases cAMP via adenylate cyclase (AC) through stimulatory G-protein (Gαs), whereas AC activity is decreased through inhibitory G-protein (Gαi ) linked to D2/D3/D4 receptors. cAMP can enhance or decrease the action of intracellular messengers that have numerous targets, including acting on DNA to initiate or suppress gene expression that alters cell activity. Methamphetamine and amphetamine (METH/AMPH) also influence DA neurotransmission, however, through multiple mechanisms.

METH/AMPH reverses the DAT (1) and the VMAT (2), preventing DA from being inactivated, and induces mobilization and release of vesicular DA (3), increasing neurotransmitter levels in the synapse.

Positive subjective effects through brain reward circuitry are the primary reason that some people continue to take drugs, particularly in the early stages of drug use. However, the continued drive and the compulsion to use drugs build over time and extend beyond simple pleasure seeking. Chronic drug administration eventually leads to abnormal synaptic plasticity and neurotransmission that contributes to continued drug use. Reversal or normalization of this aberrant neurotransmission is essential for treatment of drug-induced NPD (Haile et al. 2012).

Clinical Diagnoses Patients with an SUD need an assessment that can detect the particular substance and develop a diagnosis with a rating of severity. For an accurate diagnosis, various screening instruments, such as the CAGE-D (CAGE adapted to include drugs) (Mayfield et al. 1974), Michigan Alcoholism Screening Test (MAST; Selzer 1971), or Alcohol Use Disorders Identification Test—Consumption (AUDITC; 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 alcoholrelated tests include γ-glutamyltransferase (GGT) and percent carbohydrate deficient transferrin (%CDT). GGT is a membranebound 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 substanceinduced 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 alcoholdependent 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 (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. 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.

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. 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.

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 γsecretase 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 αsecretase 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 γsecretase activity are associated with increased production of Aβ peptides. The 42-amino acid Aβ species is the most likely to associate into fibrils, which are the precursor to plaque formation. Fibrils aggregate into extracellular deposits in an insoluble β-pleated sheet configuration. Previously, parenchymal deposition of Aβ was assumed to be the crucial step in the AD pathophysiology. There is growing evidence, however, that prefibrillar, diffusible oligomeric assemblies of Aβ are toxic to neurons and synapses, suggesting that the disease process is under way prior to plaque formation. The exact mechanism by which neuronal dysfunction and death occur in AD is unknown. Glycoproteins similar to APP are associated with cell surface interactions and nuclear signaling, which suggests that APP or its normal derivatives might play a role in maintaining synaptic function and neuronal health (Kamenetz et al. 2003). Aβ also is an activating trigger for microglial cells, leading them to

produce several inflammatory cytokines with cytotoxic properties, including tumor necrosis factor α. Activation of microglia may contribute to a self-propagating cycle of local inflammation and neuronal dysfunction (Block et al. 2007). Although most models of AD pathophysiology place Aβ in a causative role, other approaches suggest oxidative stress or bioenergetic failure as a triggering factor in the amyloid cascade (Swerdlow and Khan 2004). It is possible that Alzheimer’s dementia is a disorder with heterogeneous origins, with different primary mechanisms resulting in similar patterns of neuronal failure and pathological expression in different individuals.

Neurochemical Abnormalities Acetylcholine ACh is important for the cognitive functions of attention and memory. Alzheimer’s dementia severity correlates with loss of cerebral cortical markers for ACh metabolism. Choline acetyltransferase (CAT), responsible for ACh synthesis, and acetylcholinesterase (AChE), which degrades ACh, are both depleted. The degree of cholinergic reduction in the cortex is closely associated with the amount of cellular loss in the septal and basal forebrain cholinergic (Ch) nuclei, where the neurons that produce much of the cortical ACh are located. These include the septal nucleus (Ch1) and vertical limb of the diagonal band of Broca (Ch2), which supply the hippocampus; the horizontal limb of the diagonal band of Broca (Ch3), which supplies the olfactory bulb; and the nucleus basalis of Meynert (Ch4), which supplies extrahippocampal limbic and paralimbic cortices and widespread neocortical areas.

Monoamines Deficiencies in NE and 5-HT also contribute to both cognitive and noncognitive symptoms, especially mood and anxiety. NE is important for arousal, learning, and memory. The major site of

ascending NE projections is the locus coeruleus in the upper brain stem, which undergoes significant cell loss in Alzheimer’s dementia. Decreased markers of 5-HT activity in the cortex and loss of 5-HT– producing cells in the median and dorsal raphe nuclei in the upper brain stem are also observed in Alzheimer’s dementia.

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

Primary Clinical Manifestations of Alzheimer’s Dementia Although this chapter will address losses in domains like memory, praxis, visual processing, and executive dysfunction separately, it is important for clinicians to remember that intact human cognition is a seamless and interdependent whole. Parsing cognitive function into specific domains reflects the conveniences of taxonomy and testing rather than physiological reality. The DSM-5 criteria require evidence for impairments in memory, learning, and at least one other cognitive domain (American

Psychiatric Association 2013) (Box 20–1). Factor analysis of cognitive testing on 663 patients with probable AD revealed that memory, language, and praxis are the principal cognitive deficits in AD (Talwalker 1996). Although that study did not include careful assessment of executive function, more recent studies indicate executive dysfunction is present in a majority of Alzheimer’s dementia patients (Stokholm et al. 2006). Other focal cognitive deficits associated with temporoparietal lesions, such as spatial disorientation, acalculia, and left-right disorientation, also develop in many patients (Table 20–1).

BOX 20–1.DSM-5 Criteria for Major or Mild Neurocognitive Disorder Due to Alzheimer’s Disease A.

The criteria are met for major or mild neurocognitive disorder.

B.

There is insidious onset and gradual progression of impairment in one or more cognitive domains (for major neurocognitive disorder, at least two domains must be impaired).

C.

Criteria are met for either probable or possible Alzheimer’s disease as follows: For major neurocognitive disorder: Probable Alzheimer’s disease is diagnosed if either of the following is present; otherwise, possible Alzheimer’s disease should be diagnosed. 1. 2.

Evidence of a causative Alzheimer’s disease genetic mutation from family history or genetic testing. 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.

D.

Clear evidence of decline in memory and learning.

2.

Steadily progressive, gradual decline in cognition, without extended plateaus.

3.

No evidence of mixed etiology (i.e., absence of other neurodegenerative or cerebrovascular disease, or another neurological or systemic disease or condition likely contributing to cognitive decline).

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 Memory

Impairment

Typical Onset

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

Ideomotor apraxia

Late

Ideational/conceptual apraxia

Late

Limb-kinetic apraxia

Late

Impaired directed attention

Early

Poor object or person recognition

Late

Spatial confusion

Late

Poor planning

Early

Poor judgment

Early

Impairment on complex tasks

Early

Disinhibition

Late

Praxis

Visual processing

Executive function

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 wellremembered 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

Paranoid delusions

Early or late

Delusional misidentification

Late

Hallucinations (visual and/or auditory)

Late

Depression

Early

Anxiety

Early

Nonspecific motor behaviors, including wandering and/or pacing

Late

Verbal aggression

Late

Physical aggression

Late

Confusion and agitation

Late

Psychosis

Mood disorders Agitation

Sundowning

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 evidencebased 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. 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.

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 wordfinding 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 threedimensional 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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CHAPTER 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.

The Lewy body

disorders are a group of neurodegenerative disorders that share the common pathology of fibrillar aggregates of αsynuclein protein in selective populations of neurons and glia. The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association 2013) presents current criteria for major or mild neurocognitive disorder with Lewy bodies and their applications in clinical practice. In this chapter, these conditions will be collectively referred to as dementia with Lewy bodies (DLB) when the cognitive-behavioral symptoms are the initial presentation and as Parkinson’s disease (PD) or Parkinson’s disease with dementia (PDD) if

the movement disorder is the initial presentation and substantially precedes cognitive-behavioral symptoms. The underlying pathological lesion in these disorders is the intracellular aggregation of α-synuclein. Aggregates of α-synuclein are present in neurons as neocortical Lewy bodies and dystrophic Lewy neurons in DLB, PD, and PDD, or as cytoplasmic inclusions in oligodendrocytes in less common Lewy body disorders such as multiple system atrophy. However, α-synuclein pathology can be present in many other neurodegenerative diseases, such as Alzheimer’s disease (AD) and Down syndrome (Table 21–1). The Lewy body disorders are broadly characterized by variable degrees of progressive decline in cognitive, motor, behavioral, and autonomic function. TABLE 21–1. Disorders with synuclein pathology Synuclein pathology commonly found

Synuclein pathology may be found

Dementia with Lewy bodies

Amyotrophic lateral sclerosis

Parkinson’s disease (with and without

Pick’s disease

dementia) Alzheimer’s disease (particularly autosomal dominant forms)

Creutzfeldt-Jakob disease 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

Condition

Memory Executive Attention and Visuospatialand functioningconcentration abilities learning

Language and communication

Alzheimer’s disease

+ to +++

+ to +++

+ to ++

+++

+ to +++

Parkinson’s disease

0 to ++

0 to ++

0

0 to +

0

Parkinson’s disease with dementia

++ to +++

++ to +++

+ to +++

0 to +++

0 to ++

Dementia with Lewy bodies

++ to +++

++ to +++

+ to +++

0 to +++

0 to ++

0=no impairment; impairment.

+=mild

impairment;

++=moderate

impairment;

+++=severe

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, threedimensional 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 threequarters of patients have a significant number of arousals not accounted for by medication, periodic limb movements during sleep, or sleep apnea (Boeve et al. 2001).

Rapid Eye Movement Sleep Behavior Disorder REM sleep behavior disorder (RBD) is characterized by loss of normal muscle atonia during REM sleep, associated with excessive activity while dreaming. Increased muscle activity during REM sleep

occurs along with dream content and can range from elevated muscle tone to complex behavioral sequences, such as acting out dreams. RBD is associated with synucleinopathies, including DLB, PD, and multiple system atrophy, and may precede the onset of other symptoms by years, but it rarely occurs in tau-predominant conditions such as AD (Boeve et al. 2001).

Autonomic Dysfunction Autonomic dysfunction is a common feature in Lewy body disorders (McKeith et al. 2005). Autonomic dysfunction is not specifically included in the criteria, but some of the supportive features, such as recurrent falls and transient loss of consciousness, might be explained by autonomic dysfunction. Although many of these autonomic features occur later in the disease process, there have been cases with early and prominent involvement. There is also evidence of involvement of the peripheral nervous system, with numerous Lewy bodies in the sympathetic neurons and autonomic ganglia. The most serious manifestation of autonomic dysfunction is orthostasis, which is symptomatic in approximately 15% of patients with DLB (Karantzoulis and Galvin 2013; McKeith et al. 2005). Other features include decreased sweating, sialorrhea, seborrhea, heat intolerance, urinary dysfunction, diarrhea, and erectile dysfunction. A history of chronic constipation beginning two to three decades before other symptoms is a common complaint.

Neuroleptic Sensitivity Approximately 57% of patients with DLB, 39% of patients with PDD, and 27% of patients with PD develop severe neuroleptic sensitivity (Aarsland et al. 2005). It is not possible to predict the occurrence of these adverse motor reactions, but they are generally more common with the neuroleptics that are potent dopamine D2 receptor antagonists. Both classic and atypical neuroleptics, as well as some antiemetics (e.g., metoclopramide), can worsen parkinsonism and exacerbate other

features such as sedation and orthostatic hypotension (Zweig and Galvin 2014). The greatest concern with the use of typical neuroleptics in persons with DLB is neuroleptic malignant syndrome (NMS), which is sometimes fatal. NMS is caused by central blockade of dopamine and includes muscle rigidity, hyperthermia, and autonomic instability. While NMS is perhaps the most serious side effect, a similar but more common adverse reaction, neuroleptic sensitivity reaction (NSR), can be seen in DLB, PD, and PDD (Zweig and Galvin 2014). NSR, which can occur in 30%–50% of DLB patients, includes sedation, increased confusion, rigidity, and immobility that may occur after taking a neuroleptic medication. NSRs are just as likely to occur in patients with mixed pathology, including AD, supporting the need for accurate diagnosis (Aarsland et al. 2005).

Differential Diagnosis Baseline and longitudinal differences in motor, cognitive, psychiatric, and functional deficits may facilitate distinguishing between DLB and AD. Motor features that facilitate distinguishing among these and other neurodegenerative disorders are reviewed in Table 21–3. Men are more likely to have DLB, whereas AD occurs more often in women. Patients with DLB are more likely to exhibit psychiatric symptoms and greater functional impairment in the early stages of DLB, whereas such problems are more common in the later stages of AD. Furthermore, the diffuse cortical and subcortical Lewy body pathology produces cognitive impairment with predominant visuospatial and psychomotor deficits (Johnson et al. 2005; Karantzoulis and Galvin 2013); although these problems may develop in AD, they are not typical of this condition.

TABLE 21–3. Comparison of extrapyramidal features in neurocognitive disorders Condition

Specific findings

Alzheimer’s disease

Parkinsonism tends to be later in course; rigidity, bradykinesia, and tremor (resting or postural) most obvious.

Parkinson’s disease

Masked facies, stooped posture, and reduced arm swing; unilateral or asymmetric rigidity, bradykinesia, resting tremor, and postural instability; signs clearly are L-dopa responsive.

Parkinson’s disease with dementia

Same as in Parkinson’s disease, but over time, bilateral involvement, marked postural instability, and loss of L-dopa responsiveness.

Dementia with Lewy bodies

Masked facies, stooped posture, and reduced arm swing similar to that in Parkinson’s disease with or without dementia, but tremor is less asymmetric and more postural.

Multiple system atrophy

Rigidity less asymmetric and minimally L-dopa responsive in the striatonigral variant; ataxia and spasticity prominent in the olivopontocerebellar atrophy variant; orthostatic hypotension prominent in the Shy-Drager syndrome variant.

In a survey of 962 DLB caregivers, an initial diagnosis other than DLB was given in 78% of cases: Parkinson’s disease (39%), Alzheimer’s disease (26%), frontotemporal degeneration (4%), mild cognitive impairment (6%), or other unspecified dementia (12%), as well as primary psychiatric diagnoses (24%). The initial DLB diagnosis was made by a neurologist the majority of the time (62%), followed by psychiatrists, geriatricians, psychologists, and primary care providers.

Once the diagnosis was established, around 50% of DLB patients had to see two or more clinicians for symptom management, and 58% of caregivers reported difficulty with managing the care among different providers (Galvin et al. 2010).

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

Risk Factors for Cognitive Decline in Parkinson’s Disease Dementia develops only in a subset of individuals with PD-related cognitive impairment. Nonthreatening visual hallucinations, commonly reported in PD even prior to the use of L-dopa, are the strongest clinical predictor of dementia (Galvin et al. 2006). Advancing age is another important risk factor for dementia in PD (Aarsland et al. 2004). Advanced axial extrapyramidal involvement, such as bradykinesia, rigidity, or postural instability, also appears to increase the risk of dementia and the rate of cognitive decline once dementia develops. Among the motor predictors, bilateral onset of motor symptoms and declining response to L-dopa may also increase the risk of dementia.

Cognitive Profile

The cognitive profile of PDD is similar to that of DLB, with marked executive dysfunction and marked impairment in attention and visuospatial and constructional abilities (Johnson and Galvin 2011). Aside from verbal fluency, cortical functions such as language, limb praxis, and perceptual processing are relatively preserved in the early stages. Memory impairment is less prominent than in AD, and recall may be relatively preserved (Karantzoulis and Galvin 2013). Compared with PD patients who do not have dementia, PDD patients are more likely to have visual or auditory hallucinations, delusions, and depression. They also tend to have a higher frequency of aphasia and impairment in visuoconstructional tasks such as clock drawing. Other distinctive clinical features of PDD include sensitivity to neuroleptic medications, fluctuations in cognition, myoclonus, and sleep disturbances (Galvin 2006; Goldman et al. 2014).

Executive Function Patients with PD have impaired ability to plan, organize, and regulate goal-directed behavior. Controlling for bradykinesia and tremor during interpretation of psychometric testing is important to ensure that changes in cognitive domains are measured rather than impairments in motor control and speed.

Visuospatial Abilities Impairment in visuoperceptual and visuomotor abilities is seen in PD with and without dementia (Karantzoulis and Galvin 2013). These deficits may precede impairments in other domains by several years (Johnson and Galvin 2011).

Memory Patients with PD have impaired semantic and episodic memory with preserved recognition memory and benefit from cuing. The deficit in PD is mostly associated with impaired registration or retrieval of information during the early retention phase of short-term memory.

Language Language processing and comprehension are relatively well preserved in PDD compared with AD, but verbal fluency is more compromised in the former. Patients with PDD have also been reported to have naming deficits and difficulties with sentence comprehension. Decreased content of spontaneous speech is also seen, but to a lesser degree than in AD. These patients exhibit motor speech abnormalities in the form of dysarthria, agraphia, decreased phrase length, and impaired speech melody.

Psychiatric Features Approximately 61% of patients with PD exhibit neuropsychiatric disturbances. The most common are depression (38%), hallucinations (27%), delusions (6%), anxiety, sleep disturbances, and inappropriate sexual behavior. Visual hallucinations are aggravated by dopaminergic treatment. Cognitive impairment is the main risk factor for hallucinations induced by L-dopa in PD patients. Other clinical correlates of psychosis in PD are old age, advanced disease, a history of depression, and cooccurring 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.

Autonomic Dysfunction 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 Condition

Pattern of atrophy (MRI)

Hypoperfusion (SPECT) or hypometabolism (FDG-PET)

Alzheimer’s disease

Maximal in hippocampi, generalized cortical atrophy evolves over time

Maximal in temporoparietal cortex

Parkinson’s disease

Minimal to no significant cortical or hippocampal atrophy

Normal or minimally abnormal

Parkinson’s disease with dementia

Minimal to no significant cortical or hippocampal atrophy

Maximal in frontoparietooccipital cortex

Dementia with Lewy bodies

Minimal to no significant cortical or hippocampal atrophy

Maximal in parieto-occipital cortex

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 99mTcpositron emission tomography (FDG-PET) and 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 offlabel 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. Shortacting 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.

Autonomic Dysfunction 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 Karen E. Anderson, M.D.

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 cytosineadenine-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 lengthdependent 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 obsessivecompulsive/repetitive behaviors in HD, although clomipramine may also be useful as monotherapy. Antipsychotics and anticonvulsant mood stabilizers may be considered augmentation strategies for these behaviors when first-line interventions are only partially effective.

Future Treatment Options There are currently numerous agents under development for treatment of HD symptoms and for slowing disease progression. Improved approaches to symptomatic treatment are being developed (e.g., modification of tetrabenazine to potentially decrease doselimiting 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 Geoffrey A. Kerchner, M.D., Ph.D. Michael H. Rosenbloom, M.D.

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 FTD syndrome Behavioral-variant FTD

Symptoms

Cognitive exam findings

Behavioral disinhibition

Deficits in executive tasks

Apathy or inertia

Relative

Loss of sympathy or empathy Early perseverative,

preservation of memory and visuospatial function

stereotyped, or compulsive ritualistic

Neuroimaging

Motor findings

Right-hemispheric frontal and/or anterior temporal atrophy, particularly involving the orbitofrontal, insular, and anterior cingulate cortices

Motor neuron disease (10%–15%)

Left posterior fronto- insular atrophy on structural MRI

Right hemibody apraxia, parkinsonism, dystonia, alien limb

Parkinsonism (20%) or

Neuro FT FT FT Oth

supranuclear gaze disturbance (less common)

behaviors Hyperorality Nonfluent/agrammaticvariant primary progressive aphasia

Progressive expressive aphasia characterized by slow, effortful speech with decreased output; dysarthria; and progression to mutism

Agrammatism Inconsistent speech sound errors and distortions and apraxia of speech Impaired comprehension of syntactically complex sentences Spared singleword comprehension and object knowledge Relative preservation of memory and visuospatial function

Left posterior fronto- insular

Progression to

SPECT

corticobasal

hypoperfusion

syndrome or

or PET

progressive

hypometabolism

supranuclear palsy

FT

FTD syndrome Semantic-variant primary progressive aphasia

Symptoms

Cognitive exam findings

Left predominant

Left predominant

Word-finding

Impaired

difficulties Comprehension difficulties Right predominant Prosopagnosia Poor emotional recognition Disinhibition Mental rigidity Food fads Compulsions

confrontational naming Impaired single-

Neuroimaging Asymmetric left and/or right anterior and lateral temporal atrophy on structural MRI

Motor findings Less common

Neuro FT

word comprehension Impaired object knowledge Surface dyslexia Spared repetition, grammar, and motor speech 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