Behavioral Health Neurpsycatric

JUNE 2018
VOL. 24 NO. 3 Behavioral Neurology

and Psychiatry
Guest Editor: Morris Freedman, MD, FRCPC, FAAN
668 Editor’s Preface

Editor-in-Chief: Steven L. Lewis, MD, FAAN
REVIEW ARTICLES
672 Bedside Approach to the Mental Status Assessment

David F. Tang-Wai, MDCM, FRCPC; Morris Freedman, MD, FRCPC, FAAN
704 Clinical Assessment of Prefrontal Lobe Functions

Alexandre Henri-Bhargava, MDCM, MScCH, FRCPC;
Donald T. Stuss, OC, O Ont, PhD, FRSC, FCAHS, CPsych, ABPP-CN;
Morris Freedman, MD, FRCPC, FAAN
727 Memory Dysfunction

G. Peter Gliebus, MD
745 Primary Progressive Aphasia and Stroke Aphasia

Murray Grossman, MDCM, FAAN; David J. Irwin, MD
768 Apraxia, Neglect, and Agnosia

H. Branch Coslett, MD, FAAN
783 Aggression and Agitation in Dementia

M. Uri Wolf, MD, FRCPC; Yael Goldberg, PhD, CPsych;
Morris Freedman, MD, FRCPC, FAAN
804 Mood Disorders

Jeffrey Rakofsky, MD; Mark Rapaport, MD
828 Obsessive-Compulsive Disorder

DENOTES CONTINUUM
AUDIO INTERVIEW Peggy M. A. Richter, MD, FRCPC; Renato T. Ramos, MD
DENOTES SUPPLEMENTAL 845 Psychosis

DIGITAL CONTENT
Lindsey A. Schrimpf, MD; Arpit Aggarwal, MD; John Lauriello, MD
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

861 Conversion Disorder
Anthony Feinstein, MD, PhD
873 Assessment and Management of Posttraumatic Stress Disorder

Janet Ellis, MBBChir, MD, FRCPC; Ari Zaretsky, MD, FRCPC
893 Diagnosis and Management of Anxiety Disorders

Peter Giacobbe, MD, MSc, FRCPC; Alastair Flint, MD, FRCPC, FRANZCP
ETHICAL AND MEDICOLEGAL ISSUES
920 Assessment of Medical Decision-making Capacity in Patients

With Dementia
Joshua J. Rodgers, MD; Joseph S. Kass, MD, JD, FAAN
PRACTICE ISSUES
926 Coding for Behavioral Neurology and Psychiatry

Raissa Villanueva, MD, MPH, FAAN; Bruce H. Cohen, MD, FAAN
SELF-ASSESSMENT AND CME
658 Learning Objectives and Core Competencies
937 Instructions for Completing Postreading Self-Assessment and CME Test

and Tally Sheet
939 Postreading Self-Assessment and CME Test
955 Postreading Self-Assessment and CME Test—Preferred Responses
967 Erratum
968 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS
Morris Freedman, MD, Bruce H. Cohen, MD, FAAN

FRCPC, FAAN Director, NeuroDevelopmental
Guest Editor Science Center, Akron
Department of Neurology, Children’s Hospital, Akron,
University of Toronto; Baycrest Ohio; Professor of Pediatrics,
Health Sciences; Rotman Northeast Ohio Medical
Research Institute of Baycrest University, Rootstown, Ohio
Centre; Department of
Relationship Disclosure: Dr Cohen serves on
Neurology, Mt. Sinai Hospital, the board of directors of the Mitochondrial
Toronto, Ontario, Canada Medicine Society, on the board of trustees of
the United Mitochondrial Disease Foundation,
Relationship Disclosure: Dr Freedman and on the editorial boards of Mitochondrion,
serves as a trustee for the World Federation Brain & Life, and Pediatric Neurology.
of Neurology and on the editorial boards Dr Cohen serves as a consultant for Stealth
of Brain and Cognition and Journal of BioTherapeutics Inc and receives research/
Parapsychology; has received support grant support from BioElectron Technology
from and served on an advisory board for Corporation; Horizon Pharma plc; the
Eli Lilly and Company Canada and receives National Institutes of Health (subaward 8;
publishing royalties from Oxford University GG006326-03); Reata Pharmaceuticals, Inc;
Press; receives research/grant support and Stealth BioTherapeutics Inc. Dr Cohen
from the Alzheimer Society of Canada, Brain receives publishing royalties from Elsevier.
Canada Foundation, Centre for Aging and
Brain Health Innovation, Canadian Institutes of Unlabeled Use of Products/Investigational
Health Research, and Westin Brain Institute; Use Disclosure: Dr Cohen reports
receives support from the Behavioural no disclosure.
Neurology Physician Recognition Covenant
Fund at Baycrest, the Morris Kerzner
Memorial Fund, and the Saul A. Silverman
Foundation as part of the Canada H. Branch Coslett, MD, FAAN
International Scientific Exchange Program William N. Kelley Professor of
project; and holds stock in companies
producing or planning to produce medical Neurology, Perelman School
marijuana and is listed on a provisional of Medicine at the University
patent related to methods and kits for
differential diagnosis of Alzheimer disease.
of Pennsylvania, Philadelphia,
Pennsylvania
Unlabeled Use of Products/Investigational
Use Disclosure: Dr Freedman discusses Relationship Disclosure: Dr Coslett serves
the unlabeled/investigational use of on external advisory boards for National
medications for the treatment of aggression Institutes of Health Center grants for the
and agitation in dementia, none of which University of Nevada, Reno (R21 NS099645,
are approved by the US Food and 1R01 DC013196, R21NS089084, 1R01 NS099061)
Drug Administration. and for a US Department of Veterans Affairs
grant for the VA Boston Healthcare System.
Dr Coslett serves on the editorial boards of
Brain and Language and Cortex and as an
Arpit Aggarwal, MD editor for volume 151 of the Handbook of
Clinical Neurology (“The Parietal Lobe”).
Assistant Professor of
Psychiatry, University of Unlabeled Use of Products/Investigational
Missouri, Columbia, Missouri Use Disclosure: Dr Coslett reports
no disclosure.
Relationship Disclosure: Dr Aggarwal reports
no disclosure.

Use Disclosure: Dr Aggarwal reports no
disclosure.
660 JUNE 2018

Janet Ellis, MBBChir, MD, FRCPC Peter Giacobbe, MD,
Director of Psychosocial Care MSc, FRCPC
in Trauma, Medical Psychiatrist, Clinical Head, Harquail
Sunnybrook Health Sciences Centre for Neuromodulation,
Centre; Lecturer, Department Mood and Anxiety Program,
of Psychiatry, University of Sunnybrook Health Sciences
Toronto, Toronto, Ontario, Canada Centre; Assistant Professor,
Department of Psychiatry,
Relationship Disclosure: Dr Ellis reports
no disclosure. University of Toronto, Toronto,
Ontario, Canada
Use Disclosure: Dr Ellis reports no disclosure. Relationship Disclosure: Dr Giacobbe serves
on the advisory board of Janssen Canada
and receives research/grant support from
the Canadian Institutes of Health Research
Anthony Feinstein, MD, PhD (MOP 125880, MOP 326627) and the National
Professor of Psychiatry, Institutes of Health (1R01AG042165-O1A1,
University of Toronto, Toronto, 2U01MH062446-O6A2).
Ontario, Canada Unlabeled Use of Products/Investigational

Use Disclosure: Dr Giacobbe discusses
Relationship Disclosure: Dr Feinstein serves the unlabeled/investigational use of
on the editorial board of the Multiple Sclerosis D-cycloserine, gabapentin, pregabalin,
Journal and receives personal compensation propranolol, and quetiapine for the
for speaking engagements for EMD Serono, treatment of anxiety disorders.
Inc; F. Hoffman-La Roche Ltd; Novartis AG;
Sanofi Genzyme; and Teva Pharmaceutical
Industries Ltd. Dr Feinstein receives research/
grant support from the Multiple Sclerosis
Society of Canada and publishing royalties G. Peter Gliebus, MD
from Amadeus Press, Cambridge University
Press, and Johns Hopkins University Press. Department of Neurology
Interim Chairman, Assistant
Professor of Neurology,
Use Disclosure: Dr Feinstein reports
no disclosure. Director of Behavioral
Neurology and Neuropsychiatry
Fellowship, Drexel University
Alastair Flint, MD, College of Medicine; Director,
FRCPC, FRANZCP Cognitive Disorders Center,
Professor of Psychiatry Drexel Neurosciences Institute,
and Vice Chair of Research, Philadelphia, Pennsylvania
University of Toronto, Toronto,
Relationship Disclosure: Dr Gliebus receives
Ontario, Canada research/grant support from the Drexel
Clinical and Translational Research Institute.
Relationship Disclosure: Dr Flint receives
research/grant support from the Alzheimer’s Unlabeled Use of Products/Investigational
Association, Brain Canada Foundation, Canadian Use Disclosure: Dr Gliebus reports
Frailty Network, Canadian Institutes of no disclosure.
Health Research, Centre for Aging & Brain
Health Innovation, National Institute of
Mental Health, Ontario Brain Institute, and
Patient-Centered Outcomes Research Institute.

Use Disclosure: Dr Flint discusses the
unlabeled/investigational use of
D -cycloserine, gabapentin, pregabalin,
propranolol, and quetiapine for the
treatment of anxiety disorders.
C O N T I N U U M J O U R N A L .C O M 661

CONTRIBUTORS (CONTINUED)
Yael Goldberg, PhD, CPsych Alexandre Henri-Bhargava,

Clinical Psychologist, MDCM, MScCH, FRCPC
Neuropsychologist, Baycrest Clinical Assistant Professor of
Health Sciences, Toronto, Neurology, University of British
Ontario, Canada Columbia; Medical Director,
Neil and Susan Manning
Relationship Disclosure: Dr Goldberg reports
no disclosure. Cognitive Health Initiative,
Vancouver Island Health
Use Disclosure: Dr Goldberg discusses
Authority, Victoria, British
the unlabeled/investigational use of Columbia, Canada
medications for the treatment of aggression
and agitation in dementia, none of which Relationship Disclosure: Dr Henri-Bhargava
are approved by the US Food and has received funding for clinical trials from
Drug Administration. AstraZeneca, Boehringer Ingelheim Ltd, Eli
Lilly and Company, F. Hoffman-La Roche
Ltd, and TauRx and has provided expert
legal testimony in personal injury litigation in
Murray Grossman, British Columbia.
MDCM, FAAN Unlabeled Use of Products/Investigational

Professor of Neurology, Use Disclosure: Dr Henri-Bhargava reports
University of Pennsylvania, no disclosure.
Philadelphia, Pennsylvania
Relationship Disclosure: Dr Grossman David J. Irwin, MD
serves as an associate editor of Neurology;
as a consultant for the Association for Assistant Professor of
Frontotemporal Degeneration, Bracco, Neurology, University of
and UCB, SA; and on the scientific
advisory boards of the Association for
Pennsylvania Perelman
Frontotemporal Degeneration and Biogen. School of Medicine,
Dr Grossman receives research/grant Philadelphia, Pennsylvania
support from the National Institutes of
Health (AG017586, AG052943, AG038490, Relationship Disclosure: Dr Irwin receives
and NS053488), and Piramal Enterprises Ltd. research/grant support from the
BrightFocus Foundation and the National
Unlabeled Use of Products/Investigational Institutes of Health (K23 NS088341-01).
Use Disclosure: Dr Grossman reports
no disclosure. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Irwin reports no
disclosure.
662 JUNE 2018

Joseph S. Kass, MD, JD, FAAN Jeffrey Rakofsky, MD
Associate Dean, Office of Assistant Professor, Director
Student Affairs; Professor of Medical Student Education,
of Neurology, Psychiatry, and Department of Psychiatry and
Medical Ethics; Director, Behavioral Sciences, Emory
Alzheimer’s Disease and Memory University, Atlanta, Georgia
Disorders Center, Baylor College
Relationship Disclosure: Dr Rakofsky
of Medicine; Chief of Neurology, receives research/grant support from
Ben Taub General Hospital, ACADIA Pharmaceutics Inc; the American
Board of Psychiatry and Neurology;
Houston, Texas Assurex Health; AstraZeneca; Janssen
Global Services, LLC; the National Institute
Relationship Disclosure: Dr Kass serves as
of Mental Health (RO1MH073719-05A1,
associate editor of ethical and medicolegal
7R01MH104964-02); and the National
issues for Continuum, as an associate editor
Center for Complementary and Integrative
for Continuum Audio, as a neurology section
Health (1UG3AT008857).
editor of Ferri’s Clinical Advisor for Elsevier,
and as co-editor of Neurology Secrets,
Sixth Edition. Dr Kass has received personal
Use Disclosure: Dr Rakofsky discusses the
compensation for CME lectures from
unlabeled/investigational use of buspirone,
Pri-Med Medical Group and has received
pramipexole, and thyroid hormone as
personal compensation as a medicolegal
adjuncts to an antidepressant in the
consultant in legal cases involving criminal
treatment of major depression and ketamine
cases, malpractice, and personal injury.
for treatment-resistant patients who are
depressed and suicidal.
Use Disclosure: Dr Kass reports no
disclosure.
Renato T. Ramos, MD
John Lauriello, MD Associate Professor of
Professor of Psychiatry, Psychiatry, University of
Department of Psychiatry Toronto; Staff Psychiatrist,
Chairman, Robert J. Douglas, Frederick W. Thompson Anxiety
MD, and Betty Douglas Disorders Centre, Sunnybrook
Distinguished Faculty Scholar Health Sciences Centre,
in Psychiatry, University of Toronto, Ontario, Canada
Missouri, Columbia, Missouri Relationship Disclosure: Dr Ramos reports
no disclosure.
Relationship Disclosure: Dr Lauriello has
served as an advisor for Alkermes; Otsuka Unlabeled Use of Products/Investigational
America Pharmaceutical, Inc; and Teva Use Disclosure: Dr Ramos discusses
Pharmaceutical Industries Ltd and on the the unlabeled/investigational use of
event monitoring board for Alkermes. neuromodulation technology (deep brain
Dr Lauriello has served on the editorial board stimulation, electroconvulsive therapy,
of Academic Psychiatry. Dr Lauriello receives and repetitive transcranial magnetic
research/grant support from Florida Atlantic stimulation) and pharmacologic agents
University/Otsuka America Pharmaceutical, (citalopram, escitalopram, desvenlafaxine,
Inc and the Missouri Foundation for Health duloxetine, mirtazapine, and venlafaxine)
and receives publishing royalties from Oxford for the treatment of obsessive-compulsive
University Press and UpToDate, Inc. disorder (some of which are approved for
use in depression and psychosis).
Use Disclosure: Dr Lauriello reports
no disclosure.

CONTRIBUTORS (CONTINUED)
Mark Rapaport, MD Peggy M. A. Richter, MD, FRCPC

Reunette W. Harris Professor Head, Frederick W. Thompson
and Chair, Department of Anxiety Disorders Centre;
Psychiatry and Behavioral Director, Clinic for
Sciences, Emory School of Obsessive-Compulsive
Medicine; Chief of Psychiatric Disorder and Related Disorders,
Services, Emory Healthcare, Sunnybrook Health Sciences
Atlanta, Georgia Centre, Toronto, Ontario, Canada
Relationship Disclosure: Dr Rapaport serves Relationship Disclosure: Dr Richter serves
as editor-in-chief of Focus: The Journal on the editorial board of the Journal
of Lifelong Learning in Psychiatry and on the of Obsessive-Compulsive and Related
editorial boards of CNS Neuroscience Disorders, has received personal
and Therapeutics; CNS Spectrums; compensation for speaking engagements
Current Psychiatry; Depression Research from Lundbeck, and receives grant/research
and Treatment; Innovations in Clinical support from the Canadian Institutes of
Neuroscience; Journal of Addictive Health Research.
Behaviors, Therapy & Rehabilitation; The
Journal of Clinical Psychiatry; and Shanghai Unlabeled Use of Products/Investigational
Archives of Psychiatry. Dr. Rapaport receives Use Disclosure: Dr Richter discusses the
research/grant support from the National unlabeled/investigational use of
Center for Complementary and Integrative neuromodulation technology (deep brain
Health (UG3 AT008857-01, R01 AT009169-01) stimulation, electroconvulsive therapy,
and the National Institute of Mental Health and repetitive transcranial magnetic
(MH100023-01,1R25MH101079-01). stimulation) and pharmacologic agents
(citalopram, escitalopram, desvenlafaxine,
Unlabeled Use of Products/Investigational duloxetine, mirtazapine, and venlafaxine)
Use Disclosure: Dr Rapaport discusses the for the treatment of obsessive-compulsive
unlabeled/investigational use of buspirone, disorder (some of which are approved for
pramipexole, and thyroid hormone as use in depression and psychosis).
adjuncts to an antidepressant in the
treatment of major depression and ketamine
for treatment-resistant patients who are
depressed and suicidal. Joshua J. Rodgers, MD
Director, Behavioral Neurology
& Neuropsychiatry, The
Menninger Clinic; Assistant
Professor of Psychiatry
and Behavioral Sciences,
Baylor College of Medicine,
Houston, Texas
Relationship Disclosure: Dr Rodgers reports
no disclosure.

Use Disclosure: Dr Rodgers reports no
disclosure.
664 JUNE 2018

Lindsey A. Schrimpf, MD Raissa Villaneuva, MD, MPH,
Assistant Professor of Clinical FAAN
Psychiatry, University of Assistant Professor,
Missouri, Columbia, Missouri Department of Neurology,
University of Rochester Medical
Relationship Disclosure: Dr Schrimpf reports
no disclosure. Center, Rochester, New York
Unlabeled Use of Products/Investigational Relationship Disclosure: Dr Villanueva

Use Disclosure: Dr Schrimpf reports reports no disclosure.
no disclosure.
Use Disclosure: Dr Villanueva reports
no disclosure.
Donald T. Stuss, OC, O Ont,
PhD, FRSC, FCAHS, C Psych,
ABPP-CN M. Uri Wolf, MD, FRCPC
University Professor Emeritus, Geriatric Psychiatrist,
University of Toronto; Baycrest Health Sciences;
Adjunct Senior Scientist, Lecturer, Department
Sunnybrook Health of Psychiatry, University
Sciences Centre, Toronto, of Toronto, Toronto,
Ontario, Canada Ontario, Canada
Relationship Disclosure: Dr Stuss serves Relationship Disclosure: Dr Wolf reports
on the advisory board of Spindle Strategy no disclosure.
Corporation and has received personal
compensation for speaking engagements Unlabeled Use of Products/Investigational
for Bennett Jones LLP. Dr Stuss receives Use Disclosure: Dr Wolf discusses the
publishing royalties from Cambridge unlabeled/investigational use of medications
University Press. for the treatment of aggression and agitation
in dementia, none of which are approved by
Unlabeled Use of Products/Investigational the US Food and Drug Administration.
Use Disclosure: Dr Stuss reports
no disclosure.
Ari Zaretsky, MD, FRCPC

David F. Tang-Wai, MDCM, Professor of Psychiatry,
FRCPC University of Toronto; Chief,
Associate Professor of Department of Psychiatry,
Neurology and Geriatric Sunnybrook Health Sciences
Medicine, University of Toronto; Centre, Toronto, Ontario,
Co-Director, University Health Canada
Network Memory Clinic,
Toronto Western Hospital, Relationship Disclosure: Dr Zaretsky reports
no disclosure.
Toronto, Ontario, Canada
Relationship Disclosure: Dr Tang-Wai has Use Disclosure: Dr Zaretsky reports
provided expert legal testimony for the no disclosure.
Canadian Medical Protection Association on
a case determining if a patient had cognitive
impairment.

Use Disclosure: Dr Tang-Wai reports no
disclosure.

SELF-ASSESSMENT AND CME TEST WRITERS
James W. M. Owens Jr, Allison L. Weathers, MD, FAAN

MD, PhD Associate Chief Medical
Associate Professor of Information Officer, Cleveland
Neurology and Adjunct Clinic; Assistant Professor,
Associate Professor of Cleveland Clinic Lerner College
Pediatrics, University of of Medicine, Cleveland, Ohio
Washington School of
Relationship Disclosure: Dr Weathers serves
Medicine, Seattle, Washington on the editorial board of Continuum and as
chair of the adult neurosciences specialty
Relationship Disclosure: Dr Owens serves as steering board for Epic.
CME co-editor for Neurology and receives
publishing royalties from UpToDate, Inc. Unlabeled Use of Products/Investigational
Use Disclosure: Dr Weathers reports
Unlabeled Use of Products/Investigational no disclosure.
Use Disclosure: Dr Owens reports
no disclosure.
666 JUNE 2018

EDITOR’S PREFACE
Reversing Neglect and Amnesia

for Cognitive, Behavioral, and
Psychiatric Disorders
This issue of Continuum is devoted to the diagnosis and management
of our patients with psychiatric, cognitive, and behavioral disorders,
the latter two of which in particular pique the interest of so many of
us early on, likely leading to many of our career choices. Nonetheless,
these common, fascinating, and often devastating syndromes are
arguably underemphasized in our educational curricula. To help alleviate this
problem, Guest Editor Morris Freedman, MD, FRCPC, FAAN, has created a volume
to inform us about the many disorders of cognition and behavior that we may
encounter and the psychiatric disorders that may occur (or overlap with neurologic
disorders) in patients presenting to us.
The issue begins with an overview of the bedside The management of aggression and agitation in
approach to the mental status assessment by Drs David our patients with dementia is an important aspect
F. Tang-Wai and Morris Freedman, an article that of many neurologic practices, and the article by
serves as an important introduction to the articles on Drs M. Uri Wolf, Yael Goldberg, and Morris
behavioral neurology that follow. Next, Drs Alexandre Freedman will be of immense help in creating the
Henri-Bhargava, Donald T. Stuss, and Morris safest and most effective approach to these
Freedman discuss the prefrontal lobes (clarifying the distressing behaviors.
distinction between prefrontal lobe and other frontal Next, the issue moves from behavior to more
lobe functions) and the clinical assessment of their classic “pure” psychiatric disorders. This section
functions and syndromes of dysfunction. begins with the article by Drs Jeffrey Rakofsky
Dr G. Peter Gliebus reviews the various aspects and Mark Rapaport, who review the diagnostic
of memory and the relevant anatomy, methods of criteria and management of the mood disorders,
testing, and syndromes of memory dysfunction. including major depressive disorder and bipolar
Drs Murray Grossman and David J. Irwin then disorder. Drs Peggy M. A. Richter and Renato T.
discuss the aphasias, using the examples of the Ramos then discuss the diagnosis and management of
primary progressive aphasias and stroke aphasias to obsessive-compulsive disorder, symptoms of which
clarify the clinical, anatomic, and examination often overlap with neurologic disorders. Drs Lindsey
distinctions between these syndromes. Dr H. Branch A. Schrimpf, Arpit Aggarwal, and John Lauriello next
Coslett then reviews apraxia, neglect, and agnosia, review the diagnosis and management of psychosis,
fascinating clinical syndromes that the author notes another psychiatric syndrome that can be seen in
led to the realization by founding neurologists that neurologic settings and in neurologic patients.
brain-based, rather than psychiatric, explanations for Dr Anthony Feinstein reviews the diagnostic
these behavioral syndromes were necessary. criteria, current etiologic theories, and management
668 JUNE 2018

of our patients with conversion disorder. Drs Janet Also, a reminder of the recent increase in the
Ellis and Ari Zaretsky then review the assessment maximum number of CME credits available for
and management of posttraumatic stress disorder, a readers of Continuum. After reading the issue and
syndrome that is not uncommon in neurologic taking the Postreading Self-Assessment and CME
practices and to which we need to be highly attuned Test written by Drs James W. M. Owens Jr and
diagnostically. In the final review article of the issue, Allison L. Weathers, you may earn up to 20 AMA
Drs Peter Giacobbe and Alastair Flint review the PRA Category 1 CreditsTM toward self-assessment and
diagnostic criteria, pathophysiology, and CME or, for Canadian participants, a maximum of
management of the various anxiety disorders. 20 hours toward the Self-Assessment Program
In the Ethical and Medicolegal Issues article, Drs (Section 3) of the Maintenance of Certification
Joshua J. Rodgers and Joseph S. Kass use a theoretical Program of the Royal College of Physicians and
case to illustrate the assessment of medical Surgeons of Canada. Additional credit can be
decision-making capacity in patients with dementia. obtained by listening to Continuum Audio interviews
In the coding article, Drs Raissa Villanueva and associated with this and other Continuum issues, now
Bruce H. Cohen update us on coding for behavioral available to all subscribers, and completing tests on
neurology and psychiatry. the new Continuum Audio web platform or app.
Beginning with this issue, Continuum Audio is also
accredited by the Royal College of Physicians and
Surgeons of Canada.
Now that you have seen our newly redesigned
I would like to thank Dr Freedman for print version of Continuum, watch for our new
so skillfully and diligently creating dynamic user-friendly website launching in
and honing this volume and for mid-June at ContinuumJournal.com.
I would like to thank Dr Freedman for so skillfully
inviting such a remarkable group of and diligently creating and honing this volume and
expert contributors from the fields for inviting such a remarkable group of expert
of behavioral neurology and contributors from the fields of behavioral neurology
and psychiatry to make us more attentive, reminded,
psychiatry to make us more and updated with regard to the diagnosis and
attentive, reminded, and updated management of psychiatric disorders and disorders
with regard to the diagnosis and of behavior and cognition in our patients.
management of psychiatric STEVEN L. LEWIS, MD, FAAN
disorders and disorders of behavior EDITOR-IN-CHIEF
and cognition in our patients. © 2018 American Academy of Neurology.
CONTINUUMJOURNAL.COM 669

REVIEW ARTICLE

Bedside Approach to the
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Mental Status

S U P P L E M E N T AL D I G I T A L
CONTENT (SDC)
Assessment
A VA I L A B L E O N L I N E By David F. Tang-Wai, MDCM, FRCPC; Morris Freedman, MD, FRCPC, FAAN
CITE AS:
CONTINUUM (MINNEAP MINN)
2018;24(3, BEHAVIORAL NEUROLOGY
AND PSYCHIATRY):672–703. ABSTRACT
Address correspondence to PURPOSE OF REVIEW: This article presents a clinically useful approach to
Dr David F. Tang-Wai, University obtaining the history and performing the mental status examination of
Health Network Memory Clinic,
Toronto Western Hospital, 399
patients with cognitive, language, or behavioral problems.
Bathurst St WW5-441, Toronto,
ON M5T 2S8, Canada, David. RECENT FINDINGS: Laboratory and imaging biomarkers are being developed
Tang-Wai@uhn.ca.
for accurate diagnosis of neurobehavioral disorders, yet few are currently
RELATIONSHIP DISCLOSURE:
Dr Tang-Wai has provided expert legal available for clinical use. Moreover, not all centers have access to these
testimony for the Canadian Medical potential tools. Practicing clinicians are therefore left primarily with their
Protection Association on a case skills of history taking and examination. Although geared for research,
determining if a patient had cognitive
impairment. Dr Freedman serves as a diagnostic criteria have been refined over the past several years and can
trustee for the World Federation of nevertheless aid the clinician with the diagnosis of disorders such as mild
Neurology and on the editorial boards
of Brain and Cognition and Journal of
cognitive impairment, Alzheimer disease, frontotemporal dementia,
Parapsychology; has received dementia with Lewy bodies, the primary progressive aphasias, corticobasal
support from and served on an syndrome, vascular cognitive impairment, and posterior cortical atrophy.
advisory board for Eli Lilly and
Company Canada and receives
Regularly revised criteria reflect ongoing knowledge gained from in-depth
publishing royalties from Oxford studies of these disorders.
University Press; receives research/
grant support from the Alzheimer
Society of Canada, Brain Canada SUMMARY: The focused history and mental status examination remain
Foundation, Centre for essential tools for the evaluation and diagnosis of neurologic disorders
Aging and Brain Health Innovation,
affecting cognition, language, and behavior.
Canadian Institutes of Health
Research, and Westin Brain Institute;
receives support from the Behavioural
Neurology Physician Recognition
Covenant Fund at Baycrest, the INTRODUCTION
A
Morris Kerzner Memorial Fund, and thorough history and mental status examination are necessary
the Saul A. Silverman Foundation as
part of the Canada International
requirements for the evaluation of the patient with cognitive
Scientific Exchange Program project; impairment. Both revolve around the cognitive domains of executive
and holds stock in companies function, attention, memory, visuospatial function, language, and
producing or planning to produce
medical marijuana and is listed on a behavior. While the history inquires about the patient’s abilities
provisional patent related to methods related to these domains as they pertain to his or her life, the mental status
and kits for differential diagnosis of examination tests the integrity of these domains in a clinical setting and is, therefore,
Alzheimer disease.
a formal part of the neurologic examination. The overall goal is to determine if
UNLABELED USE OF performance on each domain is normal or impaired. Longitudinal assessments
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
provide additional information to determine if a change has occurred.
Drs Tang-Wai and Freedman Memory tests assess the ability to learn new information or recall previously
report no disclosures. acquired information. The language evaluation involves an assessment of speech
© 2018 American Academy
output, comprehension, ability to name objects, and ability to repeat words and
of Neurology. sentences. It is also important to determine whether the patient has a loss of
672 JUNE 2018

grammar, such as the inability to use articles, pronouns, prepositions, or KEY POINTS
conjunctions. The visuospatial assessment evaluates spatial awareness,
● The mental status
visuospatial perception, and a patient’s ability to find things in front of him or examination tests the
her. Assessment of executive function evaluates complex processes needed for integrity of cognitive
goal-directed activity that involve task setting and monitoring.1 Deficits in these domains (executive
processes can lead to problems with performance on tasks that require function, attention,
memory, visuospatial
sequencing, abstraction, and planning.1 For more information on executive
function, language) in a
function, refer to the article “Clinical Assessment of Prefrontal Lobe Functions” clinical setting and is,
by Alexandre Henri-Bhargava, MDCM, MScCH, FRCPC; Donald T. Stuss, OC, therefore, a formal part of
O Ont, PhD, FRSC, FCAHS, CPsych, ABPP-CN; and Morris Freedman, MD, the neurologic examination.
FRCPC, FAAN,2 in this issue of Continuum. In the appropriate clinical context,
● Longitudinal
other cognitive domains could be evaluated, such as apraxia (defined as the assessments, combined
impaired ability to carry out purposeful motor activities despite intact motor with the mental status
function and sensory feedback) or agnosia (defined as the failure to recognize or examination, provide
identify objects despite intact sensory function). For more information on additional information to
determine if a change
apraxia and agnosia, refer to the article “Apraxia, Neglect, and Agnosia” by H. has occurred.
Branch Coslett, MD, FAAN,3 in this issue of Continuum.
Over the years, mental status tests have evolved from simple screening measures ● It is clinically useful to
to more in-depth evaluations that are reflective of the increased understanding of determine a patient’s
cognitive profile (a patient’s
the clinical and cognitive features of the various types of dementias (SDC 1-14-25;
relative strengths and
links.lww.com/CONT/A251). Initial tests, such as the Blessed Information- weaknesses across the
Memory-Concentration test (BIMC)4 or Delayed Word Recall (DWR),13 were cognitive domains tested) as
sufficient to detect “dementia.” Each successive cognitive assessment has added it will help the clinician, in
conjunction with the history,
more cognitive domains, such as in the Mini-Mental State Examination
elemental neurologic
(MMSE)6 or Behavioural Neurology Assessment (BNA)20; become increasingly examination, and
sensitive to detect milder changes in cognition, such as the Montreal Cognitive neuroimaging, to determine
Assessment (MoCA)21 or Toronto Cognitive Assessment (TorCA)25; or added the underlying cause of
assessments of behavior, such as in the Addenbrooke’s Cognitive Examination cognitive impairment.
(ACE)/Addenbrooke’s Cognitive Examination Revised (ACE-R).17,18,22 Most of ● It is important to obtain

the recent cognitive assessments evaluate memory, orientation, language, the history from a collateral
visuospatial function, and executive function. In addition, these assessments can informant in addition to the
objectively monitor the change in a patient’s cognition over time. patient to clarify the
presenting symptom, to
Although dysfunction in a cognitive domain reflects disruption of neural determine the chronologic
networks or connectomes,26 it is clinically useful to localize each cognitive progression of the signs and
domain/function to a specific area of the brain. Moreover, additional clinical symptoms, and to determine
utility exists in determining a patient’s relative strengths and weaknesses across the course of the
progression (gradual,
the cognitive domains tested, representing the patient’s cognitive profile, in
fluctuating, or stepwise).
addition to determining the overall score. It is the cognitive profile—knowing the
most impaired cognitive domain and its localization within the brain—that will ● The collateral historian
help the clinician (in conjunction with the history, neurologic examination, and need not always be a family
neuroimaging) determine the underlying cause of cognitive impairment. member but can be anyone
who has observed cognitive
This article focuses on the important aspects of the history, identification of difficulties, can comment on
the cognitive profile on mental status examination, and localization of the brain them by providing specific
lesion based on the results of the cognitive assessment. examples, and can report
whether the observed
cognitive difficulties have
OBTAINING A HISTORY caused any impairment with
A new specific skill set is not required when obtaining the history of a patient the patient’s usual ability to
with cognitive or behavioral symptoms but rather a conceptual approach for perform instrumental
eliciting specific information about the patient’s cognition, behavior, and daily activities of daily living.
function. This involves obtaining the history from a collateral informant in

MENTAL STATUS ASSESSMENT
addition to the patient, clarifying the presenting symptom, and determining the
chronologic progression of the signs and symptoms. It is also important to
determine whether the onset was gradual, acute, or subacute and whether any
decline has been gradual, fluctuating, or stepwise.
Importance of a Collateral History

When obtaining the history, it is imperative to try to obtain a collateral history
from a person who knows the patient well, since patients with cognitive
impairment (eg, due to probable Alzheimer disease [AD]) often are unaware of
their own cognitive and functional deficits. The collateral historian need not
always be a family member but can be anyone who has observed cognitive
difficulties, can provide specific examples, and can report whether the observed
cognitive difficulties have caused any impairment with the patient’s usual
ability to perform instrumental activities of daily living (ADLs). This approach
provides the clinician the ability to determine the affected cognitive domains
and whether the patient meets the criteria for mild cognitive impairment, in
which instrumental ADLs are spared, or dementia, in which these activities are
impaired. TABLE 1-1 provides some examples of difficulties that might be
TABLE 1-1 Sample Comments From Collateral Historians and Disorders to Consider by
Presenting Symptom
First Symptom Noticed Affected Cognitive Domain Disorders to Consider

Repeats him/herself; rapidly forgets Anterograde memory loss Alzheimer disease
conversations
Cannot recall people he/she sees on the Prosopagnosia Semantic dementia variant of
street; does not recognize familiar people at frontotemporal dementia
a party; cannot recognize his/her own house
Cannot align things; has problems seeing, Visuospatial dysfunction Alzheimer disease (posterior cortical atrophy
reading; blurry vision; cannot fill out a form; variant), dementia with Lewy bodies
cannot find things in the refrigerator; cannot
read a map; misplaces items; gets
lost/geographic disorientation
Inability to fix things Apraxia, executive dysfunction, Corticobasal syndrome, Alzheimer disease,
visuospatial dysfunction, dementia with Lewy bodies, vascular
attentional dysfunction cognitive impairment
Forgets words; describes words, talks Language (anomia) Primary progressive aphasia (nonfluent,
around them; mixes up words, mispronounces logopenic, or semantic variants)
words; forgets what a word means
Sometimes able to do things and sometimes Attention (fluctuations) Dementia with Lewy bodies
appears more confused and cannot do things
Cannot plan, multitask, or stay on task; Executive dysfunction Alzheimer disease, vascular cognitive
must do everything in single steps, cannot impairment, behavioral variant
combine tasks frontotemporal dementia (behavioral
abnormalities must also be present for this
diagnosis), dementia with Lewy bodies
674 JUNE 2018

reported by the collateral historian, the cognitive domains affected, and some of KEY POINTS
the disorders to consider based on these symptoms.
● The ideal documentation
should include the onset of
Identifying Patient Features the condition (insidious or
The age when the first symptoms developed determines if the process is either acute), presenting symptom,
early onset (defined as before age 65) or late onset (defined as age 65 or older). course of the condition
(gradually progressive,
Although not exclusionary, older age of onset likely predicts that a neurodegenerative
stepwise, fluctuating, or
process is the etiology, while genetic, vascular, infectious, or metabolic causes are improving), and duration.
more often found in younger patients. However, it is important to note that ischemic
cerebrovascular disease is commonly associated with neurodegenerative disorders, ● It is important not to
such as AD. interpret each “memory”
complaint as an impairment
Handedness can provide information regarding the lateralization of cognitive in anterograde (short-term)
functions in the brain. In 95% of right-handed patients, language function is memory as it is common for
lateralized to the left hemisphere. In contrast, 22% of left-handed patients have an an informant to describe any
atypical language lateralization within either the right hemisphere or both cognitive deficit as a
memory deficit. Instead, ask
hemispheres.27 In addition, it is useful to note a change in use of preferred hand (ie, for examples of the
development of a preference for use of the nondominant hand) as this can imply presenting symptom to
either weakness or apraxia on the dominant side. Furthermore, slowing of rapid determine accurately what
alternating movements of the patient’s dominant hand on the neurologic examination the informant means by
“memory deficits.”
should alert the clinician to consider either weakness or extrapyramidal causes.
Education and occupational history provide information about the patient’s ● The history must include a
premorbid level of intelligence and function as well as information that is helpful description of the patient’s
for interpretation of the cognitive test results. For example, consider a trial cognitive, behavioral,
physical, and functional
lawyer, who ought to perform well on language tests, generating 11 words on decline.
letter fluency (producing as many words as possible beginning with a given
letter, such as F, in 1 minute). Although this may be considered “normal” on the ● Changes in behavior can
MoCA, it should be considered as possibly impaired as the lawyer might be accompany any patient with
cognitive impairment and
expected to produce more than 11 words. Depending on the patient’s occupation,
can occur before the onset
the clinician may need to alter the line of questioning to determine changes or of cognitive symptoms,
impairment in instrumental ADLs. progress with the cognitive
symptoms as a major feature
Clarifying the Presenting Symptom and Course of the Illness of the dementia, or be part
of a recognized symptom
At the beginning of the interview, we recommend that the following information complex, such as in limbic
be obtained: (1) onset of the condition (insidious or acute), (2) presenting symptom, encephalitis.
(3) course of the condition (gradually progressive, stepwise, fluctuating, or
improving), and (4) duration. These pieces of information can often identify the ● It is best to obtain the
chronologic sequence of the
underlying dementia syndrome and determine a rational approach to diagnostic
changes in a patient’s
investigations (TABLE 1-2). cognitive, behavioral,
Both the onset of the condition and its duration can be described as acute physical, and functional
(minutes to days), subacute (weeks to months), or chronic/insidious (years). decline. Although many
When either an acute onset or rapidly progressive duration is reported, the neurodegenerative
dementias have overlapping
clinician should verify the accuracy of the information as informants can impairments, the
underestimate the duration of illness because of a tendency to link symptom chronologic sequence of
onset to a major life event or illness.28 It is best to determine a timeline of changes events may help determine
in cognition or behavior so as not to overlook changes that have been incorrectly the type of dementia.
attributed to normal aging. Posing the simple question “When was the last time
the person was able to independently…?” can be useful in this situation.
When asked for the presenting symptoms, the informant often will describe
any cognitive deficit as a memory deficit. Therefore, it is important not to interpret
each “memory” complaint as an impairment in anterograde (short-term)

memory; instead, the clinician should ask for examples of the presenting symptom
to determine accurately what the informant means by “memory deficits.” For
example, an informant may report memory deficits, but the examples provided
may be indicative of word-finding difficulties and thus indicate an underlying
anomia or language impairment as the presenting sign. Otherwise, the rest of the
history will overemphasize an amnestic problem that would be suggestive of AD.
The course of the condition can be described as progressive, static, fluctuating, or
improving. Depending on the course of the disorder, it can further indicate an
etiology (TABLE 1-2).
TABLE 1-2 Onset of the Presenting Symptom and Course and Duration of Illness
That Will Help Determine Etiology of the Cognitive Change
Onset
◆ Acute (seconds to days)
◇ Stroke
◇ Infection (viral, bacterial)
◇ Metabolic
◆ Subacute (weeks to months)
◇ Metabolic
◇ Infection (Creutzfeldt-Jakob disease, fungal, spirochete)
◇ Endocrine
◇ Paraneoplastic
◆ Chronic (years)
◇ Neurodegeneration
◇ Chronic cerebrovascular disease
Progression
◆ Improving
◇ Stroke
◇ Metabolic
◇ Delirium
◆ Static
◇ Stroke (fixed deficit)
◆ Fluctuating
◇ Epilepsy
◇ Paraneoplastic
CONTINUED ON PAGE 677
676 JUNE 2018

One example of a clarified chief complaint and course is “the insidious onset
(onset) of progressive (course) anterograde memory decline (presenting symptom)
that has worsened over 2 years (duration).” This example should indicate to
the clinician that the patient most likely has AD, although this must be supported
and verified by obtaining the rest of the history. Another example of a chief
complaint would be an “acute onset (onset) of a fixed (progression) anterograde
memory loss associated with prosopagnosia and visual hallucinations (presenting
symptoms) of 1-day duration (duration),” which would be suggestive of a right
posterior cerebral artery infarction.
CONTINUED FROM PAGE 676
◇ Metabolic
◇ Dementia with Lewy bodies
◆ Progressive
◇ Infection (Creutzfeldt-Jakob disease)
Duration
◆ Acute (seconds to days)
◇ Stroke
◇ Metabolic
◆ Subacute (weeks to months)
◇ Metabolic
◇ Infection (Creutzfeldt-Jakob disease, fungal, spirochete)
◇ Endocrine
◇ Paraneoplastic
◆ Chronic (years)
First Symptom Noticed
◆ The presenting symptom often determines the type of dementia (TABLE 1-1)
◆ Not all causes of dementia present with true anterograde/short-term memory loss

What to Obtain in the History

The clinician should obtain a description of the patient’s cognitive,
behavioral, physical, and functional decline from the informant. The areas of
cognitive changes include memory, language, praxis, visuospatial function,
attention, and executive function. The first column in TABLE 1-1 lists
descriptions from informants (not an exhaustive list) describing the affected
cognitive domain. If a cognitive domain has not been addressed spontaneously,
then the clinician should inquire about it to determine if a change has
TABLE 1-3 Sample Questions to Probe Each Cognitive Domain
Cognitive Domain Probes/Sample Questions
Executive function Does the patient:
Have difficulty planning/organizing (eg, vacations)?
Have difficulty multitasking (eg, planning or cooking a meal)?
Show poor judgment/bad decisions?
Have difficulty with problem solving?
Show mental rigidity or inflexibility?
Attention and concentration Does the patient:
Lose track of thoughts?
Have difficulty following TV program or movie?
Get easily distracted?
Memory Does the patient:
Forget names?
Misplace objects?
Repeat questions and/or conversations?
Rapidly forget what is told to him/her?
Use compensatory strategies (eg, makes notes as reminders)?
Mix up dates?
Forget appointments?
Leave stove on/faucet running?
678 JUNE 2018

occurred that the informant had neither appreciated nor brought up
(TABLE 1-3).
Both types of ADLs, instrumental and basic, should be asked about. With
impairment in instrumental ADLs, complex skills required to live independently
are lost, such as managing finances, driving, preparing meals, using devices, and
shopping. Impaired instrumental ADLs are required to satisfy the criteria for
dementia. Since every patient is unique and their instrumental ADLs vary,
questions should be derived from tasks in their occupation and their usual
Cognitive Domain Probes/Sample Questions
Language Does the patient:
Have word-finding difficulty (eg, peoples’ names, common words/objects)?
Make speech sound/word errors (phonemic and/or semantic paraphasias)?
Show comprehension deficits (eg, with complex oral instructions, simple oral instructions,
written text)?
Have pronunciation/articulation deficits?
Show loss of word meaning?
Have slurred speech?
Not always make sense when speaking?
Have reduced speech?
Visuospatial/geographic Does the patient:

orientation
Have trouble navigating (eg, gets lost in familiar places, in unfamiliar territory, own household)?
Have prosopagnosia (ie, trouble recognizing familiar faces, objects/buildings)?
Have trouble finding objects in a refrigerator or drawer or directly in front of them?
Have trouble parking the car, resulting in new dents, or drive too close to others?
Personality/behavior Does the patient:
Show disinhibition (eg, socially inappropriate behavior; loss of manners or decorum;

impulsive, rash, or careless actions)?
Show changes in social interpersonal conduct/loss of social graces?
Show apathy or inertia (eg, loss of interest, drive, and motivation; decreased initiation
of behavior)?
Show changes in emotional expression/reactivity/empathy/sympathy (eg, diminished

response to other people’s needs or feelings; diminished social interest, interrelatedness,
or personal warmth)?
Show changes in eating habits (eg, altered food preferences, binge eating, increased
consumption of alcohol or cigarettes, oral exploration or consumption of inedible objects)?
Show perseverative, stereotyped, compulsive/ritualistic behavior (eg, simple repetitive

movements or complex compulsive or ritualistic behaviors)?

function at home. The ability for patients to perform their basic ADLs (eg,
grooming, managing hygiene, bathing, eating, dressing) should be determined.
Changes in basic ADLs usually occur in the later stages of dementia, and the
descriptions range from fully independent to needing reminders, requiring some
help, and fully dependent.
Changes in behavior can accompany any patient with cognitive impairment
and can occur before the onset of cognitive symptoms,29 progress with the
cognitive symptoms as a major feature of the dementia,30 or be part of a
recognized symptom complex, such as limbic encephalitis.31 Mild behavioral
impairment is a recently described condition in which patients who are cognitively
normal develop neuropsychiatric symptoms consisting of decreased motivation,
affective dysregulation, impulse dyscontrol, social inappropriateness, or abnormal
perception or thought.29 Patients with mild behavioral impairment are at greater
risk to develop cognitive decline when compared to patients without
neuropsychiatric symptoms. Many patients with dementia will develop
changes in their behavior as the dementia progresses. For example, patients
with AD can develop apathy or short-temperedness during their illness. Patients
with behavioral variant frontotemporal dementia (bvFTD) have early and
prominent changes in behavior (apathy, disinhibition, social inappropriateness,
indifference) as a hallmark of this disorder.30 In limbic encephalitis, changes in
behavior, such as irritability, depression, or psychotic symptoms, occur
characteristically with other symptoms of memory loss, seizures, and sleep
changes. This recognizable pattern should alert the clinician to the possibility of a
disorder affecting the limbic system, such as a paraneoplastic syndrome.32
Chronologic Approach to the History

It is best to obtain the chronologic sequence of the changes in a patient’s cognitive,
behavioral, physical, and functional decline. Although many neurodegenerative
dementias have overlapping impairments, the chronologic sequence of events may
help determine the type of dementia. For example, in the amnestic presentation of
AD, the sequence of impairment in the cognitive domains would be an initial
deficit in memory, then executive function, followed by language, visuospatial
function, and, finally, behavior. In contrast, a patient with bvFTD would
classically present with impairment in behavior, then executive function, followed
by language and then memory. Although the same cognitive domains are affected,
it is the sequence of impairment that can help determine the cause. In addition, it
has become increasingly clear that certain neurodegenerative syndromes may
evolve to incorporate other distinct clinical syndromes, and this is being reflected
in revised diagnostic criteria.33,34 For example, patients presenting with a
nonfluent progressive aphasia can progress over time to develop corticobasal
syndrome, progressive supranuclear palsy, or bvFTD.33
The chronologic approach can also determine if differing pathologies are
developing in the same person. Cases have been reported in which patients developed
the core features of dementia with Lewy bodies after developing typical AD
many years earlier.35,36 This has implications for management, such as recognition
of the relatively high-risk neuroleptic sensitivity in dementia with Lewy bodies.
Ascertainment of the True Cause of the Symptom or Functional Decline

As with the nonspecific presenting symptom of “memory loss,” the clinician
should elicit additional details when the patient either has difficulties with or is
680 JUNE 2018

incapable of performing a specific function. For example, the patient who is no KEY POINTS
longer able to use a remote control could be demonstrating difficulty with
● Additional details must be
executive function affecting the task setting and monitoring that are required to elicited to determine the
plan and keep track of the appropriate steps in using the device. Alternatively, true cause of the disability
visuospatial deficits may be affecting the ability to recognize the remote control when the patient either has
itself or its parts, language impairment may be affecting interpretation of what difficulties with or is
incapable of performing a
the buttons mean, physical weakness may be limiting the ability to press the buttons,
specific function.
or apraxia may be affecting higher motor control, such as organization or sequencing
of movements. A combination of these factors may also exist. The informant ● Be mindful of multiple
will only report that the patient has an inability to perform a task, and it is up to the medications used to
clinician to determine the reason based on the history and examination. treat a condition (eg,
hypertension); although it
may be a medically resistant
Other Points to Emphasize in the History condition, it could also
When obtaining a medication history, a list of prescription and over-the-counter indicate noncompliance
medications the patient is taking should be obtained. Many over-the-counter because of forgetfulness
that the prescribing
medications, especially those that advertise promotion of sleep, are anticholinergic physician is unaware of.
or antihistaminergic, and both can affect cognition. In addition, the clinician
should be mindful of multiple medications used to treat a condition (eg, ● The cognitive assessment
hypertension); although it may be a medically resistant condition, it could also should not only determine
the domains that are
indicate noncompliance because of forgetfulness that the prescribing physician
impaired but also determine
is unaware of. the domains on which the
Attention should be drawn to medical and neurologic disorders in the past patient may perform
medical history that could affect cognition, such as endocrinopathies, chronic normally.
organ failure, and chronic neurologic disorders such as Parkinson disease,
● A profile of impaired
multiple sclerosis, and epilepsy. The presence and control of cerebrovascular memory with preservation
risk factors should be noted, such as coronary artery disease, hypertension, of function in other domains,
hypercholesterolemia, transient ischemic attack, and stroke. If the patient has a together with intact
history of stroke, it is important to determine symptoms to localize the area of the activities of daily living,
suggests amnestic mild
stroke and determine if a direct temporal relationship to cognitive decline is cognitive impairment.
present. A history of concussion or traumatic brain injury must also be obtained.
Confusion following recent surgeries may suggest an underlying neurologic ● Clinicians should use the
disorder affecting cognition combined with limited cognitive reserve. Moreover, information obtained in the
history to guide them in
caregivers may date the onset of a dementia to a surgical procedure/anesthesia
selecting and interpreting a
when, likely, the dementing symptoms predate the surgery but were either cognitive assessment as no
unnoticed or dismissed. Inquiry regarding the patient’s habits should include single cognitive test can
alcohol consumption, smoking, and illicit drug use. accurately diagnose all
conditions; each test has
some limitations in its
MENTAL STATUS EXAMINATION sensitivity to detect
The cognitive domains assessed in many cognitive assessments are memory, abnormal function as well
orientation, language, visuospatial function, and executive function (SDC 1-1; as limitations in specificity.
links.lww.com/CONT/A251), with each of those functions classically localized to
specific areas of the brain. The cognitive assessment should determine not only
the domains that are impaired but also the domains on which the patient may
perform normally. Although the various tests appear to examine all of these
cognitive domains, it is the degree of in-depth evaluation of each domain that
differentiates each test, leading to the possibility of either underestimating the
impairment or not assessing the involved symptom.37 For example, the MMSE is
an easy and quick-to-administer test but has limitations for detecting mild
cognitive impairment and early dementia and for identifying the various types of
dementias.38,39 In addition, some bedside assessments do not examine all domains,

TABLE 1-4 Localization of Cognitive Domains and Tests to Explore Each Domaina
Cognitive Domain
and Localization General Administration Additional Office Tests to Consider
Executive function Executive function can be assessed by Trail Making Test1
Lateral prefrontal examining component processes of tasks Phonemic (letter) word list generation or fluency1
Left frontal: Task setting that involve task setting and monitoring; for
Right frontal: Monitoring example, on clock drawing, planning the Luria hand sequences1
contour size and shape, number placement, Go/no-go task1
and time setting involve task setting, and
avoiding duplication of numbers involves Similarities1
monitoring1
Clock drawing1
Alternating patterns1
Attention Tests vigilance by asking the patient to Serial subtractions1

Frontal perform a single sustained task (eg, serial
subtractions, digit span) or when given Digit span (forward and reverse) 1
distractors (eg, letter cancellation)
Letter cancellation tests1
Language All components of language should be

tested individually in patients who present
with a primary language disorder; short
screening bedside tests may not be
sufficient to characterize the disorder, and
additional tests are required
Sentence repetition Ask the patient to repeat words and Sentence repetition test40
Left perisylvian area phrases
Montreal Cognitive Assessment sentence
repetition21; the only caveat, if patients have
impaired working memory, they will perform
poorly on this test as the sentence has too many
words for them to learn and repeat
Repetition items of the Toronto Cognitive

Assessment (TorCA)25
Naming Ask the patient to name various objects Multilingual Naming Test41
Left temporal lobe for with increasing difficulty, for example,
isolated naming naming a watch, then face (of the watch) or Boston Naming Test42
deficits crystal (of the watch), then stem (of the
watch); another example is to ask the
patient to name a shoe, followed by the
sole (of the shoe), then eyelet or laces
(of the shoe)
682 JUNE 2018

Cognitive Domain
Reading, writing Ask patient to write a sentence and read a Written and oral description of the cookie theft
Left parietal/inferior passage of text, for example from a picture
parietal lobule for magazine
isolated reading and
writing deficits (alexia
with agraphia)
Comprehensionb Ask the patient to perform tasks in the Sentence comprehension tasks43 that assesses
Left temporal-parietal office using simple instructions (eg, point to grammar comprehension
the floor) that increase in complexity (eg,
point to the surface that you walk on; point
to the floor after pointing to the ceiling)
Semantic knowledge Ask the patient to define objects (living and Semantic knowledge test25,43
Left temporal lobe inanimate)
Visuospatial
Parietal/occipital/ In general, this is assessed by asking Benson complex figure copy32
temporal patients to copy a figure; can also assess
for additional visuospatial functioning such Rey-Osterrieth Complex Figure Test44
as simultanagnosia and optic ataxia,
elements of Balint syndrome; need to Necker cube copy11,21
ensure that no primary ocular problem is
present, such as macular degeneration, that Judgment of Line Orientation test45
would confound the interpretation
Identifying overlapping figures (Montreal
Cognitive Assessment Basic)46; assesses
simultanagnosia
Identifying numbers on the Ishihara plates47;

assesses simultanagnosia
Describing a complex picture, such as the Cookie

Theft Picture; assesses simultanagnosia if the
patient cannot describe the whole picture but
only parts of it
Asking the patient to reach out to an object;

assesses optic ataxia (in the absence of
cerebellar findings) if the patient misses the
object48
Frontal visuospatial This is assessed by asking the patient to None

draw to command (which will be impaired)
but patient is able to copy the figure


Cognitive Domain
Memory Verbal or visual memory tests always have Bedside assessments generally evaluate verbal
Temporal lobe/ two parts: an initial learning task and memory with three to five words; if additional
hippocampus/medial delayed recall task measures are required to examine further,
temporal consider a robust verbal list learning with delayed
The learning task employs at least one recall that has 10 to 15 elements, such as the
Dorsomedial thalamus49 learning trial and has multiple elements to Consortium to Establish a Registry for Alzheimer’s
(in cases of stroke) learn (eg, 3 to 15 words; >10 elements on Disease (CERAD) Verbal List14 or Free-Cued Test50
paragraph/story learning; >10 visual
elements) Testing orientation is also considered as a
memory test25
The delayed recall task usually occurs after
several minutes and after several Visual memory can be assessed by copying a
distractors are introduced from the learning complex figure (see Visuospatial above) followed
task so as not to have the patient rehearse by recall after a 5- to 10-minute delay; some
the words in between bedside tests have incorporated this, such as the
TorCA
The recall task always involves a free recall
without cueing; some tests then allow a
cued recall, such as with a category cue
Recognition should also be assessed by

providing patients with the correct target
stimuli and incorrect items and asking them
to choose the correct items
Impaired delayed recall with impaired

recognition suggests a true memory
problem with loss of information, whereas
impaired delayed recall with good delayed
recognition suggests a retrieval problem
due to frontal system damage
Calculations This is assessed by asking the patient to Example from the Short Test of Mental Status11:
Left parietal/inferior perform simple arithmetic (subtraction,
parietal lobule multiplication, division or addition), but not 5 × 13 =
using 1, 2, 5, or 10 as this is too easy, or asking 65 – 7 =
from the multiplication tables as this may
58 ÷ 2 =
test memory rather than calculations
29 + 11 =
a
Note: Localizations listed in this table represent classic clinical-anatomic relationships; however, brain lesions in other regions may produce
similar deficits. For example, although frontal lesions are classically associated with attentional deficits, impaired attention can also be due to right
parietal lesions. In addition, although isolated naming deficits can occur following left temporal lesions, impaired naming occurs as part of aphasic
disorders due to lesions in the left frontal, temporal, or parietal lobes.
b
Patients may fail comprehension tests if they have deficits in semantic knowledge. However, patients with semantic knowledge deficits often
perform better with phrases than single words because they can benefit from the context, whereas patients with comprehension deficits tend to
have more trouble as the length of what they are asked to comprehend increases.
684 JUNE 2018

A 78-year-old right-handed man with 14 years of education was brought CASE 1-1
into the clinic urgently for assessment of the acute onset of “confusion.”
He had been evaluated 4 days previously to assess his 2-year history of
the insidious onset of progressive anterograde memory loss that affected
his usual instrumental activities of daily living. Neuroimaging at that initial
visit revealed bilateral hippocampal and parietal atrophy. At the initial
visit, he was diagnosed with Alzheimer disease. He had been well over
the intervening 4 days but in the morning, his family noted that he
appeared confused and requested an urgent reassessment. His medical
history was remarkable for hypertension, type 2 diabetes mellitus, and
hypercholesterolemia.
On cognitive testing, he scored 17/38 on the Short Test of Mental Status11,12;
he had scored 25/38 at the initial evaluation 4 days earlier. The elements of
each test and his scores for each area are listed below. His elemental
neurologic examination was normal on both visits.
Given the acute clinical change and the results of the clinical assessment at
the second visit, he was clinically diagnosed with an acute left parietal stroke
and sent to the emergency department for urgent neuroimaging. Brain CT
revealed an acute left parietal intracerebral hemorrhage.
Short Test of Mental Status Domain Score at Initial Visit Score at Follow-up Visit
Total score 25/38 17/38
Orientation 6/8 5/8
Attention 6/7 4/7
Learning (number of trials) 4/4 (1 trial) 4/4 (2 trials)
Calculations 4/4 0/4
Similarities 2/3 2/3
Construction/drawing 3/4 0/4
Information 4/4 3/4
Delayed recall 0/4 0/4
This case illustrates that cognitive testing can aid with the localization of COMMENT
brain lesions. When comparing the two test results, a marked and focal
difference is seen in this patient’s ability to perform calculations and draw
items, and both functions localize to the left parietal lobe. Given the acute
change reported, the clinical conclusion was an acute stroke affecting the
left parietal lobe.

and additional tests should be considered. Once the assessment has been
completed, the pattern of the patient’s cognitive difficulties relative to their
overall performance (ie, their cognitive profile) can be used to help determine the
etiology of the impairment. For example, a profile of impaired memory with
preservation of function in other domains, together with intact ADLs, suggests
amnestic mild cognitive impairment.
Classic Localization of Cognitive Domains

Although cognitive function is mediated by networks that span different brain
regions, an association exists between each cognitive domain and specific lobes
within the brain (TABLE 1-440–50). For example, anterograde memory function is
localized to the temporal lobe, specifically the hippocampus or medial temporal
lobe. However, it should be noted that lesions in the dorsomedial nucleus of the
thalamus can also impair anterograde memory function.49 Nevertheless, the
mental status examination can aid the clinician with lesion localization (CASE 1-1).
In addition, some classic syndromes, each with a specific localization, consist of a
typical constellation of cognitive symptoms and signs (eg, Gerstmann syndrome
and Balint syndrome [TABLE 1-5]) that are found in some neurodegenerative
dementias and after focal lesions. By clinically determining the possible damaged
areas of brain that may account for the cognitive deficits, the clinician can focus
TABLE 1-5 Classic Eponymous Cortical Cognitive Syndromes
Syndrome Clinical Components Office Tests to Consider Localization Disorders to Consider

47
Balint Simultanagnosia (the Ishihara plates ; Bilateral occipitoparietal Posterior cortical
syndrome inability to see objects overlapping figures46 atrophy; watershed
simultaneously) infarcts
Optic ataxia (the inability Impaired finger-nose

to reach a target under (misreaching) in absence of
visual guidance) other cerebellar findings38
Oculomotor apraxia (the Test saccades and observe

inability to purposefully for failure to initiate the
move the eyes to a target) movement
Gerstmann Acalculia (the inability to See calculations in TABLE 1-4 Left inferior parietal Posterior cortical
syndrome perform arithmetic) lobule atrophy; left middle
cerebral artery infarct
Right-left difficulties (the Ask the patient to
inability to recognize the demonstrate the right
left from right sides) and left sides of parts of
their body
Agraphia (the inability See writing in TABLE 1-4

to write)
Finger agnosia (the Ask the patient to identify

inability to discriminate fingers
and therefore name
the individual fingers
of the hand)
686 JUNE 2018

A 55-year-old right-handed man with 17 years of formal education CASE 1-2
presented with the insidious onset of progressive word-finding
difficulties of 3 years in duration. In conversations, he knew that he
should know some words, but he had forgotten what they meant.
Although he could recognize colleagues, he did not recall their names. He
had no change in personality or behavior.
On cognitive testing, he scored 30/38 on the Short Test of Mental
Status,11,12 with the following breakdown of the subitems: orientation
8/8, attention 5/7, learning 4/4 words but in three trials, calculation 4/4,
construction/drawing 4/4, information 3/4, and delayed recall 3/4. His
elemental neurologic examination was normal.
Additional cognitive testing
revealed normal performance on the
Rey-Osterrieth Complex Figure Test44
(a test that involves copy and recall
of a complex figure and measures
several functions, including
visuospatial ability, planning, and
visual memory), Logical Memory
subtest of the Wechsler Memory
Scale52 (a test of memory in which
the patient learns and recalls
elements of a story), and Rey
Auditory Verbal Learning Test53
(a test of memory in which the
patient learns and recalls a
list of unrelated words). However, FIGURE 1-1
he obtained 5/30 on the Boston Axial fluid-attenuated inversion
Naming Test, generated seven recovery (FLAIR) MRI of the patient in
animals for semantic fluency, and CASE 1-2 showing focal left anterior
temporal lobe atrophy.
generated 25 words on verbal letter
fluency (C, F, L).
Brain MRI revealed focal left anterior temporal lobe atrophy (FIGURE 1-1).
Brain single-photon emission computed tomography (SPECT) revealed left
more than right anterior bitemporal hypoperfusion. A diagnosis of semantic
variant primary progressive aphasia was made.
This case illustrates the limitation of certain bedside screening tests and COMMENT
the need to add additional tests to adequately evaluate a patient to reach a
diagnosis. The patient had scored reasonably well on the Short Test of
Mental Status, losing points for difficulties in learning words as additional
points are deducted for learning after one trial. This test also does not
adequately evaluate language; therefore, additional language tests were
administered as language deficits were the patient’s presenting symptom.
Furthermore, his deficits were clinically localized to the left temporal lobe,
which was confirmed on MRI.

on these areas when reviewing CT or MRI scans of the brain for potential
lesions, such as stroke, mass lesion, or focal areas of cortical atrophy.
Selection of an Appropriate Cognitive Test and Knowing Its Limitations

Current bedside cognitive tests provide a structured and easily administered
approach for the evaluation of patients with either dementia or mild cognitive
impairment38,51 as well as patients with cognitive complaints who perform
normally on testing. In the absence of the clinical history, no single cognitive
test can accurately diagnose all conditions, as each test has some limitations in
CASE 1-3 An 80-year-old right-handed man presented with the insidious onset of
progressive short-term memory of 2 years in duration. Initially, his family
observed that he repeated the same questions and parts of conversations
that they had. In addition, he misplaced items around the home.
About 1 year earlier, he could only complete one task at a time and
could not multitask. A family member took over the family business, as
the patient forgot details of business contracts. His emails got shorter,
with shorter sentences, and had spelling and grammatical errors. For
example, he wrote “I were doing something.” He was still able to drive
and cook. He was independent with his basic activities of daily living.
His neurologic examination was normal. Results of his cognitive testing
with the Toronto Cognitive Assessment (TorCA)25 are shown. Brain
MRI revealed bilateral hippocampal and mild biparietal atrophy. His
presentation was consistent with the diagnosis of Alzheimer disease (AD).
COMMENT This case illustrates several points. The nature of the presenting symptom
suggested a neurodegenerative disorder, likely AD, given the insidious
onset, anterograde memory impairment presentation, and progression
over years. The history was consistent with a dementia, as it revealed
impairments in multiple cognitive domains, including memory (rapid
forgetting and repeating the same questions), language (short sentences,
agrammatism), and executive function (inability to multitask) associated
with a decline in his instrumental activities of daily living (inability to work).
Interpretation of cognitive testing revealed impairments in memory
(impaired delayed verbal more than visual recall as well as impaired
delayed recognition), language (mild impairment in naming), and executive
function/attention/working memory (reverse digit span). Memory was
most affected compared to the other affected domains. His cognitive
profile was predominantly amnestic, with medial temporal lobe localization
(impaired delayed recall and impaired delayed recognition). In addition, a
discrepancy was seen between letter F fluency and semantic animal
fluency, with only the latter being impaired. This is consistent with
temporal lobe dysfunction. Therefore, multiple pieces of clinical evidence
indicated medial temporal lobe pathology. This was supported by the brain
MRI findings. Given all the information, the patient’s presentation is
consistent with AD.
688 JUNE 2018

its sensitivity to detect abnormal function and limitations in specificity. The
history obtained should guide the clinician on which cognitive assessment
to use.
A common approach is to choose a standard cognitive test that is routinely
administered as a cognitive screen, such as the MoCA. However, when
administering such a cognitive test, it is useful to know the limits of the test.
When the test is insufficient because either the patient’s symptoms are too mild
to be detected by the test or the patient’s symptoms are not well assessed by the
test (eg, the MMSE is relatively insensitive to deficits in executive function), a
Domain Test Segment Results

Memory Orientation Normal
Verbal memory
Learning (10 words in three trials) 1, 5, and 7 words on trials 1, 2, and 3, respectively
Delayed free recall 0/10; impaired
Delayed recognition recall 17/20; impaired
Visual memory
Delayed free recall 6/17; mild impairment
Delayed recognition recall Normal
Attention Serial subtractions Normal
Digit span, forward Normal
Digit span, reverse Mild impairment
Executive function/ Similarities Normal

attention/working memory
Letter fluency (F words) 13 words (normal >12)
Trail Making Test Parts A and B Normal
Visuospatial Benson complex figure copy Normal
Clock drawing Normal
Language Naming Mild impairment
Sentence repetition Normal
Animal fluency 6 words (normal >15)
Sentence comprehension Normal
Semantic knowledge Normal

KEY POINTS different test should be chosen or the test should be supplemented with
additional bedside tests that would further examine the cognitive issues
● When the cognitive test is
insufficient because either
(TABLE 1-4). For example, if a patient presents with a progressive aphasia and a
the patient’s symptoms are clinician chooses to administer the MoCA, additional tests should be considered
too mild to be detected by to further evaluate language (CASE 1-2).
the test or the patient’s One clinically useful bedside test to add to any assessment, if not already
symptoms are not well
included, is semantic or category fluency. Similar to letter or phonemic
assessed by the test, a
different test should be fluency, the patient is given 1 minute to list as many items in a specific category,
chosen or the test should be such as animals or vegetables, as he or she can, and the score represents the
supplemented with number of items generated. When analyzed together with letter fluency,
additional bedside tests that
semantic fluency can provide additional information regarding localization of
would further examine the
cognitive issues. dysfunction. Letter fluency is impaired with prefrontal lesions, whereas deficits
in semantic fluency occur following left temporal lobe lesions. However, the
● Common cognitive number of words generated on semantic fluency is generally greater than for
profiles/patterns include letter fluency. For example, healthy individuals older than 50 years of age should
amnestic, executive
dysfunction, visuospatial
be able to generate more than 16 animal names in 1 minute and more than 12
impairment, and language words beginning with the letter F.25 Thus when the number of words on the
dysfunction. semantic task is abnormally low, it may indicate left temporal lobe dysfunction,
such as in AD (CASE 1-3). When the letter fluency is low, it may indicate a
● In the amnestic pattern,
prefrontal lesion.
the major difficulty is on
tests of delayed recall and Clock drawing is another easy and quick-to-administer bedside test. Patients
recognition. are provided with a blank piece of paper with instructions to draw the face of a
clock, put in the numbers, and set the hands at 10 after 11.25 This task is called a
● In the executive free-drawn clock. The clock-drawing test provides useful information about
dysfunction or
frontal-subcortical pattern, multiple cognitive processes, including executive and visuospatial functions. The
major difficulties on tests executive functions of the clock-drawing test include task setting (defined as
include impairments on the planning the size and shape of the contour, placement of the numbers, and time
Trail Making Test Part B setting) and monitoring (defined as avoidance of duplication, such as numbers or
(letter-number sequencing)
and in digit span, letter
extra hands, and self-correction of errors). Choosing the time at which patients
cancellation, phonemic are asked to set the clock affects the sensitivity of clock drawing for detecting
fluency (number of words executive function deficits. “Ten after 11” (not 11:10) is one of the more sensitive
beginning with a certain times because the 10 must be recoded so that the minute hand is set to the 2.
letter generated in 1 minute),
similarities, or serial
Patients with frontal lesions tend to have difficulty with this abstraction and
subtractions, with relative make the stimulus-bound error of placing the minute hand on the 10 instead of
preservation in the other the 2.1,54 Visuospatial function is required to place the elements of the clock in the
cognitive domains. correct location and orientation.
● In the visuospatial
impairment pattern, Determining the Cognitive Profile
patients have difficulties on In addition to the total score (or overall performance) that many bedside tests
tasks that require drawing, provide, it is clinically useful to determine the specific areas of impairment (ie, the
whether copying a figure cognitive profile). Examples and interpretation are shown in TABLE 1-6. Common
(eg, Benson complex figure,
intersecting pentagons) or cognitive profiles/patterns include amnestic, executive dysfunction, visuospatial
drawing an object (eg, impairment, and language dysfunction. In a given patient, more than one area can
free-drawn clock). be affected; however, one area is usually disproportionately more affected than
other areas. Over time, as the cognitive impairment advances in neurodegenerative
dementias, all domains become involved equally in the later stages, and it is
difficult, in the absence of clinical history, to determine a profile or etiology.
In the amnestic pattern, the major difficulty is on tests of delayed recall and
recognition. Orientation may be impaired as well. This pattern can be seen in
amnestic mild cognitive impairment or AD (CASE 1-3).
690 JUNE 2018

In an executive dysfunction or frontal-subcortical pattern, major difficulties
on tests include impairments on the Trail Making Test Part B (letter-number
sequencing) and in digit span, letter cancellation, phonemic fluency (number of
words beginning with a certain letter generated in 1 minute), similarities, or
serial subtractions, with relative preservation in the other cognitive domains.
Disorders that commonly demonstrate this pattern include vascular cognitive
impairment (CASE 1-4); normal pressure hydrocephalus; and disorders
associated with parkinsonism, such as Parkinson disease dementia (CASE 1-5),
dementia with Lewy bodies, progressive supranuclear palsy, Huntington disease,
and corticobasal degeneration. Given the multiple differing etiologies that can
provide the same cognitive profile, it will be the combination of the history,
mental status examination, elemental neurologic examination, and
neuroimaging that will determine a final diagnosis.
In the visuospatial impairment pattern, patients have difficulties on tasks that
require drawing, whether copying a figure (eg, Benson complex figure,
intersecting pentagons) or drawing an object (eg, free-drawn clock). Additional
difficulties may be seen on tests that examine other domains but require intact
visuospatial skills,55 such as the Trail Making Test, a test that examines executive
function. Patients with visuospatial impairment will have difficulties on the Trail
Making Test as they try to find or to “see” the next element in the sequence.
Thus, they will take longer to complete the test. Similarly, they may have an
impairment in naming, not necessarily due to language impairment but rather to
difficulty in accurately perceiving the stimuli being named (CASE 1-6). This is
called nonaphasic misnaming.
In patients with language dysfunction, depending on the severity and type of
the language dysfunction, difficulties may be seen with naming in association
with poor performance on sentence repetition, semantic knowledge, writing,
comprehension, and reading and writing (CASE 1-2). For more information on
the variants of aphasia, refer to the article “Primary Progressive Aphasia and
Stroke Aphasia” by Murray Grossman, MDCM, FAAN, and David J. Irwin,
MD,56 in this issue of Continuum. Patients with aphasia generally do very poorly
on cognitive assessments that are heavily language based, such as the MMSE and
Cognitive Profiles/Patterns Seen on Cognitive Testing TABLE 1-6
Major Deficit Seen on Testing Pattern Example Conditions

Orientation, delayed word recall Amnestic Mild cognitive impairment (amnestic),
Alzheimer disease
Planning and monitoring, attention, Executive dysfunction, Dementia with Lewy bodies, Parkinson
sequencing (eg, three-step command), frontal-subcortical dysfunction disease dementia, vascular dementia
word list generation for letters
Drawing Visuospatial impairment Posterior cortical atrophy, dementia with

Lewy bodies, corticobasal degeneration
Naming, repetition, writing Aphasia Primary progressive aphasia
Normal testing Not applicable Can be seen in behavioral variant

frontotemporal dementia, subjective
cognitive impairment

CASE 1-4 A 74-year-old right-handed man with 14 years of education presented

with a 2-year history of progressive slowness of thought, apathy, and
difficulties with multitasking. His past medical history was significant for
diabetes mellitus, hypertension, and hyperlipidemia, without any known
clinical stroke. He was able to work but was noted to be slow and was at
risk of losing his job. He took longer to memorize his shopping list and
wrote the items down on a list.
On cognitive testing, he scored 22/30 on the Montreal Cognitive
Assessment (MoCA)21, as shown in the test results. On neurologic
examination, he was slow to respond on cognitive testing and had a mild
left hemiparesis. He had no signs of parkinsonism. Brain MRI revealed
diffuse ischemic white matter changes and old subcortical infarcts
(FIGURE 1-2). His presentation was felt to be most consistent with vascular
cognitive impairment.
FIGURE 1-2
Axial fluid-attenuated inversion
recovery (FLAIR) MRI of the patient in
CASE 1-4 showing diffuse ischemic
white matter changes and old
subcortical infarcts.
COMMENT This patient with cerebrovascular risk factors developed frontal-subcortical

cognitive slowing in the absence of parkinsonism. Cognitive testing primarily
revealed impairments in prefrontal functions, specifically impairment on the
Trail Making Test Part B and in letter cancellation, letter fluency, and similarities,
with preservation of memory. Although his overall performance/score on the
MoCA was low, examination into the specific areas of impairment indicate that
it was not due to memory impairment and likely not consistent with Alzheimer
disease when considering the presentation and the neurologic examination.
692 JUNE 2018

Domain/Test Segment Score
Executive function/visuospatial
Trail Making Test Part B 0/1
Cube copy 1/1
Clock drawing 3/3
Naming 2/3
Memory
Learning (5 words) 4 words (trial 1),

5 words (trial 2)
Attention
Digit span (forward, reverse) 1/2
Letter cancellation 0/1
Serial 7s 2/3
Language
Sentence repetition 2/2
Letter fluency (F words) 0/1 (8 words)
Abstraction 0/2
Delayed recall 5/5
Orientation 6/6

CASE 1-5 An 84-year-old right-handed man with 18 years of formal education

presented with a 3-year history of progressive slowness of thought and
verbal blocking that caused him to stop working. Seven years ago, 4 years
before the onset of the cognitive difficulties, he developed levodopa-
responsive parkinsonism, with the onset of resting tremor in his left hand,
rigidity, and stooped posture. About 1 year ago, he developed
spontaneous nonthreatening visual hallucinations described as seeing
small children sitting in the living room.
On cognitive testing, he scored 17/30 on the Montreal Cognitive
Assessment (MoCA)21, as shown below and in FIGURE 1-3. Neurologic
examination revealed left more than right rigidity in the arms and legs,
resting tremor in his left hand, slow rapid alternating movements with
fatiguing, and narrow-based gait with stooped posture, reduced stride
length, and absent arm swing. Brain MRI did not reveal any focal
cortical atrophy. His presentation was consistent with Parkinson
disease dementia.

Cube copy 0/1
Clock drawing 1/3
Naming 2/3
Memory

3 words (trial 2)
Attention
Serial 7s 2/3
Language
Abstraction 2/2
Delayed recall 3/5
Orientation 5/6
694 JUNE 2018

FIGURE 1-3
Performance on the Montreal Cognitive Assessment (MoCA) for the patient in CASE 1-5
demonstrating executive dysfunction on the Trail Making Test Part B (A) and visuospatial
dysfunction on the rectangle copy (B) and clock drawing (C).
This case illustrates another example in which cognitive testing revealed COMMENT
primarily executive dysfunction, with relative preservation of memory,
similar to the cognitive profile in CASE 1-4. However, in this case, an
additional visuospatial impairment indicated frontal and parietal
dysfunction. With the history and neurologic examination consistent with
parkinsonism, the overall presentation is consistent with Parkinson disease
dementia. The profile of both executive dysfunction and visuospatial
dysfunction is typically seen in Parkinson disease dementia and dementia
with Lewy bodies. This case demonstrates that all pieces of information
combined, not in isolation of each other, are required to make a diagnosis.

CASE 1-6 A 45-year-old right-handed businesswoman with 14 years of formal

education presented with the insidious onset of progressive difficulties
seeing, reading, writing, and performing calculations of 2 years in
duration. When typing, she could not “find” the letters on her keyboard.
She also saw faces of people in trees. She noted difficulties with spelling
and had to sound out words to help her. About 1 year before presentation,
she started to have difficulty performing simple arithmetic and began to
rely on a calculator. She also noted difficulties with reading and had to
use her finger to follow a line of text and read letter-by-letter for each
word. She had no history of symptoms of parkinsonism or rapid eye
movement (REM) sleep behavior disorder. She had been recently
diagnosed with major depressive disorder as she had become anxious
and depressed in the absence of a prior history of any psychiatric disorder.
On cognitive examination, she scored 21/30 on the Montreal
Cognitive Assessment (MoCA)21, as shown. Additional bedside tests
were administered to fully examine her cognitive issues, as shown in
test results and in FIGURE 1-4.
Neurologic examination revealed full extraocular movements, normal
visual fields with absent visual neglect, absent optic ataxia and ocular
apraxia, absent signs of parkinsonism, normal primary sensation, and
absent tactile neglect;
however, agraphesthesia was
noted on both sides and
right-left confusion and finger
agnosia were present. She had
mild difficulties with body
placement when sitting on the
edge of the examining bed and
when navigating toward a chair.
Her brain MRI revealed
asymmetric left more than right
parietooccipital cortical
atrophy, normal hippocampi,
FIGURE 1-4 and no ischemic white matter
Drawing performance on the Benson complex
figure copy for the patient in CASE 1-6
changes or strokes. She was
demonstrating marked visuospatial impairment diagnosed with posterior
in copying the figure. cortical atrophy.
696 JUNE 2018

Cube copy 0/1
Clock drawing 2/3
Naming 2/3
Memory

5 words (trial 2)
Attention
Serial 7s 2/3
Language
Abstraction 2/2
Delayed recall 1/5
Orientation 5/6
Test Score
Trail Making Test (TMT)
Part A Stopped after 90 seconds; could only complete 10 out of 25 elements
Part B Stopped after 4 minutes; could only complete 9 elements
Calculations 0/4
Multilingual Naming Test (MiNT) 13/15
Reading single words 3/12; could only read letter-by-letter and visually; lost track reading on
a sheet of paper
Sentence comprehension Normal
Sentence repetition Normal
Benson complex figure copy 2/17; impaired
Overlapping figures (from Montreal Cognitive 2/10 objects identified

Assessment-B49)
CONTINUED ON
PAGE 698

KEY POINTS MoCA. It is important to be aware of this so these patients are not misclassified
as having a severe dementia.
● In patients with language
dysfunction, depending on
the severity and type of the ELEMENTAL NEUROLOGIC EXAMINATION
language dysfunction, The elemental neurologic examination is a necessary component in the evaluation
difficulties may be seen with of a patient with dementia. In most cases of dementia due to AD, the general
naming in association with
neurologic examination is usually normal. In other causes of dementia, the
poor performance on
sentence repetition, presence of specific extraocular movement abnormalities, upper motor neuron
semantic knowledge, signs, or parkinsonism can be particularly diagnostically useful (TABLE 1-7).
writing, comprehension, and With the history, mental status examination, and the general neurologic
reading and writing.
examination, a diagnosis or reasonable differential can be determined at the
● In most cases of dementia bedside (TABLE 1-8).
due to Alzheimer disease,
the general neurologic
examination is normal. In CONCLUSION
other causes of dementia, it
is clinically useful to
With limitations on both time and resources, an efficient deductive process is
determine the presence of required to obtain and distill the key elements from the history, mental status
specific extraocular examination, elemental neurologic examination, and ancillary investigations to
movement abnormalities, determine the etiology of a patient’s cognitive impairment. The documentation
upper motor neuron signs, or
parkinsonism.
must contain elements that indicate the timing of the onset, type of progression,
presenting symptom, and duration. The history should expand on this and obtain
the chronologic progression of the patient’s abilities in other cognitive domains,
including changes to his or her personality or behavior and ability to function
in both instrumental and basic ADLs. Administration of the mental status
CONTINUED FROM
PAGE 697
COMMENT This patient presented with the insidious onset of both a partial Gerstmann
syndrome (TABLE 1-5) and visuospatial impairment suggestive of
simultanagnosia (TABLE 1-5) that progressed over 2 years, all suggestive of a
progressive neurodegenerative disorder affecting, at minimum, the left
parietal and occipital regions. Other bedside tests, in addition to the MoCA,
were performed to further examine her cognitive symptoms and determine
areas of normalcy. Examination of the cognitive testing mirrored her clinical
presentation and revealed that her cognitive profile showed predominantly
visuospatial impairment with the inability to copy figures and identify
overlapping figures (simultanagnosia). Although she also performed poorly
on the reading tasks and on the Trail Making Test, this was caused by neither
language impairment nor executive dysfunction but rather by her profound
visuospatial impairment. Additional tests of her language and executive
function were normal. She also demonstrated all elements of Gerstmann
syndrome after testing. Examination results concurred with the clinical
assessment with a predominant left parietal and bilateral parietoocciptal
involvement. Brain MRI revealed cortical atrophy in those areas without
ischemic changes. All the information in this case was consistent with the
diagnosis of posterior cortical atrophy.40,47
698 JUNE 2018

examination requires that the chosen assessment tool adequately examines the
patient’s primary symptom in addition to the other cognitive domains. If not,
additional bedside tests should be added to the assessment. Alternatively, the
clinician can administer a single test that includes a more in-depth assessment
than the brief screening measures. Examples of more in-depth assessment tools
are the short form of the Behavioural Neurology Assessment20 for assessment
of dementia and the TorCA25 for assessment of mild cognitive impairment.
Synthesis continues with analyzing the patient’s performance on cognitive
testing to determine his or her cognitive profile. This will then aid in the
Elemental Neurologic Examination Findings in Neurodegenerative Disease TABLE 1-7
Examination Element Examination Findings Disorders to Consider
Extraocular movements Initiation of saccades (indicates an ocular Corticobasal syndrome, progressive

apraxia and can be seen in corticobasal supranuclear palsy, posterior cortical atrophy
syndrome or posterior cortical atrophy); slow
saccade velocity (indicates the possibility of
progressive supranuclear palsy); limitation of
extraocular movement (indicates the possibility
of progressive supranuclear palsy)
Upper motor neuron signs Pyramidal distribution weakness (weakness Cerebrovascular disease (stroke), corticobasal
pattern in arms: extensors > flexors; in legs: syndrome, intracranial mass lesion
flexors > extensors); hyperreflexia; presence of
a Babinski sign (extensor plantar response)
Assessment for Bradykinesia; bradyphrenia; masked facies; Parkinson disease with dementia, dementia
parkinsonism limitation/absence of downgaze (progressive with Lewy bodies, corticobasal syndrome,
supranuclear palsy); rigidity with or without progressive supranuclear palsy,
cogwheeling (distinguish between axial cerebrovascular disease
[progressive supranuclear palsy] versus
appendicular [Parkinson disease, dementia with
Lewy bodies, corticobasal syndrome] rigidity);
rest tremor (not typically seen in dementia with
Lewy bodies, progressive supranuclear palsy,
corticobasal syndrome); fatiguing (rapid
alternating movements such as finger tapping,
opening/closing hands, festinating gait,
progressive hypophonic speech); early postural
instability (progressive supranuclear palsy)
Assessment for early focal Balint syndrome (some or all components): Posterior cortical atrophy, corticobasal
cortical dysfunction simultanagnosia (inability to see objects syndrome
simultaneously), optic ataxia (inability to reach a
target under visual guidance); ocular apraxia
(inability to move the eyes to a target purposefully)
Gerstmann syndrome (some or all components): Posterior cortical atrophy, corticobasal

right-left confusion, finger agnosia, acalculia, syndrome, logopenic progressive aphasia
dysgraphia
Dressing apraxia Posterior cortical atrophy, corticobasal

syndrome
Ideomotor apraxia Corticobasal syndrome, Alzheimer disease
Language (anomia) Primary progressive aphasias

TABLE 1-8 Common History, Cognitive Profile, and Neurologic Examination Findings in
Neurodegenerative Causes of Dementia
General Physical
History/Initial Presentation Cognitive Profile Examination Cranial Nerves
Rapid forgetting Amnestic Normal (including vitals) Normal
Visuospatial difficulties Visuospatial Normal (including vitals) Normal; visual field cut; visual
neglect
Anomia Anomia; acalculia Normal Normal
Slow, executive dysfunction, Executive dysfunction; slow Signs of peripheral and Normal
inattention cardiovascular disease
Behavioral changes (apathy Normal; executive dysfunction Normal Normal

or disinhibition)
Anomia/circumlocution Anomia Normal Normal
Anomia; loss of semantic Anomia Normal Normal

knowledge; prosopagnosia
Visuospatial difficulties, Executive dysfunction; slow; Normal Normal

slow, fluctuations visuospatial
Anomia; parkinsonism; Executive dysfunction; slow; Normal Normal; slow initiation of

apraxia; visuospatial language; apraxia; visuospatial saccades with normal velocity
difficulties dysfunction
Early falls, executive Executive dysfunction; slow; Normal Downgaze limitation; slow
dysfunction language dysfunction saccade velocity but normal
initiation
localization within the brain. The cases in this article are presented with each
piece of information required for the clinical diagnosis. When all the pieces
of information concur, a diagnosis can often be made confidently.
ACKNOWLEDGMENTS
This work was supported by the Saul A. Silverman Family Foundation as a part of
Canada International Scientific Exchange Program project and Morris Kerzner
Memorial Fund (Dr Freedman).
700 JUNE 2018

Deep Tendon Reflexes
Motor Examination and Babinski Sign Gait Disorder to Consider
Normal Normal Normal Alzheimer disease
Normal Normal Normal Posterior cortical atrophy

(Alzheimer disease)
Normal Normal Normal Logopenic variant primary

progressive aphasia (Alzheimer
disease)
Upper motor neuron Hyperreflexia; Babinski sign Normal; slow; decreased Vascular cognitive impairment
pattern of weakness stride length,
hemiparetic gait
Normal; upper motor Normal; hyperreflexia; Normal Behavioral variant frontotemporal

neuron pattern of Babinski sign dementia with or without motor
weakness; lower motor neuron disease
neuron pattern of
weakness
Normal; upper motor Normal; hyperreflexia; Normal Nonfluent/agrammatic variant

neuron pattern of Babinski sign primary progressive aphasia
weakness; lower motor (frontotemporal dementia) with or
neuron pattern of without motor neuron disease
weakness
Normal; upper motor Normal; hyperreflexia; Normal Semantic variant primary

neuron pattern of Babinski sign progressive aphasia
weakness; lower motor (frontotemporal dementia) with or
neuron pattern of without motor neuron disease
weakness
Appendicular rigidity with Normal Slow, narrow-based, Parkinson disease with dementia;
or without resting tremor short strides dementia with Lewy bodies
Asymmetric rigidity with or Hyperreflexia; Babinski sign Slow, narrow-based, Corticobasal degeneration
without unilateral upper short strides; (corticobasal syndrome)
motor neuron signs hemiparetic gait
Axial rigidity Normal Narrow-based gait with Progressive supranuclear palsy

early postural instability
and retropulsion
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REVIEW ARTICLE
 Clinical Assessment of
Prefrontal Lobe
CONTINUUM AUDIO INTERVIEW
AVAILABLE ONLINE
Functions
CITE AS:
AND PSYCHIATRY):704–726.
Address correspondence to
By Alexandre Henri-Bhargava, MDCM, MScCH, FRCPC;
Dr Alexandre Henri-Bhargava,
Island Medical Program, Donald T. Stuss, OC, O Ont, PhD, FRSC, FCAHS, CPsych, ABPP-CN;
University of Victoria, PO Box 1700 Morris Freedman, MD, FRCPC, FAAN
STN CSC, Victoria, BC V8W 2Y2,
Canada, alexhb@uvic.ca.
Dr Henri-Bhargava has received
funding for clinical trials from ABSTRACT
AstraZeneca, Boehringer Ingelheim
PURPOSE OF REVIEW: Whereas it was previously thought that there was a single
Ltd, Eli Lilly and Company, F.
Hoffman-La Roche Ltd, and overarching frontal lobe syndrome, it is now clear that several distinct
TauRx and has provided expert cognitive and behavioral processes are mediated by the frontal lobes.
legal testimony in personal injury
litigation in British Columbia. Dr Stuss
This article reviews these processes and the underlying neuroanatomy and
serves on the advisory board of provides an approach to the assessment of prefrontal lobe functions at
Spindle Strategy Corporation and the bedside.
has received personal compensation
for speaking engagements for
Bennett Jones LLP. Dr Stuss RECENT FINDINGS: Cognitive and behavioral frontal lobe functions are mediated
receives publishing royalties from
by the prefrontal regions rather than the frontal lobes as a whole. At least
Cambridge University Press. Dr
Freedman serves as a trustee for five separate prefrontal functions have been defined: energization, task
the World Federation of Neurology setting, monitoring, behavioral/emotional regulation, and metacognition.
and on the editorial boards of Brain
and Cognition and Journal of
Energization is mediated by the superior medial prefrontal cortices
Parapsychology; has received bilaterally, task setting by the left lateral frontal cortex, monitoring by the
support from and served on an right lateral prefrontal cortex, behavioral/emotional regulation by the
Company Canada and receives orbitofrontal cortex, and metacognition by the frontal poles. Only task
publishing royalties from Oxford setting and monitoring are considered executive functions.
University Press; receives research/
grant support from the Alzheimer
Society of Canada, Brain Canada SUMMARY: Distinct cognitive and behavioral processes are mediated by
Foundation, Centre for Aging and different parts of the frontal lobe. Lesions in these areas result in
Brain Health Innovation, Canadian
Institutes of Health Research, and
characteristic clinical deficits that are discussed in this article. Key
Westin Brain Institute; receives messages are that prefrontal regions mediate the higher cortical functions
support from the Behavioural (as opposed to the frontal lobes in general) and that prefrontal functions
Neurology Physician Recognition
Covenant Fund at Baycrest, the
are not equivalent to executive functions.
Morris Kerzner Memorial Fund, and
the Saul A. Silverman Foundation as
part of the Canada International
Scientific Exchange Program project; INTRODUCTION
U
and holds stock in companies nderstanding the functions of the prefrontal lobes can be daunting at
producing or planning to produce
medical marijuana and is listed on a times, in part because varying terminology exists. In this article, the
provisional patent related to terminology used aims to be both accurate and useful for clinicians.
methods and kits for differential
The terms frontal functions and prefrontal functions are often used
diagnosis of Alzheimer disease.
UNLABELED USE OF PRODUCTS/ synonymously to mean the higher-order cognitive and
INVESTIGATIONAL USE DISCLOSURE: social-emotional functions associated with the frontal lobes. However, parts of
Drs Henri-Bhargava, Stuss, and
the frontal lobes, such as the motor cortices, supplementary motor areas, and
Freedman report no disclosures.
frontal eye fields, are associated with more basic brain functions that are not
of Neurology. usually considered to be higher-order cognitive or social-emotional functions;
704 JUNE 2018

therefore, these are not discussed in this article. The more precise term prefrontal KEY POINTS
functions is used in this article to avoid ambiguity.
● The terms frontal
The term executive functions, which is often associated with prefrontal lobe functions and prefrontal
functions, also has myriad possible definitions. This article defines executive functions are often used
functions as a set of interrelated cognitive processes required for complex synonymously to mean the
goal-directed activity, whose disruption is most often observed after damage to higher-order cognitive and
social-emotional functions
the lateral parts of the prefrontal cortex.1 Although the terms prefrontal functions
associated with the frontal
and executive functions are sometimes used synonymously, executive functions lobes. However, the more
comprise only a subset of prefrontal functions. Prefrontal functions include precise term is prefrontal
cognitive and social-emotional processes in addition to those usually considered functions.
to be executive functions. Furthermore, some aspects of executive functions are
● Although the terms
dependent upon brain regions outside of the frontal lobes (FIGURE 2-12). prefrontal functions and
executive functions
ANATOMY OF THE PREFRONTAL CORTICES are sometimes used
As with all aspects of the neurologic examination, to understand the assessment synonymously, executive
functions comprise only a
of the prefrontal cortex, it is best to view it within the context of neuroanatomy. subset of prefrontal
Models and concepts that are useful for the neurologic examination of prefrontal functions.
functions are presented here. Despite major advances in neuroscience, modern
neurology remains rooted in the concepts of structural localization. Thus, localizing
specific deficits to associated brain areas remains a useful clinical heuristic.
However, it is increasingly recognized that most cognitive processes are not
modular and are dependent on connectivity between large-scale networks in
the brain. These networks are not discussed in detail here.
Structural Anatomy and Connectivity of the Frontal Lobes

Broadly speaking, the frontal lobes can be divided into three major regions
defined by function and Brodmann architectonic (cellular) organization:
primary motor cortex, premotor and supplementary motor cortices, and the
association cortices comprising the prefrontal lobes. The prefrontal lobes can
then be structurally divided in multiple
ways, but this article focuses on four areas:
the superior medial prefrontal cortex,
which includes the anterior cingulate
cortex; the lateral prefrontal cortex; the
orbitofrontal cortex; and the frontal poles.
The prefrontal cortices do not function
as a single unit but are connected
by several connection networks, including
cortical, limbic, cerebellar, and subcortical.
Best known are the cortico-striatal-
pallidal-thalamic loops (often referred
to as frontal-subcortical circuits), which
help clarify the differentiation of function
within the prefrontal lobes. Alexander
and colleagues3 proposed a model with
distinct, parallel frontal-subcortical loops FIGURE 2-1
that subserve different frontal lobe The relationship between prefrontal
functions. With a few modifications, their lobe functions and executive functions.
Reprinted with permission from
model is generally accepted today Henri-Bhargava, et al.2
(FIGURE 2-2). It is recognized that © 2016 Nova Science Publishers.

PREFRONTAL LOBE FUNCTIONS
loops are involved in basic motor function originating from the primary motor
cortex and supplementary motor area as well as the frontal and supplementary
eye fields. In addition, loops originating from the dorsolateral prefrontal cortex,
lateral prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex
subserve cognitive and social-emotional prefrontal functions.4 These frontal
networks (and the fact that the functions associated with the prefrontal cortices
tend to be less hard-wired and automatic) suggest that damage to the
connections may sometimes result in a clinical profile that has similarities with
dysfunction of the prefrontal cortex itself. For example, patients with lesions in
the dorsomedial thalamus may exhibit symptoms of prefrontal lobe injury.5
However, careful analysis will likely show differentiation depending on the site
of damage within such networks.6 In addition, by definition, complex tasks
demand multiple processes in many brain regions. Here, the primary focus is on
the prefrontal cortices themselves.
Functional Anatomy of the Prefrontal Lobes

Understanding the functional neuroanatomy of the prefrontal cortex is
challenging because different models exist of prefrontal functions. To some
extent, these models are shaped by the methods used in the research that
FIGURE 2-2
Frontal-subcortical circuits, based on Alexander, Delong, and Strick’s model. Note that these
loops are simplified; additional areas project to the striatum, including areas outside of the
frontal lobes. Multiple cortico-cortical and cortico-limbic connections also interconnect these
loops. ACC = anterior cingulate cortex; DLPFC = dorsolateral prefrontal cortex; FEF = frontal
eye fields; GPi = globus pallidus pars compacta; LatPFC = lateral prefrontal cortex; MDmc =
medialis dorsalis, pars magnocellularis; MDmf = medialis dorsalis, pars multiformis; OFC =
orbitofrontal cortex; PMC = premotor cortex; SEF = supplementary eye fields; SMA =
supplemental motor area; SNpr = substantia nigra pars reticulata; VAmc = ventralis anterior,
pars magnocellularis; VApc = ventralis anterior, pars parvocellularis; VL = ventrolateral; VLo =
ventralis lateralis, pars oralis.
Reprinted with permission from Henri-Bhargava, et al.2 © 2016 Nova Science Publishers.
706 JUNE 2018

developed them. This article relies upon the model of prefrontal function KEY POINTS
developed by Stuss and colleagues.7 This model is helpful for neurologists
● Five component
because it has been refined by examining neurologic patients with focal processes have been
prefrontal lobe lesions.8 Starting from this model, five component processes identified as separate
have been identified as separate prefrontal lobe functions: energization, task prefrontal lobe functions:
setting, monitoring, behavioral/emotional regulation, and metacognition. energization, task setting,
monitoring, behavioral/
Energization is the process of initiating or sustaining any nonreflex response.
emotional regulation, and
Any activity that requires getting one’s “mental clutch” out of the neutral metacognition.
position requires energization. In studies of patients with prefrontal lesions,
deficits in energization were associated with bilateral damage in the superior ● Energization is the
medial prefrontal cortex, including the anterior cingulate gyrus.9 process of initiating or
sustaining any nonreflex
Task setting and monitoring are the two processes that fit the definition of response. This is mediated
executive functions. Task setting refers to developing and implementing a plan for by the superior medial
carrying out activities such as paying bills. Monitoring is the process of checking frontal regions bilaterally.
that one remains on task over time, with adjustments in behavior as required
● Task setting and
for successful completion. In studies of patients with prefrontal lesions, deficits in monitoring are the two
task setting were associated with lesions in the left lateral frontal region, whereas prefrontal lobe processes
deficits in monitoring were associated with lesions of the right lateral frontal area.9 that fit the definition of
Patients who have lesions in the orbitofrontal cortex exhibit difficulty with executive functions.
behavioral and emotional regulation. Damage to the frontal poles causes impairment
● Task setting refers
of metacognitive processes, including self-awareness and the ability to attribute to developing and
mental states to others, ie, theory of mind.8,10 implementing a plan for
carrying out activities such
Linking Structural and Functional Anatomy as paying bills. This is
mediated by the left lateral
One reason the model of functional anatomy discussed here is clinically useful is frontal region.
that it can be linked to the anatomic frontal-subcortical circuits. The main function
of the superior medial prefrontal cortex loop (FIGURE 2-2) is energization. The ● Monitoring is the process
main functions of the left and right dorsolateral prefrontal cortex loops, respectively, of checking that one remains
on task over time, with
are task setting and monitoring. An additional lateral prefrontal cortex loop has been adjustments in behavior as
argued to be involved in processes of inhibition.11 Although growing evidence required for successful
indicates that the concept of inhibition is useful and descriptive, most “inhibitory” completion. This is
tasks can be explained by the more fundamental energization and executive mediated by the right lateral
prefrontal region.
processes outlined above.9,12–14 The orbitofrontal cortex loop is involved in behavioral
and emotional regulation. The frontal poles are involved in metacognitive processes ● Behavioral and emotional
but are not part of any frontal-subcortical circuit. Instead, it is believed that the frontal regulation is mediated by
poles integrate information from diverse prefrontal cortices, but the mechanisms the orbitofrontal cortex,
whereby this leads to metacognitive processes are poorly understood.15 while metacognitive
processes are mediated by
the frontal poles.
CLINICAL ASSESSMENT OF PREFRONTAL FUNCTIONS
Prefrontal functions mediate cognitive activities and behaviors that may not be
apparent in the artificially constrained environment of a clinical encounter and
only manifest in the outside real world. Therefore, it is important to pay special
attention to assessment of these functions if any clinical reason exists to think
that they may be impaired. Many prefrontal functions are best assessed by
carefully asking specific questions during history taking. For some functions,
this can be supplemented by administering cognitive tests to patients.
Precursors to Assessing Prefrontal Functions

In assessing prefrontal function, the history is paramount and may be more
important than the clinical examination. Many prefrontal functions are related to

behaviors, emotions, and social actions, all of which a patient may be unable to
describe adequately or may even be unaware of. History from a collateral
informant who knows the patient well is critical, but specific behaviors or
symptoms must often be probed as collateral informants will not always
intuitively relate behaviors that they have observed to the patient’s problem.
When possible, the collateral history should be obtained separately from the
patient but with his or her consent, as this will allow collateral informants to
more freely describe their observations without fear of retribution for divulging
potentially embarrassing accounts. It should be stressed that “normal” human
behavior spans a diverse range and not all abnormal behavior is due to neurologic
disease; thus, it should be determined whether aberrant behaviors demonstrate a
marked change from the patient’s previous functioning.
When performing a comprehensive neurologic assessment, the clinician must
first determine that basic neurologic processes are intact before assessing more
complex processes. In the assessment of prefrontal lobe functions, it is important
to first determine that the patient is fully alert and not in a confusional state or
delirium. For tests requiring motor responses, such as drawing, writing, or
tapping, it is important to determine that basic sensorimotor functions are intact.
Because many bedside tests of prefrontal functions rely on spoken instructions or
verbal responses from the patient, it is important to determine whether the
patient is aphasic. If language function is sufficiently impaired to make verbal
responses or comprehension unreliable, the examiner should focus on tests that
do not require language comprehension or a verbal response. If comprehension is
significantly affected, most cognitive tasks (including prefrontal tasks) will be
difficult to administer since the patient may not be able to follow instructions.
No single test can examine a specific cognitive function in total isolation,
but rather certain tests are more or less reliant upon component functions.
Many tests described here should not be conceived as tapping exclusively into
a specific function but are more properly understood as being sensitive to a
specific dysfunction.
Superior Medial Prefrontal Functions

Dysfunction of the superior medial prefrontal cortex leads to deficits in
energization to various degrees. Initially, this is assessed by history and careful
observation of the patient. At one extreme, a very severe deficit of energization
will cause akinetic mutism, a total inability to initiate any internally derived
activity but with intact basic sensory and motor functions and retained ability
to react to external stimuli. Akinetic mutism is usually seen with lesions
simultaneously affecting both hemispheres, either in bilateral medial prefrontal
cortices16 or bilateral medial prefrontal-subcortical regions5 (CASE 2-1). Although
it is not difficult to recognize that something is seriously wrong when patients
exhibit akinetic mutism, this rare syndrome can be mistaken for locked-in
syndrome or a psychiatric illness such as depression.
Less severe forms of energization deficit produce reduced initiation of motor,
cognitive, or combined psychomotor responses despite preserved basic
attention. The term abulia is often used to describe decreased initiation of
cognitive responses, but it is a term that lacks precise definition.20 Apathy is the
term used to describe a less severe expression of lack of initiation. In the history,
the patient will often be described as lacking motivation, and this may be
misattributed to a psychological crisis, psychiatric illness such as depression, or
708 JUNE 2018

even general fatigue. Collateral informants may say, “I think she is depressed.” KEY POINTS
However, it is important to validate whether this is true directly with the patient.
● History from a collateral
When the patient experiences a syndrome of decreased energization, during the informant who knows the
history and physical examination, the examiner will observe that the patient’s patient well is critical when
eyes properly track the examiner and that the patient does not appear distracted, assessing prefrontal
yet the patient either initiates speech or action less often than normal or is slow function.
in initiation.
● Phonemic word fluency
Phonemic word fluency (also known as lexical word fluency, the ability to (also known as lexical word
generate words starting with a particular letter) can be a useful index of fluency) can be a useful
energization.21 To administer this task as an index of energization, it is important index of energization.
to first establish that the patient does not have aphasia. The patient is then asked
to generate as many words that begin with a certain letter as possible within a
defined time interval (generally 1 minute). Usually patients are asked to exclude
proper nouns, numbers, and multiple versions of a single word (eg, farm,
farming). If the patient generates significantly fewer words later in the time
interval, this is particularly sensitive to dysfunction of the superior medial
prefrontal region as opposed to other prefrontal regions.9,21 A popular version
of this task is the FAS test, in which patients are asked to perform the task 3 times
using each of the letters F, A, and S. Normative performance values are available
for the FAS test.22
The astute examiner will realize that patients with an energization deficit
take longer to accomplish almost any task. They may run out of time when
completing timed tasks, despite performing them properly.8 Computerized
cognitive assessment tools can automatically record reaction times and the total
time taken to perform a task.23 This includes the electronic form of the popular
Montreal Cognitive Assessment (MoCA)24; however, direct correlation with
timed performance on computerized tasks and medial prefrontal damage has not
been adequately studied. At the bedside, it may be more useful to simply note
that a patient is slow to perform cognitive tasks rather than to rely on any specific
time cutoff. It is also important to allow patients time to complete the task to test
the limits of abilities.
Apathy may, in some cases, represent the least severe form of energization
deficit; however, different forms of apathy have been described that probably
have different neural bases, and only some of these may be considered truly
due to energization deficits.25 Furthermore, the terms apathy and abulia are
sometimes used interchangeably given that both are defined in various ways.26
Apathy has been defined as an amotivational syndrome, and, indeed, lack of
motivation will decrease speed of response; however, apathy may better be
defined as a syndrome characterized by lack of initiation and drive, as it is clear
that not all patients with abulia or apathy lack motivation in the sense of the will
to act. Nevertheless, it is useful for the clinician to understand that apathy can
stem from medial prefrontal cortex damage. The presence of apathy is usually
determined by careful history taking; here again, care must be taken not to
confuse apathy with depression. Specific rating scales, such as the Apathy
Evaluation Scale, can provide helpful information in quantifying the degree
of apathy. The Apathy Evaluation Scale is available in self-administered,
informant-administered, and clinician-administered versions and is free and
easy to use.27
Although deficits in energization and the amotivational syndromes they
produce have been classically described as arising from damage to the superior

medial prefrontal cortex and associated subcortical circuits, these syndromes

can also develop with damage to other prefrontal-subcortical circuits. It appears
that sufficiently decreased output from the basal ganglia within any of the
frontal-subcortical circuits may produce deficits in energization.28 This is
frequently seen in extrapyramidal disorders such as Parkinson disease, in which
slowed motor responses, cognitive responses, or both are a hallmark feature of
the disease.29
Lateral Prefrontal Functions

It has already been noted that different measures described for testing prefrontal
functions may not be specific. In addition, some concern exists about sensitivity,
since other factors (such as premorbid intelligence and experience) may mitigate
against task performance in general. It is also important to note that many of
bedside tests were first validated in patients with rather large lesions, which may
CASE 2-1 A 69-year-old retired physician was referred for a neurologic

consultation. Four months before presentation, his wife had noticed that
he was less interested in his usual activities. He did not initiate his usual
summertime plans to golf or go on a trip. He reported feeling tired and
nonspecifically unwell but denied any depression or other mood
changes. As symptoms progressed, he stopped initiating conversations,
and his physical movements became slowed and sparse. He spent his days
literally doing nothing and just sat on the couch unless asked to do
something. Four weeks before presentation, he also developed difficulty
initiating gait, saying that his feet were stuck to the ground, and he walked
with very small steps.
On examination, he had paratonic rigidity (inability to relax muscles
during assessment of tone while conscious, often seen with dysfunction of
frontal-subcortical circuits) in the lower limbs, but no tremor or abnormal
movements. Muscle power was normal, although he did not move his
limbs spontaneously unless asked. Tendon reflexes were brisk but without
clonus. Plantar responses were flexor. Upper and lower limb tests of
coordination were all performed quite slowly, but rhythmically, with
normal amplitude and no past pointing. Sensation was normal. On
examination of gait, he had a widened stance, significant retropulsion, and
difficulty initiating a step. He was alert but sat passively in his wheelchair,
looking at the examiner but otherwise not offering much spontaneous
interaction. He answered questions in monosyllabic answers. He did not
have much facial expression until one of his favorite childhood treats was
presented to him, at which point his face brightened, he exclaimed
“Humbugs!” and reached for a candy. He then told a story from
his childhood in a few short, slow sentences.
Brain MRI revealed a “butterfly” glioma compressing medial anterior
structures including superior medial prefrontal cortices (FIGURE 2-317).
The patient and family elected for palliative care, and he succumbed to
progressive neurologic deficits after 6 months.
710 JUNE 2018

include extension to nonfrontal regions. Thus, patients may not show deficits
when lesions are smaller and confined to the frontal lobes. It is also important
to look for consistency of impairment before concluding that frontal deficits
are present. A complete neuropsychological examination using a series of
standardized tests will assist in this regard.
Patients with damage to the lateral prefrontal cortex demonstrate deficits
in task setting and monitoring, both of which are components of executive
function. The lateral prefrontal lobes are also important for working memory, the
ability to consciously retain and manipulate information in the short term.30
Whether or not this can be explained by disruption of other executive functions
or whether working memory is a distinct construct that is a more basic process of
different integrated neuronal regions continues to be debated,31,32 but from a
clinical perspective, it is useful to conceptualize this as a distinct aspect of
prefrontal function that can be examined.
This case demonstrates several features COMMENT

of the superior medial prefrontal
syndrome with progressive deficits in
energization. The patient initially became
passive and no longer initiated activity;
however, he had no other obvious
“neurologic” signs. At this stage, his
symptoms could be called apathy or
abulia, highlighting that these terms are
often imprecise. The abulia became more
pronounced, and he developed general
psychomotor slowing, worsening to the
point where he stopped initiating most
internally generated goal-directed
FIGURE 2-3
activity despite having the basic
Butterfly glioma in the superior medial neurologic capacity to do so with intact
prefrontal cortex similar to the patient in sensorimotor function. When presented
CASE 2-1. Axial postcontrast with an emotionally powerful external
T1-weighted brain MRI at the level
of the centrum semiovale. A
stimulus (his favorite childhood candy),
heterogeneously enhancing mass is he did interact. This degree of
seen in the region of the superior energization deficit usually requires the
medial prefrontal cortex with mild presence of a lesion affecting both
mass effect as seen by effacement
superior medial prefrontal cortices, such
of the lateral ventricles. Radiologic
diagnosis was consistent with a as this patient’s tumor. Eventually, he had
glioblastoma exhibiting a “butterfly” associated neurologic features that can
glioma shape. This diagnosis was be seen with medial prefrontal damage,
confirmed pathologically.
Reprinted with permission from Dr. Frank
including a fairly rapid progression of
Gaillard, Radiopaedia.org, rID: 2589.17 so-called apraxia of gait or frontal gait
disorder18,19 as well as urinary
incontinence.

The first clues that a patient has difficulty with task setting can be obtained with
careful history taking. Such patients may be able to complete previously learned
routines but will have difficulty in carrying out something novel. In more severe
cases, completing even more familiar tasks in a logical manner can be impaired. If
the onset of this symptom is insidious, the collateral informant may only come to
realize its presence when specifically asked. For example, a patient may
previously have been actively involved in planning family vacations, booking
hotels, and researching travel routes, but now the spouse does all these tasks.
CASE 2-2 A 58-year-old man was referred for assessment of cognitive difficulties.
He had been working as a successful real estate agent for over a
decade, but 2 years before referral, he began not following through on
arrangements, made seemingly impulsive decisions, and, ultimately could
not sell properties. He took on simpler jobs but could not fill out his work
schedule properly. He sought medical help, and, although he denied feeling
depressed, he was prescribed antidepressants. He stopped assisting in
grocery shopping and doing basic household chores, leading to marital
discord, although the patient expressed remorse for the difficulty he was
putting his wife through. He maintained personal decorum and social rules.
The patient had appropriate insight and concern into his difficulties. He
could only name three words beginning with the letter F in 1 minute, and he
named nine animals in 1 minute. He exhibited normal registration but mild
difficulty with verbal and visual recall. His digit span was seven forward
and three backward. He could not do serial subtractions of 7 from 100.
He was concrete in assigning pairs of words to their superordinate category:
he said that train and bicycle were alike “because they have wheels,”
fork and knife were alike because “you have them at dinner,” and man and
tree were alike because “a man can be in a tree.” He could not perform the
Luria hand sequences (palm, fist, edge) without the examiner doing them
simultaneously. He made the performance errors on the tasks shown in
FIGURE 2-4, FIGURE 2-5, FIGURE 2-6, and FIGURE 2-7. Brain MRI revealed widespread
moderate supratentorial atrophy without any lobar predilection. Brain
perfusion scanning revealed left parietal hypoperfusion.
A clinical diagnosis of the behavioral/dysexecutive variant of Alzheimer
disease was made.33 Over the next 5 years, his deficits progressed and
broadened considerably; prominent amnesia and mild aphasia emerged
within 18 months of consultation. He began to develop almost total
dependence on his wife and became extremely anxious if she was not
directly within his sight.
712 JUNE 2018

Patients who previously liked to try new recipes may begin to fall back
on recipes they have memorized that have fewer steps and require less
multitasking. Patients may also be described as needing to eliminate all
distractions to accomplish tasks they could previously incorporate into a
multitasked routine; for example, a patient may not be able to do the laundry
without missing crucial steps if any distractions are present (CASE 2-2).
Further clues to the presence of lateral prefrontal cortex dysfunction can be
obtained by listening to the patient’s narrative discourse during history taking.
FIGURE 2-4
Abnormal performance on the alternating sequences task in the patient in CASE 2-2. The
patient was given a page with an alternating square and triangle pattern (dotted underline)
with the instructions “start here [end of dotted underlined section] and continue with the
same design until you reach the end of the page.” The patient made an initial task-setting
error; instead of beginning with a square, he began with a triangle. He then continued to
copy his initial incorrect “triangle-triangle-square” pattern instead of the correct
“square-triangle” pattern (monitoring error).
FIGURE 2-5
Abnormal performance on the multiple loops task in the patient in CASE 2-2. The patient was
given a page with three triple loops in the top left corner (dotted underline) with the
instructions “start here [end of dotted underlined section] and continue with the same
design until you reach the end of the page.” Despite multiple repeat instructions, the
patient proceeded to copy the pattern down vertically instead of horizontally (task-setting
error). On the fourth try (fourth column), the patient began to make monitoring errors: some
of his triple loops are double loops that resemble the number 3. CONTINUED ON
PAGE 714

CONTINUED FROM
PAGE 713
FIGURE 2-7
Abnormal performance on the Trail
FIGURE 2-6 Making Test Part B in the patient in
Abnormal performance on the clock CASE 2-2. The patient was instructed
drawing task in the patient in CASE 2-2. “Please draw a line going from a
The patient was given a blank page number to a letter in ascending order.
and instructed “Draw a clock, put in the Begin here [1] and draw a line from 1 to A
numbers and set the hands at ten past then to 2 and so on.” The patient was
nine.” He put the numbers in the not able to follow the sequence
counterclockwise order (monitoring correctly, joining the letters C and D
error). He set the time at an irrelevant and the numbers 3 and 4 incorrectly
option and did not clearly indicate a together without noticing his error
longer minute hand (task-setting errors). (monitoring error). Basic visual scanning
He neglected to have the hands meet was intact as he was able to locate all
at the middle and escaped the of the circles.
boundaries of the clock with one of
the hands (monitoring errors).
COMMENT This case illustrates several features of the dysexecutive syndrome typical
of lateral prefrontal cortex dysfunction. As in many cases of problems
with executive function, the patient was initially not specific about his
descriptions of what was wrong because it was not immediately clear.
Poor performance on several tasks pointed to lateral prefrontal cortex
dysfunction.
In this case, prefrontal dysfunction was inferred from the patient’s
symptoms and cognitive examination, since a structural lesion was not
seen. This suggested either a psychiatric or neurodegenerative etiology,
and the history was more compatible with the latter. The differential
diagnosis included behavioral variant frontotemporal degeneration
(bvFTD) and the behavioral/dysexecutive variant of Alzheimer disease,
with the latter being more probable according to diagnostic criteria.34,35
The case also serves as a reminder that the deficits seen early in bvFTD are
usually (but not always) the behavioral and emotional dysregulation of
orbitofrontal cortex dysfunction, which this patient did not have, rather
than lateral prefrontal dysfunction.
714 JUNE 2018

Patients with lateral prefrontal lesions can have defective recruitment of KEY POINTS
procedures necessary for complex language assembly.36 They may speak in
● The lateral prefrontal
grammatically correct sentences with normal syntax, but the content may be lobes are important for
described as vague or confused. Such patients will be prototypical bad historians. working memory, the ability
If this pattern represents a substantial change from the previous mode of to consciously retain and
discourse, making note of this “frontal” speech pattern may provide the first clue manipulate information in
the short term.
to prefrontal lobe injury. Examiners could ask patients to discuss or write down
examples of how they would go about planning something new and note the ● The digit span test is a
response. For example, the examiner could ask, “Suppose you were to make a simple test of working
career change and decide to open up a florist business. How would you go about memory that is often used
this?” A patient with higher-order task-setting difficulties will answer in at the bedside.
generalities or may skip important steps.

The digit span test is a simple test of working memory that is often used at the
bedside. In this test, the patient is presented with progressively longer strings
of digits and asked to repeat them back in the same order as they were presented.
Usually the test involves allowing two attempts at a certain length of digits
(albeit with different numbers used). Digit span backward involves the patient
having to repeat the digits in the reverse order and may be more reliant on lateral
prefrontal cortex processes.37 In addition to taxing working memory, this test
relies on intact task setting and monitoring. The difference between forward
and backward digit span (usually two or less) may indicate the degree to which
executive functions are impaired. When administering digit span tests, it is
important for the examiner to present the digits at an even cadence approximately
1 second apart and to use consistent and neutral voice inflection, except for the
last digit, for which the voice may be lowered to signal the end of the series
of digits.
Some useful simple bedside tests that tap into lateral prefrontal cortex
function were developed in the mid-20th century by Alexander Luria, including
the Luria hand sequences.38 In this test, patients are asked to place their hands on
a table in a repeated palm, fist, edge sequence. Patients with basic difficulty in
task setting will have difficulty repetitively and automatically performing this
sequence correctly (although it has been shown that even neurologically healthy
individuals may have initial difficulty).39 Patients with basic monitoring
difficulties will have difficulty maintaining this sequence over several repetitions
and may perseverate (ie, repeat the same movement 2 or more times in a row
without switching). A written equivalent that is commonly tested involves
asking the patient to continue drawing a sequence of alternating connected
square- and triangle-like sequences (FIGURE 2-4). The multiple loops task is a
related task that is more sensitive to deficiencies of monitoring; patients are
asked to repeatedly draw a series of three loops across a page.40 Patients with
monitoring difficulties may either draw the number 3 (FIGURE 2-5), which is a
prepotent response (the action that has priority over others because of primacy
during development, having been done recently, or having the greatest
relevance) or will continue to draw more than three loops (FIGURE 2-8).
Another test developed by Luria that remains popular and easy to administer
in various forms is the go/no-go task. In Luria’s description of the task, the
patient must raise one finger in response to one tap (go) but must not make
any movement in response to two taps (no-go). A nonrepeating sequence of
single and double taps is presented, and the patient must respond appropriately
throughout the sequence. Patients with difficulty in task setting will have

difficulty in completing the task

despite multiple instructions.
Those with difficulty in
monitoring will make errors. The
conflicting instructions task is a
modification of the go/no-go task
that is often administered in
addition to it. In this task, the
patient must raise two fingers in
response to one tap and one finger
in response to two taps.
The Trail Making Test is a
popular test with myriad versions
and is thought to be a sensitive
FIGURE 2-8
Abnormal performance on the multiple loops task measure of executive function
in a patient with dorsolateral prefrontal cortex and lateral prefrontal cortex
dysfunction. The patient was given a page with damage.41 In the most popular
three triple loops in the top left corner with the form, patients are first presented
instructions “start here [end of first three triple
loops] and continue with the same design until
a sheet of paper with 25 circles,
you reach the end of the page.” Instead of with the numbers 1 through 25
drawing only three loops for every set, the printed inside the circles. This is
patient perseverated, drawing progressively Part A of the test. Patients must
longer sets of loops. This demonstrates an error
in task monitoring.
connect the circles in the correct
order as quickly as possible
without errors and are timed.
Part A is particularly sensitive to energization deficits (specifically basic
motor speed and visual search speed), but this also tests basic visuomotor
attention and scanning. In Part B, the 25 circles contain the numbers 1 to 13 and
the letters A to L. Patients must alternate numbers and letters in ascending
order as quickly as possible without errors (FIGURE 2-7). Thus, Part B relies
more on task setting (remembering to shift mental set) and monitoring of
errors than does Part A. Although this test is widely interpreted as sensitive
to lateral prefrontal cortex damage, careful analysis indicates that it is a
multifactorial test and affected by damage to many brain regions; controlling
for these factors has pointed to the influence of the superior medial
frontal region.42
Phonemic (lexical) word fluency has already been discussed as a task that can
be sensitive to medial frontal damage due to decreased energization, resulting
in reduced initiation and production of responses. However, successful completion
of this task also requires planning and searching, as well as language processing.
In fact, impairment in phonemic fluency is greatest in patients with left lateral
prefrontal cortex damage.21 A notable discrepancy from the better performance
on semantic fluency (generation of words within a defined category, such as
animals) is often seen. Design fluency is the analogous nonverbal generation
task. In its simplest form, patients can be asked to draw as many unique figures
as possible in a given amount of time.43 More systematized versions place some
constraints. In one popular version of the task, patients are shown an array of
dots and asked to make as many unique figures as possible in 1 minute by using
straight lines to join the dots.44 Design fluency is most impaired in patients with
right lateral prefrontal cortex damage.45 In sum, fluency tasks are good tests of
716 JUNE 2018

component executive functions and are sensitive to lateralized lateral prefrontal KEY POINTS
cortex damage.
● Tests of abstract thinking
Tests of abstract thinking are used to test executive function and tap into are used to test executive
task-setting functions. Interpretation of proverbs are often proposed as such46; function and tap into
however, the correct interpretation of a proverb more likely depends upon recall task-setting functions.
of previously learned knowledge regarding the proverb’s semantic meaning
● Clock drawing is a very
rather than the generation of a novel abstract idea.47 Many people with normal
popular bedside cognitive
prefrontal function will not be able to correctly interpret a proverb they have test that taps into prefrontal
never heard; thus, proverbs are not a reliable test of prefrontal functions. function.
Another task that may also depend upon semantics, albeit less so, is the
similarities test. Patients are presented with a pair of stimuli (words or pictures) ● Behavioral disinhibition,
emotional dysregulation,
and asked in which way they are alike. The correct answer requires the patient and altered social cognition
to place the stimuli into the same superordinate category (ie, the category to are seen in patients with
which both stimuli belong, such as fork and knife both belong to the category orbitofrontal cortex lesions.
utensils and song and painting both belong to the category art). Performance
on this test activates left perisylvian prefrontal regions.48 Reliance on
semantics may be reduced by giving clear instructions; rather than asking
“How are these two things alike?” the examiner can say “I will give you
two words, and I would like you to tell me to what category they
belong.”49
Visuospatial function involves multiple top-down visual processing aspects
that involve the lateral prefrontal cortex.50 Many of these involve task-setting
functions that can be assessed by asking patients to draw a particular item
without a model to copy (eg, asking them to draw a three-dimensional cube
without showing them a drawing of a cube). If patients have difficulty executing
the task, it must subsequently be determined whether they possess basic
bottom-up visual processing that does not employ the prefrontal cortices. This
can be done by asking the patient to trace or copy the figure in question. If the
patient can copy the figure but is not able to draw it from command, it may
suggest difficulty with task setting.
Clock drawing is a popular bedside cognitive test that expands on drawing to
command.51 Although successful clock drawing requires multiple cognitive
processes including visuospatial abilities, it can be sensitive to prefrontal damage
with respect to execution of the task, including processes that involve planning
and monitoring. Most variations of this test involve instructions such as “Draw
the face of a clock, put in the numbers, and set the hands at [a particular time].”
The time chosen is important; for maximum sensitivity, it should involve a time
where the correct positioning of the hands on the clock requires the patient to
overcome prepotent responses. “Ten past eleven” and “five past four” are good
choices. Patients who lack adequate task setting or monitoring and adopt literal
responses will place the hands at 10 and 11 (9:55 or 10:50) instead of 11 and 2 in the
former, and at 5 and 4 (4:25 or 5:20) instead of 5 and 1 in the latter. They may also
duplicate numbers, draw extra hands, or fail to self-correct. Patients with
significant difficulty with task setting may become stuck and not know
how to approach drawing the contour, placing the numbers, or setting the time on
the clock (FIGURE 2-6 and FIGURE 2-952).
Orbitofrontal Functions
Behavioral disinhibition, emotional dysregulation, and altered social cognition
are seen in patients with orbitofrontal cortex lesions. These can include

FIGURE 2-9
Frontal errors in the clock drawing task. In both instances, the patient was asked to draw a
clock and set the hands to 10 past 11. A, The patient planned the clock face properly,
including numbers, but made a monitoring error and was pulled to a prepotent response
(the numbers 10 and 11) when setting the time. An additional monitoring error was failing to
differentiate the short hour hand from the long minute hand. B, Another patient had more
severe task-setting and monitoring difficulties. They placed the numbers incorrectly,
originally in the wrong place, then perseverated. They were not able to initiate the task of
setting the hands and instead wrote “10-11” inside the clock face.
52
Panel B reprinted with permission from Henri-Bhargava A, Freedman M, CMAJ.
© 2011 Canadian Medical Association.
environmental dependency (the need to touch and feel things), hyperphagia or

altered food preferences, sexually inappropriate behavior, inappropriate jocularity,
loss of social decorum, argumentativeness, capriciousness, narrowed
preoccupations, and even criminal behavior. These apparently loosely related
behavioral disturbances may all stem from a more basic disturbance in the
evaluation of outcomes and options for action.53
The clinical examination of patients with orbitofrontal cortex lesions can
be challenging; if their deficits are circumscribed, they will perform normally
on most tests of executive function described earlier in this article. Therefore,
clues to the presence of orbitofrontal cortex dysfunction usually arise in
careful history taking from informants. Aberrant behavior must be specifically
asked about and examples elucidated. In progressive disease, such as
dementia, informants may initially find plausible excuses to explain the
patient’s behavior, and it is only with time that a pattern of aberrant
behavior diverging from previous behavior becomes clearly apparent
(CASE 2-3). Formal clinical scales can be helpful to guide history taking.
The Neuropsychiatric Inventory (NPI)54 can be used to elucidate many types
of behavioral impairment, although these are not specific to the behavioral
derangements seen in orbitofrontal cortex dysfunction. The Frontal
Behavioral Inventory55 is another assessment questionnaire that a clinician can
administer to an informant to probe the spectrum of behaviors seen in
behavioral variant frontotemporal dementia (bvFTD), a disease in which the
degeneration includes the orbitofrontal cortex. Key questions asked on the
Frontal Behavioral Inventory that are particularly pertinent to orbitofrontal
cortex dysfunction include questions regarding patient personal neglect,
718 JUNE 2018

perseveration and obsession, hoarding, socially inappropriate behavior, KEY POINT
excess jocularity, poor judgment and impulsivity, aggression, hyperorality,
● The frontal poles
hypersexuality, and environmental dependency (the tendency to automatically integrate information from
touch, grab, and use objects in one’s own immediate environment). Other questions other prefrontal regions
on the Frontal Behavioral Inventory are more pertinent to lateral prefrontal cortex, and are involved in
superior medial prefrontal cortex, or frontal pole dysfunction, so looking at the metacognitive functions
such as theory of mind, (ie,
pattern of responses is important. The Frontal Behavioral Inventory has been shown
being able to take the
to be sensitive to orbitofrontal cortex injury in traumatic brain injury.56 perspective of others and
self-awareness).
Frontal Pole Functions
The frontal poles integrate information from other prefrontal regions and
are involved in metacognitive functions, such as being able to take the
perspective of others and self-awareness. This includes perceiving one’s own and
others’ emotional states. The ability to be aware of one’s own state of mind and
that of others is called theory of mind.57 Some researchers have proposed
distinguishing cognitive theory of mind (understanding what others think),
affective theory of mind (understanding what others feel), and conative theory
of mind (being able to influence others’ mental states based on one’s own
understanding of them). The frontal poles may be variably involved in all of these.58
It is, therefore, important to pose questions to collateral informants about
whether the patient demonstrates preserved sympathy, which is the ability to
generate an emotion in reaction to another’s emotional state, as well as preserved
empathy, which is the ability to recognize others’ emotional states. Spouses, close
friends, and relatives will usually be the best informants but may not think to
volunteer information about the patient’s emotional state and responses unless
they are specifically asked about them. Patients with frontal pole dysfunction and
reduced theory of mind may often have behavioral/emotional dysregulation due
to orbitofrontal cortex dysfunction given the proximity of these two regions and
the fact that these two regions may often be injured or degenerate simultaneously
in various conditions.
Theory of mind is not routinely tested in the neurologic mental status
examination, and the practical application of research-oriented tests of theory of
mind from neuropsychological experiments to routine clinical practice remains
underexplored. One test that could be used to assess theory of mind is the false
belief task, commonly administered as the “Sally-Anne test,”59 in which a story
or skit is presented to the patient as follows. Sally hides a ball in the presence of
Anne and then leaves the room. While Sally is out of the room, Anne moves the
ball to a different location. Sally returns into the room. The participant is then
asked where Sally believes the ball is. They must understand that Sally believes
that the ball is still in its original location. This test specifically examines cognitive
aspects of theory of mind, as do asking the patient to explain humor in cartoons
or to demonstrate comprehension of stories that require the reader to understand
a mind state.60 Tasks that require the participant to identify facial expressions
corresponding to emotions of the subjects in a story could be used to assess
affective aspects of theory of mind.61
Patients with focal injury to the frontal poles may demonstrate deficiency in
theory of mind.62 Deficits in theory of mind have also been demonstrated in
degenerative diseases that affect the frontal poles or the connections to them,
including Parkinson disease,63 Alzheimer disease,64 and bvFTD.63,64 This is
usually inferred from the patient’s history (CASE 2-3).

CASE 2-3 A 72-year-old retired university department head was assessed at the
request of his family, who reported a 4-year history of progressively odd
behavior. First, his son had recently gained access to his emails and
discovered that his father had engaged in extensive correspondence with
scammers and had given away $200,000 in payments to them. This was
totally uncharacteristic of a man who would have previously been described
as no-nonsense and very frugal. Surprisingly, the patient was unable to
understand why his family was upset and that the scenarios presented by
the scammers were unrealistic. He could not see irony in the fact that he
seemed to care more about unrealistic hypothetical kidnapping victims than
his own family. Decreased emotional responsiveness worsened, and he
became cold and distant in all everyday matters. He no longer comforted
his wife when she was upset, although he became very emotional about
football scores. He began to openly consume large amounts of Internet
pornography. He developed binge eating and would consume an entire
carton of ice cream at one sitting.
When directly questioned, the patient denied, minimized, or confabulated
about many of the behaviors. He could answer direct questions fluently but
would often wander from topic to topic and give empty responses.
His neurologic examination was normal, including a score of 29/30 on the
Montreal Cognitive Assessment (MoCA). Brain MRI showed atrophy of the
prefrontal cortices, particularly the orbitofrontal cortex and frontal insula
(FIGURE 2-10A, 2-10B, and 2-10C). Brain perfusion scanning demonstrated
frontotemporal hypoperfusion (FIGURE 2-10D and 2-10E).
The patient met consensus criteria35 for probable behavioral variant
frontotemporal dementia. His behaviors were treated unsuccessfully with
trials of multiple agents, including benzodiazepines, selective serotonin
reuptake inhibitors (SSRIs), trazodone, and antipsychotics. He was actively
followed by a multidisciplinary health team to minimize the consequences of
his behaviors while he continued to live at home.
COMMENT The patient in this case presented with prominent symptoms of prefrontal
lobe dysfunction, particularly the behavioral and emotional dysregulation
of orbitofrontal cortex dysfunction, the metacognitive deficits of frontal
pole dysfunction, and, to a lesser extent, some passivity suggesting
decreased or aberrant energization as seen in superior medial prefrontal
cortex dysfunction. The case highlights several important points regarding
assessment of these symptoms. First, the general neurologic examination
and office cognitive assessment, including basic tests of executive
function, were normal, and the diagnosis of prefrontal lobe dysfunction
relied on facts obtained during a careful history. Healthy people may
have difficulty describing their behavior, and when insight and other
metacognitive functions are impaired (as in this case), it is very unlikely that
patients will be able to give an accurate account of their behavior.
Collateral history is, therefore, essential for diagnosis.
720 JUNE 2018

FIGURE 2-10
Neuroimaging of the patient in CASE 2-3. Axial (A), coronal (B), and sagittal (C) T1-weighted
brain MRI sequences demonstrating focal atrophy of the prefrontal cortex bilaterally, right
greater than left, in behavioral variant frontotemporal dementia. Axial (D) and sagittal (E)
sections of hexamethylpropyleneamine oxime (HMPAO)–single-photon emission computed
tomography (SPECT) brain perfusion scan. Normal perfusion (orange) is seen in the cerebellum
and occipitoparietal regions, whereas frontotemporal areas demonstrate marked reduction
in perfusion (purple).

TEST BATTERIES
Because there are many ways to test cognitive functions, neurologists often like
to rely on test batteries that can assist in remembering tests to be used and allow
for standardized repeated measurement. The Mini-Mental State Examination
(MMSE)65 is one such test that is very widely used, but one of its major
drawbacks is that it is not sensitive to prefrontal cortex dysfunction. However,
cognitive test batteries that are useful for examining prefrontal functions have
been developed, although many of the tests in these batteries are primarily
sensitive to lateral prefrontal cortex functions (TABLE 2-166–70). The Executive
Interview (EXIT-25) is a 25-item battery that was developed specifically to
address the need to assess executive functions in patients with dementia. It does
not require any special equipment apart from a freely available stimulus booklet,
and it can be administered in a clinical office setting.66 It focuses on tasks that
require task setting and maintenance at a very basic level and therefore mainly
assesses lateral prefrontal cortex function. The Frontal Assessment Battery is a
similar battery that is shorter and easier to administer, yet correlates with the
EXIT-2567,68; it regroups many tests discussed earlier, including the similarities
test, phonemic word fluency task, Luria hand sequences, go/no-go and
conflicting instructions tasks, and a test of environmental dependency, which
asks the patient not to touch the examiner’s outstretched hands. The MoCA is a
freely available and popular tool for testing cognitive function that aims to test a
variety of cognitive domains.69 This includes tests of executive function, such as
the modified Trail Making Test Part B (FIGURE 2-7), clock drawing, similarities,
and phonemic word fluency.71 These batteries may all be helpful in detecting
basic impairments of task setting and monitoring and so may be most useful for
TABLE 2-1 Test Batteries for Office Assessment of Prefrontal Functions
Approximate Time
Test Battery Name to Administer Focus Advantages Disadvantages
Executive Interview 15 min Lateral prefrontal Tests executive May be overly lengthy and
(EXIT-25)66 functions functions in several ways complex to administer67
Frontal Assessment 5 min Lateral prefrontal Relatively easy to learn Not sensitive to mild
Battery (FAB)68 functions and administer; feasible dysfunction
assessment of prefrontal
function in diverse
populations
Montreal Cognitive 10 min Various cognitive Widely used; easy to Components of the test that
Assessment (MoCA)69 domains, including administer focus on prefrontal functions
lateral prefrontal are not all grouped together;
functions not sensitive to mild
dysfunction
Executive and Social 30 min Lateral prefrontal More sensitive to Not widely used; requires
Cognition Battery and orbitofrontal orbitofrontal cortex special stimuli and training
(ESCB)70 functions dysfunction to administer
722 JUNE 2018

detecting lateral prefrontal cortex dysfunction. Patients with energization
deficits due to superior medial prefrontal dysfunction may be slow in performing
the tasks on these batteries as in all other cognitive tasks. However, patients with
the significant metacognitive deficits typical of frontal pole dysfunction or the
emotional and behavioral dysregulation typical of orbitofrontal cortex
dysfunction may still perform normally on these batteries. Such test batteries,
therefore, lack sensitivity for some types of prefrontal dysfunction.
Few office tests are commonly used that are sensitive to orbitofrontal
cortex and frontal pole dysfunction. The Executive and Social Cognition Battery
(ESCB) has been developed to try to test prefrontal dysfunction in a real-life
environment, specifically in the context of bvFTD.70 However, this battery may
be more useful for neuropsychologists than neurologists as it requires specific
stimuli, including specialized card decks that may not be readily obtainable.
The validity of standard prefrontal cortex neuropsychological tests has been
completed in a series of studies.72 They are excellent examples of the complexity
of administering and interpreting these tests in the context of the individual’s
neurologic, medical, and social history.
CONCLUSION
Lesions in the prefrontal regions of the frontal lobes may result in distinct
cognitive and behavioral deficits depending on the site of the damage. Cognitive
processes affected include energization, task setting, and monitoring, of which
only task setting and monitoring are considered executive functions. These
processes can easily be tested at the bedside. Other prefrontal processes include
behavioral/emotional regulation, which is best assessed by careful history.
Metacognition, which includes theory of mind, is another important prefrontal
process. However, a need remains to develop easy-to-administer tests to assess
metacognition at the bedside.
ACKNOWLEDGMENTS
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726 JUNE 2018

Memory Dysfunction REVIEW ARTICLE

By G. Peter Gliebus, MD C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article reviews the current understanding of memory
system anatomy and physiology, as well as relevant evaluation methods
and pathologic processes.
RECENT FINDINGS: Our understanding of memory formation advances each

year. Successful episodic memory formation depends not only on intact
medial temporal lobe structures but also on well-orchestrated
interactions with other large-scale brain networks that support executive
and semantic processing functions. Recent discoveries of cognitive
control networks have helped in understanding the interaction between
memory systems and executive systems. These interactions allow access
to past experiences and enable comparisons between past experiences
and external and internal information. The semantic memory system is less
clearly defined anatomically. Anterior, lateral, and inferior temporal lobe
regions appear to play a crucial role in the function of the semantic
processing system. Different but tightly interconnected cortical regions,
such as the prefrontal region, may play a controlling role in this system. The
presentation of clinical disease affecting memory is the result of the
selective vulnerability of the memory system. An understanding of current
concepts of memory anatomy, physiology, and evaluation plays a central
role in establishing an accurate diagnosis.
SUMMARY: Different memory systems rely on separate but overlapping

distributed brain networks. Certain pathologic processes preferentially
CITE AS:
affect memory systems. An understanding of memory formation stages will CONTINUUM (MINNEAP MINN)
enable more accurate diagnosis. 2018;24(3, BEHAVIORAL NEUROLOGY
INTRODUCTION Dr G. Peter Gliebus, 245 N
M
emory is the ability to capture externally or internally 15th St, NCB 7102, MS 423,
presented information, store it, and reconstruct it later. We are Philadelphia, PA 19102,
Gg65@drexel.edu.
consistently presented with a flow of new information, which
needs to be processed and sometimes acted upon. For us to RELATIONSHIP DISCLOSURE:
adapt and survive, our brain, through the evolutionary Dr Gliebus receives
research/grant support from
process, developed a well-calibrated mechanism to capture our experiences, the Drexel Clinical and
which then shape our actions. This mechanism enables the species to adapt more Translational Research Institute.
quickly to a changing environment and to respond to a stimulus by comparing it
UNLABELED USE OF
with past experiences. Memory also plays a crucial role in human advancement; PRODUCTS/INVESTIGATIONAL
without it, we would be in a perpetual cycle of reinvention. USE DISCLOSURE:
Forgetfulness is one of the most frequent symptoms in patients presenting to Dr Gliebus reports no disclosure.
cognitive disorders clinics. This article approaches memory function and © 2018 American Academy
dysfunction from a clinical perspective. of Neurology.

MEMORY DYSFUNCTION
MEMORY CLASSIFICATION
Several memory classifications exist. One widely used classification is based on
the involvement of consciousness in memory use. Consciously evoked memories
are declarative (explicit), while memories that do not need conscious
involvement are nondeclarative (implicit).1 Declarative memory can be further
classified into episodic and semantic memory. Episodic memory is the ability
to store and retrieve past episodes and experiences, while semantic memory
refers to general knowledge of people, objects, words, and concepts without
reference to a specific autobiographical episode. Nondeclarative memory is
frequently acquired with practice and can be used without conscious involvement.
Procedural memory is a memory for motor skills and belongs to the nondeclarative
memory group. Priming (an attribute of memory in which prior exposure to a
stimulus may influence later response) and classical conditioning are other
examples of this group of memories.
Working memory refers to the ability to keep the information trace active in
the brain for a short period of time after the initial stimulus is no longer available
in the environment. Working memory function is typically considered a part
of the executive system, although the importance of this process in establishing a
more permanent trace in the brain demonstrates the blurred lines between
various cognitive functions.
It is important to stress that the temporal lobes play an important role in declarative
memory function (the medial regions for episodic memory and anterior, lateral,
and inferior regions for semantic memory). In clinical practice, physicians most
frequently evaluate declarative memory function, which is the focus of this article.
NEUROANATOMY OF MEMORY
The following section reviews anatomic structures involved in the function of
different types of memory.
Working Memory
The working memory system supports actively holding on to information after it
is no longer present in the environment. This buffer system is supported by the
networks connecting the prefrontal cortex with association temporoparietal
cortical regions.2 The prefrontal cortex plays an executive role in relation to
association temporoparietal regions, where the actual information is represented.
This system is further subdivided into specialized networks to actively maintain
verbal, spatial, and object information.3,4 While this function is an important step
in memory formation, it does not mean that people who have working memory
deficits are unable to form long-term memories.
Episodic Memory
Memory formation and retrieval is a fluid process, although to simplify the
clinical approach, this process can be divided into three stages: encoding, storage,
and retrieval. Accumulating scientific data indicate that memory function is not
localized to one brain region but rather is distributed through interconnected
brain networks. One of the most crucial memory formation steps is the ability to
create a trace of the event or fact in the brain that, in many cases, will be
transferred from immediate to long-term storage. Multiple behavioral,
electrophysiologic, and neuroimaging studies have demonstrated that medial
temporal lobe structures (the entorhinal cortex and hippocampus) play a critical
728 JUNE 2018

role in linking information from different cortical regions. This allows the KEY POINTS
integration of information and the ability to store it for a long period of time.
● Memory is classified
Association and limbic cortical regions connect to the hippocampal formation into declarative and
through several synaptic relays via entorhinal, perirhinal, and parahippocampal nondeclarative forms.
cortices.5 The efferent projections from hippocampal formations reach Declarative memory is
association cortices through projections from parahippocampal regions. further classified into
episodic and semantic.
Damage to medial temporal lobe structures produces significant impairment
Nondeclarative memory is
in the formation of new memories as well as in the storage and retrieval of classified into procedural
recently acquired information. Damage to medial temporal lobe structures memory, priming, and
frequently leaves the retrieval of memories formed a long time ago intact. This classical conditioning.
supports the hypothesis that memories become less dependent on medial
● Working memory is the
temporal lobe structures over time. This process is known as consolidation.6 brain’s ability to keep
Medial temporal lobe structures play a central role in information transfer information active after it is
from short-term to long-term storage, ie, in episodic memory retention. Current no longer available in the
functional imaging data demonstrate that, in addition to medial temporal lobe environment.
structures, other large-scale networks support successful encoding and retrieval ● Working memory function
processes: executive control and semantic processing networks are activated is supported by brain
during new information encoding, while the retrieval process is associated with networks connecting
increased activity in regions associated with executive control and default mode frontal, parietal, and
temporal lobes and has
networks.7–10 This should not be surprising as these steps require attention
specialized parts for holding
allocation, guided control, organization, and monitoring of information along verbal, object, and spatial
with its semantic processing (FIGURE 3-1). information.
The activation of the dorsolateral prefrontal cortex along with medial
temporal lobe structures during the encoding process increases the chances of ● The episodic memory
formation process can be
information being encoded.11 In addition to executive network activation, the divided into encoding,
semantic network regions (primarily involving temporal poles and the lateral storage, and retrieval
temporal cortex) are also activated during encoding, presumably for semantic stages.
information processing.8
● Medial temporal lobe
Along with the medial temporal lobe structures, frontal lobe regions associated structures (entorhinal cortex
with executive control and medial parietal regions are also activated during the and hippocampus) play a
retrieval process.7,10,12 This possibly facilitates and monitors the appropriateness critical role in linking
of the information to be retrieved for the current situation. Memory retrieval information represented in
different cortical regions
errors occur because of impaired monitoring by the executive control system or
and its transfer from
impaired interactions between large-scale networks. The posterior cingulate short-term to long-term
cortex and precuneus (regions overlapping with default mode network areas) are storage.
also activated during information retrieval, although their exact roles are yet to
be established. Some studies did not demonstrate impaired retrieval with damage ● Executive control
networks are active along
in these areas. medial temporal lobe
It is important to understand that the actual information (separate features of structures during memory
memory) is represented in association cortical regions. Medial temporal lobes encoding and retrieval.
bind these separate features through several cortical connections into one Semantic processing
networks are also activated
cohesive memory. Scientific data also suggest that hemispheric specialization during information
exists for information encoding (eg, verbally based memories appear to lateralize encoding.
more to the left hemisphere and visuospatially based memories appear to
lateralize to the right hemisphere).13,14 ● An anatomically and
functionally intact Papez
The external information relayed through the association cortex reaches the
circuit is important in
hippocampus through the entorhinal cortex. Hippocampal cells project to information transfer from
mammillary bodies, which, in turn, project to the anterior thalamic nuclei and short-term to long-term
the cingulate gyrus and then back to the hippocampus. The cingulate gyrus also storage.
has extensive cortical connections. This is known as the Papez circuit, and

MEMORY DYSFUNCTION
interactions between these

structures are important in
long-term memory formation
(FIGURE 3-2).15
Human cognitive control
depends on well-calibrated
interactions between the lateral
frontoparietal central executive
network, the medial frontoparietal
default mode network, and the
medial frontoinsular salience
network. The central executive
network is active during many
cognitive tasks requiring
information processing and
decision making, especially
regarding externally presented
information. In contrast, the
default mode network is active
during internal mentation,
autobiographical memory
retrieval, and social cognition.
Data also demonstrate that the
frontoparietal control network can
be coupled with the default mode
network during self-referential
goal-directed activity.16 The
salience network is important in
identifying behaviorally
important stimuli and redirecting
the action of other executive
networks toward those stimuli. To
successfully guide our decisions
and behaviors, these networks have
to be (and are) well connected
with the memory system. Because
memories also undergo semantic
processing, the memory system
FIGURE 3-1 is also well connected with the
Systems involved in episodic memory formation. semantic system. The amygdaloid
Original drawing by Jennifer Ann Ross.
complex, orbitofrontal cortex,
and insula play a role in the
emotional enhancement of memories,17 increasing the probability that
information will be encoded.
Semantic Memory
Semantic memory neuroanatomy and functional organization are less defined.
Semantic memory relates to general knowledge rather than specific episodes;
thus, it is not surprising that networks supporting this system are widely
distributed throughout the brain. Studies have demonstrated that anterior,
730 JUNE 2018

KEY POINTS
● The amygdaloid complex

plays a role in the emotional
enhancement of memories,
increasing the probability
that information will be
encoded.
● The semantic network

consists of interconnected
anterior, lateral, and inferior
temporal; dorsolateral
prefrontal; and lateral
parietal regions.
● Procedural memory is a
memory system for motor
skills. The structures that
are involved in procedural
memory include the
FIGURE 3-2 supplementary motor
Papez circuit. cortex, superior parietal
Original drawing by Jennifer Ann Ross. lobule, basal ganglia, and
cerebellum.
inferior, and lateral temporal cortical regions are important in supporting the
semantic system. The anterior portions of the temporal lobes have been
suggested to act as an important “amodal” hub for binding distinct association
modality-specific regions that are involved in information representation.18
Recent discoveries also demonstrated that the lateral temporal, inferior parietal,
and prefrontal regions are involved in semantic information processing at one
stage or another. More specific functions for these regions are yet to be
determined, although it is possible that the prefrontal cortex plays a role in
organizing and retrieving specific semantic information.19
The described episodic and semantic memory systems rely on distinct brain networks.
The boundaries between these networks overlap anatomically and functionally.
Procedural Memory
Memory for motor skills is called procedural memory. Acquired motor skills
usually operate automatically without substantial involvement of consciousness,
as with the skills needed to drive a car or ride a bicycle. As the operation of this
system is not associated with conscious awareness, it belongs to a group of
nondeclarative (or implicit) memories. The anatomic procedural memory
system relies on interconnected regions of supplementary motor areas as well as
the superior parietal lobule, basal ganglia, and cerebellum.20
MEMORY EVALUATION
The following section provides a general overview of the office-based evaluation
of memory.
Screening Evaluation
It is important to evaluate level of consciousness, alertness, attention, and
language function before assessing memory, because abnormalities in these

MEMORY DYSFUNCTION
cognitive domains may affect the results on tests of memory. An adequately

functioning neurovisual system is also necessary for visual memory function.
Working memory can be evaluated in the office by giving the patient a series
of numbers to repeat and increasing the number of digits with each trial until the
patient fails (digit span). On average, people with normal working memory
should be able to recite seven digits (plus or minus two). The test can be made
more complex by asking the patient to recite numbers in reverse sequence;
backward span is normally not less than the same forward span minus two. The
Serial 7s test can also be used for working memory evaluation; this test also
involves mental calculations and is thus a measure of working memory only if the
patient is able to carry out the required mental arithmetic. The subject is asked to
subtract 7 from 100 and to keep subtracting 7 from each consecutive number.
Serial 3s can be used as a simpler version of the same test. Reciting months of the
year in reverse order is an alternate test of working memory that does not involve
mental calculations.
Various memory tests evaluate different aspects of episodic memory. General
episodic memory screening consists of inquiring about recent autobiographical
and current news events. This general screening can help establish if the amnesia
is anterograde or retrograde. The most commonly used and easy-to-perform
memory tests often provide the patient with a number of words (commonly 3 to
10) for verbal-based memory or geometric shapes for visual-based memory. The
patient is asked to reproduce the words or shapes after sufficient time has passed
(usually 10 minutes or more). More complex testing determines if the patient
remembers specific items placed in specific locations in the testing area. As a
substitution to learning random words or shapes, the examiner can read a story to
the patient and later ask the patient to repeat it. This test also involves logical
organization of the information. Retrograde amnesia can be detected by testing
the knowledge for events that occurred before the onset of illness.
The Three Words-Three Shapes Test is an easy test to assess verbal and nonverbal
memory.21 The patient is initially provided with three words and three shapes, then
asked to write them on a sheet of paper without further instructions. FIGURE 3-3
demonstrates three words and three shapes, which are taken from the original test.
The six items are then taken away, and the patient is asked to write the words and
draw the items from memory. This step tests the patient’s incidental recall ability.
FIGURE 3-3
Three Words-Three Shapes Test.
Reprinted with permission from Weintraub S, Mesulam MM.21 © 1985 FA Davis.
732 JUNE 2018

The same items are presented to the patient up to 3 more times until the patient KEY POINTS
correctly registers at least five items. This is called effortful encoding. If memory
● A suboptimal level of
is more strongly affected, the patient may not be able to register several items consciousness, alertness,
even after three extra trials. The patient is then asked to reproduce the six items attention, language, or
from memory after 10 to 15 minutes. This portion evaluates delayed recall. If neurovisual function can
some of the items are missing or incorrect, the patient is presented with lists of affect memory
performance.
multiple words and shapes that include the original items and asked to identify
the original three words and three shapes. This step evaluates recognition. ● Neuropsychological
The Three Words-Three Shapes Test evaluates several aspects of memory. testing objectively evaluates
The inclusion of verbal and nonverbal items evaluates both verbal and nonverbal the performance of
memory. Immediate (working memory) recall is tested when the patient is asked different cognitive domains
(including memory).
to present the items immediately following exposure to them. The patient’s
ability to encode information is evaluated according to the number of times he or
she must be exposed to the items before registering them. The ability to store and
retrieve the information is tested when the patient is asked to actively recall the
items, while the storage (retention) function is tested by evaluating recognition ability.
Semantic memory could be tested by asking the patient to name pictures,
match pictures with words, or recognize objects and their parts, or by evaluating
semantic fluency (eg, by asking the patient to name as many animals as possible
in 1 minute).
Neuropsychological Testing
Neuropsychological evaluation was designed to objectively evaluate different
aspects of cognition and is more comprehensive than screening tests used in
a typical medical office setting. An in-depth discussion of different
neuropsychological tests is beyond the scope of this article; only general
principles are discussed.
Working memory can be evaluated during neuropsychological testing using
digit span or visual span tests from the Wechsler Adult Intelligence Scale–Fourth
Edition22 and Wechsler Memory Scale–Fourth Edition,23 among others. The
neuropsychological memory evaluation addresses several aspects of memory,
including immediate and delayed recall, verbal and nonverbal memory, and
recognition. The tests most commonly used in a neuropsychological assessment
typically include both word list learning tasks (eg, California Verbal Learning
Test–Second Edition,24 Rey Auditory Verbal Learning Test25) and memory tasks
involving narratives/stories (eg, Wechsler Memory Scale–Fourth Edition Logical
Memory Test23).
Nonverbal memory can be evaluated with the Rey-Osterrieth Complex Figure
Test26 and the Visual Reproduction Test from the Wechsler Memory Scale. This
test indicates memory impairment only when other neurovisual functions (eg,
construction, spatial functions) are preserved.
For practical reasons, the clinician should determine in a neuropsychological
evaluation what stages of episodic memory are affected, because this may guide
localizing the process that will help in establishing the diagnosis. If memory
storage/retention is demonstrated to be affected the most, then the pathology
should localize to the medial temporal lobe structures or other structures that are
part of the Papez circuit (such as the mammillary bodies, anterior thalamic
nuclei, or fornix). If encoding, retrieval, or both are significantly affected, then
the pathology usually localizes in more distributed networks (refer to the
discussion on memory neuroanatomy).

MEMORY DYSFUNCTION
Semantic knowledge is also evaluated during neuropsychological testing.

Examples of tests used include a category fluency test, the Boston Naming Test,27
vocabulary testing, and certain parts of the Wechsler Adult Intelligence
Scale–Fourth Edition and Northwestern University Famous Faces Test.28
MEMORY DYSFUNCTION CLASSIFICATION

The following section reviews different types of memory impairment.
Classification of Amnesias
Memory impairment, or amnesia (from the Greek word amneesya, meaning
“without memory”), is frequently divided into anterograde (impaired ability to
form new memories) and retrograde (impaired recall of events occurring before
the pathologic insult). Retrograde amnesia frequently has a temporal gradient:
memories that were formed closer to an insult are more likely to be forgotten
than memories formed further from the insult. This is a possible reflection of a
consolidation process.
The etiology of amnesia can be suspected based on the timeline of disease
development. In this regard, amnesias can be classified into acute and nonacute.
Acute amnesias can be further divided into persistent and transient. Persistent
acute amnesias are usually due to a cerebrovascular event or traumatic brain
injury. Transient acute amnesias may be caused by transient ischemic event,
transient global amnesia syndrome, or epileptic events. Nonacute amnesias may
be caused by metabolic factors (such as thiamine deficiency), neurodegenerative
conditions, space-occupying lesions, demyelinating disorders, or other etiologies.
For practical reasons, episodic memory impairment can be classified in a
simplified way into two groups: (1) amnesias primarily presenting with impaired
retention due to dysfunction of the medial temporal lobes and connected limbic
structures (temporolimbic system) and (2) amnesias that result from inadequate
memory encoding, retrieval, or both, involving the medial temporal lobes and
executive networks. This is an artificial classification; it is rarely absolute and
should only be used as a guideline.
Impaired Working Memory

Working memory can be affected by many neurologic and psychiatric disorders.
This may not be surprising because of the wide distribution of the working
memory system through the brain. Examples of conditions that may affect
working memory include delirium from any cause, cerebrovascular disease
(ischemic and hemorrhagic); traumatic brain injury; and neurodegenerative,
demyelinating, and psychiatric conditions.
Impaired Retention of Episodic Memory

Effective information retention is primarily dependent on an intact medial
temporolimbic system. The structures that are important in information
retention include the hippocampi with surrounding parahippocampal cortical
regions as well as the fornix, mammillary bodies, anterior and mediodorsal
thalamic nuclei, and cingulate cortex.
Impaired retention can be recognized in testing by the rapid decay of new
information after ensuring that the information was (at least partially) encoded.
Patients with impaired retention demonstrate an inability to hold information for
a longer period of time; during testing, this presents with a loss of information
734 JUNE 2018

with a time delay. This manifests with an inability to retrieve information as well KEY POINTS
as an inability to recognize previously presented information (CASE 3-1).
● Amnesias are divided into
Retention deficits have multiple etiologies. These etiologies vary from focal anterograde and retrograde.
lesions affecting the brain regions previously discussed to progressive Retrograde amnesias
pathologies that tend to affect these regions. frequently have a temporal
gradient; memories that
were formed closer to an
ALZHEIMER DISEASE. Alzheimer disease (AD) is the most common age-related insult are more likely to be
progressive neurodegenerative disorder. In most cases, it presents with an forgotten than memories
impaired ability to retain new memories, and this feature remains the most formed further from
salient as the disease progresses. Histopathologically, AD is characterized by the insult.
extracellular fibrillary amyloid deposition and intracellular neurofibrillary tangle ● Amnesias can be also
aggregation. These two pathologic changes initially occur in distinctive brain divided into acute and
regions: fibrillary amyloid begins accumulating in certain cortical regions nonacute. Acute amnesias
(posterior cingulate cortex, precuneus, and prefrontal regions), while can be further divided into
persistent and transient.
neurofibrillary tangles begin forming in neurons of the medial temporal
lobe structures.29,30 ● Working memory
dysfunction can be seen in
OTHER PROGRESSIVE AMNESTIC DISORDERS. Progressive amnestic disorders due many neurologic and
psychiatric conditions.
to suspected non-Alzheimer pathophysiology are conditions that present with
clinical characteristics that are similar to AD but do not demonstrate amyloid ● Impaired retention of
deposition with in vivo amyloid imaging.31 These conditions include medial episodic memory can be
temporal tauopathy without amyloidosis,32 late-onset hippocampal sclerosis,33 seen when pathologic
and (yet to be further characterized) argyrophilic grain disease.34 These processes affect the medial
temporal lobe and related
conditions are diagnosed during histologic evaluation and cannot reliably be limbic structures. Clinically,
distinguished from AD in the clinic. it presents with a rapid
decay of newly learned
OTHER NEURODEGENERATIVE DISEASES. Other neurodegenerative diseases can information.
also involve an amnestic component, although this frequently occurs later in
disease progression. These diseases include frontotemporal dementia,
Creutzfeldt-Jakob disease, and more advanced cases of Lewy body spectrum
disorders.
SPECIFIC CEREBROVASCULAR SYNDROMES. An amnestic syndrome with severe

retention deficits can be observed after ischemic or hemorrhagic damage to
specific structures involved in memory formation. Cerebrovascular events in one
or both hippocampi due to occlusion in the posterior cerebral artery hippocampal
branches can manifest with amnesia. Bilateral hippocampal strokes are more
likely to produce overt amnesia than unilateral strokes, although amnesia can
frequently be detected during neuropsychological evaluation even with
unilateral damage.35 Similar amnestic syndromes can be observed with
diencephalic vascular insults occurring in thalamic arterial branch territories.36
Amnestic syndromes are also associated with anterior communicating artery
cerebrovascular events involving basal forebrain structures, although the clinical
symptoms are usually less severe.
THIAMINE DEFICIENCY (KORSAKOFF SYNDROME). Korsakoff syndrome is usually

preceded by Wernicke encephalopathy, which presents with abrupt-onset
confusion that is associated with cerebellar dysfunction and oculomotor
impairment. If this condition is not treated promptly with thiamine
supplementation, patients are usually left with a significant amnestic disorder.

MEMORY DYSFUNCTION
Classic symptoms of Korsakoff syndrome include disorientation, confabulation,

and anterograde and retrograde amnesia. Patients with Korsakoff syndrome
show difficulties with episodic memory and the temporal order of events. The
regions implicated in Korsakoff syndrome include the mediodorsal thalamic
nuclei and mammillary bodies.37
TRAUMATIC BRAIN INJURY. Traumatic brain injury is a mechanical brain injury

caused by acceleration and deceleration forces. These forces cause distinct
microstructural and biochemical changes at the microscopic level, disrupting
axonal and synaptic functions. Posttraumatic amnesia can occur due to injury to
distinct medial temporal lobe structures, although a significant proportion of
patients do not demonstrate any specific lesions when using conventional
structural brain imaging techniques. More advanced structural and functional
imaging studies demonstrate that patients in this category have widespread
network disruptions. In particular, it was demonstrated that posttraumatic
amnesia is associated with damage in the parahippocampal subdivision of the
CASE 3-1 A 75-year-old woman was brought to the clinic by her daughter for
forgetfulness. The daughter had noticed some “benign” memory slips
starting about 2 years ago but initially did not think much of it. More
recently, her mother had started asking the same questions fairly
frequently and was sometimes retelling the same stories within a short
time frame. While the patient still lived alone and managed her
household, she had recently been asking for help organizing her bills. She
sometimes realized that she was becoming more forgetful. No
geographical disorientation, difficulty in expressing herself or
understanding what other people were saying, or recognition deficits
were reported. She did not report any symptoms of anxiety, mood, or
psychotic disorders. No other neurologic symptoms were reported,
including changes in motor function or occurrence of tremor. The patient
reported restful sleep. As she lived alone, it was not known if she had any
sleep-related nocturnal behaviors. The patient’s appetite was good, and
her weight was stable. Past medical history was significant for
hypertension and a mildly elevated low-density lipoprotein cholesterol
level. Her family history was unremarkable.
The patient was awake, alert, and fully oriented. Attention was
preserved, as was demonstrated by normal performance on the Serial 7s
test. The patient made two mistakes but was able to self-correct during a
Trail Making Test Part B. The patient was given the Three Words-Three
Shapes Test and was able to recall two words and two shapes on the
incidental part. She needed two extra trials to register all six items, was
able to recall one word and one shape in 10 minutes, and correctly
recognized one word and two shapes. Language examination
demonstrated mild anomia but was otherwise normal. Visuospatial
testing was normal. General neurologic examination was unremarkable.
736 JUNE 2018

cingulum bundle and reduced connectivity between the parahippocampus and
posterior cingulate cortex.38
HYPOXIC-ISCHEMIC BRAIN INJURY. Hypoxic-ischemic brain injury occurs when

the oxygen supply or blood flow falls below the threshold needed to support
normal neuronal metabolism. Hippocampal pyramidal CA1 cells are among the
most sensitive to a lack of oxygen and can be irreversibly damaged after ischemia
lasting 3 to 5 minutes.39 Amnesia with significant retention deficit can be the only
residual symptom even if ischemia is promptly reversed.
INFECTIOUS AND INFLAMMATORY ENCEPHALITIDES AFFECTING LIMBIC AND

ASSOCIATED STRUCTURES. Certain infectious and inflammatory encephalitides
affect limbic and associated structures. Limbic encephalitis can be caused by a
virus, such as herpes simplex 1, or by an immune system–mediated mechanism,
either idiopathic or cancer-related (paraneoplastic).40 These diseases frequently
have a pronounced amnestic-retentive syndrome.
Routine blood work was performed,

which included vitamin B12 and
thyroid-stimulating hormone (TSH)
levels, with normal results. MRI of
the brain was performed and
demonstrated mild generalized brain
atrophy that was possibly more
pronounced in posterior regions and
also involved medial temporal lobe
structures (FIGURE 3-4).
The patient was referred for a
detailed neuropsychological
examination. The results
demonstrated episodic memory
impairment primarily affecting the
memory retention stage. Mild
FIGURE 3-4
impairments in executive and Coronal T2-weighted brain MRI of the
language functions were also present. patient in CASE 3-1 demonstrating
generalized brain atrophy, particularly
involving bilateral medial temporal
lobe regions.
Evaluation in the office and neuropsychological testing results COMMENT

demonstrated that the patient’s forgetfulness was primarily based on
impaired memory retention. Combining this impression with a normal
general workup and abnormal structural imaging findings, the patient was
suspected to have a cognitive disorder primarily affecting medial temporal
lobe structures. Epidemiologically, the highest suspicion would be for an
underlying Alzheimer-type pathology.

MEMORY DYSFUNCTION
SPACE-OCCUPYING LESIONS. Memory retention can be affected if a space-occupying

lesion (eg, infectious, inflammatory, or tumor) is located in the temporolimbic region.
TRANSIENT GLOBAL AMNESIA. Transient global amnesia is a syndrome that

presents with a transient (typically several hours but less than 24 hours in
duration) inability to form new memories (anterograde amnesia), associated
with repetitive comments and questions and some retrograde amnesia during the
attack.41 This condition usually develops in patients who are in their fifties to
seventies and may recur in some patients. When a careful history is taken, it is
commonly noted that the patient was involved in a characteristic precipitating
activity at the onset of the attack, such as extreme physical exertion, acute
immersion in cold water, sexual intercourse, or severe pain or emotional
distress.42 MRI studies using diffusion-weighted imaging (DWI) in patients
with transient global amnesia have shown unilateral or bilateral punctate
hippocampal lesions in some patients, peaking in detection rate on the third day
after the event.43 The etiology of this syndrome remains controversial.41,44,45
AMNESTIC SYNDROME RELATED TO MEDIAL TEMPORAL LOBE EPILEPSY. An

amnestic syndrome related to medial temporal lobe epilepsy may occur if
epilepsy is accompanied by hippocampal sclerosis.46 The syndrome of transient
epileptic amnesia is a unique mesial temporal lobe epilepsy syndrome that
presents as recurrent transient amnestic attacks that should be clinically
distinguished from transient global amnesia. As noted by Butler and colleagues,47
characteristic features of transient epileptic amnesia include episodes that are
frequent (median of 12 per year) and brief (median 30 to 60 minutes) and often
occur on awakening. Patients with transient epileptic amnesia typically have the
onset of their condition later in life (mean onset 62 years of age), and their
attacks typically cease with administration of an antiepileptic agent. Patients
with transient epileptic amnesia may or may not have evidence for other findings
or symptoms of temporal lobe epilepsy, such as epileptiform EEG abnormalities
or other clinical features such as lip smacking or olfactory hallucinations
associated with the attacks.47 Although attacks typically are well controlled with
antiepileptic agents, Butler and colleagues48 have also noted that transient
epileptic amnesia is associated with a unique interictal amnestic syndrome
including accelerated long-term forgetting and autobiographical amnesia.
Impaired Encoding and Retrieval of Episodic Memory

The memory formation step of the incorporation of information traces within
neuronal networks in the brain is called encoding. In contrast, retrieval is the
allocation and reconstruction of information that was previously encoded. As a
general rule, executive frontoparietal networks act together with the medial
temporolimbic system during information encoding and retrieval. The broader
anatomic distribution of systems involved during these steps explains why
encoding and retrieval can be affected by pathologic processes located in
multiple brain regions.
Upon examination, impaired encoding can be demonstrated by a patient’s
inability to register new information. Impaired retrieval manifests with
diminished recall of encoded information; however, the patient demonstrates at
least a partially preserved recognition of originally presented stimuli, thereby
demonstrating at least a partially functioning retention mechanism (CASE 3-2).
738 JUNE 2018

Any pathology affecting the limbic system and its associated structures can KEY POINTS
affect encoding, retrieval, and retention. The pathologic processes that can affect
● Impaired encoding or
encoding and retrieval include the following: retrieval of episodic memory
or both can be observed
u Alzheimer disease when pathologic processes
affect the medial temporal
u Non-Alzheimer neurodegenerative conditions, such as Lewy body spectrum disorders or lobe, executive networks, or
frontotemporal dementia both. Clinically, impaired
u Traumatic brain injury encoding presents with a
diminished ability to register
u Space-occupying lesions new information. Impaired
u Hydrocephalus retrieval presents with the
impaired active recall of
u Demyelinating disorders encoded information, with
u Vascular cognitive impairment at least partially preserved
recognition of the
information that was
As already noted, vascular insults located in the limbic and associated originally presented.
regions can present with episodic memory retention impairment; however,
vascular insults can also affect encoding and retrieval of memories. Clinicians ● Impaired semantic
frequently encounter brain scans of the patients that demonstrate more memory can present when
the pathologic process
diffusely distributed presumed ischemic changes based on microvascular affects the main hubs of the
changes that are located in hemispheric white matter. These changes affect the semantic network.
tracts connecting the various brain regions necessary for optimal information Clinically, it presents with
encoding and retrieval. Some of these patients present with stepwise the loss of word, object, and
concept meaning.
deterioration, although a significant proportion presents with slowly
deteriorating cognitive function.49
It is important to stress that anxiety, mood, and psychotic disorders can also
affect memory formation at any stage.
Impaired Semantic Memory

Semantic knowledge impairment can be seen acutely with stroke involving
dominant temporal and parietal cortices, traumatic brain injury, and infectious
(particularly herpes encephalitis) and inflammatory conditions. The prototypical
disorder initially targeting the semantic system is the semantic variant of primary
progressive aphasia. For more information on aphasia, refer to the article
“Primary Progressive Aphasia and Stroke Aphasia” by Murray Grossman,
MDCM, FAAN, and David J. Irwin, MD,50 in this issue of Continuum. Other
neurodegenerative disorders, such as AD, can also present with the progressive
loss of semantic knowledge.51 Focal lesions involving anterior, lateral, and
inferior temporal lobes can also present with impaired semantic knowledge.
Clinically, these patients demonstrate impaired knowledge of objects, words, and
concepts. Language is affected and becomes empty of meaning. Patients also
frequently demonstrate two-way naming deficits: they are unable to either name
the object or point to the correct object when prompted. The patient begins to use
superordinate category names for specific objects (eg, referring to a dog as an
animal) or to use semantic paraphasias as a substitution for an actual name.52
Impaired Procedural Memory

Procedural memory is tested less frequently in the clinical setting. As noted
previously, anatomic regions involved in procedural memory impairment
include the supplementary motor cortex, superior parietal lobule, basal
ganglia, and cerebellum. Focal lesions in these regions, such as stroke or tumor,

MEMORY DYSFUNCTION
can produce procedural memory deficits. Progressive neurodegenerative

conditions, such as corticobasal syndrome and Parkinson disease, can also
affect this system.
MEMORY DISTORTIONS
While memory loss is one of the most frequently encountered symptoms in
memory clinics, clinicians may also see patients with memory distortions.
Memory distortions can affect the content or temporal relations of events. While
benign memory distortions can be seen in healthy people, significant distortions
usually signify brain dysfunction and result in confabulations. Confabulations
do not have to be logical or even consistent, and the patient may say two things
that contradict each other. Patients are usually not concerned about the errors
if they are pointed out to them. As confabulations are deficits of retrieval, it is not
surprising that frontally based executive control network dysfunction plays a
role in their development.53 Confabulations have been described in patients with
the involvement of various frontal lobe regions, although the inferior medial
prefrontal system may play a crucial role.54 As one can expect, confabulations are
associated with diseases that affect these brain regions, rather than the disease
process itself. Confabulations more frequently involve episodic memories,
CASE 3-2 An 80-year-old woman presented to the clinic with her son for evaluation
of forgetfulness that became apparent several years ago. The
forgetfulness had slowly worsened over time. The son described his
mother as being easily distracted and repeating the same questions within
a short time frame. The patient lived
alone and managed her household
seemingly without any difficulties,
although her son had started questioning
her ability to drive safely after she
recently missed several stop signs. The
patient had never become lost in a
familiar area. Her son did not notice any
changes in her language or behavior. She
did not report any symptoms of anxiety,
mood, or psychotic disorders. No other
neurologic symptoms were reported,
including changes in motor function,
occurrence of tremor, or balance
deficits. Her past medical history was
significant for hypertension and treated
hypothyroidism. Her father suffered a
FIGURE 3-5 stroke at age 85, and her mother died
Coronal T2-weighted brain MRI of the from ovarian cancer.
patient in CASE 3-2 demonstrates
significant periventricular and
The patient was awake, alert, and
subcortical white matter changes and fully oriented. Attention testing
generalized brain atrophy. revealed difficulties performing the
740 JUNE 2018

although semantic memories could be affected as well. Confabulations are
observed not only in patients with memory disorders but also in patients with
deficits in other domains (anosognosias), such as confabulations in patients with
cortical blindness (Anton syndrome).
CONCLUSION
The human brain has a finely tuned mechanism to form and store memories.
Memory formation is a fluid process involving memory encoding, which
provides the ability to store and retrieve memories. The boundaries between
different stages of memory formation are not as clear. As this process involves
many interconnected and widely distributed brain regions, it is not surprising
that encoding can be affected by various pathologic processes. It is important to
understand that memory impairment is a result of the disruption of these
mechanisms and that certain pathologic processes tend to affect one or another
stage of memory formation. The first step in evaluating forgetfulness is to clarify
what type of memory is impaired at what formation stage. This will become a
guiding step to identify the underlying pathologic process that causes
this impairment.
Serial 7s test and difficulties switching between the letters and numbers
during the Trail Making Test Part B. The patient was able to recall one word
and one shape on the incidental part of the Three Words-Three Shapes
Test. She needed four extra trials to register all six items but was able to
recall one correct word, one false word and two shapes after 10 minutes.
She was able to recognize all six items correctly. Language and visuospatial
testing were unremarkable.
The patient had routine blood work performed, including vitamin B12 and
thyroid-stimulating hormone (TSH) levels, with normal results. MRI of the
brain was performed and demonstrated at least moderate periventricular
and subcortical white matter changes and mild generalized brain volume
loss (FIGURE 3-5). She was referred for a detailed neuropsychological
examination. The results demonstrated episodic memory impairment
primarily affecting memory retrieval and, to a lesser extent, encoding
stages. There was also a fairly pronounced impairment in executive
functions. Other cognitive domains were spared.
Based on evaluation in the office and neuropsychological testing results, this COMMENT
patient’s forgetfulness was suspected to be due to the dysfunction of
frontal executive networks rather than medial temporal lobe and related
structures. Combining testing results with findings from structural imaging,
the most likely etiology for this patient’s symptoms would be vascular
cognitive impairment. Without further evaluation with biomarkers, dual
pathology of this syndrome cannot be excluded.

MEMORY DYSFUNCTION
ACKNOWLEDGMENTS
The author would like to thank his teachers, Dr Carol Lippa, Dr M.-Marsel
Mesulam, and Dr Sandra Weintraub, for igniting his interest in cognitive and
behavioral aspects of neurology and being patient while guiding him. The author
would also like to thank Dr Janice Jurkus, Dr Kathryn Lester, Dr Jennifer Gallo,
Ms Jennifer Ross, and Dr Robert Koenigsberg for their advice on the writing
of this article.
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744 JUNE 2018

Primary Progressive REVIEW ARTICLE

Aphasia and Stroke C O N T I N U UM A U D I O
ONLINE
Aphasia
By Murray Grossman, MDCM, FAAN; David J. Irwin, MD
ABSTRACT
PURPOSE OF REVIEW: This article summarizes the clinical and anatomic features
of the three named variants of primary progressive aphasia (PPA): semantic
variant PPA, nonfluent/agrammatic variant PPA, and logopenic variant
PPA. Three stroke aphasia syndromes that resemble the PPA variants CITE AS:
(Broca aphasia, Wernicke aphasia, and conduction aphasia) are also CONTINUUM (MINNEAP MINN)
presented. AND PSYCHIATRY):745–767.
RECENT FINDINGS: Semantic variant PPA and Wernicke aphasia are Address correspondence to
characterized by fluent speech with naming and comprehension difficulty; Dr Murray Grossman, 2 Gibson,
Department of Neurology,
these syndromes are associated with disease in different portions of the Hospital of the University of
left temporal lobe. Patients with nonfluent/agrammatic variant PPA or Pennsylvania, 3400 Spruce St,
Philadelphia, PA, 19104,
Broca aphasia have nonfluent speech with grammatical difficulty; these mgrossma@pennmedicine.
syndromes are associated with disease centered in the left inferior frontal upenn.edu.
lobe. Patients with logopenic variant PPA or conduction aphasia have
difficulty with repetition and word finding in conversational speech; these Dr Grossman serves as an
syndromes are associated with disease in the left inferior parietal lobe. associate editor of Neurology;
While PPA and stroke aphasias resemble one another, this article also as a consultant for the
Association for Frontotemporal
presents their distinguishing features. Degeneration, Bracco, and UCB,
SA; and on the scientific
advisory boards of the
SUMMARY: Primary progressive and stroke aphasia syndromes interrupt
Association for Frontotemporal
the left perisylvian language network, resulting in identifiable aphasic Degeneration and Biogen.
syndromes. Dr Grossman receives
research/grant support from
Avid Radiopharmaceuticals, the
National Institutes of Health
(AG017586, AG052943,
AG038490, and NS053488), and
INTRODUCTION Piramal Enterprises Ltd. Dr Irwin
A
phasia is a central disorder of language comprehension and receives research/grant
expression that cannot be attributed to a peripheral sensory deficit support from the BrightFocus
Foundation and the National
(such as reduced auditory acuity) and is not due to a peripheral Institutes of Health (K23
motor disorder (such as weakness of the muscles of articulation) NS088341-01).
that may mimic aphasia. Aphasia is associated with disease that
UNLABELED USE OF
affects the language network in the brain. Many different impairments can result PRODUCTS/INVESTIGATIONAL
in aphasia. This article focuses on primary progressive aphasia (PPA) and stroke USE DISCLOSURE:
Drs Grossman and Irwin report
aphasia but does not consider systemic disorders or psychiatric disorders, no disclosures.
conditions such as head trauma or surgical interventions (eg, for neoplasms or
hemorrhage following ruptured aneurysms), or transient changes in neurologic
functioning that can disturb language functioning (eg, seizures or inflammation). of Neurology.

APHASIA
PPA refers to a group of focal neurodegenerative syndromes primarily

affecting language. Primary refers to the absence of obvious structural
abnormalities, including the absence of stroke, space-occupying lesion, or head
trauma; progressive refers to the gradual worsening of the language deficit over
several years.
In 1892, Arnold Pick described a woman with a social disorder involving
disinhibition and poor insight.1 Her speech gradually worsened, and she
eventually became mute. In 1893, Paul Serieux described a patient with isolated
language decline consisting of worsening speech fluency but relatively preserved
memory and social and visuospatial functioning.2 M. Marsel Mesulam reported
a series of patients whom he characterized as having slowly progressive aphasia.3
A positron emission tomography (PET) scan of brain functioning in one of
these cases revealed reduced glucose metabolism in the left hemisphere.4
A diagnosis of PPA requires that the language impairment is the primary
cognitive deficit and that it is progressive in nature.5,6 Language difficulty should
be the primary impairment for 1 to 2 years, with minimal memory, visuospatial,
executive, or social difficulty during the early course of the disease, thereby
eliminating other neurodegenerative conditions, such as typical amnestic
Alzheimer disease (AD), in which memory difficulty can be accompanied at
times by disproportionate impairment of language. The average age of onset
tends to be in the late fifties, although a wide range of onset age is reported, and
we are only beginning to learn about the factors contributing to this substantial
variability.7 Survival is about 7 years, although estimates of prognosis vary
widely.8,9 The underlying neuropathology of PPA is heterogeneous and largely
corresponds to forms of frontotemporal lobar degeneration (FTLD); however, at
least 20% of all patients with PPA may have a nonamnestic clinical presentation
of AD due to plaque and tangle pathology, as revealed at autopsy.10 Specific
clinical syndromes of PPA have some predictive value for underlying molecular
pathology (as discussed later in this article), but these associations are
not absolute, posing a significant impediment for the development of
disease-modifying therapies based only on clinical presentation.11
Stroke is another major cause of aphasia. The manifestations of aphasia due to
stroke appear suddenly, not gradually as in PPA. As in PPA, several different
forms of stroke aphasia exist, and these are determined in large part by damage to
a portion of the language network where perfusion has been interrupted. The
specific language deficits that are seen in stroke aphasia overlap only in part with
those associated with PPA. This may be partially because stroke aphasia and PPA
often affect different portions of the language network. Moreover, a stroke
indiscriminately damages both gray matter regions of the brain that contain
neurons and nearby white matter regions that contain projections that integrate
several gray matter regions into a functional unit. Unlike PPA, in which white
matter disease is typically the result of wallerian degeneration associated with
disease in gray matter portions of the language network, the white matter tracts
damaged in stroke may be en passant fibers that happen to be near the area of
ischemia but connect brain regions unrelated to the language network. Because
of the indiscriminate damage caused by a stroke, it can be difficult to parcel out
the relative contribution of gray matter processing regions and white matter
projections in a stroke-induced language disorder. Defining the gray matter
regions and white matter regions contributing to a language disorder in a
neurodegenerative condition causing a progressive aphasia is relatively easier
746 JUNE 2018

because the physical damage is more KEY POINTS
selective compared to that seen following a
● Aphasia is a central
stroke and involves a gray matter and disorder of language
white matter network more specifically comprehension and
related to language. expression that cannot be
This article focuses on the three subtypes attributed to a peripheral
sensory deficit (such as
of PPA, one with fluent speech, one with
reduced auditory acuity) and
nonfluent speech, and one with a mixed is not due to a peripheral
form of aphasic speech. The anatomic motor disorder (such as
distribution of disease in the progressive weakness of the muscles of
FIGURE 4-1 articulation) that may
aphasias is illustrated in FIGURE 4-1.12 Anatomy of primary progressive mimic aphasia.
These are compared with three similar aphasia. The anatomic distribution of
forms of stroke aphasia, one fluent, one gray matter atrophy associated with ● Primary progressive
nonfluent, and one with mixed fluency each of the three forms of primary aphasia refers to a group of
progressive aphasia is shown, based
(TABLE 4-1). on MRI scans of cohorts of patients
focal neurodegenerative
syndromes primarily
The first form of PPA is known as meeting published criteria for these affecting language.
semantic variant PPA (also called semantic disorders: semantic variant primary
dementia). This is a fluent form of aphasia progressive aphasia (blue); nonfluent/ ● The diagnosis of primary
agrammatic primary progressive aphasia progressive aphasia requires
associated with a disorder of naming and a (red); logopenic variant primary that the language
deficit of word and object meaning. A progressive aphasia (green). impairment is the primary
somewhat similar form of stroke aphasia is Reprinted with permission from Grossman M,
12 cognitive deficit and that it is
Nat Rev Neurol. © 2010 Springer Nature.
known as Wernicke aphasia. This is also a progressive in nature.
fluent form of aphasia with impaired
naming and word meaning. Despite ● The manifestations of
aphasia due to stroke
superficial similarities, the language characteristics of semantic variant appear suddenly, not
PPA and Wernicke aphasia have several notable differences. For example, gradually as in primary
Wernicke aphasia tends to affect word meaning much more than object progressive aphasia.
meaning and is associated with a repetition deficit, while patients with semantic
variant PPA often display a distinctive impairment in reading known as
surface dyslexia.
A second variant of PPA is known as nonfluent/agrammatic variant PPA, also
called progressive nonfluent aphasia. This nonfluent form of PPA is associated with
slowed, effortful speech and an impairment of grammatical processing. Although
several forms of nonfluent stroke aphasia exist, this article focuses on Broca
aphasia, which also includes disorders of effortful speech and grammatical
processing. While the stroke and progressive forms of nonfluent aphasia are both
most notable for their nonfluent speech, as noted later in the article, some subtle
distinctions exist: nonfluent/agrammatic PPA may include a deficit of speech
sound articulation known as apraxia of speech, while Broca aphasia is associated
with impaired repetition.
Finally, it has been recognized that many patients with PPA are not easily
classified as having semantic variant PPA or nonfluent/agrammatic PPA, thus
the logopenic variant of PPA has recently been added to the PPAs. This syndrome
is characterized by significant word-finding difficulty in conversational speech
and an impairment of auditory-verbal short-term memory, resulting in profound
repetition difficulty. The analogous syndrome in classic stroke aphasia is
conduction aphasia, resulting in relatively isolated repetition difficulties. Again,
while logopenic variant PPA and conduction aphasia display mixed fluency
associated with impaired repetition, subtle distinctions between these syndromes
exist: logopenic variant PPA has more prominent lexical retrieval difficulties,

APHASIA
TABLE 4-1 Characteristics of Progressive and Stroke Forms of Aphasia
Fluent Aphasia Nonfluent Aphasia Mixed
Nonfluent/
Semantic Agrammatic Logopenic
Variant Primary Variant Primary Variant Primary
Progressive Wernicke Progressive Broca Progressive Conduction
Aphasia Aphasia Aphasia Aphasia Aphasia Aphasia
Speech features
Fluent speech Yes Yes No No Yes/Noa Yes/Noa
Speech errors Lexical Lexical Phonemic Phonemic Phonemic more Phonemic
than lexical
Apraxia of speech No No Yes No No No
Naming deficits Yes Yes Yes Yes Yes Yes
Comprehension
features
Single word deficits Yes Yes No No No No
Object deficits Yes No No No No No
Grammar deficits No No Yes Yes No No
Other
Oral reading and Surface dyslexia No Agrammatic Agrammatic No No
writing deficits and dysgraphia
Repetition deficits No Yes No Yes Yes Yes
Core anatomy
Anterior and Posterior- Left inferior Left inferior Left inferior Left inferior
ventral left superior left frontal frontal parietal and parietal
temporal temporal posterior
temporal
Clinicopathologic
correlations
FTLD- Vascular FTLD-Tau>AD> Vascular AD> FTLD- Vascular
TDP>FTLD- FTLD-TDP Tau>FTLD-TDP
Tau>AD
AD = Alzheimer disease; FTLD-Tau = frontotemporal lobar degeneration with tau pathology; FTLD-TDP = frontotemporal lobar degeneration with
transactive response DNA-binding protein 43 (TDP-43) pathology.
a
Logopenic variant primary progressive aphasia and conduction aphasia have relatively fluent speech that can by slowed by word-finding
difficulty and circumlocutions but lack motor speech or grammatical impairments.
748 JUNE 2018

while the quality of repetition impairment in conduction aphasia can have KEY POINTS
distinct characteristics depending on the precise location of the stroke.
● It is valuable to recognize
From a clinical perspective, it is important to distinguish between the each of the primary
progressive and stroke forms of aphasia. Moreover, it is valuable to recognize progressive aphasia
each of the PPA syndromes since they may be markers of a statistically increased syndromes since they may
risk of a specific form of FTLD pathology,12–14 and it is valuable clinically to be markers of a statistically
increased risk of a specific
recognize these forms of stroke aphasia since they are often associated with an
form of frontotemporal
embolic stroke that may have its origins in the heart. lobar degeneration
pathology, and it is valuable
FLUENT APHASIAS clinically to recognize the
forms of stroke aphasia
The fluent aphasias include semantic variant PPA and Wernicke aphasia. The
since they are often
major characteristics shared by these primary progressive and stroke-associated associated with an embolic
aphasias are the fluent rate of speech paired with impaired comprehension. stroke that may have its
However, these aphasic syndromes also differ in subtle but important ways. origins in the heart.
● Long-term memory for

Clinical Features concepts, such as
Long-term memory for concepts, such as knowledge of objects, actions, and knowledge of objects,
ideas, is represented in semantic memory, and this appears to be compromised in actions, and ideas, is
semantic variant PPA. The syndrome of semantic variant PPA was first described represented in semantic
memory, and this appears to
by Warrington15 and Snowden and colleagues.16 Clinical research consensus be compromised in semantic
criteria for semantic variant PPA focus on two essential features,17 with reliable variant primary progressive
and widely accepted recognition of this syndrome.5,18,19 One major clinical aphasia.
feature is profound confrontation naming difficulty (CASE 4-1).20,21 Patients
● One major clinical feature
are severely impaired at naming pictured objects or using these words in
of semantic variant primary
spontaneous speech. Analyses of naming errors suggest that patients with progressive aphasia is
semantic variant PPA may substitute the name of a prototype (eg, calling a camel profound confrontation
horse) or a more frequent and familiar object that shares many of the same naming difficulty. Patients
features as the target object (eg, calling a pelican robin).22 They may also are severely impaired at
naming pictured objects or
substitute a more general, superordinate term when a basic level name of a using these words in
specific object is difficult (eg, calling a pelican bird or animal).23,24 Even spontaneous speech. A
superordinate terms become difficult for these patients over time, and the second major clinical
meaningfulness words become increasingly vague as the disease progresses. This feature is impaired
comprehension of
interferes substantially with meaningful communication because all objects single words.
eventually are called that and thing.
A second major clinical feature of semantic variant PPA is impaired ● Since the problem in
comprehension of single words.21 Patients with semantic variant PPA are semantic variant primary
progressive aphasia
impaired at understanding basic object level names, such as camel or pelican.
appears to affect both the
Over time, this may involve difficulty in understanding superordinate terms comprehension and
such as animal, paralleling the difficulty in language expression. Because of these expression of single words,
impairments, patients with semantic variant PPA may also be impaired in the core deficit is thought to
involve semantic memory.
sentence comprehension25 and sentence expression.26
Since the problem in semantic variant PPA appears to affect both
comprehension and the expression of single words, the core deficit is thought
to involve semantic memory.21 One hypothesis is that these patients have a
deficit for all knowledge represented in semantic memory. This is consistent with
Endel Tulving’s proposed theory of human memory, which characterizes
semantic memory as a single amodal system in which all semantic knowledge
is stored.27 Another possibility involves a distributed model of sensorimotor
feature knowledge. This is called the hub-and-spoke model,21 in which most object
concepts consist of several features taken from different modalities. Thus, the

APHASIA
CASE 4-1 A 54-year-old right-handed woman presented because she was having
difficulty at work. She worked as a lawyer, and her supervising partner
told her of increasing complaints from clients about her lack of clear
communication. During phone conversations, she used incorrect or
imprecise words when discussing facts with her clients. Her assistant
also noted that she had difficulty when orally reading and reviewing
certain words in transcripts that she had recently dictated. These
symptoms had progressed over time. More recently, her assistant had
noticed that the patient had some comprehension difficulty as well. She
did not seem to have significant difficulty with memory for recent events,
and she had no problems with driving. She had no symptoms of
elementary neurologic deficits, such as difficulty with strength or
abnormal involuntary movements.
On examination, the patient was alert and fully oriented to person,
place, and time. Her speech was fluent but at times circumlocutory. She
used somewhat imprecise nouns in her speech but made no grammatical
errors. She had significant confrontation naming difficulty (this was most
notable for low-frequency words), and she substituted the names of
more frequent words, such as calling a camel horse and a pelican duck.
Repetition of phrases and sentences was intact. She had difficulty
reading sight vocabulary words, pronouncing choir as chore and dough as
dog. She appeared to make a similar error in a written sentence
describing the weather outside (writing weather as wether). Grammatical
comprehension and expression were preserved. She was able to
demonstrate the use of familiar objects such as a hammer and a saw but
did not know how to demonstrate the use of a scissors. While she had
mild difficulty with verbal memory, her visual memory for recall of a
complex visual geometric design after several minutes was intact. She
had no difficulty with visuospatial tasks, such as copying a complex
geometric design or judging whether two lines were parallel. Executive
functioning was preserved, demonstrated by orally reciting a list of
alternating letters and numbers. The remainder of the neurologic
examination was unremarkable.
COMMENT This patient had semantic variant primary progressive aphasia,

characterized by progressive difficulty with confrontation naming and the
classic substitution of high-frequency prototypes for lower-frequency
targets during naming. She had some difficulty with object comprehension
and surface dyslexia, pronouncing words during oral reading in a manner
that made use of letter-sound correspondence rules. She showed no
evidence of agrammatism or repetition difficulty.
750 JUNE 2018

concept of a camel might involve activation of associated color knowledge, KEY POINTS
activation of shape information associated with the humps of a camel, and
● It appears that patients
activation of general world knowledge that a camel lives in a desert. The pattern with semantic variant
of activation across these independent and distributed reservoirs of knowledge is primary progressive aphasia
then interpreted as camel. From this perspective, it is the coordinating hub, are disproportionately
rather than representations of knowledge, that is compromised in semantic impaired in their ability to
understand and name
variant PPA.
object concepts.
However, mounting evidence exists against a universal semantic memory
deficit in semantic variant PPA. This comes from experimental observations ● Despite their approximate
emphasizing that deficits in semantic variant PPA overwhelmingly involve comprehension of single
object concepts and the associated visual feature knowledge.28 Many patients words, patients with
Wernicke aphasia tend to
with semantic variant PPA, in fact, show the phenomenon of reversal of the have relatively preserved
concreteness effect, in which patients have greater difficulty with concrete objects comprehension of objects.
than with abstract concepts.15,29–32 Relative deficits with concrete object concepts
compared to abstract concepts have been found in large series of patients with ● Patients with Wernicke
aphasia typically have
semantic variant PPA, both in comprehension using word stimuli and in difficulty with repetition,
narrative expression.24,33–35 For example, the vocabulary of patients with whereas this is rarely
semantic variant PPA loses high-imageability words and consists of significantly evident in semantic variant
more abstract words.24,34,35 Patients with semantic variant PPA also appear to primary progressive aphasia
until the patient becomes
have relatively preserved appreciation of musical meaning,36 although others
quite impaired.
have noted difficulty with musical knowledge in music-picture matching tasks.37
Finally, patients with semantic variant PPA appear to have relatively preserved ● Patients with Wernicke
knowledge of number concepts38–40 and the class of words that includes concepts aphasia have relatively
such as most, less than half, and few (known as quantifiers),41,42 although others preserved oral reading,
whereas semantic variant
have also noted difficulty with number knowledge in patients with semantic primary progressive aphasia
variant PPA who are very impaired.43 In sum, it appears that patients with is associated with a specific
semantic variant PPA are disproportionately impaired in their ability to disorder of reading known
understand and name object concepts. as surface dyslexia.
This pattern of impairment in semantic variant PPA differs in some notable
ways from patients with the fluent stroke aphasia called Wernicke aphasia.
Patients with Wernicke aphasia also have fluent speech with considerable
confrontation naming difficulty. While this form of stroke aphasia is notable for
difficulty with both comprehension and expression, the deficit seems to be
largely restricted to words. Content words, such as nouns and verbs, are very
difficult for these patients; thus, their speech contains many nonspecific words
such as this and is often empty of content. Word comprehension in Wernicke
aphasia can be approximate for all types of words, but unlike semantic variant
PPA, there is little evidence that patients with Wernicke aphasia have relative
difficulty understanding or expressing a particular category of knowledge,
such as concrete object concepts. Thus, although they cannot access the
name of the clear container used to hold water, patients with Wernicke
aphasia rarely have difficulty knowing that a glass is a container from which
one drinks water. Despite their approximate comprehension of single
words, these patients tend to have relatively preserved comprehension
of objects.
Second, patients with Wernicke aphasia typically have difficulty with
repetition, whereas this is rarely evident in semantic variant PPA until the patient
becomes quite impaired. This has been attributed to the fact that the bundle of
fibers critical for repetition (known as the arcuate fasciculus) is compromised in
Wernicke aphasia but not in semantic variant PPA.

APHASIA
Third, patients with Wernicke aphasia have relatively preserved oral reading,
whereas semantic variant PPA is associated with a specific disorder of reading
known as surface dyslexia.21 In this condition, letter-sound correspondence rules
are preserved but sight vocabulary is lost, resulting in mispronunciation of sight
vocabulary words through the use of letter-sound correspondence rules. The
word choir may be pronounced as chore and dough may be pronounced as dog.
Nevertheless, patients with Wernicke aphasia may have difficulty understanding
what they are reading.
Anatomic Features
Semantic variant PPA has a distinctive anatomic distribution of disease. Imaging
studies associate semantic variant PPA with atrophy of left anterior and ventral
gray matter regions of the temporal lobe as well as the anterior hippocampus
and the amygdala.44,45 Changes are also seen in the white matter projections
from this area to other brain regions, including the middle longitudinal
fasciculus, inferior longitudinal fasciculus, and uncinate fasciculus.46,47 Using
a functional imaging technique known as arterial spin labeling, it appears that
the disease progresses over time from areas of established disease in the
anterior temporal lobe to adjacent regions.48 Longitudinal imaging shows
atrophy extending posteriorly and superiorly into the gray matter of the
ipsilateral temporal lobe and dorsally into the insula and the ventral frontal lobe.
While disease associated with semantic variant PPA may begin in the left
hemisphere, pathology often spreads to involve the contralateral temporal
lobe.48,49 Some investigators emphasize the role of the left anterior temporal lobe
in the semantic memory deficit of patients with semantic variant PPA,50 but
functional anatomy studies also implicate atrophic homologous regions of
the right hemisphere.51,52 Right anterior temporal lobe disease in FTLD is
associated with behavioral abnormalities and the behavioral variant of
frontotemporal dementia (bvFTD) syndrome.53 The features most commonly
seen are ritualistic and obsessive behaviors. Patients with semantic variant
PPA very often develop additional right temporal and frontal disease along
with a social disorder clinically consistent with bvFTD during the natural
history of disease. Because these behavioral features are so common in
semantic variant PPA, the authors do not view the presence of behavioral
features as a criterion for excluding a patient from the diagnosis of semantic
variant PPA.
Imaging studies have related difficulty with semantically mediated tasks
directly to left anterior and ventral temporal gray matter disease in semantic
variant PPA.28,33,34,54–56 A critical feature of the semantic deficit in semantic
variant PPA is difficulty with object concepts that depend on visual feature
knowledge. Disease in ventral regions of the anterior temporal lobe encompasses
the visual association cortex.57,58 This structure has been linked with high-level
aspects of visual perception,59 mental imagery,60 and high-level visual-object
representation.61 There is a functional anatomic gradient through the visual
processing stream. Processing of elementary visual-perceptual features such as
color and shape occurs in posterior regions of the temporal lobe, and the
association of visual-perceptual features with semantic value occurs in more
anterior portions of the visual stream, including the anterior fusiform and
parahippocampal gyri. Difficulty with the meaning of words and pictures of
objects that depend on visual feature knowledge is directly associated with
752 JUNE 2018

disease in the anterior fusiform gyrus55 and the adjacent parahippocampal KEY POINTS
gyrus28,33,34,56 in anterior portions of the ventral temporal lobe.
● Surface dyslexia refers to
These findings are consistent, in part, with a sensorimotor approach to difficulty reading sight
semantic memory, also known as embodied cognition, in which the neural vocabulary words. Patients
representation of knowledge in semantic memory is linked to areas of the brain with surface dyslexia
that are important for sensorimotor processing.62,63 In semantic variant PPA, this instead use their
preserved letter-sound
is focused on the representation of visual feature knowledge that is crucial for
correspondence rules to
representing the meaning of object concepts. Other examples of relating sound out sight words, for
sensorimotor features to concepts include activation of the motor cortex for example, reading dough
actions involving specific body parts,64 the auditory association cortex for as dog.
auditory feature knowledge,65 the gustatory cortex for appetizing foods,66 and
● Imaging studies associate
the olfactory cortex for feature knowledge associated with smell.67 semantic variant primary
Patients with semantic variant PPA also have white matter disease. This progressive aphasia with
includes reduced fractional anisotropy in white matter projections of the atrophy of left anterior and
anterior temporal lobe.46,47,49 Connectivity with other brain regions becomes ventral gray matter regions
of the temporal lobe as well
compromised over time,46,48,49 and this, too, may contribute to a semantic as the anterior hippocampus
memory deficit in semantic variant PPA. These observations emphasize that the and the amygdala.
semantic memory deficit in semantic variant PPA is due, in part, to the disruption
of a large-scale neural network involving multiple gray matter regions and white ● Right anterior temporal
lobe disease in
matter projections.68
frontotemporal lobar
Patients with semantic variant PPA frequently have pathology that is degeneration is associated
associated with the accumulation of transactive response DNA-binding protein with behavioral
43 (TDP-43), an RNA-binding protein that functions normally in the nucleus to abnormalities and the
behavioral variant
help regulate DNA and RNA processing.20,69,70 Patients with semantic variant
frontotemporal dementia
PPA with TDP-43 pathology often have additional right anterior temporal syndrome, and patients with
TDP-43 pathology along with a social disorder clinically consistent with bvFTD. semantic variant primary
Although up to 40% of all forms of FTLD have a family history and roughly 20% progressive aphasia often
have a pathogenic mutation in the main genes associated with FTLD-TDP (ie, develop additional right
temporal (and frontal)
progranulin [GRN] or C9orf72) or FTLD-tau tauopathies (MAPT),71 the form disease along with a social
of FTLD-TDP found in association with semantic variant PPA is most often disorder clinically
sporadic, without a strong family history or pathogenic mutation.72 Less consistent with behavioral
common neurodegenerative pathologies associated with semantic variant PPA variant frontotemporal
dementia during the natural
include Pick disease and AD pathology.12 history of disease.
Other causes of a pattern of semantic memory difficulty resembling semantic
variant PPA may also be encountered, such as herpes encephalitis,50,73,74 but ● Imaging studies have
these are often subacute in onset and do not have the slow evolution of semantic related difficulty with
semantically mediated tasks
variant PPA. Some forms of closed head trauma may resemble semantic
directly to left anterior and
variant PPA, but these are easily distinguished by their sudden onset and ventral temporal gray matter
nonprogressive course. disease in semantic variant
Many of the language features that distinguish Wernicke aphasia from primary progressive aphasia.
semantic variant PPA result because these two conditions affect different areas of
● Patients with semantic
the left hemisphere. In contrast to the anterior and ventral temporal anatomic variant primary progressive
distribution of disease in semantic variant PPA, more posterior and superior aphasia frequently have
areas of the temporal lobe are compromised in Wernicke aphasia. This tends to pathology that is associated
be associated with the portion of the comprehension network important for with the accumulation of
transactive response
lexical access, and disease in this area particularly compromises lexical DNA-binding protein 43, an
comprehension and lexical retrieval.75,76 Since the visual association network is RNA-binding protein that
relatively intact in Wernicke aphasia, object comprehension is correspondingly functions normally in the
well preserved. The repetition deficit found in Wernicke aphasia (but not in nucleus to help regulate
DNA and RNA processing.
semantic variant PPA) is also related to the anatomic distribution of disease.

APHASIA
KEY POINTS Thus, Wernicke aphasia (but not semantic variant PPA) includes insult to the
arcuate fasciculus. This fiber tract is critical for repetition and projects between
● Semantic memory
difficulty resembling
the posterior-superior temporal lobe and the inferior frontal lobe.
semantic variant primary
progressive aphasia due to NONFLUENT APHASIAS
other causes may be The nonfluent aphasias include nonfluent/agrammatic PPA and Broca aphasia.
encountered, such as in
The major clinical feature shared by these aphasic syndromes is the
herpes encephalitis, but
these are often subacute in characteristically effortful and slowed speech. However, these syndromes also
onset and do not have the differ in some subtle but important ways.
slow evolution of semantic
variant primary progressive
Clinical Features
aphasia. Some forms of
closed head trauma may The clinical hallmark of nonfluent/agrammatic PPA is slowed, effortful, nonfluent
resemble semantic variant speech. The effortful nature of speech in PPA was first described by Mesulam3 as
primary progressive aphasia, slowly progressive aphasia. The linguistic characteristics of this disorder were
but these are easily described several years later with the designation progressive nonfluent aphasia.77
distinguished by their
sudden onset and While effortful speech has long been recognized clinically,77,78 quantification of
nonprogressive course. slowed speech rate has only been documented more recently.79–81 Speech is
produced by patients with nonfluent/agrammatic PPA at an average rate of
● In contrast to the anterior about 45 words per minute. By comparison, the speech rate is about 140 words
and ventral temporal
anatomic distribution of
per minute in healthy age-matched adults and about 90 words per minute in
disease in semantic variant other PPA syndromes. While patients with nonfluent/agrammatic PPA have
primary progressive aphasia, many lengthy pauses in their effortful speech, speech remains significantly
more posterior and superior slowed even when pauses of more than 2 seconds in duration are taken
areas of the temporal lobe
into consideration.82
are compromised in
Wernicke aphasia. The rate of speech in these patients appears to be more acceptable when
producing overlearned sequences, such as counting or reciting the alphabet.
● The clinical hallmark of Careful analyses have allowed investigators to test several hypotheses about the
nonfluent/agrammatic basis for the slowed, effortful speech found in nonfluent/agrammatic PPA. One
primary progressive aphasia
is slowed, effortful, essential characteristic of nonfluent/agrammatic PPA speech is its impoverished
nonfluent speech. grammatical features (CASE 4-2).79–81 Grammatical deficits in speech are highly
correlated with effortfulness and slowed words per minute. In semistructured
● One essential speech samples that involve describing a single picture26 or a lengthier, wordless
characteristic of speech in
nonfluent/agrammatic
picture story,79,82 analyses reveal that the variety of grammatical forms is
primary progressive aphasia impoverished, and grammatical forms are simplified with fewer utterances
is its impoverished containing features such as a subordinate clause or the passive voice.
grammatical features. Grammatical simplifications also result in a shortened mean length of utterance
(fewer words per statement). When syntactic features are produced, they are
● It is important to
distinguish the nonfluent more likely to contain errors. Grammatical morphemes may be omitted, including
speech associated with the inflections such as the past tense ending -ed and freestanding morphemes such
grammatical simplifications as was and articles such as a. Inappropriate grammatical inflections may also be
and errors seen in used. It is important to distinguish the nonfluent speech associated with the
primary progressive aphasia grammatical simplifications and errors seen in nonfluent/agrammatic PPA from
from the pattern of reduced the pattern of reduced speech output seen in fluent forms of aphasia in which
speech output seen in fluent searching for words can slow speech output in the absence of grammatical deficits.
forms of aphasia, in which Some patients with nonfluent/agrammatic PPA appear to have a motor
searching for words can
slow speech output in the
disorder that may contribute to their effortful speech. Patients with an
absence of grammatical extrapyramidal disorder, such as progressive supranuclear palsy or corticobasal
deficits. syndrome, have poor control of the motor apparatus, and this can affect their
speech just as it affects the use of their hands for motor tasks and compromises
their gait.83 This is known as apraxia of speech. The combination of these
754 JUNE 2018

linguistic and speech characteristics has led to clinical research consensus criteria
for the syndrome known as nonfluent/agrammatic PPA,17 which has reliable
and widely accepted recognition.5,18,19
Apraxia of speech involves impaired coordination and planning of the motor
articulators. Clinical characteristics of apraxia of speech include the production
of incorrect speech sounds and sequences of sounds that do not occur in the
speaker’s native language, groping for the correct sound although not necessarily
producing the intended target after several attempts, and oddly placed pauses
in the speech stream. These speech disorders occur independently of oral apraxia
or the demonstration of nonlinguistic oral gestures such as blowing out a match.
However, the association between apraxia of speech and oral apraxia is
inconsistent. While these clinical features of nonfluent/agrammatic PPA have
A 62-year-old right-handed man reported progressive difficulty with his CASE 4-2
speech. He was a smartphone salesman and was experiencing increasing
difficulty expressing himself during sales to clients. His speech had
become progressively slowed, although he typically used the correct
words. At times, he sounded like an old-fashioned telegram.
Comprehension otherwise was preserved. Recently, he had begun to
experience falls when walking, and these did not appear to be associated
with tripping or weakness. He also reported occasional double vision.
On examination, he was alert and fully oriented. His speech was
slowed and effortful. He made no speech sound errors, including no
speech sounds not heard in English, and had no unusual locations of
pauses in his speech. He omitted small grammatical morphemes, such as
was and the, and did not inflect verbs for past tense. His writing and oral
reading similarly omitted small grammatical morphemes, but the content
otherwise seemed preserved. He was able to repeat phrases and
sentences. His comprehension of single words, objects, and
grammatically simple sentences seemed good. However, he had some
difficulty when required to demonstrate understanding of sentences that
depended on grammatical information (eg, “Point to the window after
you point to the door”). Memory and visuospatial processing seemed
preserved. He was slow at performing measures of executive functioning.
The remainder of the neurologic examination was significant for difficulty
with the fast phase of ocular movements in an assessment of
opticokinetic nystagmus and some mild neck rigidity.
This patient had nonfluent/agrammatic primary progressive aphasia. He COMMENT

had agrammatic speech and comparable changes in writing and oral
reading. Comprehension of single words and grammatically simple
sentences was preserved, but he had difficulty with grammatical
comprehension. Repetition was also preserved. He had mild difficulty with
executive functioning, although he did well in other aspects of cognitive
functioning. He had experienced falls and had mild difficulty with saccades
in the vertical axis, raising a question of progressive supranuclear palsy.

APHASIA
been incorporated into diagnostic criteria for progressive supranuclear palsy and
corticobasal syndrome,84–86 apraxia of speech can occur without any other
observable motor disorder.10,87
It is crucial to quantify apractic speech disorders objectively so that these
observations can be reproduced reliably in other laboratories. In one attempt to
quantify speech errors consistent with apraxia of speech in nonfluent/agrammatic
PPA, phonetic errors involving misarticulated speech sounds that are not
part of the English speech sound system were used as markers of misplaced
articulators related to an impaired motor coordination system.88 Patients with
nonfluent/agrammatic PPA were found to produce significantly more speech
errors than controls, consistent with other observations.84,87 However, only 21%
of speech errors in nonfluent/agrammatic PPA could be attributed to a motor
speech planning disorder because they were distortions that are not part of the
English speech sound system. In another study, duration of syllable production
was lengthened and stress of initial versus subsequent syllable was disordered in
apraxia of speech compared to controls and other PPA patient groups.89 Two
classes of speech sound errors have been identified by some authors: one consists
of speech sound errors, distortions, and substitutions and the second consists
of syllabically segmented prosodic speech patterns. The former type of error
was said to be seen more commonly in nonfluent/agrammatic PPA, while the
latter was found in individuals with isolated apraxia of speech.90
Patients with nonfluent/agrammatic PPA also are impaired in their oral
grammatical comprehension.5,77 Likewise, they exhibit grammatical errors in
their reading comprehension of written material and their writing. This provides
additional evidence that the effortful speech in nonfluent/agrammatic PPA is not
determined entirely by an apractic motor disorder. In a sentence such as “Boys
that girls hug are friendly,” for example, patients with nonfluent/agrammatic
PPA often err when asked “Who did the hugging?”91 These patients also have
difficulty pointing to one of two pictures based on a sentence in which selecting
the correct picture depends on appreciating the sentence’s grammatical
structure.25,92 Another study used an anagram task (ordering of cards with
printed words into a sentence) to show that patients with nonfluent/agrammatic
aphasia have difficulty ordering words printed on cards into a grammatically
complex question about a picture.93 Grammatical difficulties such as these may
help distinguish nonfluent/agrammatic PPA from other PPA variants.5,25,91
However, care must be taken since comprehension of center-embedded
subordinate clause constructions and complex anagram tasks are impaired
across all PPA variants: Sentences such as “The dog with white fur that the cat
chased is friendly” are lengthy and involve multiple propositions, and anagram
tasks involve planning and organizing. Thus, difficulty with these tasks may be
sensitive for nonfluent/agrammatic PPA, but they appear to be less specific. This
may be, in part, because they are vulnerable to processing resource limitations.
One example is limited working memory that may be needed to temporarily
retain a lengthy, complex sentence until its message can be interpreted by
manipulating many propositions. Likewise, substantial executive resources
underlying planning and organizing are needed for an anagram task. Patients
with nonfluent/agrammatic PPA have some working memory and executive
deficits on nonlinguistic measures, such as reverse digit span and category
naming fluency.94,95 Thus, deficits in working memory and executive
functioning may confound the ability to detect a grammatical impairment.
756 JUNE 2018

Cleft grammatical sentences, such as “It was the eagle that the hawk chased,” KEY POINTS
are more likely to be selectively impaired in nonfluent/agrammatic PPA and
● Apraxia of speech
are not significantly impaired in other patient groups because they contain only involves impaired
two propositions and are not too lengthy.25 It does not appear that nonspecific coordination and planning of
cognitive difficulty contributes substantially to comprehension impairments, the motor articulators.
as a correlation between nonspecific measures of dementia such as the Clinical characteristics of
apraxia of speech include
Mini-Mental State Examination (MMSE) and comprehension performance is
the production of incorrect
typically not found in nonfluent/agrammatic PPA. Finally, it should be speech sounds and
emphasized that nonfluent/agrammatic PPA is a progressive disorder of sequences of sounds that do
language, and several studies have shown progressive decline of grammatical not occur in the speaker’s
native language, groping for
comprehension.96,97
the correct sound although
Patients with Broca aphasia due to stroke have been shown to have slowed, not necessarily producing
effortful speech.98 A disorder of grammatical expression and grammatical the intended target after
comprehension is seen, although the precise basis for this deficit remains to be several attempts, and oddly
discovered.99 A disorder of prosody is also seen, with distortion or absence of the placed pauses in the
speech stream.
typical declination of pitch found in statements and distortion or absence of
the terminal rise in pitch for a yes/no question. Thus, considerable overlap exists ● Patients with
in the language and speech characteristics of patients with Broca aphasia and nonfluent/agrammatic
patients with nonfluent/agrammatic PPA. primary progressive aphasia
are impaired in their oral
However, some features appear to distinguish Broca aphasia from grammatical
nonfluent/agrammatic PPA. For example, nonfluent/agrammatic PPA may comprehension.
include apraxia of speech, while this appears to occur much less often in Broca
aphasia. An impairment of repetition is less common in nonfluent/agrammatic ● Patients with
PPA, while Broca aphasia is often associated with impaired repetition. Indeed, a
qualitative analysis of the repetition deficit in Broca aphasia often reveals have some working memory
grammatical errors. Patients with nonfluent/agrammatic PPA also appear to be and executive deficits on
more vulnerable to anagram tasks and the executive resource demands of nonlinguistic measures, such
sentences with many propositions. as reverse digit span and
category naming fluency.
Anatomic Features ● Patients with Broca

Extensive imaging evidence suggests that a clinical marker for nonfluent/agrammatic aphasia have slowed,
PPA is focal disease centered in the left frontal lobe. Structural MRI studies effortful speech.
emphasize gray matter atrophy in the inferior frontal region of the left
● Nonfluent/agrammatic
hemisphere.45,77,91,100 This typically extends beyond the pars opercularis and primary progressive aphasia
pars triangularis (regions in the inferior frontal lobe colloquially known as the may include apraxia of
Broca area) to involve the frontal operculum and anterior insula, left prefrontal speech, while this appears
to occur much less often in
regions that are more dorsal and anterior, and superior portions of the left
Broca aphasia. An
anterior temporal lobe.79,81 Functional imaging techniques such as PET confirm impairment of repetition is
structural imaging observations. PET also shows deficits in the left inferior less common in
frontal lobe, including the frontal operculum and the anterior insula, as well as nonfluent/agrammatic
the anterior-superior temporal lobe.77,101 Gray matter atrophy and reduced PET primary progressive aphasia,
while Broca aphasia is often
glucose metabolism is said to be centered in the superior lateral premotor cortex associated with impaired
and supplementary motor area. Associated white matter disease involves repetition.
premotor components of the superior longitudinal fasciculus and extends into
the body of the corpus callosum.85
Regression analyses have been used to link the slowed effortful characteristic
of speech in nonfluent/agrammatic PPA directly to these left frontal regions.79–81
Grammatical simplifications observed in semistructured speech samples have
been related to gray matter atrophy in inferior frontal and anterior-superior
temporal regions of the left hemisphere.79–81 Motor speech abnormalities in

APHASIA
patients with movement disorders such as progressive supranuclear palsy are

associated with atrophy of deep gray matter structures, such as the striatum and
supplementary motor areas involved in motor planning.86
Sentence comprehension appears to be related to regional gray matter atrophy
in nonfluent/agrammatic PPA as well. In a study of simple, dichotomous
(yes/no) probes of simpler and more complex sentences, impaired grammatical
comprehension was associated with the posterior-inferior frontal and
anterior-superior temporal regions of the left hemisphere.91 In a two-alternative,
forced-choice, sentence-picture matching task, comprehension of grammatically
complex sentences in nonfluent/agrammatic PPA was related to left inferior
frontal and anterior-superior temporal gray matter atrophy.25 Grammatical
comprehension was related to left inferior frontal atrophy in a heterogeneous
group of patients with progressive aphasias that included individuals with
nonfluent/agrammatic PPA.92
It is important to point out that neurodegenerative disease, such as that found
in nonfluent/agrammatic PPA, interrupts large-scale neural networks; this is
emphasized by the white matter disease that is also found in nonfluent/agrammatic
PPA. This disease implicates pathways containing reciprocal projections involving
the left inferior frontal lobe. Interrupted pathways important for language and
speech include the anterior corpus callosum, which integrates left and right inferior
frontal regions; the arcuate/superior longitudinal fasciculus complex, which
constitutes the so-called dorsal stream projecting between frontal and
posterior-superior temporal regions; and the inferior frontooccipital fasciculus and
the inferior longitudinal fasciculus, which are part of the so-called ventral stream
between frontal and posterior temporal regions.102–105 White matter disease in
nonfluent/agrammatic PPA also appears to involve the uncinate fasciculus, which
contains projections between the inferior frontal lobe and the anterior temporal
lobe. This is consistent with observations of patients with autopsy-confirmed
nonfluent/agrammatic PPA, who have imaging evidence of white matter
disease in the superior longitudinal fasciculus, inferior frontooccipital fasciculus,
and uncinate fasciculus.103,106
Regression analyses have linked large-scale networks of disturbed anatomy
directly to language deficits in nonfluent/agrammatic PPA. Three gray
matter-white matter networks for language expression have been identified.106
In the first network, disease in the left inferior frontal cortex and white matter
disease in the anterior corpus callosum projections to the right inferior frontal
lobe appear to be related to slowed, effortful speech rate. Speech errors may
also be related to this network. In a second network, the left frontal lobe
and tracts in the arcuate/superior longitudinal fasciculus project to posterior
perisylvian cortical regions (the so-called dorsal stream), and this is disrupted
by white matter disease in nonfluent/agrammatic PPA. The dorsal stream is
thought to mediate, in part, long-distance syntactic dependencies in
sentences,107 and disease in this network may contribute to deficits in
sentence-level grammatical expression and comprehension in nonfluent/
agrammatic PPA. The third large-scale neural network that is disrupted in
nonfluent/agrammatic PPA includes the left inferior frontal lobe and the
inferior frontooccipital fasciculus projecting through the external capsule to
posterior-superior temporal regions. This is the so-called ventral stream, which
may support lexical representations important for grammatical processing, such
as the major grammatical category of words.108 Interruption of this network by
758 JUNE 2018

white matter disease in the left inferior frontal lobe and the left inferior KEY POINTS
frontooccipital fasciculus is associated with difficulty in understanding
● Structural MRI studies
grammatically complex sentences.25 emphasize gray matter
Functional MRI (fMRI) has also been used to assess the neuroanatomic atrophy in the inferior
basis for grammatical processing in nonfluent/agrammatic PPA. In one study, frontal region of the
patients with nonfluent/agrammatic PPA did not appear to recruit the left inferior left hemisphere in
frontal cortex during comprehension of grammatically complex sentences,
primary progressive aphasia.
although they recruited dorsal portions of the left frontal lobe associated with
working memory and left posterior-superior temporal regions associated with ● Sentence comprehension
comprehension of nongrammatical language material.109 Another fMRI study appears to be related to
showed greater left inferior frontal activation during grammatically complex regional gray matter atrophy
in left inferior and
sentences compared to simple sentences in controls, while patients with dorsolateral prefrontal
nonfluent/agrammatic PPA did not show a difference in left inferior frontal regions in nonfluent/
activation between these two types of sentences.92 In a 2016 study, activation of an agrammatic primary
extensive left hemisphere language network was disrupted in patients with progressive aphasia.
grammatical comprehension difficulty due to nonfluent/agrammatic PPA.110 ● Neurodegenerative
Thus, language deficits in nonfluent/agrammatic PPA appear to be attributable, in disease, such as that found
part, to interruption of large-scale neural networks centered in left perisylvian in nonfluent/agrammatic
regions that support language processing. primary progressive aphasia,
interrupts large-scale neural
Nonfluent/agrammatic PPA is most often associated with forms of FTLD
networks; this is
involving the accumulation of the microtubule-associated protein tau (FTLD-tau), emphasized by the disease
as seen at autopsy.10,12–14 Less commonly, AD pathology or FTLD-TDP can found in white matter
present with language features consistent with nonfluent/agrammatic PPA.12 projections between the
gray matter areas of the
Nonfluent/agrammatic PPA with TDP-43 pathology may be associated with
language network in
GRN mutations,111–113 while C9orf72 mutations are rarely associated with any nonfluent/agrammatic
form of PPA.114 primary progressive aphasia.
Broca aphasia due to stroke is often associated with ischemia centered in the left
inferior frontal lobe.115,116 The ischemic area typically extends into more dorsal ● Nonfluent/agrammatic
regions of the frontal lobe as well as the anterior superior temporal lobe and into is most often associated
the white matter deep in the frontal lobe. In addition to effortful, agrammatic with forms of
speech, this type of lesion is also associated with impairment of grammatical frontotemporal lobar
comprehension.117 Thus, considerable overlap exists between the progressive and degeneration involving the
accumulation of the
stroke forms of nonfluent aphasia associated with left anterior perisylvian disease. microtubule-associated
The impairment of repetition found in Broca aphasia more often than protein tau, as seen
nonfluent/agrammatic PPA has been attributed to ischemia that also involves the at autopsy.
arcuate fasciculus. Smaller ischemic lesions restricted to the frontal operculum
● Broca aphasia due to
tend to manifest clinically as aphemia. This is a disorder of slowed speech
stroke is often associated
expression but without the sound distortions found in apraxia of speech, and with ischemia centered in
aphemia is associated with minimal comprehension difficulty.116 the left inferior frontal lobe.
APHASIAS WITH MIXED FLUENCY

Aphasias with mixed fluency include logopenic variant PPA and conduction
aphasia. These syndromes hold in common variable rates of speech fluency
because speech rate depends on the content of speech.
Clinical Features
With the increased clinical recognition of PPA, it has become clear that many
patients have a language disturbance that does not clearly fit into the category of
either nonfluent/agrammatic PPA or semantic variant PPA. Patients with periods
of slowed, hesitant speech due to prominent lexical retrieval difficulties in

APHASIA
conversational speech (ie, “logopenia”) and phonologic loop disturbance were

first described by Gorno-Tempini and colleagues.45,118 Lexical retrieval difficulty
is ubiquitous to some extent in all variants of PPA. However, the distinguishing
feature of the logopenic variant of PPA appears to be the disturbance of the
phonologic loop. The phonologic loop is a component of auditory-verbal
short-term memory that contributes to the processing of verbally coded
information, such as a lengthy sentence.119 Thus, the hallmark of logopenic
variant PPA is impaired repetition. The current clinical criteria for logopenic
variant PPA include core elements of lexical retrieval difficulties in spontaneous
speech and impaired repetition, with supportive features of phonologic
paraphasic errors or speech-sound substitutions and the absence of motor
speech and single-word/object comprehension difficulties.17
Some refer to logopenic variant PPA as “mixed,” because many of these
patients have some language features that can resemble both nonfluent/agrammatic
PPA and semantic variant PPA.120 Patients with logopenic variant PPA resemble
patients with nonfluent/agrammatic PPA in that they may also have at times
slowed, hesitant speech because of circumlocutions and lexical retrieval
difficulties. However, the average quantitative rate of speech production is about
90 words per minute, or about twice the rate of nonfluent/agrammatic PPA.26
Grammatical expression and comprehension can be limited for lengthy sentences
because of the short-term memory deficit, although these patients tend to have
better comprehension for shorter sentences and written material that does not
depend on short-term memory.25,118 Moreover, a relative absence of motor
speech difficulties is seen in logopenic variant PPA as compared to
nonfluent/agrammatic PPA.
Patients with logopenic variant PPA may also superficially resemble patients
with semantic variant PPA because of some overlapping characteristics. The
often-severe word-finding difficulty with circumlocutory speech in logopenic
variant PPA may be difficult to distinguish from the single-word expression
difficulties found in semantic variant PPA. Patients with logopenic variant
PPA may also demonstrate some word comprehension difficulty similar to what
is seen in semantic variant PPA. However, successful responses following
prompts (eg, “it is used for cutting; it’s a wood…”) or gestures demonstrated
by the patient with logopenic variant PPA during confrontation naming (eg,
demonstrating a cutting motion for the use of a saw despite the inability to
retrieve the word saw) distinguish these patients from patients with semantic
variant PPA. Likewise, patients with logopenic variant PPA have preserved
knowledge of objects.
Patients with conduction aphasia following stroke resemble those with
logopenic variant PPA. The key feature of conduction aphasia is a profound
repetition deficit.121,122 Qualitative analysis of repetition errors reveals that
some patients have grammatical errors in their repetition, while others may
have limited repetition based solely on length. Patients with conduction aphasia
may also have some word-finding difficulty, occasionally display circumlocutory
speech, and have mild comprehension limitations for lengthy sentences.
Patients with conduction aphasia also often display some ideomotor apraxia.
Anatomic Features
The phonologic loop, the component of auditory-verbal short-term memory
responsible for the processing of verbally coded information, is often associated
760 JUNE 2018

with inferior parietal and superior temporal regions.119 MRI studies show KEY POINTS
that patients with logopenic variant PPA have atrophy in the inferior parietal
● The current clinical
and superior temporal lobes.45,123 Studies using in vivo PET imaging of criteria for logopenic variant
amyloid pathology find a high rate of AD pathology in these patients.124,125 primary progressive aphasia
Since being introduced into modern clinical criteria for PPA, the diagnostic include core elements of
criteria for logopenic variant PPA have been examined in autopsy cohorts.113,126 lexical retrieval difficulties
in spontaneous speech and
Published logopenic variant PPA diagnostic criteria are relatively specific for
impaired repetition, with
underlying AD pathology but are less sensitive since many patients with PPA supportive features of
with AD pathology do not meet criteria for logopenic variant PPA because of phonologic paraphasic
either the absence of the core clinical criterion of difficulty in repetition or the errors or speech-sound
substitutions and the
presence of additional motor speech or semantic features. Indeed, the current
absence of motor speech
criteria for logopenic variant PPA are largely unreliable,5,18,19 as lexical retrieval difficulties and
difficulty is common for all forms of PPA and other supporting features of single-word/object
logopenic variant PPA are largely based on the absence of core features of comprehension difficulties.
nonfluent/agrammatic PPA and semantic variant PPA rather than the presence
● Patients with logopenic
of specific features of language. Furthermore, it has been challenging to variant primary progressive
implement an operational definition of impaired repetition using traditional aphasia resemble patients
measures. Phonologic loop impairment results in length-dependent repetition with nonfluent/agrammatic
difficulty in which increasing difficulty is encountered with multisyllabic primary progressive aphasia
in that they may also have
words or increased length of phrases.118 Data from the authors’ autopsy series slowed, hesitant speech
associated AD pathology with reduced performance on a quantitative measure of because of circumlocutions
phonologic loop functioning (forward digit span [ie, repeating a short list of and lexical retrieval
numbers]), and this impairment was related to pathology in superior temporal difficulties that can
superficially resemble
and inferior parietal regions that are more commonly diseased in AD than in
forms of FTLD.111 Finally, some patients with PPA without prominent primary progressive aphasia.
phonologic loop dysfunction instead display mixed features of single-word However, the quantitative
and object comprehension difficulties and expressive speech disturbance that are rate of speech production is
about 90 words per minute,
not classifiable.113 The underlying neuropathology of these patients with mixed
or about twice the rate of
PPA is varied and includes AD, FTLD-tau, and FTLD-TDP. nonfluent/agrammatic
Conduction aphasia following stroke, from the classic connectionist primary progressive aphasia.
perspective, is associated with damage to the arcuate fasciculus, the white matter
that carries projections between the inferior parietal and superior temporal ● The often-severe
word-finding difficulty with
region known as the Wernicke area and the inferior frontal region known as the circumlocutory speech in
Broca area.122,127,128 This fiber bundle is thought to be crucial in the lateralization logopenic variant primary
of language since it is much thicker in the left hemisphere than the right progressive aphasia may be
hemisphere.129 However, others have argued instead that repetition deficits difficult to distinguish from
the single-word expression
are due in part to a limitation in auditory-verbal short-term memory,119,130 difficulties found in
and this difficulty is associated with disease in the inferior parietal lobule.131 semantic variant primary
progressive aphasia.
INTERVENTIONS
Traditional speech therapies are often recommended; these are symptomatic
interventions. Some interventions involve attempts to improve the underlying aphasia have preserved
speech and language difficulty. While few large-scale well-designed (ie, knowledge of objects.
placebo-controlled) trials have been conducted, interventions involving traditional
speech therapies do not appear to be very successful. Some smaller experimental ● The key feature of
conduction aphasia is a
studies targeting specific aspects of comprehension or expression have shown profound repetition deficit.
some success, but larger cohorts are needed to demonstrate reliable efficacy.
Another class of speech therapy involves training in alternate modes of
communication. These focus on the underlying purpose (communicating a
message to others) and are less concerned with oral speech production or aural

APHASIA
KEY POINTS comprehension.132 Examples of alternative communication modalities include

the use of picture dictionaries and gestures instead of word use. Recently, speech
therapies have been augmented by the use of transcranial direct current
aphasia have atrophy in the stimulation. While this remains highly experimental, some success has been
inferior parietal and achieved in single-blind, crossover trials.133–138
posterior temporal lobes.
● Studies using in vivo

positron emission CONCLUSION
tomography imaging of Progressive aphasia and stroke aphasia result in relatively discrete disorders
amyloid pathology find a
high rate of Alzheimer of language. Both fluent and nonfluent forms of aphasia exist that are
disease pathology in progressive or associated with an acute stroke. Semantic variant PPA is a
patients with logopenic fluent form of PPA that interferes with word meaning and object knowledge
variant primary progressive and thus also interferes with lexical retrieval. Wernicke aphasia, while a fluent
aphasia.
form of aphasia, is largely limited to difficulty with comprehension and
● Logopenic variant primary expression of content words; object knowledge is relatively preserved.
progressive aphasia Distinctions between progressive and stroke forms of fluent aphasia may be
diagnostic criteria are due, in part, to the anatomic locus of disease. The aphasia syndrome associated
relatively specific for
with semantic variant PPA is centered in anterior and ventral portions of the
underlying Alzheimer
disease pathology but are left temporal lobe, while Wernicke aphasia follows stroke to the posterior
less sensitive since many perisylvian regions of the left hemisphere.
patients with primary The nonfluent forms of progressive and stroke aphasia tend to have more
progressive aphasia with
overlap in the locus of disease, and thus the syndromes associated with these
Alzheimer disease
pathology do not meet nonfluent aphasias tend to be more similar. Nonfluent/agrammatic PPA
criteria for logopenic variant compromises the ability to understand and express the grammatical characteristics
primary progressive aphasia of language. These are needed to link together the words composing a sentence.
because of either the Without these structural features of a sentence, speech tends to be slow and
absence of core clinical
criteria of difficulty in effortful, and comprehension and expression of grammatically complex sentences
repetition or the presence of is compromised. Apraxia of speech is more common in nonfluent/agrammatic
additional motor speech or PPA than in Broca aphasia.
semantic features. Logopenic variant PPA is a syndrome of impaired phonologic loop functioning
● Conduction aphasia
due to disease in the inferior parietal and posterior temporal lobes that accounts
following stroke, from the for some, but not all, patients with PPA who do not meet clinical criteria for
classic connectionist semantic variant PPA or nonfluent/agrammatic PPA. Future work in prospectively
perspective, is associated assessed patients with antemortem biomarkers for molecular pathology and
with damage to the arcuate
postmortem autopsy confirmation will improve diagnostic criteria for PPA to
fasciculus, the white matter
that carries projections predict specific proteinopathies.
between the inferior parietal
and superior temporal
region known as the
Wernicke area and the ACKNOWLEDGMENT
inferior frontal region known
This work was supported by grants from the National Institutes of Health
as the Broca area.
(AG017586, AG052943, AG038490, and NS053488, Dr. Grossman;
● Distinctions between K23 NS088341-01, Dr. Irwin).
progressive and stroke
forms of aphasia may be
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REVIEW ARTICLE

Apraxia, Neglect,
ONLINE
and Agnosia
By H. Branch Coslett, MD, FAAN
ABSTRACT
PURPOSE OF REVIEW: In part because of their striking clinical presentations,
disorders of higher nervous system function figured prominently in the
early history of neurology. These disorders are not merely historical
curiosities, however. As apraxia, neglect, and agnosia have important
clinical implications, it is important to possess a working knowledge of the
conditions and how to identify them.
RECENT FINDINGS:Apraxia is a disorder of skilled action that is frequently

observed in the setting of dominant hemisphere pathology, whether
from stroke or neurodegenerative disorders. In contrast to some
previous teaching, apraxia has clear clinical relevance as it is associated
with poor recovery from stroke. Neglect is a complex disorder with
CITE AS: many different manifestations that may have different underlying
CONTINUUM (MINNEAP MINN) mechanisms. Neglect is, in the author’s view, a multicomponent disorder
in which impairment in attention and arousal is a major contributor.
Finally, agnosias come in a wide variety of forms, reflecting impairments
Address correspondence to ranging from low-level sensory processing to access to stored
Dr H. Branch Coslett, Department knowledge of the world (semantics).
of Neurology, 3400 Spruce St,
Philadelphia, PA 19104,
hbc@pennmedicine.upenn.edu. SUMMARY: The classic behavioral disorders reviewed here were of immense
interest to early neurologists because of their arresting clinical
Dr Coslett serves on external
phenomenology; more recent investigations have done much to advance
advisory boards for National the neuroscientific understanding of the disorders and to reveal their
Institutes of Health Center grants clinical relevance.
for the University of Nevada,
Reno (R21 NS099645, 1R01
DC013196, R21NS089084, 1R01
NS099061) and for a US
Department of Veterans Affairs
grant for the VA Boston INTRODUCTION
I
Healthcare System. Dr Coslett nterest in higher functions of the nervous system, including those discussed
serves on the editorial boards of
in this article, figured prominently in the early days of neurology as the field
Brain and Language and Cortex
and as an editor for volume 151 of diverged from psychiatry. Phenomena such as apraxia and agnosia became
the Handbook of Clinical the subjects of intense interest in the latter part of the 19th century and early
Neurology (“The Parietal Lobe”).
20th century; these and other disorders were noteworthy at the time in part
UNLABELED USE OF
because “psychiatric” explanations of the disorders were not considered to be
PRODUCTS/INVESTIGATIONAL viable, necessitating brain-based (ie, neurologic) explanations of the disorders.
USE DISCLOSURE: This article reviews three of the disorders of higher brain function described
Dr Coslett reports no disclosure.
by early neurologists that continue to be of clinical and neuroscientific
relevance—apraxia, neglect, and agnosia—to assist neurologists in recognizing
of Neurology. and treating these important and fascinating disorders.
768 JUNE 2018

APRAXIA KEY POINT
Apraxia is a disorder of skilled action and tool use that cannot be attributed to
● Ideomotor apraxia is
weakness, tremor, or other primary sensorimotor deficit or generalized cognitive conceptualized as a loss of
impairment. The term apraxia is sometimes extended to include a wide range of knowledge regarding skilled
disorders that have little or nothing to do with skilled action; dressing apraxia, action. Ideational apraxia is
oculomotor apraxia, and constructional apraxia, for example, are not relevant to this often considered to be a
disorder of planning and
discussion as this article uses the term apraxia to refer specifically to disorders of
sequencing that is most
skilled action, most commonly involving the upper extremity. apparent in multistep
actions, such as preparing
History a letter to be mailed.
Liepmann1,2 was the first to systematically explore disorders of skilled action. In
his landmark manuscript published in 1908, he reported data from 89 patients
with chronic stroke, 47 with left-brain damage and 42 with right-brain damage.1
He noted for the first time that apraxia was associated with left hemisphere
lesions and that the disorder was usually evident in both the right and left hands.
He also demonstrated that, although apraxia and aphasia often co-occur, they are
dissociable. Finally, he noted that patients with apraxia typically performed least
well when asked to pantomime the use of a tool, somewhat more reliably when
asked to imitate the use of a tool (as demonstrated by the examiner), and best
when provided the object to use. All these observations have been confirmed in
many subsequent studies.
Liepmann described three different types of apraxic disorders. The first is limb
kinetic apraxia, a disorder in which even simple movements lack precision and
fluency. Whether this represents a disorder of stored motor knowledge or a
primary low-level sensorimotor disorder has been debated. The second form of
the disorder noted by Liepmann is ideomotor apraxia, which Liepmann believed
reflects a failure to access stored kinematic patterns or “space-time engrams” that
specify the activation parameters and timing of the contraction of muscles that
would generate the desired movement. Finally, Liepmann described ideational
apraxia, in which errors are not typically observed with simple movements but
in the setting of complex multistep sequences, such as addressing and mailing
an envelope. In contrast to ideomotor apraxia and limb-kinetic apraxia, this
disorder is not specific to the body part used for the task. Ideomotor apraxia and
ideational apraxia may co-occur. Geschwind3 resurrected the study of apraxia
in the 1960s in the context of disconnection syndromes and provided an
anatomic model of the disorder. Geschwind proposed that action knowledge
was supported by the temporoparietal cortex and that this information was
transmitted to the left premotor cortex, where the action plans were
implemented. Like Liepmann, he attributed the fact that most patients with
apraxia show deficits in both hands to the belief that the motor plans are
communicated from the left premotor cortex to the right premotor cortex by
means of transcallosal fibers. Support for this assumption comes from the
phenomenon of callosal apraxia (CASE 5-1).4
In a series of influential manuscripts, Rothi and colleagues6 developed a
cognitive model of apraxia reminiscent of the information-processing reading
models of the 1980s. They proposed distinct auditory verbal, visual object, and
visual gestural inputs to “lexicons” that included distinct types of stored
representations, including an action input lexicon that was assumed to contain
motor engrams (stored motor programs specifying a familiar action) that specified
object-specific actions. Gesture production was accomplished by activation of

APRAXIA, NEGLECT, AND AGNOSIA
CASE 5-1 A 45-year-old right-handed man with a history of recent stroke presented
with weakness and clumsiness of his right leg and difficulties in using
his left hand. Examination showed moderate spastic weakness of the
entire right leg, with increased reflexes and a Babinski sign. His right and
left hands exhibited normal dexterity, power, and tone, and his language
was normal. MRI demonstrated a stroke in the left anterior cerebral
artery territory with involvement of the deep white matter tracts in the
frontal lobe, consistent with the right leg
upper motor neuron deficit.
To evaluate his difficulty is using
his left hand, the patient was first
asked to demonstrate the use of a
hammer and how to flip a coin with
his right hand. He performed these
and similar gestures to command
flawlessly. When asked to do the
same with left hand, he waved his
hand purposelessly in the air and
indicated verbally that what he
was doing was not correct. When
again asked to execute the same
gesture with his right hand, he did
FIGURE 5-1 so perfectly while appearing bemused.
Sagittal T1-weighted MRI showing He was shown a hammer and asked
infarction of the corpus callosum in a
to demonstrate its use with his
patient with callosal apraxia.
Reprinted with permission from Watson RT, left hand but again waved his
et al, Brain.5 © 1985 Oxford University Press. hand randomly.
COMMENT What does such a case reveal about the anatomic bases of knowledge of
skilled action? First, as noted by Liepmann,1 Geschwind,3 and Watson and
Heilman,4 this and similar patients demonstrate that stored information
supporting skilled action is lateralized to the dominant hemisphere. This
case also demonstrates that this knowledge reaches the premotor cortex
of the right hemisphere via fibers that connect premotor regions by means
of the anterior body of the corpus callosum. The role of the white matter
tracts connecting the premotor regions of the hemispheres in the
transmission of knowledge regarding skilled action is demonstrated by the
development of callosal apraxia in a patient with an infarct largely limited
to the corpus callosum (FIGURE 5-15).
770 JUNE 2018

entries in the output lexicon that specified the timing of the innervation of limb KEY POINTS
effectors. This model has been further developed in recent years.7
● The ventrodorsal and
Building on the dual-route framework that distinguishes between a ventral dorso-dorsal streams are
route for object recognition and a dorsal or “how to” route for visuospatial particularly important in the
processing and action, Binkofski and colleagues8 elaborated an influential theory production of meaningful
of apraxia that distinguishes between two components of the dorsal stream: and meaningless gestures,
respectively.
dorso-dorsal and ventrodorsal. In this theory, the dorso-dorsal pathway,
which is supported by superior parietal/intraparietal sulcus regions ● Apraxia is best assessed
connecting to the dorsal premotor cortex, is considered crucial for reaching by asking the patient to
and grasping. In contrast, the ventrodorsal pathway, supported by the execute an action to
posterior temporal lobe and inferior parietal lobule and projecting to the command or, if unable to do
so, to imitate a meaningful
inferior prefrontal cortex, is considered crucial for object use; this system gesture made by the
specifies the representations of object-specific actions, precisely the type of examiner.
information postulated by Liepmann to be disrupted in patients with apraxia.
Support for this theory is found in studies of patients as well as in anatomic
studies in primates.8 Although beyond the scope of this article, it should be
noted that an extensive literature is emerging regarding the neural basis of tool
use, a topic closely related to apraxia.9
Clinical Assessment
Apraxia is often, but not always, associated with aphasia; thus, to assess for
apraxia, the examiner must first demonstrate that the patient understands what
he or she is being asked to do and has sufficient movement capacity to execute
the requested movement. Comprehension permitting, the patient should first be
asked to pantomime a specific movement, such as flipping a coin, hammering a
nail, or pouring water from a pitcher into a glass. If the patient does not
understand or is unable to execute the command, the examiner should
demonstrate the gesture and the patient should be asked to copy the action
precisely. If the patient is unable to do this, he or she should be asked to perform
the action with the appropriate object (ie, the patient should be offered a
screwdriver, for example, and asked to demonstrate its use).
As ideomotor apraxia is often body-part specific, performance should be
assessed with each hand, the face, and the body. In the case of the extremities,
both transitive (object-related) and intransitive gestures should be assessed as
performance on the two types of actions may dissociate. Transitive gestures
include demonstrating the use of a tool (eg, a comb), whereas intransitive
gestures do not use objects and include gestures such as waving or saluting. To
assess oral-buccal-facial praxis, patients may be asked to blow out a candle or
drink through a straw. Praxis for midline body movements may be assessed by
asking patients to show the posture of a boxer or dancer.
The adequacy of the patient’s response is assessed at the bedside based on the
precision, timing, and location of the movements. For example, when asked to
pantomime brushing one’s teeth, patients should exhibit back-and-forth
movements of the arm and hand at the mouth with the teeth bared and with
fingers curled as if gripping the object. A commonly observed error is the “body
part as object” response. When asked to pantomime brushing one’s teeth, the
patient may extend the index finger and mimic using the finger as the utensil.
Gesture substitutions may also be observed. In this case, when asked to
pantomime hammering a nail, a patient may incorrectly pantomime using a saw;
many of these errors are semantically based.

The ability to understand gestures should also be assessed. To this end,

patients may be shown a gesture, such as hammering a nail, and asked to indicate
what act is being performed. Alternatively, for patients with aphasia, language
requirements may be minimized by asking them to simply match a verbal label to
a gesture. Patients should also be asked to produce meaningless gestures. To
assess this, patients may be instructed to assume random body postures or
execute an unfamiliar sequence of specific finger, hand, and arm movements;
for example, a patient may be asked to imitate the examiner’s posture, in which
the right index finger is placed at the top of the head and the left thumb over
the sternum. A double dissociation between the ability to produce meaningful
and meaningless gestures may be observed. Some patients demonstrate apraxia
(ie, an impairment in producing familiar, meaningful gestures); as noted above,
this may be seen in patients with a lesion of the ventrodorsal pathway. Other
patients do not demonstrate apraxia but are impaired in the production of
meaningless movements; this may be observed in patients with a lesion of the
dorso-dorsal pathway. It should be noted that the inability to copy meaningless
movements or assume static body positions is not considered to be apraxia
because it reflects a deficit in translating visual information into motor
coordinates rather than a deficit in stored knowledge of action sequences.
Several short screening tests appropriate for bedside testing have been
developed, including the Short Screening Test for Ideo-motor Apraxia
(STIMA)10 and the Short Test for Apraxia.11
Neural Correlates
Liepmann1,2 reported that in right-handed individuals, apraxia was associated
with left hemisphere lesions, particularly involving the parietal lobe. Although
more recent studies have refined and extended this picture, left hemisphere
lateralization has been persistently reported. Studies that evaluated groups of
patients using the lesion-symptom mapping approach have demonstrated that
tool use deficits and imitation of meaningless gestures are associated with lesions
in a fronto-temporo-parietal network.7,9 Impaired recognition of action has been
associated with damage to the left posterior temporal lobe12 and left inferior
frontal gyrus.13
NEGLECT
Neglect is an acquired asymmetry in the processing of information from
one side of the body or space. The deficit is typically manifested on the
contralesional side of the body or space and is typically more severe and
persistent after right cerebral lesions. Neglect is a heterogeneous and
multicomponent disorder with protean manifestations. For example, neglect
can involve one side of the body, one side of peripersonal space (roughly the
space to which one can reach), or one side of extrapersonal space (beyond
peripersonal space). Additionally, neglect may be evident for all objects in a
region of space or may be stimulus-centered, involving one side of an object
or word regardless of its location. These different forms of neglect may be
observed alone or in combination. Neglect may also be observed in mental
imagery for locations or arrays.14,15 Although most investigations have
emphasized the sensory manifestations of neglect, the disorder may also be
manifest in action; motor neglect is a disorder in which patients do not use the
contralesional limbs despite having the power to do so. The following sections
772 JUNE 2018

review these and other aspects of the syndrome as well as theoretical models of KEY POINTS
the disorder.
● Inability to imitate
meaningless body postures
Spatial Neglect and Frames of Reference or gestures is not a disorder
The world around a person can be divided into the right and left sides (or of skilled action but reflects
hemispaces). The distinction between the right and left may be based on at least an impairment in the
procedures for translating
three different frames of reference centered on the body midline, head midline,
visual information into motor
and visual field. In the classic anatomic position with the head and eyes directed coordinates.
forward, the three hemispaces are aligned; in many activities, however, they are
dissociated. For example, if a person’s head is turned 45 degrees to the left while ● Hemispace refers to the
sitting at a dining service, the fork is in left body hemispace but right head hemispace. side of a person’s
environment and may be
Evidence exists that hemispace defined by all three coordinate frames can defined with respect to at
influence neglect. Many investigators have demonstrated that phenomena such least three axes: head,
as line bisection are influenced by the location of the stimulus to be bisected16 body, and eye position.
defined with respect to the body midline, with performance better on the Manifestations of neglect
may be influenced by all
right than the left side of the body. Additionally, tactile extinction may be three coordinate frames.
influenced by the location of the hands being tested: patients with neglect may
show less neglect of the left hand when both hands are placed on the right side ● Results of tests for
of the head or body. Similarly, bisecting a line in the midline may be improved neglect are very frequently
influenced by the location of
by turning the patient’s head to the left, thereby putting the line in the right
the stimulus or response; for
head hemispace. Finally, even visual field deficits may be modulated by head example, patients may
and body position. Kooistra and Heilman17 reported a patient who appeared to extinguish tactile stimuli on
have a left hemianopia with head and eyes directed ahead but demonstrated the left hand when it is
much improved visual detection when the eyes were deviated to the right and located in left hemispace
but not when it is in right
much of the left visual field was in the right head and body hemispace. hemispace.
Hemispatial effects may also be observed in patients without overt neglect.
The author has reported hemispatial effects on motor and language processing in ● A wide range of
patients with right and left parietal lesions, sometimes in the absence of other phenomena, such as
extinction, are commonly
manifestations of neglect.18 Although the effects of head, body, or eye position on observed in neglect but may
neglect are not observed in everyone, they are common, occurring in dissociate and are not
approximately 25% of patients in the author’s experience. considered by many to be a
core part of neglect.
Associated Deficits
A number of deficits are often seen in association with neglect but are not clearly
part of the syndrome, because they may not be present in patients with hemispatial
neglect or may be observed in the absence of other manifestations of the disorder.
The most common of these is extinction (the tendency to report only one of two
stimuli presented simultaneously). Although it is most commonly seen in the setting
of neglect and many patients with clear neglect will exhibit extinction as they
improve, extinction is considered by many to be independent of neglect.19
Disorders of the body schema, such as somatoparaphrenia, are most
frequently encountered in patients with right hemisphere lesions, many of whom
have neglect. In this condition, patients may deny ownership of a part of the
body, usually the left arm. Often patients will treat the body part as foreign,
sometimes demanding that the left arm be removed from their bed. Disorders
such as somatoparaphrenia may be more common than previously reported.
Antoniello and Gottesman20 reported that 61% of patients with acute right
middle cerebral artery stroke exhibited disorders of limb misidentification
acutely; the phenomenon was observed in 15% of patients at 1 week. When
evaluating patients with neglect, it is often useful to ask specifically if they feel

that their body is well formed, as some patients are reluctant to mention that
their body feels distorted for fear of appearing unhinged.
Finally, anosognosia for hemiparesis or spatial deficit is commonly observed in
patients with neglect. In the former condition, patients may be unaware of frank
hemiplegia21; they may develop elaborate explanations for their deficits.
Furthermore, even if patients acknowledge their weakness or sensory deficit,
their behavior may not reflect this insight. Patients may, for example, concede that
they cannot move the left side but immediately thereafter attempt to walk to
the door.
Theoretical Models of Neglect

Perhaps because the manifestations are so variable, no satisfactory theoretical
model of neglect exists; work in recent years is converging on the view that the
clinical syndrome of neglect is not a single disorder but a combination of
disorders, perhaps with differing pathophysiologies.22 Several of the major
theories to explain at least some aspects of the disorder are reviewed here.
Many theories attribute neglect to a failure of attention, a broad and often
ill-defined theoretical construct. One theory attributes neglect to failure to direct
attention to or to act in the contralateral hemispace.22,23 The fact that neglect is
more commonly observed after right hemisphere lesions is attributed to the fact
that the right hemisphere mediates attention to both the right and left sides,
whereas the left hemisphere mediates attention only to the right side.23 An
alternative view first proposed by Kinsbourne24 suggests that each hemisphere
manifests a vector of attention toward the contralateral side; the hemispheres
differ in that the left hemisphere vector of attention is strongly lateralized to the
right, whereas the right hemisphere vector of attention is only weakly lateralized
to the left. In this theory, each hemisphere is inhibited by the opposite
hemisphere. Left neglect is explained by hypothesizing that a right hemisphere
lesion reduces inhibition of the left hemisphere, thereby unmasking the left
hemisphere’s strong rightward bias of attention. In contrast, Bisiach and
Luzzati25 suggested a “representational deficit” in neglect. They reported patients
who, when asked to imagine the establishments on the Piazza Del Duomo in
Milan, reported primarily landmarks on the right when facing the cathedral at
one end of the square.25 When asked to imagine the square while facing in the
opposite direction, however, the patients again reported the landmarks on the
right, ignoring the previously reported landmarks.
The author and others believe that neglect should be conceptualized as a
multicomponent disorder with an impairment in arousal26 or capacity for effort27
as a prominent feature. A number of studies show that right hemisphere lesions
impair (nonspatial) tonic arousal.26–28 In this account, the effects of lateralized
attentional asymmetries are exacerbated by a decreased attentional capacity or
arousal. Consistent with this view, Robertson and colleagues28 reported that
patients with neglect were impaired in judging whether a visual stimulus on the
left preceded or followed a stimulus on the right. A warning sound, presented
from either the right or left, eliminated neglect on a visual task, suggesting that
the benefit was conferred by increasing arousal rather than enhancing processing
in the neglected hemispace. Consistent with the claim that deficits in sustained
attention and arousal are an important component of neglect, the author and
colleagues29 reported that the severity of nonlateralized attentional deficits
correlated with the overall severity of neglect.
774 JUNE 2018

Clinical Examination KEY POINTS
The assessment of neglect should commence as soon as the clinician encounters
● Neglect is a
the patient. In the author’s experience, neglect may often be diagnosed by heterogeneous and
observing the way patients orient to the examiner and the qualities of the multicomponent disorder
patient’s spontaneous movements. Many patients with neglect, for example, of which attentional
will show clear differences in the degree to which they attend to stimuli from asymmetries and disorders
of arousal are common
the right and left. Although some neglect behaviors may be overt and
components.
unmistakable, other behaviors may be more subtle. For example, it is common
for patients to be slower in turning the head and eyes to a speaker standing on ● Neglect may be assessed
the contralesional side. It is often useful for the examiner or team to address with a wide range of bedside
the patient from both the ipsilesional and contralesional sides to look for tasks and formal batteries.
It is important to note,
differences in orienting. Many patients with neglect have an associated however, that careful
hemiparesis that makes motor neglect difficult to observe. In patients with observation of the patient
mild or no weakness, akinetic movements or hypometric movements, or both, may reveal subtle deficits
are frequently encountered. For example, patients with motor neglect will that bedside tasks, such as
line bisection, do not
often use the ipsilesional hand for grooming and gesturing even when this identify.
would not be the usual motor sequence (eg, scratching the left ear with the
right hand).
A number of simple bedside tasks may also be useful in the assessment
of neglect. Line bisection and cancellation tasks are often used to assess
peripersonal neglect. In the former, patients are shown lines, preferably of
varying lengths and locations on the paper, and asked to place a mark at the
middle of the line. Except for short lines in which a “crossover” effect may be
observed, patients with peripersonal neglect bisect lines to the right of the
midline. Cancellation tasks require patients to identify targets displayed on a
paper or screen. In general, cancellation tasks with a larger number of targets
and distractors are more difficult, as are tasks in which distractors are visually
similar to the targets. The stimuli for cancellation and bisection tasks may
be placed in the midline or to the patient’s right or left side to assess for
hemispatial effects.
Personal neglect is often evident in grooming and other everyday activities.
Patients may fail to dress one side of the body, shave one side of the face, or, in
extreme cases, fail to recognize part of their body as their own. When asked to
touch the neglected side of the body, patients may fail to do so; it is not
uncommon for patients with neglect to touch the stimulated location on the
ipsilesional side of the body, a phenomenon known as allesthesia. The fluff test
and variants may be useful in the assessment of personal neglect. In these tasks,
Velcro or cotton balls are attached with tape or a weak adhesive to various parts of
the right and left side of the body and the patient is asked to remove the stimuli
with his or her eyes closed. Patients with personal neglect may fail to remove all
the stimuli from the side of the body with neglect.
Drawing tasks are also useful in the assessment of neglect. Patients may be
asked to draw a house, clock, flower, or other common object from memory or to
copy a figure; patients with neglect tend to omit or distort features from the
contralesional side of the object. Many patients with neglect will also show a
spatial distortion characterized by placing the drawn or copied object on the right
side of the paper. To test for hemispatial effects, the location of the stimuli
presented or action executed should be systematically varied. Finally, the
examiner should manipulate the patient’s posture to assess the effects of the
head, eye, and body position.

A number of test batteries have been developed that provide quantitative

measures of neglect. Perhaps the most commonly used is the Behavioral
Inattention Test,30 which includes tasks that assess cancellation, bisection, and
several more naturalistic functions (eg, menu reading). The Catherine Bergego
Scale31 provides a good measure of personal neglect. In this 10-item task, an
observer rates the degree to which the patient attends to the left side of the body
in naturalistic tasks.
Extinction can occur in three sensory modalities: vision, touch, and audition.
For all three types of stimuli, a suprathreshold stimulus is presented to the right,
left, or both sides and patients are asked to point to or name the side at which the
stimulus was presented. It is important to perform multiple trials of each type
and to include “catch” trials in which no stimulus is presented to minimize
guessing. The severity of extinction is determined in large part by the salience of
the stimulus. Extinction is more likely to be evident with stimuli that are close to
the detection threshold.
Anatomic Basis
Neglect has traditionally been associated with right posterior parietal lesions. If
attention is mediated by large-scale distributed networks, however, one might
expect neglect to be observed with lesions that involve different components of
the attentional network (eg, dorsal frontal cortex, thalamus, posterior parietal
cortex, posterior superior temporal gyrus), including the white matter tracts that
connect them. This has been observed in animals and human subjects; for
example, neglect may be associated with lesions involving subcortical structures,
such as the thalamus and basal ganglia, as well as the dorsal frontal cortex.
Additionally, damage to white matter tracts may underlie neglect in
some patients.16
More recently, a number of studies have attempted to identify the
pathologic substrate of distinct subtypes of neglect phenomena. Pedrazzini
and colleagues,32 for example, contend that space-based neglect is associated
with lesions of the temporoparietal junction, whereas object-based neglect
is associated with lesions of the posterior superior intraparietal sulcus.
Although some inconsistencies between the theories may be identified, recent
developments in techniques for linking lesions and behavior at a voxel level
offer hope that at least some of the variability exhibited by patients with
neglect will prove to be predictable from the location and size of the
precipitating lesion.
Natural History and Treatment

Neglect is a disabling disorder with a poor long-term prognosis. The
often-profound spatial asymmetries tend to resolve over weeks to months; for
example, in a series of 166 patients with neglect, lateral attentional asymmetry
was clinically apparent at 6 months after the stroke in approximately only 10% of
patients.29 Despite this improvement in the spatial aspects of neglect, the
disorder has a poor prognosis and has been demonstrated to be associated with a
poor functional outcome.33
Although considerable effort has been expended to develop treatments for
neglect, all current therapies remain generally unsatisfactory. Prism therapy and
noninvasive brain stimulation with transcranial magnetic stimulation and
transcranial direct current stimulation have shown promise.34
776 JUNE 2018

AGNOSIA KEY POINTS
The agnosias are a class of disorders in which a failure of recognition is present
● Extinction may be
that cannot be attributed to low-level visual or sensory deficits. Perhaps the first observed in vision, touch,
description of visual agnosia was provided by Munk,35 who noted that lesioning and audition independently
the bilateral parietooccipital cortex in dogs rendered them unable to recognize or in combination. Stimuli
objects despite the fact that they could navigate through their environment that are near the detection
threshold are more likely to
without substantial difficulty. The first systematic discussion of the visual
identify extinction.
agnosias was provided by Lissauer,36 who introduced the distinction between
apperceptive agnosia and associative agnosia that continues to animate many ● Neglect is most
discussions of the topic. This section first considers Lissauer’s contribution and frequently associated with
then briefly reviews the major types of agnosic disorders. lesions in the right parietal
lobe but may be caused by
pathology in a distributed
Agnosias as Disorders of Recognition attentional network that
Visual object recognition is a process by which information presented to the includes the right inferior
retina is transformed in a cascade of processes involving the lateral geniculate frontal lobe, thalamus, basal
ganglia, and white matter
and successively “higher” visual cortices to generate an internal representation of tracts connecting them.
the object that permits stored knowledge of an entity to be consciously accessed.
For example, when a person is presented with an apple, information about the ● In the traditional
size, shape, color, and other visual attributes of the stimulus are decoded at the nosology, apperceptive
agnosias result from a failure
retina, lateral geniculate, and primary visual cortex before being processed in a
in sensory processing,
series of visual regions specialized for different visual features and attributes. whereas associative
This visual information is subsequently integrated in the inferior occipitotemporal agnosias are caused by a
cortex (the “what” system) into a mental model of an apple. The specific failure to contact stored
information about an object
properties of the mental model (eg, whether it is “visual” or multimodal)
after an adequate
continue to be the topic of research. This internal representation of an apple then perceptual representation
contacts the totality of the individual’s stored information relating to apples, has been constructed.
including, for example, the taste, feel, color, and manner of harvesting.
Lissauer reported the first detailed description of a patient who had difficulty
in this process; despite adequate vision and knowledge of objects, the patient was
unable to name or otherwise show recognition of the objects. To make sense of
these deficits, Lissauer proposed that two types of disorder of recognition be
distinguished. The first he designated apperceptive agnosia, which he considered
to be an impairment in the integration of visual form and feature information
that precluded the generation of an internal representation of the object. The
second subtype of recognition disorder he termed associative agnosia. In this
condition, processing of the visual information is at least relatively intact but
relevant stored information cannot be contacted. In Teuber’s37 apt summation,
associative agnosia is characterized by a “normal percept stripped of its meaning.”
Lissauer’s operational definition of the distinction between the apperceptive
agnosia and associative agnosia relates to the ability to draw or copy a stimulus;
patients with apperceptive agnosia are unable to generate a depiction of an entity,
whereas patients with associative agnosia are able to copy (often in a slavish,
piecemeal fashion) or draw an object but are unable to provide information about
the object that they have just drawn. Although sorely lacking in detail, Lissauer’s
general account continues to frame the discussion of the agnosias.
Category-Specific Visual Agnosia

A number of patients who were more accurate in naming nonliving entities
than living entities have been reported38; for example, they were more likely to
name a hammer as compared to an elephant, even when the visual stimuli were

KEY POINTS controlled for potentially confounding factors such as the visual complexity or
familiarity of the stimuli. Subsequently, different performance as a function of
● Prosopagnosia is a
disorder of visual
the semantic category has been repeatedly confirmed, and many other
recognition specific to dissociations have been reported. For example, other patients with agnosia may
faces. In this disorder, which recognize animals better than inanimate objects, and more fine-grained
may be either acquired or distinctions, such as differential performance with fruits and vegetables, have
developmental, patients
been observed (CASE 5-2). The implications of these observations for the
often recognize a face as a
face and, in some instances, organization of the semantic system remain a topic of considerable interest
derive substantial and debate.40
information about the
stimulus such as age,
Material-Specific Agnosia
gender, and emotional
expression but are unable to Although impairment in the processing of visual objects is the most common
identify the individual. type of agnosia, recognition of other classes of visual stimuli may also be
impaired, sometimes selectively. Prosopagnosia is a disorder of visual
● Agnosias may be recognition specific to faces. In this disorder, which may be either acquired or
distinguished by the specific
nature of the stimuli rather
developmental, patients often recognize a face as a face and, in some instances,
than the sensory modality of derive substantial information about the stimulus such as age, gender, and
the input; for example, in emotional expression but are unable to identify the individual. The deficit may be
the visual domain, so profound that some patients with prosopagnosia may be unable to recognize
material-specific agnosias
are observed that
their own faces in the mirror.
selectively impair Pure alexia, sometimes designated agnosic alexia, is a disorder that is
recognition of faces or traditionally considered in the context of disorders of language. As patients with
words. the disorder are typically unable to recognize words but may demonstrate no
impairment with visual stimuli or auditory language, the disorder represents a
● Pure word deafness is a
disorder in which patients type of modality-specific agnosia. Optic aphasia is a visual modality–specific
can identify environmental impairment in the recognition of objects and words; patients with optic aphasia
sounds (eg, a car horn, a often “recognize” objects and words in the sense that they may be able
telephone ringing) but to demonstrate the use of an object but are unable to name the object. Optic
cannot understand speech
despite at least largely aphasia is distinguished from anomia by the fact that patients with optic aphasia
normal ability to read, write, have no problem naming objects from description or on the basis of palpation.
and speak. Recent work supports previous suggestions that agnosia for words and agnosia
for faces dissociate, arguing that the cognitive processes underlying face and
● Modality-specific
agnosias are disorders of
word processing are at least partially distinct.41
recognition that involve one
type of sensory input, such Modality-Specific Agnosia
as vision, audition, or touch. Agnosia is most commonly observed in the visual domain but may also be
observed for auditory and tactile inputs. Generalized auditory agnosia is
characterized by an inability to recognize all types of sounds in the absence of
deafness. Pure word deafness is a disorder in which patients can identify
environmental sounds (eg, a car horn, a telephone ringing) but cannot
understand speech despite at least largely normal ability to read, write, and
speak. The disorder is associated with lesions involving the primary auditory
cortex bilaterally or a left superior temporal gyrus lesion. Auditory sound agnosia
is a very rare but perhaps underreported syndrome in which speech recognition
is largely intact but recognition of environmental sounds is poor.
Agnosia in Neurodegenerative Disorders

The most common setting in which agnosias are observed in clinical practice is
in the setting of neurodegenerative diseases. Visual object agnosia is frequently
seen in Alzheimer disease but may be obscured by co-occurring semantic,
778 JUNE 2018

A 50-year-old man awoke from cardiac surgery with difficulty recognizing CASE 5-2
people, objects, and words. After a few months, he improved, but he
continued to have trouble recognizing people and objects. Except for
close family members, he only recognized people based on their voices.
Head CT showed a right inferior occipitotemporal infarct, which was felt
to be an underestimate of the full extent of his lesions.
The patient presented for evaluation 10 months after the onset of
symptoms. He exhibited a mild visual agnosia; he performed well on a
wide range of spatial tasks and accurately copied complex figures but
performed poorly in naming objects and faces. However, he performed
differently with different types of stimuli; he was much more accurate
naming drawings of nonliving objects (eg, hammer; 91% correct) than
living beings (eg, dog; 41% correct) that were matched for the complexity
of the visual image.
How can this patient’s pattern of performance be explained? Knowledge COMMENT

of objects comes in different forms; one not only knows what a telephone
looks like but also how it feels, how it is held, how to make a call, and the
sounds that it makes. Recognition of an object then may be determined
not only by the degree to which the visual image matches the stored
representation of the object but also by means of other kinds of
information conveyed by the image. This patient, who had normal praxis
and visuospatial skills, was able to use the image of the object to access
information about the manner in which the object was used. If
sensorimotor information about object use can supplement information
about object form to aid in object recognition, one might expect objects
for which the patient has sensorimotor information pertinent to the
object’s use to be named more accurately than objects for which no such
information is available. This prediction was tested in a series of
experiments, which found that this patient’s ability to name visual stimuli
was predicted by factors such as the manipulability of the stimulus.39 This
was true for both man-made and naturally occurring stimuli. Thus, the
difference in performance between living and nonliving things exhibited by
this patient was not a function of the semantic category of the stimulus but
a reflection of the richness of his sensorimotor knowledge of the stimuli.
While this account is not likely to explain all the category-specific agnosias,
it illustrates that multiple factors influence what appears to be the
straightforward task of object naming and that information from multiple
types of sensory and motor representations may be integrated to influence
performance. Object recognition requires not only the ability to generate
an accurate mental model of an object but also access to semantic
information specifying the sound, smell, action, and use of the object.

KEY POINTS language, or amnestic disorders. In the syndrome of posterior cortical atrophy,
however, a visual processing disorder is the most prominent feature, and other
● Patients with posterior
cortical atrophy may have
impairments are, at least early in the course, relatively minor.42 Patients with
problems recognizing faces, this disorder may have problems recognizing faces, words, and objects and are
words, and objects and are particularly impaired in the recognition of complex scenes, often showing
particularly impaired in the elements of Balint syndrome. Posterior cortical atrophy is caused by Alzheimer
recognition of complex
disease in approximately two-thirds of patients but is also caused by dementia
scenes, often showing
elements of Balint with Lewy bodies, corticobasal degeneration, and prion diseases. The pathology
syndrome. tends to be in the occipital, posterior parietal, or posterior temporal lobe; in
different individuals, the disorder may preferentially impair visuospatial
● Posterior cortical atrophy processing, object processing, or even lower-level visual processes.
is caused by Alzheimer
disease in approximately Prosopagnosia is not uncommon in frontotemporal dementia, particularly in
two-thirds of patients but is patients with right anterior temporal lobe atrophy.43
also caused by dementia
with Lewy bodies, Assessment
corticobasal degeneration,
and prion diseases.
The hallmark of visual agnosia is impairment in naming visually presented
objects. As naming deficits occur for a variety of reasons, impaired naming alone
● Visual agnosias are is not sufficient to support a diagnosis of agnosia. One factor that helps to
frequently observed in distinguish aphasia from agnosia is the nature of naming; in contrast to
Alzheimer disease and
patients with aphasia, who generally produce phonologic (sound-based) or
frontotemporal dementia.
semantic (meaning-based) errors, most errors generated by patients with
● Recognition is a complex agnosia reflect an impairment in the visual decoding of the stimulus; for
process that should be example, a patient with agnosia may call a bicycle a pie, presumably reflecting
assessed by more than the fact that the patient failed to “see” the entire object and misconstrued the
simply asking patients to
name an object; patients wheel as a pie. The recognition of visual stimuli should also be assessed by
may also be asked to point asking patients to point to a named object in an array. Copying figures and
to named objects and to drawing a familiar figure should also be assessed. Considering the category- and
demonstrate the manner in material-specific agnosias described earlier in this section, it is important to
which an object may be
used.
assess recognition for a wide range of stimuli, including animate and inanimate
objects, words, faces, complex arrays, and sounds. Should patients be unable
to name an object, they should be asked to indicate knowledge of the object in
other ways, such as by generating the appropriate gesture or verbalizing where
it might be found or its function. As patients with agnosia often perform better
in naming real objects as compared to identifying line drawings, it is useful to
assess performance with both types of stimuli. Two useful batteries for
assessing visual object processing are commercially available: the Birmingham
Object Recognition Battery (BORB)44 and the Visual Object and Space
Perception Battery (VOSP).45
CONCLUSION
Apraxia, neglect, and agnosia are classic neurologic disorders that continue to be
of relevance to 21st century neurologists for several reasons. All three disorders
are of considerable interest to cognitive neuroscientists because the patterns of
deficits exhibited by patients with these disorders tell us much about the
processes underlying motor planning, attention, and visual recognition. The
conditions are also highly relevant to clinical practice because of their prevalence
and their implications for functional recovery. It is hoped that this brief
introduction to these disorders will enhance neurologists’ ability to provide
state-of-the-art care.
780 JUNE 2018

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782 JUNE 2018

Aggression and Agitation REVIEW ARTICLE
in Dementia
C O N T I N U UM A U D I O
ONLINE
By M. Uri Wolf, MD, FRCPC; Yael Goldberg, PhD, CPsych;

Morris Freedman, MD, FRCPC, FAAN CITE AS:
ABSTRACT Address correspondence to

Dr M. Uri Wolf, Baycrest Health
PURPOSE OF REVIEW: This article reviews the treatment of aggression and
Sciences, 3560 Bathurst St,
agitation in dementia. Both nonpharmacologic and pharmacologic Toronto, ON M6A 2E1, Canada,
approaches to responsive behaviors are discussed. Practical treatment uwolf@baycrest.org.
strategies are applied to common behavioral symptoms. RELATIONSHIP DISCLOSURE:

Drs Wolf and Goldberg report no
disclosures. Dr Freedman serves
RECENT FINDINGS: Aggressive and agitated behavior is common in dementia. as a trustee for the World
Behavioral symptoms lead to reduced quality of life and distress for both Federation of Neurology and on
the editorial boards of Brain and
patients and caregivers. They can also lead to poor outcomes and are Cognition and Journal of
associated with significant financial implications for the individual and Parapsychology; has received
health care system. A wide range of difficult behaviors exists, with limited support from and served on an
evidence for deciding on treatment. Clinicians should integrate the Company Canada and receives
available evidence with practical and commonsense strategies to target publishing royalties from Oxford
these difficult-to-treat behaviors. University Press; receives
research/grant support from the
Alzheimer Society of Canada,
SUMMARY: Treating aggression and agitation in dementia is challenging. Brain Canada Foundation, Centre
for Aging and Brain Health
Viewing behaviors as a response to either internal or external stimuli can
Innovation, Canadian Institutes
help guide treatment. Treatment should emphasize nonpharmacologic of Health Research, and Westin
approaches as an initial step, using practical and commonsense strategies. Brain Institute; receives support
from the Behavioural Neurology
Caregivers and family should be actively involved in the planning and Physician Recognition Covenant
implementation of behavioral plans. It is essential to minimize both Fund at Baycrest, the Morris
medical and nonmedical factors that may be contributing to behaviors. Kerzner Memorial Fund, and the
Saul A. Silverman Foundation as
When pharmacologic options are required, it is important to choose part of the Canada International
medications that will target specific behavioral goals, having both practical Scientific Exchange Program
consideration and the best evidence in mind. project; and holds stock in
companies producing or
planning to produce medical
marijuana and is listed on a
provisional patent related to
INTRODUCTION methods and kits for differential
B
diagnosis of Alzheimer disease.
ehavioral symptoms are common in dementia and are a source of
significant concern to all involved.1,2 Poor management of behavioral UNLABELED USE OF
symptoms leads to reduced quality of life for the patient with PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
dementia, increased distress in the caregiver, and, in some cases,
Drs Wolf, Goldberg, and
distress in the clinician.3–6 Difficult behaviors can pose barriers to Freedman discuss the unlabeled/
providing necessary medical investigation and treatment for patients. These investigational use of medications
for the treatment of aggression
behaviors can accelerate disease progression and functional decline, leading to and agitation in dementia, none of
greater utilization of health care services and prolonged inpatient stays in which are approved by the US
long-term care facilities or hospitals.1 This has significant financial implications Food and Drug Administration.
at personal, institutional, and government levels.4,5,7 Thus, neurologists and © 2018 American Academy
other physicians have a vested interest in effectively treating the behavioral of Neurology.

AGGRESSION AND AGITATION IN DEMENTIA
KEY POINTS symptoms of dementia, drawing on both nonpharmacologic and

pharmacologic approaches.
● To develop an effective
intervention, it is important
to view difficult behaviors as UNDERSTANDING BEHAVIORS IN DEMENTIA
a response to a stimulus in It is helpful to view aggressive and agitated behavior as responsive behavior
the patient’s internal or that manifests in response to a stimulus in the patient’s internal or external
external environment.
environment.8–10 These behaviors can represent the patient’s attempt to
● Before treating responsive communicate an unmet need to the caregiver, such as the experience of physical
behavior, it is important to pain, hunger, loneliness, or boredom. Responsive behaviors can also occur in
accurately define and reaction to a stimulus perceived as stressful because of the patient’s increased
describe the nature and vulnerability to stress and reduced coping skills. Examples include noise,
magnitude of the problem.
temperature, and relationship distress. Disruptive behaviors can be learned
● Obtaining collateral through modeling or reinforcement. For example, if a patient receives attention
information from multiple in response to a problem behavior (eg, screaming), the reaction of others
sources who are involved (ie, attention) may unintentionally serve to increase the likelihood of the behavior
with the patient will give a
richer and more accurate
recurring in the future.3 Preexisting personality factors, life experiences, current
history. medical status, and history of trauma can also contribute to behavioral
presentations.1 Considering potential causes of responsive behavior will facilitate
the development of appropriately targeted interventions.
Reviewing the patient’s medical status is important for understanding triggers
for responsive behavior. For example, an abrupt change in behavior can signal
the development of delirium. Pain and discomfort can also trigger behaviors
(CASE 6-1).8,11 It is important to note that a patient with dementia who has pain
may not report discomfort because of significant cognitive impairment that
prevents effective communication.
In addition, some medications, such as antipsychotics and serotonergic agents,
can cause akathisia or restlessness. These signs may occur at high doses or if
patients have significant sensitivity to these drugs. In addition, dopaminergic
medications that are often used in Parkinson disease can result in psychosis.
Finally, drug interactions and impaired renal or hepatic function can lead to
higher effective doses than planned and thus may result in the emergence of
signs and symptoms of agitation and aggression.
ASSESSMENT OF BEHAVIOR
The first step in treating responsive behavior is to properly define and assess
the specific behaviors being reported.6 Agitated behavior is defined as “socially
inappropriate verbal, vocal, or motor activity that is not a necessary by-product
of a medical condition.”12 Agitation is a term used to describe a constellation
of symptoms, including pacing, aimless wandering, performing repetitious
mannerisms, and general restlessness. Aggression, categorized by both verbal and
physical behavior, includes hitting, kicking, pushing, throwing or tearing things,
spitting, biting, scratching, destroying property, grabbing people, grabbing
objects away from people, hurting oneself or others, making sexual advances,
cursing, and screaming.3
Although a patient may be described as “aggressive” or “agitated,” it is
important to obtain specific examples to determine if consensus exists about what
has been witnessed. Obtaining a thorough understanding of the problematic
behavior may take time, but it will ultimately save hours of frustration for all
those involved by directing management down the correct course. Assessment of
the behavior should include information about frequency, duration, whom it
784 JUNE 2018

affects, potential triggers, reinforcements of the behavior, and severity (ie, how
significant or disruptive the consequences of the behavior are and whether it
is manageable or not). The occurrence of responsive behaviors may have an
identifiable pattern, such as occurring at a specific time of day, after a particular
activity, or with a specific person. This information is important for identifying
possible triggers that can be modified. The physician should also assess the
degree of risk posed to the patient and others by the specific behavior. While
all behaviors can be unpleasant, not all of them are dangerous. For example,
hoarding does not put anyone at immediate risk, whereas pushing does. The
physician should act quickly and effectively to address any behavior that puts the
patient, another patient, staff, or a family member in harm’s way. A thorough
assessment of the situation will facilitate proper identification of the behavior
and degree of risk, which will then dictate the course of action.
Information can be gathered in several ways as part of a thorough behavioral
assessment. A primary source of information will be family members and close
friends who have known the patient for a long time (ideally before the onset
of the disease), who not only can identify current symptoms but can comment
on the progression of symptoms over time. Family members are particularly
essential to the assessment process when a patient is still living at home. When
An 86-year-old man was admitted to the hospital upon transfer from his CASE 6-1
long-term care facility for symptoms of verbal and physical aggression
and agitation. He had been diagnosed with Alzheimer disease 4 years
before the referral. His medical history included hypertension, benign
prostatic hypertrophy with an indwelling catheter, and recurrent urinary
tract infections. His family history was notable for Alzheimer disease in
one of his siblings. He had a 2-year history of behavioral symptoms. On
the day of transfer, he had physically attacked nursing home staff and
was taken to the hospital by police.
On admission, he had an indwelling Foley catheter. Since he did not
allow the Foley catheter to drain into a bag, it drained directly into an
incontinence brief. He was confused, disoriented, and resistive to care.
He was unpredictably aggressive and agitated. Following initial
assessment, nursing staff identified a single behavioral trigger, which was
the wetness he felt on his skin when the incontinence brief was soiled
with urine. Since the patient refused to use a drainage bag, nursing staff
decided to cap the catheter to prevent flow and emptied it every 2 hours.
This creative solution kept the patient dry and eliminated all disruptive
behaviors. No medication changes were made, and the patient was ready
for discharge back to long-term care within a matter of days.
This case illustrates how pain or discomfort can trigger and maintain COMMENT
aggressive and agitated behaviors. It also demonstrates the need to think
creatively to resolve behavioral disturbances and that an intervention does
not have to be complicated to make a significant impact on symptom
reduction.

attempting to get an accurate history from family members, it is important to ask

questions, such as:
u What was the first thing you noticed that caused you concern? When was this?
u Why have you brought the person in now?
u Is this a change from how the person used to be? How so?
u When did you first notice this behavior?
u Has it gotten worse lately?
u What do you notice that makes this behavior worse or better?
u What have you tried in the past and has it helped?
Family members may not be able to answer all these questions with certainty,
but if they are approached as experts on their loved one and treated as integral
to patient care, they will typically provide a wealth of useful information. At
times, responses can be verbose, potentially because of the family member’s
frustration with the disease or emotional state, and a physician must understand
how to move an interview along in a respectful manner.
The health care team is another source of information about patient behavior.
Whether the patient is in a long-term care facility or an acute hospital unit,
nursing staff who have observed behaviors can report on them knowledgeably.
It is important to consider input from nurses across all shifts, as patient behaviors
can vary depending on the time of day and environmental factors. Many facilities
use assessment tools to measure and track behavior over time (eg, the Agitated
Behavior Mapping Instrument,12 the Cohen-Mansfield Agitation Inventory,13 the
ABC [Antecedent, Behavior, Consequence] Charting Approach14). These tools
look at the antecedents, specific details, and consequences of a given behavior
and may also take into account factors such as physical and emotional health,
intellectual ability, environment, congruence between remaining capabilities and
assigned tasks, and sociocultural background that may be contributing to the
exhibited behavior.15 Therefore, in addition to the types of questions asked of
family members, nursing staff should be asked to describe behavior, report on
behavioral triggers and ameliorators, and highlight factors contributing to the
presentation of behavior.
Obtaining a good understanding of the behaviors at baseline will optimize
behavior management over the course of treatment. Establishing the rhythm
of a patient’s day can inform when a nonpharmacologic or pharmacologic
intervention will be most helpful. If informants report that aggression is worse
before care provision, the physician may decide that medication should be
administered just before care. If informants report that a patient is particularly
agitated just after lunch, routine behavioral intervention after lunch may be
recommended, such as going for a walk or engaging in a music session. Over time,
exhibited behaviors can be compared to baseline to determine the effectiveness
of both nonpharmacologic and pharmacologic interventions and help shape
next steps. Overall, available resources should be maximized when conducting
behavioral assessments that serve as the foundation of effective intervention.
NONPHARMACOLOGIC INTERVENTIONS
Many nonpharmacologic approaches to intervention are effective not only
in managing behavioral signs and symptoms but often also in targeting the
786 JUNE 2018

underlying causes of the behavior without the adverse side effects or possible KEY POINTS
drug interactions of medications.16–18 Nonpharmacologic interventions should be
● Using formal assessment
tried before contemplating pharmacologic interventions unless an acute risk tools to measure and track
of harm exists.3,8 If acute safety concerns are identified, aggressive treatment, behavior can inform
including both nonpharmacologic and pharmacologic strategies, should be behavior management.
initiated quickly.
● Whenever possible,
Nonpharmacologic approaches need not be complicated but do require some
nonpharmacologic
creativity (CASE 6-1). Often, choosing a small change in approach or introducing interventions should be tried
a thoughtful intervention may be enough to make a significant difference. before pharmacologic
One study demonstrated effective treatment of vocally disruptive behavior interventions.
in a patient with frontotemporal dementia by simply giving the patient a
● Using some creativity
lollipop.19 TABLE 6-120,21 provides a summary of some of the most common can allow for simple, but
nonpharmacologic strategies used in responsive behavior management.3 These effective, nonpharmacologic
strategies may be adapted to target a specific situation. interventions.
Several factors should be considered in selecting appropriate behavioral
● Nonpharmacologic
interventions, including the type of behavior and its associated degree of risk, the
interventions should be
resources available to implement the strategy, the patient’s personal preference tailored to suit the patient,
and level of motivation, the patient’s premorbid status (hobbies, interests, caregivers, and environment.
educational and occupational background, trauma history), the patient’s current
capabilities and strengths, and any medical barriers to engagement in certain
activities. For example, unsupervised walking should not be recommended for a
patient with unsteady gait who is at risk of falls, and physical exercise should only
be considered if appropriately trained staff or family members are available to
assist. Pet therapy should not be recommended if a patient is afraid of animals,
and word games should only be recommended for a patient with minimal
cognitive impairment. Appropriate interventions must be selected on an
individualized basis, taking into account a host of factors, including intellectual
capacity, physical and mental health, sociocultural background, and premorbid
personality factors, to meaningfully address targeted behaviors in a
patient-centered way.8,16,22,23 Here again, the input of family, friends, and the
interprofessional care team is key in providing the physician with sufficient
understanding of the patient’s clinical presentation to facilitate the selection of
appropriate interventions.
After strategies are identified as being potentially useful for a given patient,
the physician should capitalize on the strengths of the individuals involved in
the patient’s care by delegating implementation of these interventions to
family members, caregivers, and other members of the health care team (eg,
psychologist, physical therapist, occupational therapist, recreational therapist,
music therapist, dietitian, speech language pathologist, nurse). Team
engagement is greatest when the instructions to delegates are respectful, specific,
and concise and include the desired frequency, setting, time of day, location of
supplies, and any other elements needed for the selected behavioral intervention.
Because every patient is different and how the patient will respond to a given
strategy is unknown, ongoing monitoring of the intervention’s effectiveness
is imperative. Thus, the physician should engage in behavioral assessment of
the patient often during treatment. Once again, the physician may rely on
assessment tools (as mentioned earlier in this article) and input from others
(eg, family, interprofessional health care team) to ascertain if targeted behaviors
have changed following the implementation of specific interventions. Looking
at one or two time points is insufficient to make this determination, and the

physician should examine the overall net outcome over a predetermined length
of time, typically 1 week, to determine if a behavior has improved.
PHARMACOLOGIC INTERVENTIONS
Limited evidence exists when it comes to deciding which medication to use for
many behavioral symptoms. It is important to be familiar with the available
evidence, but because medications are often ineffective in treating responsive
behaviors, it may be necessary to improvise when evidence is lacking. It is often
TABLE 6-1 Common Nonpharmacologic Intervention Strategies for Managing

Behavioral Symptoms of Dementia
General Strategy Specific Examples
Physical activity Structured exercise program (group or individual setting), walking indoors around the unit or
hallways, walking outdoors
Sensory enhancement For stimulation: music, sound-amplification devices, corrective eyeglasses, light therapy,a
multisensory stimulationa
For relaxation: music, massage, touch, white noise, noise-canceling headphones or earplugs,
aromatherapy,a sleep therapy, quiet room
Social interaction With people: live visits from family, friends, or elder clowns, one-on-one conversations with
health care staff, simulated presence therapy (audio or video recordings of family or friends
played to the person with dementia)a
With pets: live pet visits, pet therapy, robotic pet interaction21
Purposeful engagement Activities that are meaningful and relevant to patients based on their current capabilities
and previous interests, including games (ball toss, cards, jigsaw puzzles, crossword
puzzles), music (attending concerts, singing, listening to the radio, music therapy), arts and
crafts (painting, needlepoint, coloring, drawing, beadwork), technology (playing games on
tablet, watching favorite sports games, watching a movie or TV show), and social
interaction (see above)
Environmental design Designated areas for wandering/pacing, group activities, and eating; using an established
“quiet room” for behavior de-escalation; strategically preparing all designated spaces by
painting appropriate murals to elicit the desired mood and patient response; using
appropriate aesthetic materials (eg, avoiding multitonal flooring); using appropriate labeling
for patient rooms, bathrooms, and common areas and personal items; removing all
unnecessary clutter from rooms
Differential reinforcement Reinforcing desired behavior with rewards6; using a token economy; modeling desired behavior
Staff/caregiver education Training in building empathy for patients; using a gentle persuasive approach with patients;
proper documentation of observed behaviors; psychoeducation regarding disease symptoms
and progression; appropriate responses to delusional thoughts; self-care; stress management
and coping strategies
a
The evidence for these particular interventions is mixed.1,20
788 JUNE 2018

useful to borrow pharmacologic strategies from other conditions, such as mood KEY POINTS
disorders, anxiety disorders, obsessive-compulsive disorder, and traumatic brain
● Evaluating the outcome
injury, when similarities exist between these conditions and the responsive of nonpharmacologic
behavior. For example, a patient with repetitive, compulsivelike, disruptive interventions will help
behaviors may respond to medications for obsessive-compulsive disorder. determine if they have been
Moreover, because symptoms are often difficult to treat, can present significant helpful or if modifications
should be made.
safety concerns, and may affect quality of life, considering evidence from case
reports and open-label case series may be justified. ● The pharmacologic
Using medications in patients with dementia requires consideration of a approach to treating
number of factors. Medication interactions can cause an increase or decrease in responsive behavior
therapeutic levels of medication. This can lead to reduced effectiveness of some includes using the best
evidence available but also
medications or increased adverse reactions. It is thus important to be aware of improvising when evidence
interactions of commonly used medications when choosing pharmacologic is lacking.
treatments and to closely monitor the effects of medications. Medication should
be started at a small dose, especially in frail patients, usually about half of the ● It is important to titrate
medications slowly and
typical starting dose for younger patients. TABLE 6-224–27 lists the most common monitor for adverse effects
medications used to treat behavioral symptoms and common dosing strategies. If or worsening of behavior.
possible, dose increases should be slow and no more frequent than every 1 to
2 weeks, both to ameliorate possible side effects and to monitor for response and ● Deciding which behavior
to target first requires
adverse reactions. Making one medication change at a time makes it easier to
prioritizing safety concerns
know which change is truly responsible for an improvement or worsening of and patient and caregiver
behavior. It is reasonable to target a therapeutic dose, keeping in mind that distress as well as
effective doses vary significantly and that overshooting the effective dose can, at understanding the factors
times, exacerbate symptoms. The maximum dose is often considerably lower contributing to the behavior.
than that used in younger patients. Often, the first medication trial will not be
effective and switching to another agent will be needed. After a number of trials
of monotherapy, it may be necessary to combine medications that have different
mechanisms of action, especially if a patient shows partial response to one
medication. Common side effects in patients with dementia include sedation,
extrapyramidal signs, falls, hypotension, worsening of behavior, and emergence
of new behavioral features.
It is important to decide which behavior to target with a pharmacologic
option. When a patient has multiple problematic behaviors, the physician should
prioritize which behavior to target first, considering the severity, distress, and
concern for the patient’s or others’ safety. Some behaviors are easier to target
and more likely to respond to pharmacologic intervention and may thus be
prioritized. If multiple behaviors are problematic, hypothesizing whether they
relate to one another can help guide which behavior to target first. For example,
if a patient is restless and paranoid, it can be hypothesized that the paranoia may
be driving the restlessness. In this case, the initial target would be the paranoia.
Using a commonsense and individualized approach to pharmacologic treatment
will help steer the physician to more effective treatment of difficult behaviors.
SPECIFIC BEHAVIORS
The following are some of the most common aggressive or agitated behaviors
a physician encounters, with suggestions for how to treat them from
nonpharmacologic and pharmacologic perspectives (TABLE 6-3). The strategies
listed are not meant to be exhaustive; rather, they demonstrate an approach to
common situations that can be easily implemented and modified based on the
specifics of each case.

TABLE 6-2 Common Medications Used to Treat Behavioral Symptoms
Medication Usual Starting Dose Usual Maximum Dose
Antidepressants
Citalopram 10 mg/d once daily 20 mg/d once dailya
Escitalopram 5 mg/d once daily 10–20 mg/d once dailya
Sertraline 25 mg/d once daily 150–200 mg/d once daily
Venlafaxine XR 37.5 mg/d once daily 150–225 mg/d once daily
Duloxetine 30 mg/d once daily 60 mg/d once daily
Clomipramine 10–25 mg/d once daily 200 mg/d split dosing
Doxepin 10 mg/d usually dosed at night 100 mg/d usually dosed at night
Trazodone 25 mg/d once daily 250 mg/d split dosing
Mirtazapine 7.5 mg/d usually dosed at night 45 mg/d usually dosed at night
Antipsychotics
Risperidone 0.25 mg/d once daily 1–2 mg/d split dosing
Olanzapine 2.5 mg/d once daily 10–15 mg/d split dosing
Quetiapine 25 mg/d once daily 200 mg/d split dosing
Clozapine 6.25 mg/d usually dosed at night 50–100 mg/d split dosing
Cognitive enhancers
Donepezil 5 mg/d once daily 10 mg/d once daily
Galantamine 8 mg/d split dosing 24 mg/d split dosing
Galantamine ER 8 mg/d once daily 24 mg/d once daily
Rivastigmine 3 mg/d split dosing (oral) 12 mg/d split dosing (oral)
4.6 mg (24-hour transdermal patch) 13.3 mg (24-hour transdermal patch)
Memantine 5 mg/d once daily 20 mg/d split dosing
Memantine ER 7 mg/d once daily 28 mg/d once daily
Anticonvulsants
Gabapentin 100 mg/d once daily 900 mg/d split dosing
Carbamazepine 100 mg/d once daily 300 mg/d split dosing
Topiramate 25 mg/d once daily 100 mg/d split dosing
b
Lamotrigine 25 mg/d once daily 200 mg/d split dosing
Hormonal treatments
Cyproterone acetate 10 mg/d once daily 10 mg/d once daily
Leuprolide 7.5 mg/d IM every month 7.5 mg/d IM every month
Medroxyprogesterone 100 mg/d IM every 2 weeks 300 mg/d IM every 2 weeks
IM = intramuscular.
a
In those age 65 years of age and older, the maximum recommended dose of citalopram is 20 mg/d24 and the maximum recommended dose
of escitalopram is 10 mg/d25 (Health Canada). The US Food and Drug Administration (FDA) recommends a maximum dose of 20 mg/d for
citalopram in those older than age 60.26 For escitalopram, the recommended dose is 10 mg/d in the elderly.27
b
If drugs that inhibit metabolism of lamotrigine (such as valproic acid) are used, the starting dose is 25 mg every other day.
790 JUNE 2018

Physical and Verbal Disruptive Behaviors KEY POINTS
Physical and verbal disruptive behaviors comprise one of the main safety concerns
● If environmental factors
posed by responsive behaviors and represent the most common concerns of are triggering behaviors,
family members and health care staff. These include aggressive behaviors such as reducing the impact of
hitting, kicking, pushing, throwing or tearing things, spitting, biting, scratching, the environment on the
and destroying property. Nonaggressive physical behaviors include exit seeking patient or modifying the
environment may be helpful.
and entering the rooms or personal space of others. Verbal aggressive behavior
includes cursing, screaming, and making disruptive noises. ● Disruptive behavior can
be an expression of either
NONPHARMACOLOGIC APPROACH. Because of the pervasiveness of these physical or emotional
behaviors, it is important to assess the frequency, degree of risk, and discomfort.
potential triggers. Keeping a log of when the behavior occurs, including

antecedents and consequences, will help to establish patterns of occurrence
and identify precipitating factors. This can also help target the most
appropriate times for intervention, corresponding with the peaks of the
behavioral display.
If environmental triggers are identified, patients can be removed from the
triggering environment and kept away from what is perceived as stressful, such
as noise and overstimulation. Providing earplugs or noise-canceling headphones
can help reduce the noise and subsequent stress experienced by the patient.
Additionally, the environment can be altered to meet the needs of the patient.
Examples are introducing white noise or calming music and minimizing
stimulating noise in the environment. Small changes in the environment can
make a big difference if patients are exit seeking or entering other patients’
rooms. For example, painting the exit door to look like a bookshelf, putting a
stop sign on the door of someone’s room, or covering the doorway with a sheet
may deter a patient from attempting to go through those doorways. The sheet
serves as a visual barrier blocking entrance to the room and thus need only be
about 2 feet to 3 feet wide.
Disruptive behaviors can indicate physical or emotional discomfort. This is
especially the case with restlessness; thus, it is important to look for subtle
clues suggesting discomfort or pain. It is important to think broadly in terms of
the causes of discomfort and pain that patients may experience; for example,
rectal prolapse, hemorrhoids, and constipation should not be overlooked. In
these situations, optimizing management of behavioral triggers is essential. As
illustrated in CASE 6-1, a small change in routine service delivery can alleviate
discomfort with significant effect and eliminate disruptive behaviors.
It is also important to assess for emotional distress, looking for features of
anxiety and depression. Patients with significant cognitive impairment may not
be able to verbalize that they are anxious or depressed. Depression should be
considered if the patient is tearful or seems to be very negative, especially if
the patient has withdrawn from activities and social interactions. Associated
symptoms include lack of appetite and poor sleep. Anxiety can be identified by
the appearance of being fearful, wringing of the hands, worried facial expression,
continuous requests for help or reassurance, or repeated vocalizations (CASE 6-2).
Premorbid history of depression, anxiety, or trauma can be an important clue to
the possible presence of emotional distress.
When emotional distress is suspected, behavioral interventions should focus
on creating a safe environment for the patient. Implementing appropriate
recreational activities, especially if they can create positive experiences, may be

helpful for patients who are depressed. Patients who are anxious may benefit
from being with calming people and being positioned close to the nursing station,
where they may feel safer.
PHARMACOLOGIC APPROACH. Before initiating medications to treat disruptive

behavior, it is important to explore if existing drugs are contributing to the
behaviors. It is helpful to review recent medication changes and explore the
possibility that these may have contributed to the emergence of symptoms.
Dopaminergic medications, as well as cholinesterase inhibitors and stimulating
antidepressants such as fluoxetine, may be activating and may thus contribute to
agitation. Reducing or eliminating these medications should be the first step if
they are felt to be contributing to disruptive behavior.
TABLE 6-3 Summary of Approach to Common Behaviors
Behavior Nonpharmacologic Approach Options Pharmacologic Approach Options
Physical and verbal Modify environment to be less stimulating Reduce or eliminate activating medications
disruptive behavior or triggering
Avoid antipsychotic medications unless
Remove patient from overstimulating acute safety concerns exist or psychosis is
environment driving behavior
Treat potential physical discomfort Use antidepressants if depression is thought to
drive behavior
Create an environment that is emotionally
supportive Consider using other classes of medications,
such as anticonvulsants or low-dose
benzodiazepines, or memantine
Avoidance and Try smaller and more frequent food portions Reduce or eliminate medications that can
resistive behavior if food is refused decrease appetite
Simplify medication regimen to improve Introduce medication that can stimulate appetite
compliance
Trial a stimulant if apathy is thought to be a factor
Cautiously hide medication in food or drink
Treat psychosis or mood if these are thought to
if the medication cannot be detected
drive the behavior
Prioritize the type and frequency of care that
Use sedating or calming medications before care
is required
Develop a gentle and soothing approach to
care that is understood by the patient
Perseverative and Optimize treatment of physical or emotional Treat obsessional qualities with serotonergic
repetitive behavior discomfort antidepressant medications
Provide more acceptable sensory stimulation, Target vocalization behavior with doxepin
including textured material and sound
amplification devices
Increase engagement in activities suited to
the patient’s abilities
792 JUNE 2018

Aggressive behaviors that put the patient or others at risk should be treated
urgently. Since atypical antipsychotics such as risperidone, olanzapine, and
quetiapine have the most evidence,28 they should be considered as a treatment
option and titrated up to a tolerated and effective dose, especially if psychotic
symptoms are thought to drive the aggressive behaviors. However, these
medications may cause extrapyramidal side effects that could impair gait and
predispose the patient to falls. Thus, if the patient has parkinsonism or balance
problems for other reasons, the authors suggest avoiding antipsychotics, if
possible, and considering a trial of trazodone because of its rapid onset of action
and sedative qualities. Moreover, if a patient has responsive behaviors without
psychosis, the authors often give a trial of trazodone before prescribing an
antipsychotic because of the better safety profile of trazodone, especially as related
to risk of falls. Other commonly used options include memantine29 because of
Behavior Nonpharmacologic Approach Options Pharmacologic Approach Options

Disinhibition and Provide appropriate outlets to show affection Investigate pain or discomfort in genital areas
hypersexuality
Allow patient privacy (alone or with spouse) Reduce or eliminate dopaminergic medications and
benzodiazepines
Use differential reinforcement strategies
Trial serotonergic antidepressant medications or
hormonal treatments
Hyperoral behavior Assess nutritional intake Reduce or eliminate medications that

stimulate appetite
Remove or secure objects that are dangerous
if ingested Trial serotonergic antidepressants, stimulants,
or topiramate
Remove patient from dining room when food
is served
Use cues to distinguish nonfood from food
items
Substitute unhealthy foods with healthy
choices or other forms of oral stimulation
Hallucinations and Provide support and education to caregivers Reduce or eliminate dopaminergic medications
delusions if symptoms are not harmful or distressing
Consider a cautious trial of antipsychotic
to patient
medication
Optimize visual and auditory senses or
Trial a cholinesterase inhibitor if indicated
enhance sensory stimulation
Trial an antidepressant medication if anxiety or
Do not argue with patient about
depression is present
delusional beliefs
Explore whether symptoms are an expression
of underlying feelings or attitudes

CASE 6-2 A 71-year-old non–English-speaking man was admitted to the hospital for
treatment of aggression, restlessness, sleep disturbance, and exit
seeking in the context of a 3-year history of cognitive impairment. Other
symptoms included incoherent speech, hallucinations, and delusions. His
medical history was positive for depression, anxiety, and mild hearing
loss. The differential diagnosis included dementia with Lewy bodies and
Alzheimer disease.
During admission, the patient’s anxiety presented as constant religious
chanting, worried facial expression, and rapid breathing. The patient
talked to himself in the mirror, voided urine inappropriately overnight,
was resistive to care (including being toileted and changed into clean
clothes), and was physically aggressive toward other patients and staff.
Interdisciplinary team discussion and consultation with family members
yielded the identification of several behavioral triggers, including fear
and shame of being disrobed, fear of personal items being stolen from
him, and fear of being assaulted by other agitated patients. Several
nonpharmacologic interventions were implemented. A pocket talker
(a sound amplification device equipped with a headset and microphone,
often worn around the neck or clipped to an individual’s clothing) was
introduced to target sensory deprivation due to hearing loss. Staff
ensured that his genital area was covered during care and did not provide
liquids after 8 PM. His mirror was covered. He was taken for a walk during
shift changes and offered headphones playing audio versions of his
religious texts to calm him when anxious or restless.
The pharmacologic approach first focused on targeting his restlessness.
Antipsychotics were initially avoided because he had mild parkinsonism,
and dementia with Lewy bodies was in the differential, raising concerns
about neuroleptic sensitivity. Trazodone was started at a small dose and
slowly increased. As restlessness started improving, anxiety symptoms
became more prominent and escitalopram was started. Escitalopram was
not helpful, and he began to have difficulty sleeping at night, so it was
stopped and mirtazapine was tried with good results. Although his anxiety
and sleep improved, he had episodes of physical aggression that put other
patients and staff at risk. At this point, quetiapine was cautiously added,
and his aggressive behavior resolved.
COMMENT This case highlights the importance of gaining family input, the contribution
of cultural background, and the impact of sensory deprivation on symptom
presentation. This case also demonstrates using a strategic pharmacologic
approach that targets specific symptoms in isolation, using both
evidence-based and practical considerations.
794 JUNE 2018

its potential calming effect and selective serotonin reuptake inhibitors (SSRIs) KEY POINTS
based on literature that citalopram may be beneficial for aggression.30
● It is important to reduce
Anticonvulsants, especially carbamazepine, may have some benefit. Limited or eliminate medications
evidence exists for the use of gabapentin, lamotrigine, and topiramate.31 that may be contributing to
Cautious use of benzodiazepines, such as lorazepam as a relatively short-acting disruptive behavior.
drug, may be considered as well. If a long-acting benzodiazepine is needed,
● Avoidant and resistive
clonazepam may be considered.
behaviors can be driven by
If depression or anxiety are suspected, an SSRI, such as citalopram, medical contributors such
escitalopram, or sertraline, is often used initially. If this is not helpful, a serotonin as pain, infection, and
norepinephrine reuptake inhibitor (SNRI), such as duloxetine or venlafaxine, swallowing difficulties
may be tried. If more immediate results are needed, trazodone can be used for or by neuropsychiatric
contributors such as
its calming effect and sedative properties. Trazodone and mirtazapine may depression and psychosis.
also be helpful if a patient has associated sleep disturbance. For anxiety, a
benzodiazepine, such as lorazepam or clonazepam, in small doses may be ● Treating behaviors that
helpful. Antipsychotics, particularly quetiapine, can be helpful for mood and prevent provision of
personal care requires
anxiety symptoms, especially if a patient has associated psychotic symptoms. looking for compromises in
nonessential tasks and
Avoidance and Resistive Behavior providing education to
Patients who are resistant to taking their medication or eating food pose a family and caregivers.
common challenge.
NONPHARMACOLOGIC APPROACH. As for other behaviors, it is important to look

for common causes, including pain, infection, or other medical contributors.
Swallowing ability should also be assessed. Looking for indications of paranoia or
depression can help uncover additional factors driving these behaviors. It is
important to assess the nutritional requirements for patients refusing meals. At
times, substituting meal supplements or introducing smaller food portions more
frequently throughout the day may be an acceptable compromise that allows
for adequate nutrition. Marginally beneficial medications can be reduced and
stopped or the schedule of medication can be simplified to once or twice a day
if possible. Observing when and with which activities the patient seems to be
more compliant can aid in the selection of appropriate times to provide meals,
snacks, and medications. Crushing or substituting rapidly dissolvable or liquid
forms of medications or changing the texture of food may be helpful. Hiding
medication in food or drink can be a good strategy as long as the patient is not
able to detect the medication by vision, taste, or smell.
Refusal, avoidance, or physical and verbal aggression during provision of
care is very common in patients with dementia. Occasionally, this is prompted by
compromised intellectual capacity that limits the patient’s understanding of why
he or she is being disrobed or handled, leading to distress and subsequent
resistive behavior. Helping the caregiver prioritize the type and frequency of
care that is required can be helpful. It may be reasonable for the patient not to
shower or shave daily, although this was the norm in the past. Educating
family members about balancing the need to keep the patient calm and safe
versus hygiene factors is important, as many family members have difficulty
letting go of habitual routines. A certain level of hygiene is necessary,
however, and once it is determined that care needs to be provided, the way
care is delivered should be tailored to the patient’s cognitive capacity. It is
important to use a gentle persuasive approach and speak in a calm manner,
using short sentences and simple commands to clearly explain what will be done

before doing it. For patients whose verbal comprehension is compromised,

using visual cues to communicate the caregiver’s intentions in the form of
pictures and gestures may be useful. Establishing a care routine so that the
patient and family know what to expect can be assistive. Incorporating music
and other calming environmental stimuli may also be helpful. Wherever
possible, it is helpful to include the patient in care provision. For example,
asking the patient to hold the washcloth or toothbrush may facilitate
cooperation. Care can also be modified; for example, a sponge bath of the
genital and perineal area may be provided as opposed to a full shower if the
patient is highly agitated.
PHARMACOLOGIC APPROACH. Some medications can cause either stomach upset

or reduced appetite, leading to refusal to eat. These include cholinesterase
inhibitors and serotonergic medications. Reducing or eliminating these
medications may be helpful.
Certain medications are known to stimulate appetite and can be used if
patients refuse to eat and are losing weight. Antipsychotics, especially
olanzapine, may increase appetite and cause weight gain. This is a particularly
good option if some degree of psychotic symptoms is present. Mirtazapine also
stimulates appetite and is an especially good option if depression or anxiety is
present. Mirtazapine is also a sedating medication in low doses and can be used if
sleep disturbance is present. However, in higher doses, mirtazapine can lose its
sedating effect and become stimulating.32 The authors sometimes use megestrol,
which is used for chemotherapy-induced anorexia, to help stimulate appetite.
If apathy is thought to be driving reduced appetite, a stimulant such as
methylphenidate may be tried.33
If paranoia or psychotic symptoms are suspected to be driving responsive
behaviors, antipsychotics should be considered. Depressive and anxiety
features that may be contributing to behavioral symptoms can be treated
with antidepressants.
Behaviors during care are difficult to treat pharmacologically. A sedating or
calming medication, such as lorazepam or trazodone, can be given before care
with the hope that the medication will have some effect by the time care is
administered. At times, it is sufficient to change the timing of sedating or calming
medications to administration just before care provision. In patients who have
evidence of other symptoms during the day, such as psychosis, mood, or
agitation in general, targeting these symptoms may result in less agitation
during care.
Perseverative and Repetitive Behavior

Perseverative and repetitive behaviors are common in dementia. Examples
include repetitive banging, skin picking, asking questions, and calling out for
help. These behaviors can be disruptive to caregivers, family members, staff, and
other patients and can even be harmful to the patients themselves.
NONPHARMACOLOGIC APPROACH. These behaviors can be conceptualized as

arising from a need to self-soothe or a lack of stimulation. A patient who is banging
his or her head against the wall repetitively may be in some type of distress and
trying to self-soothe and obtain comfort. Investigating physical sources of distress,
such as pain or discomfort, is extremely important. Localizing the source of
796 JUNE 2018

discomfort can be challenging, although clues often exist. For example, repetitively KEY POINTS
picking skin on the hand and banging the hand against objects can indicate pain
● Perseverative and
or discomfort in the hand. Emotional discomfort can be targeted by providing repetitive behaviors can be
emotional support in the form of individual attention or conversation. Sensory related to physical or
deprivation can be approached by providing other, more appropriate, sources emotional discomfort or to
of sensory stimulation using several different senses. For example, patients can sensory deprivation.
be provided with nonharmful textured objects to feel, such as carpet samples
● Disinhibited and
with different textures or piles. Some children’s toys may also provide sensory hypersexual behaviors can
stimulation if the patient is able to manipulate different components that are be driven by need for
movable and can generate sounds. Sound amplification devices (such as pocket affection and intimacy and
talkers or hearing aids) and corrective eyeglasses may also provide needed mediated by difficulties
with judgment.
sensory input (CASE 6-2). Patients suspected of not having enough stimulating
purposeful activity can be engaged in activities suited to them, such as playing a
game (eg, cards), painting or drawing, and playing catch with a ball or balloon.
PHARMACOLOGIC APPROACH. The obsessional quality to these behaviors

suggests that medications commonly used in obsessive-compulsive disorder may
be helpful. These include SSRIs such as escitalopram and sertraline. Tricyclic
antidepressants, such as clomipramine, are less well tolerated but can be
helpful.34 In vocalizations, doxepin has shown some indication of benefit.35
Disinhibition and Hypersexuality

Disinhibition and hypersexual behaviors can be both distressing and harmful.
Although these behaviors are typically linked with behavioral variant
frontotemporal dementia (bvFTD),14 they can be found in other forms of
dementia as well. Common examples include taking food from other people’s
plates, disrobing, exposing the genital area, masturbating, making physical or
verbal sexual advances, and asking inappropriate personal questions of staff or
other patients.
NONPHARMACOLOGIC APPROACH. These behaviors can, at times, be driven by

the need for affection or physical or emotional intimacy. Ensuring that the
patient experiences affection even in nonsexual ways is important. The need
for affection through touch can be facilitated by providing a pet (live, toy, or
robotic) for the patient to touch and stroke.
The sexual needs of patients with dementia are an important and often
neglected topic. The patient’s partner may struggle with understanding the
physical and emotional changes in their relationship. It is important to be
supportive and allow the patient and partner permission to have open discussions
about these challenges and to help problem solve when needed. Couples often
have difficulty with intimacy in institutional settings because of lack of privacy.
Ensuring the availability of private time without interruption by staff or other
patients is important.
Some situations can evoke ethical concerns or discomfort from family or staff.
For example, a patient engaging another patient in sexual activity in an
institutional setting brings up considerations of capacity and, at times, legal
concerns. These concerns should be clarified and the family engaged to make
decisions that are in the best interest of their loved one. Another example is
disrobing or masturbating, which can elicit discomfort in staff or family. Family
and staff often benefit from education about the nature of sexual needs and urges

in the patient with dementia to allay feelings of guilt or anger at the patient for
acting on sexual urges. Allowing for behaviors that do not harm others in a safe
and private environment can be a reasonable approach.
Some disinhibited sexual behaviors are not appropriate and need to be
modified. Using behavioral techniques such as differential reinforcement to
reward patients when they do not display sexual behavior can condition them to
act more appropriately. For example, consider a patient who exposes his genitals
to others. After carefully assessing the frequency of the behavior, it is determined
that he exposes himself approximately every 20 minutes. Providing incentives or
rewards for 20-minute periods when he has not exposed himself can reduce the
reoccurrence of the genital exposure over time.
PHARMACOLOGIC APPROACH. It is important to look for medical contributors

to disinhibited and sexual behavior. Pain or discomfort in the genital area can
lead to behaviors involving the genitals, such as self-stimulation and exposing.
Dopaminergic medications can also drive these behaviors, as can benzodiazepines,
which can cause disinhibition. Reducing these medications and treating any pain
triggers are important first steps in managing these behaviors.
A number of pharmacologic treatments exist for inappropriate sexual
behavior.36 Antidepressant medications may be used to capitalize on the
common side effect of sexual dysfunction. They may also have antiobsessive
properties that can be helpful. Common antidepressants used in these situations
include trazodone, paroxetine, citalopram, and clomipramine. Some evidence
exists for the use of quetiapine. Hormonal medications, such as cyproterone,
medroxyprogesterone, and leuprolide, can also be helpful in patients with
inappropriate sexual behavior.
Hyperoral Behavior
Hyperoral behavior is a key feature in bvFTD14 but is also found in other
dementia syndromes. A spectrum of problematic behaviors that involve eating
and oral behavior exists. Increased food cravings and carbohydrate intake can
lead to significant weight gain and metabolic disorders. Food-seeking behavior
can lead to stealing or grabbing food from others, which can ultimately lead to
interpersonal conflict and physical harm. Rapid eating of food or oral exploratory
behavior can present an aspiration or asphyxiation risk. Eating nonedible objects
can be dangerous, such as in the case of a patient who ate raw meat, telephone
cords, rubber gloves, and feces.
NONPHARMACOLOGIC APPROACH. In trying to manage hyperoral behavior,

it is helpful to involve a dietitian to assess nutritional intake to ensure that meals
and appropriate nutrients are being consumed. Clearly maintaining a safe
environment is important, and objects that are harmful and can be put in the
mouth, including poisonous plants, should be secured or removed. At times, it
may be helpful to remove the patient from a common dining room when food is
present, such as during mealtimes when the patient may grab food from other
patients. Visual perceptual difficulties or deficits in object recognition may lead
the patient to identify some nonfood items as food. In these situations, using
creative cues to allow the patient to distinguish nonfood from food items can be
helpful, for example, teaching the patient that food items will only be presented
to him or her on a red placemat and that anything not on the red placement is not
798 JUNE 2018

fit for consumption. Substituting less healthy foods with other foods that have KEY POINTS
fewer calories can also be attempted. The need for oral stimulation can be targeted
● When hyperoral behavior
by using a baby chew toy, wet washcloth, or chewing gum, if deemed safe. is present, it is essential to
ensure that the environment
PHARMACOLOGIC APPROACH. Before trying to treat hyperoral behavior is safe from objects that can
pharmacologically, it is important to review the medications the patient is be harmful if ingested.
already taking. Some medications have a propensity to increase appetite and food
● Psychotic symptoms that
intake, which may be driving the hyperoral behavior. Any of the atypical are not distressing or
antipsychotics can do this, especially olanzapine and clozapine. Antidepressants harmful to others do not
also have this quality, especially mirtazapine. If feasible, these medications need to be treated.
should be reduced or eliminated.
The anticonvulsant topiramate has some evidence for reducing weight gain
related to antipsychotic medications37 and binge eating disorders38 and may play
a role in treating hyperoral behavior in dementia.39 Medications that target
obsessional behaviors, such as SSRIs40 and clomipramine,34 can be tried. Stimulants
may be helpful in treating binge eating disorder.41 Thus, trying a stimulant such
as methylphenidate may be considered if other strategies are not helpful.
Hallucinations and Delusions

Psychotic symptoms are common in dementia and are the most strongly linked
to poor outcome, long-term care placement, and caregiver stress.8,42 Although
psychotic symptoms themselves may not be agitated or aggressive behaviors,
they are commonly the driving factor for these behaviors. Psychotic symptoms
are part of the diagnostic criteria for dementia with Lewy bodies (DLB) but are
also common in other dementias, including Alzheimer disease, bvFTD, and
vascular dementia.43
NONPHARMACOLOGIC APPROACH. The most frequent perceptional abnormalities

that result in behavioral difficulties are visual and auditory hallucinations.43
Delusions are defined as “fixed beliefs that are not amenable to change in light of
conflicting evidence.”44 These can emerge in dementia and frequently lead to
behavioral difficulties. Common delusional themes in patients with dementia
include persecution (eg, someone is trying to steal from them or harm them
in some way), grandiosity (eg, they are special or have special abilities), and
infidelity (eg, spouse is being unfaithful).
Although psychotic symptoms often lead to behavioral difficulties, this is
not always the case. For example, in DLB, it is quite common for the patient to
have nondistressing or even pleasant visual hallucinations. The inability to
recognize one’s reflection in the mirror, a form of delusional misidentification
syndrome (also known as the mirror sign delusion), is common in DLB
(CASE 6-2).45 These examples highlight the fact that not every symptom
requires treatment.6 The most helpful intervention when delusions do not
require treatment is often providing education to the caregivers and family
members about the nature of the disease and providing support to deal with
these distressing symptoms.
Inadequate sensory stimulation resulting from poor vision or hearing can
contribute to the emergence of hallucinations (CASE 6-2).8 Assessing a patient’s
vision and hearing is therefore an important first step in determining the cause of
hallucinations. Optimizing the visual and auditory senses by introducing assistive
devices, such as a hearing aid, a pocket talker, or eyeglasses, can be helpful in

eliminating or reducing hallucinations. At times, it is helpful to consider

enhancing sensory stimulation through other means, such as by brightening
the lights, talking louder, or playing music. Stimulating other senses may be
beneficial as well, such as by introducing aromatherapy or massage therapy.46
In one case, a patient had a delusion in which he believed he heard people talking
about him. The muffled sounds of people talking in the hallway outside of his
room contributed to this delusion, which was resolved when a white noise
machine was used to block out the noise from the hall.
Since delusions are fixed and firm beliefs, it is not wise to argue with the
veracity of the delusion. Rather, agreeing or accepting the beliefs as the patient’s
reality is often more helpful. Caregivers and staff could, in some cases, play along
with a delusion to reduce agitation or aggression. For example, a patient who
believes that he or she is the chief executive officer of a company may benefit
from being treated as if he or she is in the office, and, where appropriate, creating
an office environment in the patient’s room may be useful.
Delusions may be an expression of an underlying feeling or attitude. For
example, in the case of a delusion regarding infidelity, the patient may be trying
to communicate feelings of abandonment, loneliness, or estrangement from
his or her spouse, which are not uncommon feelings in the disease process as
relationships undergo many changes. Awareness of these possible feelings
may facilitate management.
PHARMACOLOGIC APPROACH. When considering the use of medications to

treat psychotic symptoms, first consider whether the patient’s current
medications can contribute to the psychotic symptoms being targeted. For
example, dopaminergic medications, such as pramipexole or levodopa, are
known to contribute to psychosis.47 If medication effects are suspected,
slowly reducing the dose or discontinuing the medication should
be considered.
If nonpharmacologic strategies are not sufficient to manage the symptoms,
antipsychotic medication may be warranted. It is important to be familiar with
adverse effects of antipsychotic medications, including an elevated risk of
cerebrovascular events. Antipsychotics also carry a black box warning from the
US Food and Drug Administration (FDA) about an increased risk of mortality
with their use in dementia.48 Despite these risks, antipsychotics have the
strongest evidence for efficacy28 and are commonly used, especially if a patient is
in significant distress or safety concerns are present. Typically, substitute
decision makers will agree to these medications despite the risks when the
rationale is explained clearly. Of the antipsychotic medications, risperidone has
the advantage of being less sedating and less likely to cause orthostatic
hypotension than other antipsychotics. However, it does have a higher risk of
extrapyramidal symptoms than the other atypical antipsychotics. Olanzapine is a
sedating atypical antipsychotic and commonly causes weight gain. These
properties can be used in situations in which sedation is desired or if a
patient refuses to eat and is losing weight. Quetiapine has a low risk of
extrapyramidal symptoms and is useful when concern exists about extrapyramidal
side effects such as in Parkinson disease or DLB. It may also have some
mood-stabilizing properties. In patients with high sensitivity to extrapyramidal
symptoms, clozapine should be considered and started in low doses.49 Frequent
blood work is required when using clozapine to monitor for agranulocytosis.
800 JUNE 2018

Some evidence exists that cholinesterase inhibitors can be helpful for KEY POINT
psychotic symptoms.50,51 Therefore, it is worth considering a trial of this class
● It is not useful to argue
of drug, especially if significant concern exists about neuroleptic sensitivity. with patients about the
This is also an option if the patient’s psychotic symptoms are not severe enough veracity of hallucinations
to require urgent treatment and the patient already has an indication for a and delusions.
cholinesterase inhibitor, such as Alzheimer disease or DLB. Cholinesterase
inhibitors may also be helpful if the patient has coexisting apathy, since they can
be activating.52 If depression or anxiety is also present, using an SSRI, such as
citalopram or escitalopram, is a good option since an SSRI could treat these
symptoms and may be helpful in treating the psychotic symptoms.30
CONCLUSION
Treating responsive behaviors in patients with dementia is both rewarding and
challenging. Ultimately, as with other interpersonal interactions, the physician
must remember that responsive behavior management requires personal focus
and finesse. Adjusting to the trial-and-error nature of treatment requires
perseverance in the face of stagnation or regression and the willingness to continue
to pursue successful management despite the challenges. The physician’s ultimate
goal is not to cure the disease but rather to bring the patient’s behaviors to a
more manageable level. This definition of success can be distressing to the
physician who is accustomed to full eradication of disease or symptoms as the
primary goal. Maintaining a mindful approach to disease management that uses
both pharmacologic and nonpharmacologic strategies will help the physician more
effectively manage the behavioral symptoms of dementia.
ACKNOWLEDGMENTS
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Psychiatry 2005;7(5):238–241.

REVIEW ARTICLE

Mood Disorders
C O N T I N UU M A UD I O By Jeffrey Rakofsky, MD; Mark Rapaport, MD
ONLINE
CITE AS:
CONTINUUM (MINNEAP MINN) ABSTRACT
2018;24(3, BEHAVIORAL NEUROLOGY PURPOSE OF REVIEW: This article discusses the prevalence of the major mood
disorders (major depressive disorder and bipolar disorder) in the
community and within neurologic settings, articulates the steps taken to
Dr Jeffrey Rakofsky, 12 Executive make a diagnosis of major depressive disorder or bipolar disorder, and
Park Dr, Room 348, Atlanta, GA reviews old and newer treatment options with proven efficacy for the
30329, jrakofs@emory.edu.
treatment of these two conditions.
Dr Rakofsky receives research/ RECENT FINDINGS:New medications are available as treatment options for
grant support from ACADIA
Pharmaceuticals Inc; the American
major depressive disorder and bipolar disorder, such as intranasal and IV
Board of Psychiatry and ketamine, and somatic treatments, such as deep brain stimulation and
Neurology; Assurex Health; vagal nerve stimulators, are being used to target treatment-resistant
AstraZeneca; Janssen Global
Services, LLC; the National depression.
Institute of Mental Health
(RO1MH073719-05A1, 7R01MH10
SUMMARY: Mood disorders are common in neurologic settings. They are
4964-02); and the National Center
for Complementary and Integrative disabling and increase morbidity and mortality. Clinicians should have a
Health (1UG3AT008857). Dr high index of suspicion if they suspect their patients seem more distressed
Rapaport serves as editor-in-chief
of Focus: The Journal of Lifelong
or incapacitated than would be warranted by their neurologic disorders. If
Learning in Psychiatry and on the a patient does have a mood disorder, validating the patient’s experience,
editorial boards of CNS initiating treatment, and, if necessary, referring the patient to a primary
Neuroscience and Therapeutics;
CNS Spectrums; Current Psychiatry; care physician or psychiatrist are appropriate steps.
Depression Research and
Treatment; Innovations in Clinical
Neuroscience; Journal of Addictive
Behaviors, Therapy & Rehabilitation;
The Journal of Clinical Psychiatry; INTRODUCTION
M
and Shanghai Archives of ood disorders are a group of psychiatric illnesses that can
Psychiatry. Dr. Rapaport receives
research/grant support from the
simultaneously affect one’s emotions, energy, and motivation.
National Center for Complementary The two most prominent examples are major depressive disorder
and Integrative Health (UG3 and bipolar disorder, which are the focus of this article. Major
AT008857-01, R01 AT009169-01)
and the National Institute of depressive disorder is a psychiatric illness that has a lifetime
Mental Health (MH100023-01, prevalence of 16%,1 while bipolar disorder has a lifetime prevalence of close to
1R25MH101079-01). 5%, inclusive of all patients on the bipolar disorder spectrum.2 Both conditions are
UNLABELED USE OF
associated with poor quality of life3,4 and increased mortality,5,6 and major depressive
PRODUCTS/INVESTIGATIONAL disorder is the second leading cause of disability in the world.7 Within primary care
USE DISCLOSURE: settings, 13% to 17% of patients screen positive for symptoms of depression, while 33%
Drs Rakofsky and Rapaport discuss
the unlabeled/investigational use of
of patients seen in a neurologic outpatient setting screen positive for depressive
buspirone, pramipexole, and symptoms.8 Thus, neurologists are likely to encounter patients with major depressive
thyroid hormone as adjuncts to an disorder or bipolar disorder and should be familiar with these diagnoses, their
antidepressant in the treatment
of major depression and ketamine treatments, and the signs and symptoms that overlap neurologic illnesses.
for treatment-resistant patients
who are depressed and suicidal.
EPIDEMIOLOGY AND COURSE OF ILLNESS
The median age of onset for major depressive disorder is 32 years of age.9 The
of Neurology. average duration of a recurrent episode is about 20 weeks.10 Sixty percent of
804 JUNE 2018

patients will have a recurrence at some point after their first episode, while a 74% KEY POINTS
chance of a recurrence exists after a second episode and a 90% chance after a
● Within primary care
third episode (CASE 7-1).11,12 Women are 1.7 times more likely to develop an settings, 13% to 17% of
episode of major depressive disorder than men, and the difference in prevalence patients screen positive for
is not influenced by socioeconomic status or country of origin. This suggests symptoms of depression,
that hormonal and developmental differences in brain circuitry may contribute while 33% of patients seen in
a neurologic outpatient
more to this ratio than socioeconomic disparities between the sexes.13
setting screen positive for
Major depressive disorder has a significant genetic component associated with depressive symptoms.
its etiology. Genetic studies have revealed a heritability of 37% and a 2.8 times
increased risk for developing this illness among first-degree relatives of probands ● Genetic studies have
with major depressive disorder.14 Some individuals will have a seasonal onset revealed a heritability of 37%
and a 2.8 times increased
of depressive episodes occurring every winter or every spring. For others, risk for developing major
episodes are either triggered by stress or occur spontaneously independent of any depressive disorder among
physical or psychological stressor. Studies demonstrate that first-onset episodes first-degree relatives of
are more likely to be related to a severe life event than recurrences.15 Consistent probands with major
depressive disorder.
with the data demonstrating that major depressive disorder is more prevalent in
women than men are data linking changes in reproductive hormone levels and ● Among patients who have
mood disorders: hormonal fluctuations are thought to be key to the pathogenesis recovered from their first
of the premenstrual worsening of depression symptoms reported by some manic episode, 40% will
have a recurrence into
patients and the etiologies of postpartum onset of depression and
depression or mania within
perimenopause/postmenopause-onset depression.13 the subsequent 2 years.
Bipolar disorder consists of several different types of mood episodes
(depression, mania, hypomania, mixed episodes), which are described in more ● Nearly 75% of people with
detail later in this article. Bipolar I disorder is a diagnosis reserved for those who a lifetime history of major
depressive disorder will
have had manic episodes, while bipolar II disorder is used for those who have have another psychiatric
never had a manic episode but have had hypomanic episodes and at least one illness at some point in
major depressive episode.16 The mean age of onset is 18.2 years for bipolar I their lives.
disorder and 20.3 years for those with bipolar II disorder.2 Depressive episodes
treated naturalistically (in a clinic setting, not as part of a clinical trial) have a
median duration of 15 weeks, while the median duration is 7 weeks for manic
episodes and 3 weeks for hypomania.17 Over the course of their illness, patients
will spend more time depressed than in elevated mood states.18,19 Among patients
who have recovered from their first manic episode, 40% will have a recurrence
into depression or mania within the subsequent 2 years.20 In contrast to major
depressive disorder, in bipolar I disorder, women are just as likely to be affected
as men, whereas in bipolar II disorder, women are twice as likely to be affected.21
Bipolar disorder is considered to be highly genetic, with a heritability of 89%.22
Among first-degree relatives of a bipolar proband, the risk of having bipolar
disorder is 8.7%.23 Twin studies reveal monozygotic concordance rates of 40%
compared to dizygotic concordance rates of 5.4%.22 This suggests that while
genetics play a large role in determining illness onset, environmental factors exist
as well. Unlike major depressive disorder, bipolar disorder episodes, in particular
mania and hypomania, can be triggered by events that impact circadian rhythms
(eg, sleep deprivation, seasonal change, time zone travel) and exposure to
rewarding stimuli (eg, falling in love, starting a creative project, a period of
personal growth).24
COMORBIDITY
Nearly 75% of people with a lifetime history of major depressive disorder will
have another psychiatric illness at some point in their lives.1 Anxiety disorders

MOOD DISORDERS
are most prevalent, with nearly 60% of patients with depression meeting criteria
for one of these conditions, while substance-use disorders are seen in as many
24% of patients with major depressive disorder.1 Major depressive disorder is also
highly comorbid with other medical conditions, including obesity, hypertension,
diabetes mellitus, rheumatologic disorders, immune-mediated dermatologic
disorders, and cardiovascular disease.25 Depression is frequently observed in
patients with neurologic disorders. The prevalence rates of comorbid depression
are 30% to 50% for patients with Alzheimer disease, 20% to 72% for patients with
stroke, 40% to 50% for patients with Parkinson disease (CASE 7-1), 19% to 54%
for patients with multiple sclerosis (MS),26 and 7% to 63% for patients with
obstructive sleep apnea.27
Comorbidity is also very common in bipolar disorder. Approximately 75% of
patients with bipolar disorder are diagnosed with an anxiety disorder at one time
CASE 7-1 A 68-year-old man with a 2-year history of Parkinson disease presented
with symptoms of depression. He had experienced his first episode of
depression in his early thirties after losing a job. This episode resolved
after several months without any treatment. A second episode occurred
in his early forties after his father passed away, with this episode lasting
several months before the patient sought treatment from a psychiatrist,
who started him on the antidepressant fluoxetine, titrating the dose to
40 mg/d. Within 6 weeks, his symptoms fully resolved. He stayed on
fluoxetine for a full year without any additional depressive symptoms; at
that time, he decided to taper off the medicine. Since being diagnosed
with Parkinson disease, his motor symptoms had been well controlled
with carbidopa/levodopa 25 mg/100 mg 3 times a day.
The patient stated that over the past month, he had been waking up
feeling down in the morning. When he took his Parkinson medicine, it
helped his mood a bit, but he still felt lower than normal. He was sleeping
much later into the morning and was taking naps, both of which were
unusual for him. He no longer was interested in spending time with his
children and grandchildren, something he had always looked forward to
in the past. He denied suicidal ideation, but he felt worthless and
believed that he was no good to anyone. His wife reported that he had
recently become forgetful. When it was explained to the patient that he
might be experiencing a recurrence of depression, the patient stated that
this felt different than the depression he experienced earlier in his life.
Neurologic examination showed a depressed affect. Examination
was otherwise unremarkable other than his baseline signs of mild
parkinsonism. Laboratory evaluation, including thyroid function tests,
was normal. Brain MRI revealed mild nonspecific white matter
hyperintensities. Neuropsychological assessment revealed slight deficits
in executive function, memory, and attention. However, the report also
indicated that the patient often said, “I can’t do this” after being given
instructions on a task. When gently pushed to continue, he performed
as instructed.
806 JUNE 2018

in their life; 42.3% are diagnosed with a substance-use disorder and 62.8% with
an impulse control disorder,2 while approximately 60% are diagnosed with a
personality disorder.28 Medical illnesses, including asthma, type 2 diabetes
mellitus, hypercholesterolemia, epilepsy, kidney disease, and thyroid disease, are
up to 6 times more common among those with bipolar disorder than among
healthy controls and those with major depressive disorder.29 Neurologic illnesses
among a sample of 1720 British patients with bipolar disorder included epilepsy
(3.4%), dementia (2%), migraine (23.7%), MS (0.5%), Parkinson disease (0.6%),
and stroke (2.5%).29
PATHOPHYSIOLOGY
Over many decades, researchers have developed several theories to explain the
biological causes of major depressive disorder. It is now thought that our current
He was referred to a psychiatrist, who started him on bupropion XL

150 mg/d for 4 days, which was then increased to 300 mg/d. This led to
some improvement in symptoms over the subsequent 4 weeks, but his
depressed mood and excessive sleeping continued. The psychiatrist then
increased the dose of bupropion XL to 450 mg/d, and within a month, the
patient’s mood and cognitive symptoms resolved completely. The
psychiatrist convinced the patient to stay on the medicine for the long
term to prevent recurrences.
This case exemplifies the diagnostic complexity faced by physicians when COMMENT
treating patients with neurologic illness and symptoms of depression. This
patient had a history of major depressive disorder and had depressive
episodes that predated the onset of his Parkinson disease by several
decades. This patient had never had a manic or hypomanic episode, which
rules out bipolar disorder as a cause of the depressive episodes. As is often
the case, the patient had more than one episode of depression over the
course of his life. It is possible that the onset of his Parkinson disease brought
on a recurrence of depression, either from the psychological stress
associated with it or from its effect on brain circuitry. This patient reported
that his current episode of depression seemed different than his earlier
episodes. Given this different presentation, his cognitive symptoms, and his
comorbid parkinsonism, the neurologist was justified in ordering an MRI. The
patient’s performance, and, in particular, his tendency to avoid exerting full
effort during the neuropsychological testing are typical for depressed patients.
Although fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was helpful
for the patient’s depression in the past, now that the patient had Parkinson
disease, the use of bupropion, a medicine that affects central dopamine release,
was justified. The psychiatrist’s recommendation that the patient take
antidepressants for the duration of his life was made to help the patient prevent
future depressive episodes. The patient had already had three depressive
episodes and was likely to have more down the road.

MOOD DISORDERS
KEY POINT construct of major depressive disorder encompasses a complex heterogeneous

syndrome in which multiple different defects can lead to a cascade of events that
● It is now thought that our
current construct of major
cause the development of a depressive endophenotype. Investigations into the
depressive disorder etiologies of major depressive disorder include studies at the genetic, epigenetic,
encompasses a complex cellular, synaptic, neurochemical, circuit, and systems level.
heterogeneous syndrome in The monoamine hypothesis of depression was one of the first biologically
which multiple different
based theories of the etiology of depression. It was developed based on the early
defects can lead to a
cascade of events that observations that antidepressant medications increased synaptic levels of
cause the development of a monoamines and that acute depletion of monoamines led to a depressivelike state
depressive endophenotype. in both human and nonhuman primate models of depression. The theory
suggested that a reduction of monoamines in the central nervous system was the
underlying cause of the illness.30 However, this idea was challenged following
studies that depleted brain serotonin and norepinephrine levels in healthy
subjects and in those with major depressive disorder. Only the latter developed
depressive symptoms, suggesting that acute monoamine perturbations were only
part of the story of depression.31 Postmortem and positron emission tomography
(PET) imaging studies suggest increased levels of 5-hydroxytryptamine 1A
(5-HT1A) autoreceptors in the dorsal raphe neurons may play a role in the
development of major depressive disorder by lowering the tonic level of
serotonin within synapses.32
The neurotrophic hypothesis of the etiology of major depressive disorder
represents a second line of investigation. Proponents postulate that depression
results from a reduction in neurotrophins (eg, brain-derived neurotrophic factor
[BDNF]) that leads to neuronal atrophy, loss of glia, decreased hippocampal
neurogenesis, and impaired brain circuitry. Antidepressants have been shown to
both increase BDNF levels and reverse the atrophy.33 In line with the neurotrophic
hypothesis, subanesthetic doses of ketamine rapidly reduce symptoms of
depression and, within the same time frame, increase synaptogenesis by
increasing dendritic spine function and number in the prefrontal cortex.33
This cascade of intracellular signaling is believed to be initiated by ketamine’s
blockade of the N-methyl-D-aspartate (NMDA) receptor on inhibitory
g-aminobutyric acid–mediated (GABA-ergic) interneurons.34
Neuroinflammation has been implicated as a cause of major depressive
disorder in a subset of patients.35 A shift in the balance of proinflammatory and
anti-inflammatory cytokines toward the former can have a number of central
nervous system effects: (1) it can divert tryptophan metabolism away from
serotonin production and toward the production of excitotoxic chemicals, such
as quinolinic acid; (2) it may reduce glucocorticoid receptor sensitivity, leading
to chronic cortisol release and hippocampal damage; and (3) it can create a
greater number of reactive oxidative species and cell death in patients who may
already have decreases in antioxidant capacity.35,36
These theories and others not discussed here are a reflection of the biological
heterogeneity that is believed to underlie major depressive disorder. Many of
these same theories have been used to explain the pathophysiology of bipolar
disorder, including neuroinflammation,37 reduced antioxidant capacity,38 and
the neurotrophic hypothesis.39 One theory unique to bipolar disorder relates
mood episode recurrences to desynchronized circadian rhythms and points
to genetic polymorphisms on genes that affect the circadian timing system
(eg, circadian locomotor output cycles kaput [CLOCK], glycogen synthase
kinase 3 beta [GSK3B]); delays in melatonin secretion among people with bipolar
808 JUNE 2018

disorder; an inherent less-than-24-hour free-running circadian rhythm; and the
ability of lithium and valproate, first-line treatments for bipolar disorder, to
influence the rhythmic expression of circadian proteins and the rhythmic
function of molecular clocks.40
DIAGNOSIS
The diagnostic criteria for major depressive disorder (TABLE 7-1) and the manic
(TABLE 7-2) and hypomanic (TABLE 7-3) episodes of bipolar disorder can be
found in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5).16 The criteria for a major depressive episode are the same in bipolar
disorder and major depressive disorder. Several symptoms must be present and
other conditions must be ruled out to make the diagnosis. For major depressive
DSM-5 Diagnostic Criteria for Major Depressive Disordera TABLE 7-1
A Five (or more) of the following symptoms have been present during the same 2-week
period and represent a change from previous functioning; at least one of the symptoms is
either (1) depressed mood or (2) loss of interest or pleasure.
Note: Do not include symptoms that are clearly attributable to another medical condition.
1 Depressed mood most of the day, nearly every day, as indicated by either subjective report
(eg, feels sad, empty, hopeless) or observation made by others (eg, appears tearful).
(Note: In children and adolescents, can be irritable mood.)
2 Markedly diminished interest or pleasure in all, or almost all, activities most of the day,
nearly every day (as indicated by either subjective account or observation).
3 Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of
body weight in a month), or decrease or increase in appetite nearly every day.
4 Insomnia or hypersomnia nearly every day.
5 Psychomotor agitation or retardation nearly every day (observable by others, not merely
subjective feelings of restlessness or being slowed down).
6 Fatigue or loss of energy nearly every day.
7 Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional)
nearly every day (not merely self-reproach or guilt about being sick).
8 Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by
subjective account or as observed by others).
9 Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
specific plan, or a suicide attempt or a specific plan for committing suicide.
B The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
C The episode is not attributable to the physiologic effects of a substance or to another
medical condition.
D The occurrence of the major depressive episode is not better explained by schizoaffective
disorder, schizophrenia, schizophreniform disorder, delusional disorder, or other specified
and unspecified schizophrenia spectrum and other psychotic disorders.
E There has never been a manic episode or a hypomanic episode.
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

a
Reprinted with permission from American Psychiatric Association.16
© 2013 American Psychiatric Association.

MOOD DISORDERS
disorder, the diagnostic criteria are nearly identical in DSM-5 and the last
iteration of the DSM, the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR).12 One refinement of the criteria in
DSM-5 is the elimination of an arbitrary rule that prevented clinicians from
diagnosing major depressive disorder in an individual who presented with
symptoms within the first 2 months after the death of a loved one.41 For bipolar
disorder manic and hypomanic episodes, the DSM-5 now requires that a person
must have both a mood state change (eg elevated, euphoric, irritable) and an
increase in energy, whereas in earlier iterations of the DSM, only the mood state
change was required.16
Increasingly, primary care, obstetric/gynecologic, and psychiatric practices
across the country are using depression-screening instruments, including the
Patient Health Questionnaire-2,42 the Patient Health Questionnaire-9,43 and the
Quick Inventory of Depressive Symptomatology,44 as recommended by the US
Preventive Services Task Force.45 This practice helps identify patients most likely
to have major depressive disorder but on its own is insufficient to diagnose the
illness. Similarly, some physicians use the Mood Disorders Questionnaire46 to
uncover prior histories of mania or hypomania, a requisite to make a bipolar
disorder diagnosis. However, because of its sensitivity and specificity, full
TABLE 7-2 DSM-5 Diagnostic Criteria for Manic Episodea
A A distinct period of abnormally and persistently elevated, expansive, or irritable mood

and abnormally and persistently increased goal-directed activity or energy, lasting at least
1 week and present most of the day, nearly every day (or any duration if hospitalization is
necessary)
B During the period of mood disturbance and increased energy or activity, three (or more) of
the following symptoms (four if the mood is only irritable) are present to a significant
degree and represent a noticeable change from usual behavior:
1 Inflated self-esteem or grandiosity
2 Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
3 More talkative than usual or pressure to keep talking
4 Flight of ideas or subjective experience that thoughts are racing
5 Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli),
as reported or observed
6 Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation (ie, purposeless non-goal-directed activity)
7 Excessive involvement in activities that have a high potential for painful consequences (eg,
engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)
C The mood disturbance is sufficiently severe to cause marked impairment in social or
occupational functioning or to necessitate hospitalization to prevent harm to self or
others, or there are psychotic features
D The episode is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication, other treatment) or another medical condition

a
810 JUNE 2018

diagnostic interviews are required to avoid false negatives or false positives,
limiting its usefulness for psychiatrists.47 A few of the major depressive disorder
and mania/hypomania symptoms are discussed here since they may occur as part
of neurologic illnesses and may confound the diagnosis of major depressive
disorder or bipolar disorder. Suicide is discussed because of its relevance to
patient safety.
Sleep Changes
Patients with major depressive disorder often report insomnia or hypersomnia.
Usually, the insomnia is characterized by problems falling asleep, middle of the
night awakenings, or early morning awakenings. Hypersomnia is defined as an
increase in total sleep time of 2 or more hours as compared to one’s baseline.
Polysomnographic studies of patients with major depressive disorder revealed
decreased sleep efficiency, reduced slow-wave sleep, and increased rapid eye
movement (REM) pressure.48 All these sleep abnormalities will resolve with
effective treatment of depression. However, polysomnography is only ordered in
DSM-5 Diagnostic Criteria for Hypomanic Episodea TABLE 7-3
A A distinct period of abnormally and persistently elevated, expansive, or irritable mood

and abnormally and persistently increased activity or energy, lasting at least 4
consecutive days and present most of the day, nearly every day.
B During the period of mood disturbance and increased energy and activity, three (or more)
of the following symptoms (four if the mood is only irritable) have persisted, represent
a noticeable change from usual behavior, and have been present to a significant degree:
1 Inflated self-esteem or grandiosity
2 Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
3 More talkative than usual or pressure to keep talking
4 Flight of ideas or subjective experience that thoughts are racing
5 Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli),
as reported or observed
6 Increase in goal-directed activity (either socially, at work or school, or sexually) or
psychomotor agitation
7 Excessive involvement in activities that have a high potential for painful consequences
(eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business
investments)
C The episode is associated with an unequivocal change in functioning that is
uncharacteristic of the individual when not symptomatic.
D The disturbance in mood and the change in functioning are observable by others.
E The episode is not severe enough to cause marked impairment in social or occupational
functioning or to necessitate hospitalization. If there are psychotic features, the episode
is, by definition, manic.
F The episode is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication, other treatment).

a

MOOD DISORDERS
cases in which the physician suspects that a primary sleep disorder may be
present in addition to major depressive disorder. During mania/hypomania,
reduced sleep can be both a trigger and a symptom of the mood episode. Similar
to patients with major depressive disorder, polysomnographic studies of both
manic and depressed patients with bipolar disorder reveal reduced REM latency,
increased REM density, and low sleep efficiency.40 Euthymic patients with
bipolar disorder continue to demonstrate increased REM density and reduced
sleep efficiency, along with greater night-to-night variability of sleep patterns
and increased anxiety and fear about poor sleep.49
For depressed patients with bipolar disorder or patients with major depressive
disorder, sleep deprivation as a therapeutic intervention provides immediate
but temporary relief of depressive symptoms in some individuals; it can also
induce mania/hypomania in patients with bipolar disorder. The improvement in
depressive symptoms disappears with a night of recovery sleep.48,49
Cognitive Symptoms
Patients with major depressive disorder will often report an inability to maintain
their concentration on tasks and make simple decisions. These cognitive
symptoms are a major cause of functional disability and interfere with patients’
ability to work productively and efficiently when experiencing a depressive
episode.50 Cognitive impairment is present during and between episodes of
depression and is seen more often in those with multiple episodes or chronic
depression.50,51 Neuropsychological assessment during depressive episodes
frequently reveals deficits in executive function, memory, and attention.
Patients with major depressive disorder who are older may demonstrate
pseudodementia, or what is now referred to as depression with reversible dementia.
During testing, these patients may answer questions with “I don’t know”
(CASE 7-1), will demonstrate variable performance on tests of similar difficulty,
and will have equal deficits in remote and recent memory.52 However,
epidemiologic studies have found that patients with a history of depression have
a twofold greater risk of developing irreversible dementia,53 and a large number
of those with depression with reversible dementia will progress to irreversible
dementia within 2 to 3 years.54 Thus, an interplay clearly exists between either an
increased risk of developing a dementing illness associated with major depressive
disorder or the possibility that the stress of an episode leads to a temporary
dementialike condition that is actually a harbinger of future events.
During mania/hypomania, patients with bipolar disorder become highly
distractible, and during depressive episodes, they can develop concentration
problems similar to patients with major depressive disorder. A 2015 study of
cognition in subjects with bipolar disorder revealed worse verbal memory,
working memory, psychomotor speed, verbal fluency, attention/speed of
information processing, and executive function/problem-solving abilities
compared to healthy controls. In particular, patients with bipolar disorder who
were manic performed worse than patients with bipolar disorder who were
depressed, mixed, or euthymic, and low cognitive performance was associated
with a predominance of manic episodes.55
Fatigue
Physical fatigue is another symptom commonly reported by patients with major
depressive disorder or bipolar disorder, and it can present as low energy,
812 JUNE 2018

decreased physical endurance, tiredness, increased effort with physical tasks, KEY POINTS
weakness, or sluggishness.56 This should be distinguished from the sleepiness
● One refinement of the
that occurs from insomnia, discussed earlier in this article. Fatigue is more likely criteria in the Diagnostic and
to present in women with major depressive disorder than in men57 and is a Statistical Manual of Mental
common prodromal symptom in a patient’s first episode of major depressive Disorders, Fifth Edition
disorder.58 Reduced activity of the hypothalamic-pituitary-adrenal axis, as seen (DSM-5) is the elimination
of an arbitrary rule that
among the atypical subtype of depression (a symptom profile including
prevented clinicians from
hypersomnia, hyperphagia, extreme fatigue, and rejection sensitivity [a tendency diagnosing major depressive
to overreact to social rejection]),59 and the presence of proinflammatory cytokines disorder in an individual who
that decrease presynaptic dopaminergic inhibition of basal ganglia dopaminergic presented with symptoms
within the first 2 months
activity60 have both been postulated as explanations for major depressive
after the death of a
disorder–associated fatigue. A 2016 study of both patients with major depressive loved one.
disorder and patients with bipolar disorder who were depressed demonstrated that
elevated plasma C-reactive protein levels, a marker of inflammation, predicted ● Polysomnography is only
decreased dorsal striatal to ventromedial prefrontal cortex and presupplementary ordered in cases in which
the physician suspects a
motor area connectivity, which was correlated with decreased motor speed and primary sleep disorder may
increased psychomotor slowing.61 be present in addition to
Fatigue is a common persistent residual symptom of major depressive major depressive disorder.
disorder, with 10% to 35% of patients in remission still reporting life-altering
● Patients with a history of
problems with fatigue.62 It is always important to consider the many other
depression have a twofold
etiologies of fatigue, such as comorbid neurologic and medical disorders, occult greater risk of developing
neoplasm, obesity, sleep disorders, and the adverse effects of many different irreversible dementia, and a
classes of medications. large number of those with
depression with reversible
dementia will progress to
Suicidal Ideation/Suicide irreversible dementia within
A suicide attempt is the act of intentionally harming oneself with the objective of 2 to 3 years.
ending one’s life. The clinician should distinguish suicide attempts from other
acts of self-harm in which the intent is not death but another purpose, such as the ● Physical fatigue is a
symptom commonly
elimination of anxiety, resolution of a sense of emptiness, a desire for a sense reported by patients with
of control, or mitigating a feeling of intense rage. Wishes for death that eventually major depressive disorder or
result in suicide attempts or suicide are a common symptom in major depressive bipolar disorder, and it can
disorder. Of patients with major depressive disorder, 30% to 40% will attempt present as low energy,
decreased physical
suicide,63 while 6.67% of men and 3.77% of women will die by suicide.64 In bipolar endurance, tiredness,
disorder, 25% to 50% will attempt suicide, while 15% to 20% of patients die by increased effort with
suicide.65,66 The suicide attempts of patients with bipolar disorder tend to be more physical tasks, weakness,
lethal than attempts in the general population.66 Overlapping risk factors are or sluggishness.
associated with suicide attempts and suicide completions. Risk factors associated
● The clinician should
with attempted suicide include female sex (major depressive disorder only), distinguish suicide attempts
previous suicide attempts, high severity of depressive symptoms, young age, from other acts of self-harm
comorbid substance-use disorders, anxiety disorders, Cluster B personality in which the intent is not
disorders as described in DSM-5 (ie, antisocial personality disorder, borderline death but another purpose,
such as the elimination of
personality disorder, narcissistic personality disorder, histrionic personality anxiety, resolution of a
disorder), hopelessness, and impulsive-aggressive traits. Risk factors associated sense of emptiness, a desire
with completed suicide include the same risk factors except male instead of female for a sense of control, or
sex (major depressive disorder only), recent discharge from hospitalization, mitigating a feeling of
intense rage.
adverse life events (eg, trauma, relationship loss, homelessness), and, in the
elderly, concurrent physical illness and depressive and dysphoric-irritable
mood states (bipolar disorder only).63,66 Increased risks of suicide attempt and
completion have been reported for patients with neurologic illnesses such as MS,
epilepsy, Huntington disease, dementia, traumatic brain injury, and migraine with

MOOD DISORDERS
KEY POINTS aura, while Parkinson disease has been associated with increases in suicidal
ideation but not attempts.67 The risk of suicide attempts or completions in these
● Increased risks of suicide
attempt and completion
illnesses has been strongly associated with depression, hopelessness, and
have been reported for social isolation.67
patients with neurologic Acute hospitalization is an appropriate intervention to monitor patients felt to
illnesses such as multiple be at high risk of killing themselves and to prevent them from attempting to kill
sclerosis, epilepsy,
themselves. Encouraging patients and their families to temporarily remove
Huntington disease,
dementia, traumatic brain firearms, other weapons, and unnecessary medications from the home is an
injury, and migraine with important step to reduce harm in those unpredictable moments of despair that
aura, while Parkinson lead to suicide attempts.
disease has been associated
with increases in suicidal
ideation but not attempts. Neurologic Medications That Can Induce Mood Symptoms
DSM-5 stipulates that before making a diagnosis of any mood disorder, one
● Several neurologic must discern if the symptoms observed developed coincident with the use
illnesses can induce of substances or medications that might cause mood symptoms.16 Some
symptoms by their impact
on mood regulatory
medications used to treat neurologic disorders have been associated with
components of the brain and depressive symptoms (TABLE 7-4). These include steroids for MS, opioids for
monoamine production. severe pain disorders, and cholinesterase inhibitors for dementia. While the risk
for depressive symptom induction from these medicines is relatively low, if
symptoms emerge after starting these medicines, it is possible that the medicines
are the cause or may be contributing to the severity of the symptoms. It is
also important to recognize that medications may frequently worsen the
neurocognitive symptoms associated with major depressive disorder and bipolar
disorder. Some medications have also been associated with symptoms of
mania/hypomania (TABLE 7-4), including steroids for MS, tricyclic
antidepressants for various neurologic syndromes, and pramipexole for
Parkinson disease.
Neurologic Illnesses That Can Induce Mood Symptoms

DSM-5 also requires that clinicians rule out medical illnesses that can cause
depressive symptoms or a depressionlike syndrome before making a diagnosis
of major depressive disorder or symptoms of mania/hypomania before making a
diagnosis of bipolar disorder. Several neurologic illnesses can induce symptoms
by their impact on mood regulatory components of the brain and monoamine
production. Examples include MS, obstructive sleep apnea, stroke, Parkinson
disease, dementia, Huntington disease, traumatic brain injury, and seizures.
Treatment of the underlying condition may sometimes ameliorate the mood
symptoms, as is the case in Parkinson disease, MS, and obstructive sleep apnea.
The disinhibition exhibited by patients with frontotemporal dementia can lead a
clinician to mistakenly suspect mania and make a diagnosis of bipolar disorder.
Mental Status Examination

When conducting a diagnostic interview, psychiatrists pay close attention to the
form, volume, and content of speech along with a patient’s appearance and
movements. Such information composes the mental status examination, which is
combined with the patient’s history of illness to make the diagnosis. Although the
mental status examination items assessed vary among psychiatrists, they often
include appearance, attitude, behavior, speech, mood, affect, thought process,
thought content (hallucinations, delusions, ruminations), cognition (orientation,
concentration, immediate and delayed recall), insight, judgment, and gait. No
814 JUNE 2018

Medications That Can Induce Mood Symptoms TABLE 7-4
Medication/Class Possible Use(s) Mood Symptoms That May Be Induced
Antiepileptics Epilepsy, bipolar disorder Depression
Beta-blockers Hypertension, tremor Depression
Cholinesterase inhibitors Alzheimer dementia Depression
Dopamine agonists Parkinson disease Mania
Efavirenz Human immunodeficiency virus (HIV) Depression, mania
Integrase strand transfer inhibitors HIV Depression
Interferons Hepatitis C, multiple sclerosis Depression
Isotretinoin Acne Depression
Mefloquine Malaria Depression
Methyldopa Hypertension Depression
Montelukast Allergies, asthma Depression
Oral contraceptives Birth control Depression
Opioids Pain control Depression
Reserpine Hypertension Depression
Rilpivirine HIV Depression
Selegiline Parkinson disease Mania
Steroids Multiple sclerosis Depression, mania
Tricyclic antidepressants Migraine prophylaxis, neuropathic pain Mania
Vigabatrin Epilepsy Depression
Zidovudine HIV Mania

MOOD DISORDERS
typical mental status examination profile exists for a patient with major depressive
disorder; however, patients with more severe symptoms (eg, melancholic
subtype) may be unkempt, demonstrate behavior characterized as either
psychomotor agitation or extreme slowness, and may speak softly and sparingly.
Their thought process may be perseverative and their affect constricted and
sad. Many of these findings, such as perseverative thought process, soft speech,
and slow movements, can be seen among neurologic patients who do not have
major depressive disorder. Thus, the psychiatric mental status examination is
only one small part of the data that should be gathered to make an accurate
diagnosis of major depressive disorder.
A patient with bipolar disorder, while depressed, could have a mental status
examination similar to that of a patient with major depressive disorder. However,
when manic/hypomanic, patients may demonstrate agitation, distractibility, or fast
and pressured speech or may use rhymes or move from topic to topic, and their
conversational content may reveal grandiose delusional beliefs about themselves.
Threshold for Brain Imaging

A wealth of neuroimaging data exists demonstrating abnormalities among
people with major depressive disorder. This includes results from structural MRI
studies that show reduced gray matter volume in the anterior cingulate, insula,
thalamus, and hippocampus; diffusion tensor imaging studies that reveal
reduced white matter integrity in frontosubcortical areas of the brain;
resting-state functional MRI (fMRI) studies that show hyperactivity of the
default mode network (a collection of brain regions with activity that is highly
intercorrelated during states of wakeful rest); and PET studies showing lower
glucose metabolism in the basal ganglia, limbic system, and insula.68
In patients with bipolar disorder, fMRI studies reveal abnormally decreased
ventrolateral prefrontal cortex activity during emotion processing/regulation
tasks; abnormally increased activity in the amygdala, striatum, and medial
prefrontal cortex and decreased connectivity between the amygdala and
prefrontal cortex in response to positive emotional stimuli; increased amygdala,
orbitofrontal cortex, and temporal cortical activity during nonemotional
cognitive tasks; and increased left ventrolateral prefrontal cortex, orbitofrontal
cortex, and ventral striatum activity when exposed to reward. Structural imaging
studies reveal decreased cortical gray and white matter volume; decreased
cortical thickness in prefrontal, anterior temporal, and insular cortices; decreased
gray matter volume in the right ventrolateral prefrontal cortex and orbitofrontal
cortex; and decreased amygdala and hippocampus volumes. Diffusion imaging
studies are similar to those in major depressive disorder and report decreases in
white matter tracts linking the prefrontal and subcortical brain regions.69
Despite these findings, psychiatrists do not routinely order brain imaging
studies when trying to diagnose mood disorders. This is because the findings
listed often lack sensitivity and specificity when applied to individuals with
major depressive disorder or bipolar disorder. A lack of standardization also
exists in the imaging and analytic protocols used in neuroimaging research
studies. Practices must be standardized at the research level before they can be
employed clinically to ensure reliable findings.70
Brain imaging becomes a consideration when trying to rule out a neurologic
illness or trying to distinguish major depressive disorder or mania from a
neurodegenerative disease.71 Late age of onset of major depressive disorder or
816 JUNE 2018

symptoms of mania/hypomania or the simultaneous occurrence of neurologic KEY POINTS
symptoms may suggest the need for brain imaging.
● The mental status
examination is only one
TREATMENT small part of the data that
First-line treatments for major depressive disorder include depression-focused should be gathered to make
psychotherapy, pharmacotherapy, the combination of psychotherapy and an accurate diagnosis of
major depressive disorder.
medications, or somatic treatments, such as bright light therapy.72 About
two-thirds of patients will respond to either medication or psychotherapy with a ● First-line treatments for
50% or greater reduction in symptoms, but only 30% to 40% will have a full major depressive disorder
remission with the first treatment intervention.73 Although these treatments include depression-focused
have demonstrated efficacy among large groups of patients with major psychotherapy,
pharmacotherapy, the
depressive disorder, some patients will respond to only one of these treatments combination of
and not the other.74 At this point, no accepted ways are known to predict which psychotherapy and
treatment will help an individual patient. However, some exciting preliminary medications, or somatic
neuroimaging findings suggest that resting-state functional connectivity of treatments, such as bright
light therapy.
the left anterior ventrolateral prefrontal cortex/insula, the dorsal midbrain, and
the left ventromedial prefrontal cortex brain regions can predict treatment ● Neurologists may or may
outcome with cognitive-behavioral therapy versus antidepressant medication.75 not choose to initiate
The somatic treatments, which include bright light therapy and other forms pharmacologic treatment
for a patient’s major
of neurostimulation, are gaining more attention and are often considered
depressive disorder. Those
when psychotherapy and multiple trials of medications are ineffective. who identify the illness in a
For bipolar disorder, the first-line treatment is either pharmacotherapy or a patient and choose not to
combination of psychotherapy and medication but never psychotherapy alone. treat should, at minimum,
provide psychoeducation to
Treatment options will vary depending on the patient’s current mood state and
the patient, normalizing the
ability to tolerate the medication. The medications used are categorized as major depressive disorder
antimanic, antidepressant, and mood stabilizing (eg, lithium), which have symptoms in the context of
efficacy in preventing new bipolar disorder mood episodes. While treatment having a neurologic illness.
response prediction is also limited in bipolar disorder, a 2017 study has shown
● After psychoeducation,
that the neurons of patients who are lithium-responsive demonstrate a unique neurologists should refer
electrophysiologic profile as compared to those who do not respond to lithium,76 patients with major
while another 2017 study reported that elevated peripheral cytokines in patients depressive disorder to a
with bipolar disorder predict treatment nonresponse to an antidepressant primary care physician or
psychiatrist for treatment.
intervention.77
Neurologists may or may not choose to initiate pharmacologic treatment ● If the neurologist
for a patient’s major depressive disorder. Those who identify the illness in a suspects a patient has
patient and choose not to treat should, at minimum, provide psychoeducation to undiagnosed bipolar
disorder, the patient should
the patient (teach the patient about the illness, in particular that it is a brain
always be referred to a
illness that is treated medically and not a sign of moral failure), normalizing the psychiatrist.
major depressive disorder symptoms in the context of having a neurologic illness
(explain to the patient that it is not uncommon for people with neurologic
illnesses to also experience symptoms of major depressive disorder). Following
this discussion, they should refer the patient to a primary care physician or
psychiatrist for treatment. On the other hand, if the neurologist suspects a patient
has undiagnosed bipolar disorder, the patient should always be referred to
a psychiatrist.
Psychotherapy
Psychotherapy is a talking-based intervention performed by a social worker,
psychologist, mental health counselor, or psychiatrist. Many different
psychotherapies are effective for the treatment of major depressive disorder,

MOOD DISORDERS
including cognitive-behavioral therapy, interpersonal psychotherapy,

psychodynamic psychotherapy, and problem-solving therapy (TABLE 7-5).72
Recently, a third wave of newly developed psychotherapies have shown some
efficacy in major depressive disorder. These include mindfulness-based
cognitive-behavioral therapy, acceptance and commitment therapy, and
extended behavioral activation.78 Each of these therapies was developed from
different models of how the mind functions when a person is depressed. The
unique techniques and strategies employed during these therapies reflect the
differences in these conceptualizations of the mind and are time-limited in
duration (months versus years). Psychotherapy is particularly useful for
individuals with major depressive disorder who cannot tolerate medications
and who may also be dealing with the losses (eg, independence, functioning)
that come with comorbid neurologic illnesses. Additionally, the benefits of
psychotherapy may be more enduring than pharmacotherapy when
TABLE 7-5 Evidence-based Psychotherapies for Major Depressive Disorder and

Bipolar Disorder
Psychotherapy Strategy
Acceptance and commitment psychotherapy Helps patients accept unwanted thoughts and feelings; helps patients
set goals according to their values and commit to meeting them
Cognitive-behavioral therapy for major depressive Identifies and modifies distorted cognitions; changes maladaptive
disorder or bipolar disorder behaviors
Extended behavioral activation Increases environmental reinforcement and reduces punishment to

improve engagement in behaviors that will enhance mood
Family-focused therapy for bipolar disorder Provides psychoeducation about bipolar disorder to family members
and improves communication patterns and conflict resolution within the
family system
Interpersonal therapy Improves patient’s communication skills within interpersonal relationships

to improve management of current stressors and losses
Interpersonal and social rhythm therapy Helps strengthen the vulnerable circadian rhythms of patients with
bipolar disorder by promoting regularity of daily routines and managing
current interpersonal stressors
Mindfulness-based cognitive-behavioral therapy Combines cognitive-behavioral techniques with mindfulness and

mindfulness meditation
Problem-solving therapy Addresses negative assessments and uses focal problem solving
Psychodynamic therapy Identifies and modifies unconscious conflicts related to causes of

depression
818 JUNE 2018

pharmacotherapy is stopped after a year.73 For psychotherapy to be effective, the KEY POINTS
patient must have intact cognition in order to fully engage and must have some
● Psychotherapy is
ability to be introspective. particularly useful for
Psychotherapies have also been developed specifically for patients with individuals with major
bipolar disorder, including cognitive-behavioral therapy for bipolar disorder, depressive disorder who
Interpersonal and Social Rhythm Therapy (IPSRT), and family-focused cannot tolerate medications
and who may also be dealing
therapy for bipolar disorder. A large-scale effectiveness study demonstrated
with the losses (eg,
that patients with bipolar disorder who are depressed recovered faster from independence, functioning)
their depressive episode when receiving any of these adjunctive psychotherapies that come with comorbid
as compared to a 3-week psychoeducation collaborative care program.79 neurologic illnesses.
Psychotherapies that promote medication adherence and early recognition of
● The different classes of
symptoms have a greater effect on mania, while those that teach cognitive and antidepressants include
interpersonal coping strategies are more effective for the depression pole of selective serotonin reuptake
the illness.80 inhibitors (SSRIs), serotonin
norepinephrine reuptake
inhibitors (SNRIs), atypical
Medications antidepressants, tricyclic
A variety of medications have demonstrated efficacy in treating major depressive antidepressants, and
disorder (TABLE 7-6). The majority of these increase synaptic levels of monoamine oxidase
monoamines or act as agonists or antagonists at monoamine receptors. The inhibitors (MAOIs)
different classes of antidepressants include selective serotonin reuptake
● The first-line medications
inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), used in bipolar disorder are
atypical antidepressants, tricyclic antidepressants, and monoamine oxidase mood stabilizers, which
inhibitors (MAOIs). SSRIs, SNRIs, and atypical antidepressants (specifically include lithium, and the
anticonvulsants valproate,
bupropion and mirtazapine) may be used as first-line treatments, while tricyclic
carbamazepine, and
antidepressants and MAOIs, because of their adverse event profile, are reserved lamotrigine.
for patients who are treatment resistant.72 Tricyclic antidepressants have been
associated with seizures, tremors, delirium, QT interval prolongation, cardiac
arrhythmias, and anticholinergic adverse effects at higher blood levels, while
MAOIs can result in serotonin syndrome and hypertensive crises if drug or food
interactions with the MAOI occur.
When a patient’s symptoms respond only partially to an antidepressant,
augmentation strategies may be used. These strategies include adding
psychotherapy, lithium, thyroid hormone, buspirone, an antidepressant from a
different class, or second-generation antipsychotics to the antidepressant.72 All
the medications listed can introduce neurologic side effects, but second-generation
antipsychotics, in particular, are commonly associated with extrapyramidal side
effects.81 These effects include parkinsonism, dystonic reactions, akathisia, and
tardive dyskinesia. SSRIs may also induce extrapyramidal symptoms; however,
this occurs more often in patients who are elderly and in those with Parkinson
disease, and they occur less commonly overall as compared to second-generation
antipsychotics.82
The first-line medications used in bipolar disorder are mood stabilizers, which
include lithium, and the anticonvulsants valproate, carbamazepine, and
lamotrigine. Two second-generation antipsychotics, lurasidone and quetiapine,
and the combination of olanzapine and fluoxetine are all US Food and Drug
Administration (FDA)–approved to treat bipolar depression. Antidepressants
are used with caution in patients with bipolar disorder, almost always in
combination with a mood stabilizer to prevent manic induction. Both first- and
second-generation antipsychotics can be used on their own or in combination
with mood stabilizers to treat manic episodes. For patients with frequent manic

MOOD DISORDERS
TABLE 7-6 Antidepressants Used in Major Depressive Disorder
Class/Drug Mechanism of Action Possible Adverse Effects

Selective serotonin reuptake
inhibitors (SSRIs)
Fluoxetine, paroxetine, Blocks the 5-HT reuptake transporter Headache, nausea, yawning, sweating, fatigue,
sertraline, citalopram, insomnia, anxiety, sexual dysfunction, tremors,
escitalopram, fluvoxamine hyponatremia, serotonin syndrome
Vortioxetine Blocks the 5-HT reuptake transporter and Headache, nausea, yawning, sweating, fatigue,
blocks 5-HT7, 5-HT3, and 5-HT1D receptor; insomnia, anxiety, sexual dysfunction, tremors,
agonizes 5-HT1A receptor; partial agonist hyponatremia, serotonin syndrome
at 5-HT1B
Vilazodone Blocks the 5-HT reuptake transporter and Headache, nausea, yawning, sweating, fatigue,
is a 5-HT1A receptor partial agonist insomnia, anxiety, sexual dysfunction, tremors,
hyponatremia, serotonin syndrome
Serotonin norephinephrine
reuptake inhibitors (SNRIs)
Venlafaxine, Blocks 5-HT and norepinephrine reuptake Headache, yawning, fatigue, insomnia, anxiety,
desvenlafaxine, duloxetine, transporters decreased libido, tremors, hypertension,
levomilnacipran nausea, diarrhea, sweating
Atypical antidepressants
Bupropion Dopamine- and norepinephrine-releasing Seizures, headaches, tremors, insomnia,
agent decreased appetite
Nefazodone Blocks 5-HT2A receptor; weak 5-HT reuptake Sedation, hepatotoxicity
inhibition
Mirtazapine Blocks 5-HT2A/5-HT2C receptors, alpha 2A Weight gain, sedation
hetero- and autoreceptors, and histamine
receptors
Trazodone Blocks 5-HT2A receptor and alpha 1 Sedation, orthostatic hypotension, priapism
receptor; inhibits 5-HT reuptake
transporter and blocks 5-HT2C receptor at
high doses; partial 5-HT1A receptor agonism
Tricyclic antidepressants
Nortriptyline, amitriptyline, Blocks 5-HT and norepinephrine Headache, yawning, fatigue, sedation, insomnia,
imipramine, desipramine, transporters and acetylcholine, alpha anxiety, decreased libido, tremors, seizures,
clomipramine adrenergic, and H1 receptors delirium, arrhythmias, orthostasis, dry mouth
Monoamine oxidase
inhibitors
Tranylcypromine, phenelzine Inhibits monoamine oxidase A and B Serotonin syndrome, weight gain, insomnia,
sexual dysfunction, hypertensive crisis,
orthostatic hypotension
Selegiline Selectively inhibits monoamine oxidase B at Serotonin syndrome, weight gain, insomnia,
doses <20 mg; inhibits monoamine oxidase sexual dysfunction, hypertensive crisis,
A and B at doses ≥20 mg orthostatic hypotension
5-HT = 5-hydroxytryptamine (serotonin).
820 JUNE 2018

recurrences and poor medication adherence, long-acting injectable preparations KEY POINTS
of antipsychotics may be considered.83
● Regardless of the
For patients with Parkinson disease and depression, use of bupropion antidepressant selected,
as a first-line strategy may be advised given its dopaminergic effects,84,85 one must be careful about
although it has never been studied for this indication in a randomized clinical trial. adding an antidepressant to
Additionally, SSRIs may exacerbate Parkinson tremors and failed to demonstrate a Parkinson disease regimen
that already includes a high
superiority against placebo in a systematic review and meta-analysis (CASE 7-1).86,87
dose of the monoamine
Regardless of the antidepressant selected, one must be careful about adding an oxidase inhibitor selegiline,
antidepressant to a Parkinson disease regimen that already includes a high dose as serotonin syndrome or
of the MAOI selegiline as serotonin syndrome or hypertensive crises could ensue. hypertensive crises could
ensue.
Pramipexole, a D2/D3 receptor agonist used in the treatment of Parkinson
disease, can be used to augment an antidepressant in addition to the options ● When treating patients
listed above and should be considered in patients with Parkinson disease.88 with epilepsy,
When treating patients with epilepsy, antidepressants that lower the seizure antidepressants that lower
threshold, including tricyclic antidepressants and bupropion, should be avoided. the seizure threshold,
including tricyclic
Interest in the use of intranasal and IV forms of ketamine has increased since antidepressants and
the publication of several clinical trials demonstrating its rapid salutary effects bupropion, should be
in patients with treatment-resistant depression or suicidality.89 Side effects during avoided.
ketamine administration may include dissociation, perceptual disturbances, and
● Somatic treatments are
transient increases in blood pressure, while long-term use has raised concerns
nonpharmacologic
for the development of memory impairment and cystitis.90 interventions that involve
the application of physical
Use of Pharmacogenetic Markers for Treatment Selection forces (eg, light, electricity,
magnetism) to induce
Many medication options are available to treat mood disorders; however, some
neurochemical changes
may be more effective or more tolerable for a given patient than others. Several within specific regions of
companies have developed genetic testing services that can identify the presence the brain.
or absence of alleles relevant to the pharmacokinetics and pharmacodynamics
of psychotropic agents. These companies claim that this genetic information can
predict a medication’s efficacy and risk for an individual patient and thus guide
the clinician’s choices. Once the genetic testing is complete, these companies
provide reports identifying psychotropic agents that can be used without
concern and those that should only be used with caution. This service becomes
attractive to patients who are desperate to get better quickly and to clinicians
who feel overwhelmed by the number of psychotropic options available. The
literature to date, however, does not support the use of this testing.91 Only two
small randomized trials92,93 have studied the use of pharmacogenetics-informed
treatments versus treatment as usual. Although both showed increased remission
rates among patients whose clinicians relied on pharmacogenetic testing, only
one achieved statistical significance.93 This is a promising area of research as
psychiatry, like other fields of medicine, moves closer to personalized
treatments.
Somatic Treatments
For patients with major depressive disorder or bipolar disorder who receive no
benefit from psychotherapy and medications or cannot tolerate them, somatic
therapies should be considered. Somatic treatments are nonpharmacologic
interventions that involve the application of physical forces (eg, light, electricity,
magnetism) to induce neurochemical changes within specific regions of the brain.
Electroconvulsive therapy involves application of a brief electrical current
to the patient’s scalp to induce a generalized seizure while the patient is fully

MOOD DISORDERS
anesthetized. This procedure is safe and effective and should be offered to

patients with a high suicide risk, those with late-life depression (onset after
60 years of age), or those who are catatonic or psychotic.94 Interestingly, this
procedure may benefit the mood and motor symptoms of patients with
Parkinson disease who are depressed.94 Repetitive transcranial magnetic
stimulation involves the application of an electromagnetic coil above the scalp
to stimulate neurons in regions of the brain involved in mood regulation, such as
the prefrontal cortex. Patients receive treatments 5 days per week for a period
of 4 to 6 weeks.95 Vagal nerve stimulators, also used for refractory epilepsy, are
implanted in the chest wall and connect to and stimulate the vagus nerve. This
modulates signals sent from the vagus nerve to cortico-limbic-thalamic-striatal
regions of the brain involved in mood regulation.96 Deep brain stimulation,
originally pioneered to treat Parkinson disease, involves the implantation of a
pacemakerlike device in the chest wall that sends pulses to electrodes surgically
placed in regions of the brain that influence mood-related circuitry. Currently
considered experimental, this has been particularly promising for patients with
treatment-resistant major depressive disorder or bipolar disorder.97,98
Transcranial direct current stimulation applies a low-frequency electrical
current over the scalp and can improve symptoms of non–treatment-resistant
major depressive disorder but not treatment-resistant major depressive
disorder.99 It can improve symptoms of bipolar disorder as demonstrated in
multiple open-label studies, but randomized controlled trials are needed to
validate this.100 It is associated with few side effects and is portable and
inexpensive.99 Finally, bright light therapy requires patients to sit in front of a
light box of at least 10,000 lux daily for 2 to 5 weeks. The light is expected to
modulate the patient’s chronobiological cycle, which induces antidepressant
effects both in those with101 and those without seasonal-onset variants of major
depressive disorder.102 Bright light therapy has also been shown to be effective in
bipolar disorder103 and was more effective than medications as usual for patients
with bipolar disorder when used in combination with sleep phase advancement
and sleep deprivation.104 Light boxes and transcranial direct current stimulators
can both be purchased by patients via the Internet, and both can potentially
induce mania/hypomania in patients with bipolar disorder.
CONCLUSION
Major depressive disorder and bipolar disorder are common mood disorders that
are highly comorbid among patients with neurologic illnesses. The symptoms of
both conditions are functionally impairing, can greatly increase a patient’s
mortality and morbidity, and create challenges with adherence. In some patients,
the neurologic disorder can induce mood symptoms, while in other patients,
genetic risks exist for both a mood disorder and neurologic disorder to emerge at
some point independently of the other illness. Some medications used to treat
common neurologic disorders may induce depressive or manic/hypomanic
symptoms, and, conversely, some medications used to treat major depressive
disorder or bipolar disorder may cause neurologic side effects. It is not surprising
that somatic treatments developed to treat neurologic illnesses are now being
applied to the treatment of mood disorders. This convergence represents the
future of treatment for many patients whose underlying brain dysfunction may
822 JUNE 2018

manifest itself with a myriad of different symptoms and require a more KEY POINT
integrated approach to their care. This suggests that neurologists would be wise
● Bright light therapy is
to commonly screen for mood disorders with a valid tool, such as the Patient expected to modulate the
Health Questionnaire-9 or Mood Disorders Questionnaire, and, likewise, patient’s chronobiological
psychiatrists must be more aware of the possibility of underlying neurologic cycle, which induces
disorders. Fortunately, a wide array of treatment options is available for patients antidepressant effects both
in those with and those
with major depressive disorder or bipolar disorder.
without seasonal-onset
variants of major
depressive disorder.
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REVIEW ARTICLE

Obsessive-Compulsive
ONLINE
Disorder
By Peggy M. A. Richter, MD, FRCPC; Renato T. Ramos, MD
ABSTRACT
PURPOSE OF REVIEW: This article reviews current knowledge regarding
diagnosis, pathophysiology, and treatment trends in obsessive-compulsive
disorder (OCD), a severe, underrecognized, and chronic condition
frequently encountered in neurologic practice.
CITE AS:
CONTINUUM (MINNEAP MINN) RECENT FINDINGS:With a lifetime prevalence estimated at 2.5%, OCD is a
2018;24(3, BEHAVIORAL NEUROLOGY common condition that can also present comorbidly with neurologic
disease. The core symptoms of OCD are obsessions and compulsions.
Address correspondence to Obsessions are intrusive repetitive thoughts, urges, images, or impulses
Dr Peggy M. A. Richter, that trigger anxiety and that the individual is not able to suppress.
Sunnybrook Health Sciences
Centre, 2075 Bayview Ave, Suite
Compulsions are repetitive behaviors or mental acts occurring in response
FG47, Toronto, ON M4N 3M5, to an obsession with the intention of reducing the distress caused by
Canada, Peggy.Richter@ obsessions. Neuroimaging, neuropsychological, and pharmacologic
sunnybrook.ca.
studies suggest that the expression of OCD symptoms is associated with
RELATIONSHIP DISCLOSURE: dysfunction in a cortico-striato-thalamo-cortical circuit. Evidence-based
Dr Richter serves on the editorial treatments for OCD comprise pharmacotherapy and cognitive-behavioral
board of the Journal of
Obsessive-Compulsive and therapy. Selective serotonin reuptake inhibitors (SSRIs) are the first-line
Related Disorders, has received drugs recommended for OCD, but significant differences exist in their use
personal compensation for
for OCD compared to their use for other mood and anxiety conditions,
speaking engagements from
Lundbeck, and receives including the need for higher dosage, longer trials necessitated by a longer
grant/research support from the lag for therapeutic response, and typically lower response rates.
Canadian Institutes of Health
Research. Dr Ramos reports no
Cognitive-behavioral therapy, based on the principles of exposure and
disclosure. response prevention, shows results superior to pharmacologic treatments
with lower relapse rates on long-term follow-up and thus should be
UNLABELED USE OF
considered in the treatment plan of every patient with OCD.
USE DISCLOSURE:
Drs Richter and Ramos discuss SUMMARY:OCD and obsessive-compulsive symptoms are frequently
the unlabeled/investigational
use of neuromodulation
encountered in the neurologic clinic setting and require a high index of
technology (deep brain suspicion to effectively screen for them and an illness-specific
stimulation, electroconvulsive therapeutic approach.
therapy, and repetitive
transcranial magnetic
stimulation) and pharmacologic
agents (citalopram, escitalopram,
desvenlafaxine, duloxetine,
INTRODUCTION
O
mirtazapine, and venlafaxine) bsessive-compulsive disorder (OCD) is a severe and relatively
for the treatment of common psychiatric condition but still is underrecognized and
obsessive-compulsive disorder
(some of which are approved undertreated.1,2 The lifetime prevalence for OCD is estimated
for use in depression and at 1% to 3% in adults3,4 and adolescents,5 but it is far more
psychosis). frequently encountered in general psychiatric and medical
practice than these figures suggest because of its chronicity. The age of onset of
of Neurology. OCD reported by patients shows a bimodal pattern, with symptoms appearing
828 JUNE 2018

during childhood/adolescence more frequently in males and in early adulthood in
women.6 It has been suggested that only 14% to 56% of patients seek treatment,
and recognition and diagnosis is typically delayed by 8 to 10 years.7 The diagnosis
of OCD symptoms is frequently challenging, and management requires a unique
approach, with specific adaptations in pharmacologic and psychotherapeutic
treatments when compared to mood or other anxiety disorders.
DIAGNOSIS AND PSYCHIATRIC CLASSIFICATION
The cardinal features of OCD are obsessions and compulsions. Obsessions are
defined as intrusive repetitive thoughts, urges, images, or impulses that trigger
anxiety and that the individual is not able to suppress. Compulsions are repetitive
behaviors or mental acts that occur in response to an obsession or must be
done according to rigidly applied rules and are intended to reduce the distress
caused by obsessions. However, OCD is heterogeneous, and its symptom profile
may vary widely between patients who meet the diagnostic criteria. TABLE 8-1
describes examples of common obsessions and compulsions.8 To make the
diagnosis, the illness must be severe enough to cause significant distress, waste at
least 1 hour of time per day, or cause significant interference in functioning.
Examples of Common Obsessions and Compulsionsa TABLE 8-1
Descriptions/Examples
Obsessions
Contamination Concerns about dirt, germs, body waste, illness
Symmetry Needing things “just so,” even, or lined up a certain arbitrary way
Aggressive Most commonly focused on inadvertent harm, such as being responsible for a fire or break-in; also includes
horrific thoughts or images of deliberately harming others, such as stabbing a loved one or pushing a stranger
in front of a car
Sexual Disturbing sexual thoughts that are not consistent with an individual’s orientation or cultural norms, such
as someone with a same-sex preference having unpleasant hetero-erotic thoughts or unwanted
inappropriate sexual thoughts about children
Religious Examples include thoughts about selling one’s soul to the devil, deliberately thinking inappropriate
thoughts about major religious figures, or committing mortal sins
Somatic Exaggerated fears of contracting a serious illness such as hepatitis or a brain tumor in the absence of any
identifiable high risk
Compulsions
Washing Excessive hand washing, showering, or cleaning activities
Checking Repeatedly turning the stove on and off; rereading all emails to ensure content is appropriate; driving
around the block to ensure did not hit someone; asking for repeated reassurance
Ordering Folding clothes “just so” or arranging all cans in the cupboard so the labels are facing out
Counting Performing actions a certain arbitrary number of times, such as tapping each foot 4 times when getting out of bed
Repeating Repeatedly going up and down the stairs or flushing the toilet; typically done to cancel out a bad thought
or until it feels “right”
a
Reprinted with permission from Richter PM, Selchen S.8 © 2018 Centre for Addiction and Mental Health.

OBSESSIVE-COMPULSIVE DISORDER
The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
also includes two important specifiers (extensions to the diagnostic criteria used
to clarify important features of the diagnosis) for OCD.9 First, individuals with
OCD may present with a range of insight into their disorder-related beliefs,
including good or fair insight, poor insight, and absent insight/delusional beliefs
(complete conviction that OCD beliefs are true). The second specifier identifies
the presence of tic-related symptoms and is justified by evidence that individuals
with comorbid tic disorders differ from other patients with OCD in relation to
comorbidities, course, pattern of familial transmission, treatment, and potentially
etiology based on genetic studies.10
OCD was historically classified with the anxiety disorders, but in the DSM-5,
it was moved to its own new category called “Obsessive-Compulsive and Related
Disorders,” which includes conditions characterized by specific types of
preoccupations or repetitive behaviors.9 This change reflects the observations
that anxiety is not necessarily a core component of OCD and that, for many
individuals, avoidant behavior can minimize anxiety and become a major driver
of the illness.10 While all of these disorders have some similarities in their clinical
features, it is important to distinguish them from one another because of
significant differences in treatment.
Hoarding disorder is characterized by the accumulation of excessive belongings
unrelated to their value (ie, not exclusively related to their having perceived
monetary worth) and difficulty discarding them because of associated anxiety
and the need to save items. Many individuals affected by hoarding disorder
also have difficulty with excessive acquisition of goods. Hoarding disorder is
frequently associated with poor insight; accordingly, many individuals affected
by this condition may deny any significant distress or impairment in functioning.
However, the DSM-5 criteria allow for diagnosis if the accumulation of
belongings results in an unsafe environment for patients or those around them.
Safety hazards resulting from hoarding disorder may include the risk of fires,
infestations (ie, insects or rodents), mold and air quality issues (which can
exacerbate lung disease), risk of falls, and inability for emergency services to
access the patient’s residence.11 Although historically individuals presenting with
hoarding difficulties were often given the diagnosis of OCD, hoarding disorder is
now a separate formal diagnosis and should be distinguished from OCD as
significant differences exist in terms of treatment approaches.
Other key disorders in the DSM-5 group “Obsessive-Compulsive and Related
Disorders” include body dysmorphic disorder, defined by the preoccupation
with one or more perceived defects or flaws in physical appearance that are not
observable by or appear slight to others; excoriation (skin-picking) disorder,
defined by recurrent skin picking resulting in lesions; and trichotillomania
(hair-pulling) disorder, defined by the recurrent pulling out of hair resulting in
hair loss.9 Both of these latter conditions (hairpulling/skin picking) are also
associated with repeated attempts to reduce or stop the behavior. This diagnostic
group also includes substance- and medication-induced obsessive-compulsive and
related disorder and obsessive-compulsive and related disorder due to another
medical condition.12,13
DIFFERENTIAL DIAGNOSIS
The variability of OCD symptoms can make it harder to differentiate OCD
from other conditions. While most clinicians will readily recognize OCD in
830 JUNE 2018

individuals who check excessively for mistakes or who wash repeatedly KEY POINTS
because of contamination concerns, other patients may simply repeat actions
● The lifetime prevalence
over and over and not volunteer obsessional content, express excessive for obsessive-compulsive
concern about contracting a serious illness, or relate obsessions with frankly disorder is estimated at 1%
bizarre content, such as a fear of losing a body part or being in another to 3%, with a bimodal pattern
dimension. Thus, OCD may resemble a number of other psychiatric and of onset; symptoms start
during childhood/
neurologic conditions, such as psychosis, illness anxiety disorder, and
adolescence more frequently
stereotypic movement disorder. in males, while early
adulthood onset is more
Psychiatric Conditions common among women.
The differentiation between OCD and other OCD-related disorders is based on
● Obsessions are intrusive
specific differences in content and character of thought processes and behaviors. repetitive thoughts, urges,
In body dysmorphic disorder, the focus is exclusively on perceived defect(s) in the images, or impulses that
individual’s appearance, both in terms of thoughts and any repetitive behaviors trigger anxiety and that the
(eg, checking appearance in mirrors, seeking reassurance, or time-consuming individual is not able to
suppress.
grooming behaviors). Hoarding disorder is exclusively about difficulty with
discarding and the accumulation of belongings that results from this. In ● Compulsions are repetitive
trichotillomania and excoriation disorders, the focus is on repetitive hair pulling behaviors or mental acts
or skin picking, respectively, and not accompanied by triggering obsessions. It occurring in response to an
is important to distinguish between these conditions as significant differences obsession that must be done
according to rigid rules to
exist in the treatment approach. They can also frequently occur comorbidly in reduce the distress caused
individuals presenting with OCD. by obsessions.
Although individuals with anxiety disorders may report recurrent thoughts or
worries, these are typically about readily understandable real-life concerns. For ● Patients with obsessive-
compulsive disorder can
example, individuals with generalized anxiety disorder may express excessive present with variable insight,
worries about losing their job or about the health and welfare of their family ranging from good insight
members. In social phobia, the content is focused on exaggerated but with full appreciation of the
understandable concerns about embarrassing themselves in social interactions. excessive/irrational nature
of the symptoms to frankly
By contrast, obsessions are typically either very exaggerated or about unrealistic
delusional.
or irrational concerns and will usually be accompanied by compulsions.
Depressed individuals may also express ruminations that are typically ● The Diagnostic and
mood-congruent and not usually experienced as intrusive. These ruminations are Statistical Manual of Mental
thus not considered to be obsessions. Disorders, Fifth Edition
(DSM-5) lists obsessive-
Other frequent differential psychiatric diagnoses include: compulsive disorder in the
category “Obsessive-
u Eating disorders, in which preoccupations are exclusively focused on food, weight, or Compulsive and Related
body image. Disorders,” which also
includes hoarding
u Illness anxiety disorder, which is characterized by recurring thoughts that are exclusively disorder, body dysmorphic
related to fear of currently having a serious disease. By contrast, in individuals with disorder, excoriation
somatic obsessions, the concern is typically about contracting the illness in the future, (skin-picking) disorder, and
and other obsessional content will also be present. trichotillomania (hair-pulling)
disorder.
u Tic disorders, which are characterized by sudden, rapid, recurrent, nonrhythmic behaviors
(eg, blinking, touching, grimacing, or sniffing) that are not triggered by obsessions.
● Individuals presenting
u Psychotic disorders, which must be differentiated from patients with OCD with poor exclusively with hoarding
insight or from patients with OCD who may be delusional regarding the obsessions but do difficulties in the absence of
not display hallucinations or formal thought disorder. frank obsessions or
compulsions should not be
u Obsessive-compulsive personality disorder, which, despite the similarity in name, is not
diagnosed with
directly related to OCD. The personality disorder is characterized by a long-standing
obsessive-compulsive
pattern of perfectionism and rigidity but will be perceived by the individual as appropriate,
disorder but rather with
rather than reported as intrusive in the way that obsessions are experienced. These
hoarding disorder.
individuals will not have frank obsessions or compulsions.

KEY POINTS Neurologic Conditions

Symptoms resembling OCD features can be found in some neurologic conditions.
● It is important to
differentiate between
Huntington disease, an autosomal dominant neurodegenerative disease
obsessive-compulsive characterized by cognitive deterioration and progressive motor abnormalities, is
disorder and the obsessive- associated with a higher occurrence of OCD symptoms that tend to become more
compulsive–related severe with the progression of the disease.14 Van Duijn and colleagues,15 for
disorders as significant
example, found obsessive-compulsive behaviors in 13.2% of 1993 Huntington
differences in the treatment
approach are needed for disease mutation carriers independent from the Huntington disease stage.
each of these conditions. Although obsessive-compulsive symptoms observed in Huntington disease will
not necessarily be severe enough to fulfill DSM-5 criteria for OCD, they may be
● Obsessive-compulsive incapacitating and poorly responsive to cognitive-behavioral therapy, leaving
disorder is a frequent
comorbid condition in treatment with selective serotonin reuptake inhibitors (SSRIs) as the better
Huntington disease, stroke, therapeutic option.16
Parkinson disease, OCD, generalized anxiety disorder, and phobic disorders are among the most
Sydenham chorea, traumatic frequently observed psychiatric complications after stroke. In one of the few
brain injury, and Tourette
syndrome.
studies to specifically explore anxiety disorders poststroke, Cumming and
colleagues17 studied 149 stroke survivors assessed at 20 months poststroke and
found symptoms compatible with the diagnosis of OCD in 9% of patients
compared with a prevalence of 2% in a control group. OCD is also a frequent
psychiatric complication of traumatic brain injuries, along with depression,
substance abuse, and psychosis (CASE 8-1).18
Patients with Parkinson disease can show a peculiar behavior known as punding,
which can be misidentified as an OCD feature.19 Punding is described as a complex,
prolonged, purposeless, and stereotyped behavior; it is usually experienced as
comforting, but its interruption can result in anger. Punding is described as a
symptom of Parkinson disease, but it can also be induced by antiparkinsonian
medications and quetiapine.20 It is important to be aware that atypical
antipsychotics can also induce or exacerbate preexisting true OCD independently
of the presence of punding symptoms. The most significant culprit is clozapine;
however, problems can also arise reasonably frequently with olanzapine and, on
occasion, other drugs in this category.21 As neuroleptics are occasionally used in
individuals with Parkinson disease, this will be seen not infrequently and may then
warrant consideration of treatment targeting the comorbid OCD.
Sydenham chorea is particularly interesting as it was observed that virtually
all patients will develop OCD symptoms early in the illness.22,23 This close
relationship is attributed to the underlying mechanism, which is an autoimmune
response to streptococcal infection leading to inflammation in the basal ganglia, a
brain region strongly implicated in the neurobiology of OCD.24 This has also led
to a proposed and somewhat controversial autoimmune syndrome underlying
cases of early-onset OCD, termed pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infections (PANDAS). PANDAS criteria focus on the
abrupt onset of OCD or tics and require demonstrable association with
streptococcal infection, but the term has recently been broadened to pediatric
acute-onset neuropsychiatric syndrome (PANS), which is similar but notes the
illness may start with infectious triggers other than streptococcal. Both may be
associated with neurologic changes, such as choreiform or other abnormal
movements, behavioral regression, sensory or motor abnormalities, and somatic
signs such as enuresis or sleep disturbance. In a 2017 large-scale population-based
study of more than 1,000,000 children, Orlovska and colleagues25 found that
individuals with a streptococcal throat infection within the previous 17 years had
832 JUNE 2018

elevated risks of all mental disorders but particularly OCD and tic disorders
(incidence rate ratios of 1.51 [95% confidence interval, 1.28 to 1.77] for OCD and
1.35 [95% confidence interval, 1.21 to 1.50] for tic disorders). However, they also
found that children with a history of multiple nonstreptococcal infections
showed increased risks for OCD and other psychiatric mental disorders as well,
although less than in those who were streptococcal positive.
Tourette syndrome is a childhood-onset neurodevelopmental disorder that
usually develops before 10 years of age and improves with age. The hallmarks
of Tourette syndrome are motor tics such as blinking or grimacing, typically
showing a rostral-caudal progression, and phonic tics such as grunting and throat
clearing, but can include coprolalia (swearing tics). Complex tics and self-injurious
behaviors can also be present. Tourette syndrome symptoms may resemble OCD
rituals, especially “ticlike” compulsions such as touching, tapping, rubbing, and
repeating routine activities. However, tics are not triggered by clear obsessions, are
more severe, and frequently have a greater impact on social development.26
A 60-year-old man presented with an 8-year history of compulsive CASE 8-1

behaviors in the context of a variety of neurologic symptoms. He felt
compelled to eliminate all rocks from his large 1-acre garden; in his
effort to do this, he dug a trench 4 feet wide, 22 feet long, and 2 feet
deep over a period of several years. He spent most of his waking hours
on this project, describing any efforts to stop as anxiety provoking. He
had started washing and waxing his car daily, including the motor. He
also had random intrusive thoughts that he might have run someone
over in his car. His obsessive-compulsive disorder symptoms started at
the same time as marked memory difficulties, making it difficult for him
to find his way home, and he reported chronologic confusion,
interruptions in his speech, occasional clumsiness and difficulties
buttoning his shirts, and an erratic sleep pattern of sleeping up to
20 hours a day for months on end, followed by prolonged periods of
sleeping less than 5 hours a night. His medical history was significant for
hypertension and hypercholesterolemia.
On examination, he was noted to have complex cognitive deficits and
a dysexecutive syndrome. Serial MRIs over a period of several years
had demonstrated diffuse cortical atrophy and a number of deep brain
infarctions, and brain single-photon emission computed tomography
(SPECT) showed mild to moderate decreased activity in the mesial
temporal regions.
He was prescribed fluoxetine to a maximum of 80 mg/d, which resulted
in significant improvement in his compulsive symptoms. Unfortunately, his
neurocognitive decline continued, and he was eventually diagnosed with
corticobasal syndrome and lost to follow-up.
This case illustrates how obsessive-compulsive disorder–like features may COMMENT

develop secondary to a neurodegenerative disease and may nonetheless
respond to treatment with serotonergic antidepressants.

NEUROBIOLOGICAL BASIS
Current hypotheses concerning the neurobiological basis of OCD are derived
from neuroimaging, neuropsychological, and pharmacologic research. The most
influential model postulates that dysfunction in a cortico-striato-thalamo-cortical
loop leads physiologically to expression of OCD behaviors and is based on
imbalance between glutamatergically mediated excitatory and γ-aminobutyric
acid-mediated (GABA-ergic) inhibitory control mechanisms in this frontostriatal
circuit.27,28 FIGURE 8-1 depicts this model, summarizing its anatomic and
functional components. According to this hypothesis, OCD symptoms are not
necessarily due to a dysfunction or lesion of a specific brain region but caused by
imbalances in the interactions among these different structures, including links to
the amygdala, which is involved in the affective modulation of OCD behaviors.
Neuroimaging Studies
Overall, studies with positron emission tomography (PET) and single-photon
emission computed tomography (SPECT) show increased activity in the anterior
cingulate cortices in patients with OCD29–31 as well as different patterns of
activation in the caudate.31 These changes are frequently reduced or absent after
treatment with drugs or cognitive-behavioral therapy, and evidence suggests
that lower activity in the orbitofrontal cortex pretreatment predicts better
response to serotonergic reuptake inhibitors.32,33 Abnormalities in the posterior
cingulate cortex also seem to correlate with a better response to treatment
with fluvoxamine.32
In addition, symptom provocation studies show increased brain activity in the
anterior/lateral orbitofrontal cortex and anterior cingulate cortex34 and reduced
recruiting of the striatum, usually involved in tasks such as serial reaction time
tasks.35 Functional studies also suggest that individuals with OCD rely on the
FIGURE 8-1
Schematic of the neurocircuitry of obsessive-compulsive disorder. Blue arrows depict
glutamate (excitatory) and red arrows depict γ-aminobutyric acid–mediated (GABA-ergic)
(inhibiting) pathways. Green boxes show neurocognitive functions ascribed to each brain
structure that are relevant to obsessive-compulsive disorder.
834 JUNE 2018

frontotemporal circuits for explicit information-processing strategies to KEY POINTS
compensate for possible frontostriatal dysfunction associated with implicit
● Neuroimaging and
information-processing deficits.36 neuropsychological studies
Corticostriatal network dysfunction has been reported in children and suggest that the expression
adolescents with OCD. On inhibition tasks such as go/no-go tasks, adolescents of obsessive-compulsive
with OCD show reduced activation in brain regions connected via the inferior disorder symptoms is
associated with dysfunction
and orbital fronto-striato-thalamic pathways compared to controls. The inhibition
in a cortico-striato-thalamo-
of response in the OCD group was also associated with reduction in activation of cortical circuit.
the mesial and dorsolateral prefrontal cortex, including the anterior cingulate
gyrus. Besides confirming the involvement of a frontostriatal network during ● Neuroimaging is not
motor response inhibition, these studies suggest that tasks requiring more currently recommended
routinely for evaluation of
cognitive forms of inhibitory control, including selective and flexible use of individuals with
attention, are associated with abnormalities in extrafrontal temporal, parietal, and obsessive-compulsive
cerebellar brain regions.37,38 disorder.
Newer imaging techniques have corroborated the relevance of the
fronto-striato-thalamic model for OCD. Using resting-state functional MRI
(fMRI) to evaluate functional connectivity in unmedicated patients with OCD,
Zhang and colleagues39 found reduced functional connectivity between the
rostral anterior cingulate cortex and the dorsolateral prefrontal cortex as well as
increased connectivity between the dorsal anterior cingulate cortex and caudate.
The magnitude of these alterations was shown to correlate with total scores on
the Yale-Brown Obsessive Compulsive Scale (Y-BOCS),40 the most widely used
severity rating scale for OCD. Moreover, pretreatment resting-state fMRI may
enable prediction of response to cognitive-behavioral therapy41 and maintenance
of gains 1 year later.42
It has been questioned if the heterogeneity of OCD symptoms may limit
the applicability of general pathophysiologic models, and numerous authors
have suggested these differences should be considered in the interpretation of
functional studies. Factorial analysis supports a four-factor model of OCD
symptoms, generating separate symptom dimensions of harm obsessions and
checking, symmetry and ordering, cleanliness and washing, and hoarding.43,44
These factors seem to be relatively stable over time,29 have differential responses
to treatment,45 may differ in terms of genetics/heritability,46,47 and are associated
with different patterns of regional brain function in neuroimaging studies.48
However, to date, relatively few OCD studies have incorporated testing of
these dimensions.
In summary, substantial evidence exists for involvement of a
cortico-striato-thalamo-cortical loop in OCD, whether through structural
imaging studies or, more commonly, functional imaging using a variety of
technologies. However, notwithstanding these findings as well as work
suggesting that pretreatment imaging may correlate with response to treatment,
routine imaging is not, as yet, recommended for evaluation of individuals with
OCD as large interindividual variability limits current clinical utility.
Neuropsychology
Although the uncertainties, doubts, and ritualistic repetitions found in almost
all patients suggest a common dysfunctional cognitive component in OCD,
neuropsychological investigations frequently show inconsistent results.49
Deficits in executive functions, processing speed, visuospatial abilities, nonverbal
memory, and working memory have been reported in meta-analyses,50,51 but

some of these findings may be secondary to deficits in spontaneously initiating

verbal organization strategies during information-encoding processes and do
not necessarily reflect other specific cognitive deficits.52,53
Attention is a key function involved in the modulation of other cognitive
activities. In individuals with OCD, deficits in focused and sustained attention
and trends toward deficits in selective and divided attention paradigms are
frequently reported.49 Repetitiveness and rigidity are characteristic of OCD and
have led to the hypothesis that these individuals have reduced ability to change
their behaviors following contextual changes. In fact, cognitive flexibility as
measured by the Wisconsin Card Sorting Test seems to be reduced in OCD.53
However, some new paradigms, such as reversal learning and task switching,
suggest that the impaired performance in OCD may be due to differences in
reaction times and not in response errors, a finding that correlates with symptom
intensity and suggests a peculiar pattern of retardation in cognitive functioning
in these patients.49
Deficits in inhibitory mechanisms have also been investigated in a variety of
ways. The cognitive component of behavioral inhibition as evaluated through
the Stroop task (measuring interference in reaction time when naming the font
color of color words printed in the same color as the word [such as the word
blue printed in blue] as compared to a different or incongruent color [such as the
word blue printed in green]) shows a trend for poorer performance in patients
with OCD. These individuals also show impaired inhibitory capacity in motor
responses as evaluated by the stop-signal task, in which subjects have to inhibit
an already initiated response after the appearance of a stop cue.54 Planning and
decision making were studied in OCD because of the apparent reduced capacity
for making choices and organizing new activities observed in these patients.
Again, inconsistent results have been reported, probably because of the use of
gambling experimental paradigms, such as the Iowa Gambling Task and the
Cambridge Gambling Task, that may not be specific enough for evaluating
cognitive processes specifically associated with OCD.49
In summary, a burgeoning literature is emerging around the patterns of
neurocognitive deficits associated with OCD, including difficulties in set-shifting
and response inhibition (both cognitive and motoric) and memory deficits. It has
been suggested that these may represent helpful endophenotypes for etiologic
research going forward. Despite the evidence supporting some degree of
cognitive abnormalities in OCD, currently no clear indication exists for doing
neuropsychological evaluations routinely as part of the assessment of these
patients, although it will be interesting to see if specific targeted cognitive
remediation strategies may prove helpful in the future.
TREATMENT
A number of published guidelines exist for OCD from organizations including
the Canadian Psychiatric Association, American Psychiatric Association, and
National Institute for Health and Care Excellence (UK).55–57 The most recent
at the time of this writing are the Canadian Clinical Practice Guidelines for
OCD, published in 2014.58 The recognized first-line options for OCD are
pharmacotherapy with SSRIs and cognitive-behavioral therapy. While these
modalities are used broadly for the treatment of mood and anxiety, a number of
key differences should be kept in mind when applying them to individuals
with OCD.
836 JUNE 2018

Psychoeducation KEY POINTS
Psychoeducation is vital for patients with OCD and should ideally be provided
● Obsessive-compulsive
before beginning any program of treatment. Individuals with OCD may often be disorder is associated with a
laboring under the belief that they are alone in having “ridiculous” or “horrible” cluster of neurocognitive
(eg, violent or sexual) thoughts. It is, therefore, very important to normalize and deficits, including
destigmatize from the beginning by explaining that we all have bizarre or difficulties in set-shifting
and response inhibition.
inappropriate thoughts crossing our minds routinely and that no one can control
their thoughts to prevent this. ● Psychoeducation is
crucial in treating patients
Pharmacotherapy with obsessive-compulsive
Good Level 1 evidence exists for the use of all the SSRIs in the treatment of disorder because of the
stigma associated with the
OCD.55,59 Although citalopram and escitalopram are off-label for OCD in the illness and the general lack
United States, head-to-head trials do not demonstrate any significant of knowledge in the
differences between SSRIs, suggesting all are essentially equivalent in their community and because it
efficacy.60,61 These medications have the advantage of also working on mood will enhance treatment
compliance.
and anxiety disorders, which are so often comorbid with OCD. Two major
distinctions exist in the way these medications should be used for OCD as ● Selective serotonin
compared to depression. First, dosing is generally most effective at the upper end reuptake inhibitors are the
of the recommended range; as a result, the recommended target dose typically first-line pharmacologic
treatment for obsessive-
exceeds the dose used for depression.62 Second, the therapeutic lag is longer
compulsive disorder. They
before benefits are seen in OCD, generally 6 to 10 weeks. are generally very safe and
For these reasons, it is generally best to discuss the treatment approach and well tolerated and will also
target dose with patients, stressing that they are most likely to achieve the best work for the mood and
anxiety disorders frequently
response if they aim for the upper end of the dose range or until significant side
comorbid with obsessive-
effects occur, after which it will be important to allow at least a further 6 to compulsive disorder.
10 weeks to assess response. Using this approach, it is recommended that drug
trials in OCD continue for 12 weeks or more before considering changing to ● Pharmacologic treatment
another drug. Alternatively, lower doses in the typical depression range can be of obsessive-compulsive
disorder distinctly differs
tried, but should this prove ineffective, it may necessitate a far lengthier trial as from other mood and
the dose will then need to be increased and require a further 2 to 3 months to anxiety disorders, requiring
assess therapeutic response. a higher dose for the best
The recommended maximum/target dose for citalopram in OCD is 60 mg/d to likelihood of response
and longer trials to
80 mg/d. This exceeds both US Food and Drug Administration (FDA) and Health accommodate the longer
Canada recommendations not to exceed 40 mg/d because of the risk of cardiac therapeutic lag (typically 6
QTc prolongation63,64; however, the impact of this medication on cardiac to 10 weeks) in obsessive-
conduction is typically modest and can be managed easily with serial ECG compulsive disorder.
monitoring. Escitalopram carries a similar warning in Canada65 for doses
exceeding 20 mg/d, notwithstanding evidence in OCD for best efficacy at doses
up to 40 mg/d. Both carry recommendations regarding dosage in older
populations; the maximum recommended dose of citalopram is 20 mg/d in those
65 years of age or older according to Health Canada or those older than 60 years
of age according to the FDA.63 For escitalopram, it is recommended not to exceed
10 mg/d in those 65 and older (Health Canada) or those older than 60 years of age
in the United States (FDA) (TABLE 8-2).66
Most patients on SSRIs achieve modest improvement in OCD, with a reduction
in severity of 25% to 35% considered a treatment response. Approximately 60%
of patients will typically respond to the first medication tried, leaving many
individuals unresponsive and requiring a trial of at least a second SSRI67 and
eventually consideration of second-line agents. If a second SSRI fails, most
guidelines recommend moving on to a second-line option, such as clomipramine

or the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine.

Clomipramine has long been considered the gold-standard medication for OCD
based on efficacy, but it is relegated to second line in treatment guidelines
because of its more challenging side effect profile, impact on cardiac conduction
and seizure threshold, and toxicity in case of overdose. However, it is still
strongly recommended for patients for whom two or more SSRIs have failed.60
Monitoring of blood levels may reduce these risks but has never been systematically
evaluated. Clomipramine is also sometimes used as an augmentation agent in
combination with SSRIs, typically starting at low doses and proceeding more
cautiously to reduce risks, but, again, no controlled trials support this strategy.10
Desvenlafaxine is the active metabolite of venlafaxine and, as such, would be
expected to have efficacy similar to the parent compound, but as yet no
controlled trials have been published in OCD. The SNRI duloxetine is similarly
considered to be a second-line agent as several recent studies have supported its
effectiveness.68,69 Mirtazapine has also been listed as an alternative second-line
treatment in US and Canadian (but not UK) treatment guidelines.
It is generally recommended that pharmacologic treatment be continued for at
least 1 year, as a very significant relapse risk exists with early discontinuation.
Most experts suggest referral for cognitive-behavioral therapy, if this is available,
to reduce the risk of relapse for patients hoping to eventually come off medication.
TABLE 8-2 Medications Recommended for the Treatment of

Obsessive-Compulsive Disorder
Medications Recommended Starting Dose Recommended Dose Range
First-line
Fluoxetine 20 mg/d 20–80 mg/d
Fluvoxamine 50 mg/d 150–300 mg/d
Sertraline 50 mg/d 100–200 mg/d
Paroxetine 20 mg/d 20–60 mg/d
Citalopram 20 mg/d 20–80 mg/da
Escitalopram 10 mg/d 10–40 mg/db
Second-line
Clomipramine 50 mg/d 150–250 mg/d
Venlafaxine 37.5 mg/d 75–325 mg/d
Venlafaxine ER 37.5 mg/d 75–225 mg/d
Desvenlafaxine 50 mg/d 100–200 mg/d
Mirtazapine 30 mg/d 30–45 mg/d
Duloxetine 60 mg/d 120 mg/d
a
The US Food and Drug Administration (FDA) and Health Canada advise 40 mg/d or less.
b
Health Canada advises 20 mg/d or less. For escitalopram, it is recommended not to exceed 10 mg/d in
those 65 and older (Health Canada) or those older than 60 years of age in the United States (FDA).
838 JUNE 2018

In patients with very severe illness or for whom a number of medications have KEY POINTS
previously failed, many suggest long-term continuation of an effective medication
● A lack of response or
for maintenance of stability. partial response is more
Another frequently recommended option is augmentation with atypical common in obsessive-
antipsychotics. While Level 1 evidence exists for this, in a randomized controlled compulsive disorder than in
trial of SSRI partial responders, patients remaining on their SSRI did far better other psychiatric conditions.
In individuals who are
when randomly assigned to receive the addition of cognitive-behavioral therapy
unresponsive, guidelines
as compared to augmentation with an atypical antipsychotic or placebo, raising a suggest trying two different
question about the efficacy of this alternative in clinical practice. Furthermore, selective serotonin reuptake
long-term use of many atypical antipsychotics is associated with significant inhibitors sequentially, then
moving on to a second-line
weight gain and metabolic and cardiovascular consequences and therefore
option, such as clomipramine
requires regular monitoring, which may limit enthusiasm for this alternative. or venlafaxine. Augmentation
Regarding other commonly used psychotropics, clear evidence exists that with atypical antipsychotics
bupropion, clonazepam, and other benzodiazepines do not work in OCD and is also an option.
should be avoided for this indication.
● It is generally
recommended that patients
Psychotherapy continue on medication for a
Cognitive-behavioral therapy is the most effective treatment in OCD and the only minimum of 1 year after
form of psychotherapy for which robust evidence exists in OCD. Behavioral therapy achieving a good
therapeutic response, as
is a core component of cognitive-behavioral therapy and has long been regarded obsessive-compulsive
as a gold-standard treatment for OCD. It is based on the principles of exposure to disorder is associated with a
anxiety-provoking triggers without performance of rituals (often termed exposure very high relapse rate
and response prevention). This is now generally combined with cognitive approaches following medication
discontinuation.
in which the patient identifies and learns to modify exaggerated or maladaptive
thoughts and beliefs. Specific cognitive-behavioral therapy approaches targeting ● Cognitive-behavioral
OCD have been developed; in contrast, general cognitive-behavioral therapy as is therapy is the most
taught for depression tends to be quite ineffective for OCD. For this reason, if effective treatment in
referring a patient for treatment, it is important to ascertain if the therapist has obsessive-compulsive
disorder. It is based on the
had specific training in cognitive-behavioral therapy for OCD (CASE 8-2). principles of exposure to
In practice, a number of factors must be taken into consideration in determining anxiety-provoking triggers
if cognitive-behavioral therapy is the best option for a given patient. Insight without performance of
(ie, recognition that the OCD is excessive or unreasonable) is important, as those rituals (often referred to as
exposure and response
with poor insight may be unwilling to challenge their rituals. The extent of prevention).
comorbid conditions should be considered; for example, mild depression may
not be a barrier, but more severe depression or active suicidal ideation generally
would be. Similarly, personality disorders, if significant, may also complicate
cognitive-behavioral therapy. Motivation is, in many ways, the single biggest
factor to consider. For cognitive-behavioral therapy to succeed, patients must be
committed and actively engaged in therapy. Regular practice of homework is a
key requirement for success.
The interaction between patients and their families can serve to maintain or
worsen OCD symptoms. Family accommodation refers to how the family adapts
their routines to enable the individual with OCD to avoid triggers or minimize
rituals. Often family members will try to help their loved one by providing
regular reassurance or by accommodating (eg, locking the front door when
leaving together or doing decontamination rituals to satisfy their relative). These
behaviors, although well intended, will unfortunately serve to maintain the
obsessional fears. Family-based psychoeducation and interventions to reduce
accommodation have been shown to effectively reduce OCD and should be
integrated into cognitive-behavioral therapy.

Neuromodulatory Treatments
As OCD can be severe and often refractory to standard first- and second-line
treatments, considerable work has been done exploring alternative biological
therapies. Referral should be made to a tertiary care center with specific expertise
in OCD for individuals with very severe illness or those who have failed
conventional treatment, as neuromodulatory treatments with varying degrees of
invasiveness may be helpful.
Repetitive transcranial magnetic stimulation has shown promise in a number of
sham-controlled trials and meta-analyses, although at this point it is still
considered experimental for OCD as considerable work remains in terms of
determining the best brain target and other treatment parameters.70 Study of the
CASE 8-2 A 35-year-old man working in customer relations presented to a

psychiatric outpatient clinic reporting that he felt unable to cope. He
gave a history of minor contamination concerns since his teens that
became problematic over the past 10 years. He also reported disturbing
thoughts about harm befalling his family members. He was particularly
concerned that he might cause family members to become ill and die by
inadvertently contaminating them with germs or toxins. He washed his
hands at least 20 times a day with soap or using a hand sanitizer he carried
with him everywhere. He spent 2 hours per day cleaning his house after
work, following a 1-hour shower and change of clothes. During his
washing rituals, he repeated each step in multiples of three or until it “felt
right.” Over the past 2 years as his rituals became more time-consuming,
he began to avoid shaking hands, sharing pens and other objects in the
office, and any physical contact with colleagues. He had begun to limit
visits with his parents for fear of making them ill. He recognized that his
concerns were likely irrational but felt unable to change his behavior. He
reported feeling increasingly depressed, exhausted, and hopeless
regarding his diminished quality of life over the past 6 months.
The patient was diagnosed with obsessive-compulsive disorder (OCD),
and, following psychoeducation, he refused cognitive-behavioral
therapy as he did not feel able to challenge his fears but agreed to
medication. He was started on escitalopram 10 mg/d and increased to
20 mg/d a week later. He reported some improvement in mood within
2 weeks and in OCD symptoms after 6 weeks. After 3 months of
treatment, his hand washes were down to 6 to 10 times a day, and his
showers were completed in 20 minutes. He then agreed to a course of
cognitive-behavioral therapy, following which his OCD symptoms
became minor, with rituals occupying a maximum of 20 minutes a day
with almost no avoidance.
COMMENT This case illustrates the tendency of OCD to worsen over time. Depressive
symptoms are also frequently found in these patients. The case also
illustrates how both medications and cognitive-behavioral therapy may be
needed for optimal outcomes.
840 JUNE 2018

application of transcranial direct current stimulation71 in OCD is in its infancy but KEY POINT
has shown promise. By contrast, psychosurgery has been in use and well-studied
● For extremely severe
in OCD for many decades. The most common procedures are anterior and refractory cases,
cingulotomy and anterior capsulotomy; while both brain targets improve OCD neuromodulatory
symptoms (response rates are 41% and 54%, respectively72), capsulotomy is far treatments with varying
more frequently associated with severe adverse events, including personality degrees of invasiveness
can be helpful for
change. Deep brain stimulation has been put forward as an alternative to ablative
neurosurgery, and studies using a number of brain targets have generally shown disorder. Referral to a
positive results in OCD, with fewer and milder adverse events.73 The utility of tertiary care center with
electroconvulsive therapy in OCD is unclear; no controlled trials have been specific expertise in
published, but a 2015 systematic review provided some support for benefits in
disorder should be sought
60% of reported cases.74 for these individuals.
CONCLUSION
It is reasonable to expect the busy neurologist to be aware of OCD and the related
disorders and to have a high index of suspicion for this disorder. Neurologists
should feel comfortable routinely screening for OCD symptoms, discussing a
probable diagnosis of OCD, providing basic psychoeducation and directing
patients to published support and self-help materials, initiating referral to
specialized treatment providers when possible, and providing first-line
pharmacologic treatment while awaiting assistance from specialists with
OCD expertise.
USEFUL WEBSITES
INTERNATIONAL OCD FOUNDATION FREDERICK W. THOMPSON ANXIETY DISORDERS CENTRE,
The International OCD Foundation website provides TORONTO, ONTARIO, CANADA
booklets and fact sheets about OCD and lists OCD The Frederick W. Thompson Anxiety Disorders
programs available for both the public and Centre website offers a downloadable patient
professionals. handbook and links to other useful websites and
iocdf.org resources for patients and clinicians.
sunnybrook.ca/thompsoncentre
ANXIETY AND DEPRESSION ASSOCIATION OF AMERICA
The Anxiety and Depression Association of America
website provides resources for understanding
depression, anxiety, and stress; information about
suicide prevention; and links for treatment
and support.
adaa.org
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54 van Velzen LS, Vriend C, de Wit SJ, van den 64 Health Canada Advisory; Recalls and safety
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55 American Psychiatric Association. Practice
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Published May 7, 2012. Updated March 30, 2013.
56 Canadian Psychiatric Association. Clinical
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psychological interventions for the management j.jad.2017.03.033.
of obsessive-compulsive disorder in children/
71 D’Urso G, Brunoni AR, Mazzaferro MP, et al.
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844 JUNE 2018

Psychosis REVIEW ARTICLE

By Lindsey A. Schrimpf, MD; Arpit Aggarwal, MD; John Lauriello, MD C O N T I N U UM A U D I O
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Psychosis is a psychiatric condition that has significant
overlap with neurologic disease. This article is intended to educate the
neurologist on the psychiatric manifestations of psychosis and its
evaluation, diagnosis, and treatment. How to differentiate a primary
psychiatric cause of psychosis from psychosis secondary to a medical or
neurologic condition is also reviewed.
RECENT FINDINGS: Current research in psychotic disorders has focused

increasingly on negative symptoms and cognitive impairment in psychotic
illness, as it is now recognized that these cause the greatest impact on
functional deficits for patients. A number of new medications have also
been introduced to target negative symptoms and cognitive deficits in
psychotic illness. These have new implications in terms of treatment
overlap with medications being prescribed by providers in psychiatry, CITE AS:
neurology, and general practice. CONTINUUM (MINNEAP MINN)
SUMMARY: This article discusses the current methods for evaluating,
diagnosing, and treating psychosis. Psychosis as a primary mental health Address correspondence to
Dr John Lauriello, One Hospital Dr,
disorder is a diagnosis of exclusion, as psychosis can be a direct symptom DC 067.00, Columbia, MO 65212,
of underlying medical or neurologic disease. Delirium and dementia are the laurielloj@health.missouri.edu.
two most important disorders to rule out. This article will help readers be RELATIONSHIP DISCLOSURE:
more prepared to assess and treat the patient with psychosis. Drs Schrimpf and Aggarwal
report no disclosures.
Dr Lauriello has served as an
advisor for Alkermes; Otsuka
America Pharmaceutical, Inc;
INTRODUCTION and Teva Pharmaceutical
P
sychosis is a broad term that encompasses symptoms related to a Industries Ltd and on the event
monitoring board for Alkermes.
change in perception of reality. Psychosis alone does not mean that a Dr Lauriello has served on the
primary psychiatric disorder is present. In many cases, differentiating editorial board of Academic
Psychiatry. Dr Lauriello receives
the origin of psychosis can be very difficult. This article discusses research/grant support from
the psychiatric and medical manifestations of psychosis and reviews Florida Atlantic University/
how to evaluate, diagnose, and treat the patient with psychosis. Some useful Otsuka America Pharmaceutical,
Inc and the Missouri Foundation
components of the examination are also addressed to help the clinician for Health and receives
differentiate a primary psychiatric cause of psychosis versus psychosis secondary publishing royalties from
to a medical or neurologic condition. Oxford University Press and
UpToDate, Inc.
DEFINING PSYCHOSIS UNLABELED USE OF

In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
USE DISCLOSURE:
the chapter “Schizophrenia Spectrum and Other Psychotic Disorders” states that Drs Schrimpf, Aggarwal, and
these disorders “are defined by abnormalities in one or more of the following five Lauriello report no disclosures.
domains: delusions, hallucinations, disorganized thinking (speech), grossly © 2018 American Academy
disorganized or abnormal motor behavior (including catatonia), and negative of Neurology.

PSYCHOSIS
symptoms.”1 Defining and characterizing psychotic illness has been a continually

evolving process. The early Greek physicians were the first to have documented
delusions, paranoia, and changes in cognitive function and personality, and a
number of other historical figures have offered unique ways of characterizing
psychosis.2 However, it was Emil Kraepelin and Eugen Bleuler, physicians trained
in psychiatry and neurology, who provided what have become the dominant
characterizations of a primary psychotic disorder. Kraepelin defined the disorder
termed dementia praecox (an apparent decline in cognitive functioning at an
early age) in contrast to Alzheimer dementia. Later, Bleuler coined the term
schizophrenia, denoting a split between the content and processes of thought and
the emotions expressed.3 The patient’s feelings appear independent of the content
of thought, leading to inappropriate emotional expression, such as flat affect when
describing his or her depression. Over the years, the Diagnostic and Statistical
Manual of Mental Disorders (DSM) has modified how it characterizes and
categorizes schizophrenia and the other disorders that manifest a significant level
of psychosis. Affective disorders, such as major depressive disorder with psychotic
features and bipolar I disorder, may manifest with psychosis but are categorized
differently because the primary aberration is affective in nature, with different
clinical features and prognosis.2
Although subtle changes have been made in the diagnostic criteria and
categorization of psychotic illnesses, the basic components of psychosis have
remained fairly stable since the early characterizations by the Greeks. The DSM-5
diagnoses for schizophrenia spectrum and other psychotic disorders are listed
in TABLE 9-1, and a general description of each diagnosis is reviewed later in
this article. To diagnose patients with psychosis, it is important for clinicians to
be able to evaluate and assess the five domains of psychotic illness: delusions,
TABLE 9-1 DSM-5 Schizophrenia Spectrum and Other Psychotic Disordersa
◆ Schizotypal (personality) disorder

◆ Delusional disorder
◆ Brief psychotic disorder
◆ Schizophreniform disorder
◆ Schizophrenia
◆ Schizoaffective disorder
◆ Substance/medication-induced psychotic disorder
◆ Psychotic disorder due to another medical condition
◆ Catatonia associated with another mental disorder (catatonia specifier)
◆ Catatonic disorder due to another medical condition
◆ Unspecified catatonia
◆ Other specified schizophrenia spectrum and other psychotic disorder
◆ Unspecified schizophrenia spectrum and other psychotic disorder

a
Data from American Psychiatric Association.1 © 2013 American Psychiatric Association.
846 JUNE 2018

hallucinations, disorganized thinking (speech), grossly disorganized or abnormal KEY POINTS
motor behavior (including catatonia), and negative symptoms.
● The five domains of
Delusions psychological functioning
affected by schizophrenia
The DSM-5 defines delusions as “fixed beliefs that are not amenable to change in and other psychotic
light of conflicting evidence. Their content may include a variety of themes (eg, disorders are delusions,
persecutory, referential, somatic, religious, grandiose).”1 hallucinations, disorganized
thinking (speech), grossly
PERSECUTORY DELUSIONS. Persecutory delusions are the most common type of disorganized or abnormal
delusion and involve a belief that someone is monitoring or trying to harm the motor behavior (including
patient. For example, patients may state that the Federal Bureau of Investigation catatonia), and negative
symptoms.
(FBI) is monitoring them and has cameras in their home or may say “‘they’ are
always watching me” or “‘they’ know everything I think.” When questioned ● Delusions are fixed beliefs
further about these beliefs, the patient will not be able to reason through or that a patient will maintain
accept any explanations that the beliefs are not factual. In fact, often the person despite conflicting evidence
offered by those around
trying to help the patient reason through the illogical beliefs will then become a them. The delusions may be
part of the delusions, ie, that person may now be perceived as a member of the persecutory, referential,
FBI sent to interrogate them. somatic, religious, or
grandiose in nature.
REFERENTIAL DELUSIONS. Referential delusions involve the belief that subtle
things occurring in an individual’s environment are cues that hold significant ● With religious delusions, it
is important to differentiate
meaning. An example is a patient believing that the newscaster on the evening between culturally
news is looking directly at him or her from inside the TV and has a special appropriate beliefs
message embedded in the newscast that is meant specifically for the patient. and delusions.
SOMATIC DELUSIONS. Somatic delusions involve irrational beliefs about a

person’s body. A dramatic example would be a female patient believing she is
pregnant, even though all logical evidence says otherwise. Somatic delusions can
be subtle and lead to a number of unnecessary medical consultations, tests, and
even operative procedures.
RELIGIOUS DELUSIONS. Religious delusions are also very common (eg, believing
that one is God or an angel). A clear example one of the authors encountered
involved a patient who believed he was Jesus Christ and had been crucified
on the cross. The patient showed the scars from the nails on the palms of his
hands, even though no imperfections of the skin were noted by others. With
religious delusions, it is important to differentiate between culturally appropriate
beliefs and delusions. For example, a patient may state he or she can talk to
God. When the family is questioned about typical religious beliefs for the
patient’s religious background, it may be discovered that talking directly to
God or “speaking in tongues” is a belief in that religion and is thus
culturally appropriate.
GRANDIOSE DELUSIONS. Grandiose delusions are exactly what they sound like:
grandiose beliefs about oneself (eg, one’s own abilities, wealth, or fame). A patient
with grandiose delusions may say that he or she flew a stealth bomber in the Iraq
War and was the reason the war ended, even though he or she has no military
experience and would have been too old to serve in the military during that time.
OTHER DELUSIONS. Other, less common, delusions patients may exhibit include
erotomanic delusions (belief that a famous person is in love with them), nihilistic
delusions (belief that a major catastrophe will occur), delusions of control
(belief that a person’s will, thoughts, or feelings are under the control of external

PSYCHOSIS
KEY POINTS forces), and delusions of mind reading (belief that people can read their mind
or know their thoughts).
● Hallucinations are
perceptual experiences
that are very vivid and real to
Hallucinations
the individual experiencing According to DSM-5, “Hallucinations are perception-like experiences that occur
them. They are not under without an external stimulus. They are vivid and clear, with the full force and
voluntary control and can impact of normal perceptions, and not under voluntary control. They may occur
occur in any sensory
modality.
in any sensory modality, but auditory hallucinations are the most common in
schizophrenia and related disorders.”1
● It is important to recognize
that visual hallucinations AUDITORY HALLUCINATIONS. Typically, auditory hallucinations involve hearing
can be a component of voices, either the familiar voices of people the patient knows or unfamiliar voices.
psychosis, but many times, The patient may hear one voice or multiple voices, either talking to the patient or
especially if onset is acute,
visual hallucinations are an talking to each other. The voices may say derogatory things about the patient,
indicator for delirium, such as “You’re worthless” or “You’re a failure,” or the voices may tell the patient
dementia, or other to do things. These are termed command hallucinations (eg, “Kill yourself” or
neurologic disorders. “Kill your boyfriend; he’s going to hurt you”). Musical hallucinations are another
● Tactile, olfactory, and
form of auditory hallucination and necessitate an audiologic evaluation before
gustatory hallucinations other etiologies are investigated, as hypoacusis is the most prevalent etiology.4
are unusual in a primary
psychotic disorder, and VISUAL HALLUCINATIONS. Visual hallucinations are another common
their presence suggests hallucination observed in primary psychosis. Patients may say they can see
another underlying medical
dead family members or individuals/faces unknown to them. However, visual
or neurologic cause.
hallucinations can also be a sign of delirium or dementia, especially if they are
acute in onset,5 and can also occur in other neurologic disorders. Patients may
note insects crawling around the room or strange fantasy figures when they are
delirious from an infection, intoxicated, or withdrawing from substances.
TACTILE, OLFACTORY, AND GUSTATORY HALLUCINATIONS. Tactile, olfactory, and

gustatory hallucinations are unusual in a primary psychotic disorder, and their
presence suggests a differential diagnosis of other underlying medical or neurologic
causes.3 A sensation of bugs crawling on the skin can be a common manifestation
of delirium. Olfactory hallucinations of burning or unpleasant smells may be a sign
of mesial temporal lobe seizures. Fifteen percent of patients with seizures from a
temporal lobe tumor will have olfactory or gustatory auras.6 Hallucinations that
occur while falling asleep (hypnagogic) or waking up (hypnopompic) may be a
symptom of narcolepsy, but from a psychiatric standpoint, they are usually
considered to be within the normal range of experience.1
Disorganized Thinking (Speech)

Disorganized thinking is assessed by a person’s speech patterns and is indicative of
a formal thought disorder.1 Different patterns of disruption of speech can occur.
Patients could be described as having thought blocking if they are speaking and
stop in the middle of a sentence and pause for a prolonged period. When they
resume talking, they do not acknowledge the pause and will start speaking about
something completely unrelated to what they were talking about previously.
TABLE 9-2 lists formal thought disorders and associated speech patterns.
Grossly Disorganized or Abnormal Motor Behavior (Including Catatonia)

Disorganized behavior is observed in the patient’s inability to complete
goal-directed activities. Disorganized patients may appear disheveled and
848 JUNE 2018

malnourished, typically dressed inappropriately for the weather. They may also
be observed talking to themselves and can become agitated in an unpredictable
manner.1 Disorganized behavior can also be seen as inappropriate laughing or
childlike behavior. Catatonia is an extreme form of abnormal motor behavior in
which a patient can assume a rigid, inappropriate, or bizarre posture. Patients
may also cease any verbal or motor responses to their environment; these are
termed mutism and stupor, respectively. Catatonic excitement is the opposite of
stupor and involves excessive motor activity with no obvious cause. Other
symptoms included in this category are repeated stereotyped movements,
staring, grimacing, and echoing of speech.1
Negative Symptoms
Negative symptoms are most often seen in schizophrenia versus other psychotic
disorders. Negative symptoms include diminished emotional expression,
avolition (a lack of motivation), alogia (poverty of speech), anhedonia (lack of
the ability to experience pleasure), and asociality. Negative symptoms have been
the target of novel drug development for many drug companies, because it is
now recognized that negative symptoms gravely impair an individual’s ability to
function productively in society.
Cognitive Symptoms
Cognitive symptoms are not listed in DSM-5 as one of the five domains in psychotic
illness but are included here as they are the most related to level of functioning
in schizophrenia. Three outcome domains exist in schizophrenia: functional
Formal Thought Disordersa TABLE 9-2
Thought Disorder Associated Speech Pattern
Circumstantiality Overinclusion of trivial or irrelevant details that impede the sense of getting to the point
Clang associations Thoughts are associated by the sound of words rather than by their meaning (eg, through rhyming or
assonance)
Derailment (synonymous A breakdown in both the logical connection between ideas and the overall sense of goal
with loose associations) directedness; the words make sentences, but the sentences do not make sense
Flight of ideas A succession of multiple associations so that thoughts seem to move abruptly from idea to idea;
often (but not invariably) expressed through rapid, pressured speech
Neologism The invention of new words or phrases or the use of conventional words in idiosyncratic ways
Perseveration Repetition of out-of-context words, phrases, or ideas
Tangentiality In response to a question, the patient gives a reply that is appropriate to the general topic without
actually answering the question
Example:
Doctor: “Have you had any trouble sleeping lately?”
Patient: “I usually sleep in my bed, but now I'm sleeping on the sofa.”
Thought blocking A sudden disruption of thought or a break in the flow of ideas
a
Modified with permission from Sadock BJ, et al.3 © 2015 Lippincott, Williams & Wilkins.

PSYCHOSIS
status (or psychosocial functioning), disorder status (positive and negative

symptoms), and subjective experience (personal well-being factors). Cognition,
specifically social cognition, is a major determinant of functional status.
Functional status has been shown to have a greater relationship to functional
outcomes for patients with schizophrenia than disorder status (the presence of
psychotic symptoms). Cognition, social cognition, and motivation are the main
determinants of success in daily and community functioning. In this context,
cognition refers to the ability to accurately perceive, attend to, and remember
information. Social cognition includes the ability to identify and interpret social
cues. Motivation involves the patient’s desire to engage the community and
relates to the negative symptoms of schizophrenia.7,8
EVALUATION OF THE PATIENT WITH PSYCHOSIS

The therapeutic relationship is a key component to a successful evaluation of the
patient with psychosis. The therapeutic relationship has been called by different
names in the research literature (eg, therapeutic alliance or working alliance).
Research on the therapeutic alliance in psychotherapy and psychiatric care has
shown that it is linked with improved patient outcomes.9 In patients who are
already very distrustful and disorganized in their thinking, it is vital to establish a
good working relationship for an evaluation to be successful. It is not uncommon
for a patient with psychosis to become agitated and discontinue/disengage from
the interview. In a review of the impact of the therapeutic relationship in
psychotic disorders, it was found that a successful therapeutic relationship was
judged to be “respectful, where shared decision making is the norm and where
trust is mutual.”9 It is widely known that medication noncompliance is a major
barrier to treatment success in schizophrenia. Establishing a positive therapeutic
relationship with patients in which they are involved in the decision-making
process regarding medication and how/why it is to be taken can dramatically
improve compliance.10
As in all areas of medicine, obtaining a thorough history of present illness is
essential in establishing an accurate diagnosis. Onset, duration, precipitating/
perpetuating factors, and stressors contributing to symptoms are important to
help differentiate a primary psychotic disorder from psychosis that is secondary
to a medical or neurologic disease as well as to develop the list of differential
diagnoses for a primary psychotic disorder. As the rest of the psychiatric history
is performed, the patient’s physical appearance, mannerisms, and abnormal
movements should be noted. In the review of symptoms for psychosis, all the
areas discussed previously in this article should be addressed.
For the nonpsychiatric clinician, one of the most important goals in the
interview of patients who present with acute-onset psychosis or are experiencing
a change in the symptoms of their psychosis is to establish whether the symptoms
are related to a primary psychotic disorder or secondary to an underlying
medical or neurologic disease. Establishing a primary psychotic disorder
diagnosis is a diagnosis of exclusion. It is diagnosed once all underlying medical
or neurologic possibilities are ruled out. In the authors’ personal experience,
it is not uncommon for the psychosis related to a medical or neurologic disease
to look very similar to a primary psychotic disorder. Psychoses resembling a
primary psychotic disorder such as schizophrenia occur 6 to 12 times more
frequently in patients with epilepsy than in the general population.11 To make
matters even more complex, a recently updated Cochrane Review details the
850 JUNE 2018

multiple studies that have documented that numerous anticonvulsants can KEY POINTS
precipitate psychosis.12 A review on psychosis in multiple sclerosis (MS)
● Negative symptoms
confirmed that MS can present as acute-onset psychosis in a patient with include diminished
no previous psychiatric history. The study was not able to confirm that emotional expression,
psychotic symptoms that develop in a patient with already diagnosed MS avolition (a lack of
represent an MS flare but did find that these patients responded poorly motivation), alogia (poverty
of speech), anhedonia (lack
to antipsychotics and improved significantly with the administration
of the ability to experience
of corticosteroids.13 pleasure), and asociality. It
It is essential to rule out delirium when evaluating a psychotic patient. Wong is now recognized that
and colleagues14 found that health care workers fail to recognize more than half negative symptoms gravely
impair an individual’s ability
of delirium cases; thus, a careful cognitive assessment is key in identifying
to function productively
delirium and differentiating it from primary psychosis. Two types of delirium in society.
exist: hypoactive and hyperactive. Hypoactive delirium is characterized by
lethargy and reduced psychomotor functioning, while hyperactive delirium is ● Functional status
characterized by agitation, increased vigilance, and hallucinations. It is the (psychosocial functioning)
has been shown to have a
hypoactive form that goes unrecognized most commonly.15 In a patient with greater relationship to
dementia, it is particularly difficult to recognize delirium. The prevalence of functional outcomes in
delirium superimposed on dementia ranges from 18% to 89% in hospitalized and schizophrenic patients than
community-dwelling elderly patients. disorder status (the presence
of psychotic symptoms). In
Another important but subtle distinction in the cognitive evaluation of the particular, social cognition is
patient with psychosis is that the patient’s ability to remain oriented to his or her a major determinant of
surroundings is not impaired in primary psychosis. A patient can be floridly functional status.
psychotic and still remain oriented to person, place, and time. An example
● A positive therapeutic
seen by one of the authors was a patient who, when interviewed during
alliance is vital to a
morning rounds, described his plan to take a spaceship to Mars and even had successful relationship with
drawings of the spaceship. A few hours later he was observed on the telephone, a psychotic patient. Research
coherently negotiating his rent payment with his landlord. In a study of shows that a positive
recent-onset and chronic schizophrenia, the cognitive domains affected by therapeutic relationship in
which the patient is involved
psychosis were efficiency of problem solving, fine motor dexterity, and in the decision making and
episodic memory.16 mutual respect exists
Psychosis is commonly a symptom of dementia, and sometimes the psychosis between patient and clinician
is actually the presenting symptom. It is reported that psychosis has a lifetime can dramatically impact
treatment compliance and
risk of 23% and ranks as one of the most common conditions in late life.17 patient outcomes.
Approximately 60% of elderly patients who present with new-onset psychosis
are exhibiting symptoms of a secondary psychosis.17 An evaluation of the ● For the nonpsychiatric
“six D’s” of late-life psychosis includes delirium, disease, drugs, dementia, clinician, one of the most
important goals in the
depression, and delusions (denoting the schizophrenia spectrum disorders).17
interview of patients who
In elderly patients with chronic schizophrenia, it can be extremely difficult to present with acute-onset
differentiate whether a change in their psychotic symptoms is related to their psychosis or are experiencing
primary psychotic disorder or due to a developing dementia. In these patients, a change in the symptoms of
their psychosis is to establish
the Montreal Cognitive Assessment (MoCA) can be particularly helpful, as it has
whether the symptoms are
been shown to be a useful screening tool to detect medically or neurologically related to a primary psychotic
based cognitive deficits in patients with severe mental illness, such as disorder or secondary to an
schizophrenia, and psychiatrically hospitalized patients.18,19 A score of 23 or underlying medical or
below was determined to screen positive for medically or neurologically based neurologic disease.
Establishing a primary
cognitive deficits.18 As an interesting side-note, it has been postulated that psychotic disorder diagnosis
“‘delusions’ in dementia are not a psychotic symptom, but rather a byproduct is a diagnosis of exclusion.
of memory loss, thus deserving a different label.”20
Laboratory and radiologic evaluations of the patient with acute psychosis
should always be performed in accordance with the list of possible diagnoses

PSYCHOSIS
being considered. Diagnostic testing may include complete blood cell count,
comprehensive metabolic panel, thyroid-stimulating hormone (TSH),
vitamin B12 level, folate, rapid plasma reagin (RPR), erythrocyte sedimentation
rate, autoimmune antibody screens, human immunodeficiency virus (HIV)
testing, and toxicology screen. Either a brain MRI or CT scan should be
performed; EEG and additional testing may be ordered if the history
indicates.17
Assessment/Diagnosis of the Patient With Psychosis

Once it has been established that a patient’s cognitive status is not compromised
by delirium or dementia, the patient should be evaluated for a primary psychotic
disorder. A detailed psychiatric examination should be performed, including a
psychiatric review of systems, psychiatric history, family psychiatric history, and
social history. The mental status examination takes careful note of the patient’s
physical appearance, behavior, mood, speech patterns, thought content, thought
processes, cognition, insight, and judgment.21 In a thorough psychiatric assessment,
it is important to question a patient with a list of potential differential diagnoses
in mind (TABLE 9-1). However, it is also important to rule out affective disorders
with a psychotic component; personality disorders that have a psychotic
component, such as borderline personality disorder; and autism spectrum
disorders. The Brief Psychiatric Rating Scale is considered a clinically useful tool
in evaluating patients with psychosis and gauging their response to treatment.22
The following sections review each of the DSM-5 diagnoses listed under
“Schizophrenia Spectrum and Other Related Disorders.”
SCHIZOTYPAL PERSONALITY DISORDER. Schizotypal personality disorder is a

DSM-5 personality disorder characterized by magical thinking, illusions,
and ideas of reference. Patients with schizotypal personality disorder exhibit
odd behavior, and their speech patterns may have particular significance to
only them. In contrast to patients with psychotic disorders, these patients
do not have persistent delusions or hallucinations. Patients with schizotypal
personality disorder are very socially isolated. Schizotypal personality disorder
is diagnosed in about 3% of the population.3
DELUSIONAL DISORDER. Delusional disorder is characterized by the presence

of one or more delusions. The criteria state that the patient must hold the
delusion(s) for at least 1 month and that the delusions cannot be explained by
another mental disorder. Classically, the delusions are usually not bizarre in
nature (ie, they could happen in real life, such as being loved at a distance by
someone famous, being infected with a disease, or being followed). However,
DSM-5 now allows a subtype with bizarre (implausible) delusions. Whatever
delusions are held, the patient’s functioning is not significantly impacted, and his
or her behavior is not usually considered odd or bizarre. The incidence of
delusional disorder is 0.2% to 0.3%, making it rare.3
BRIEF PSYCHOTIC DISORDER. Brief psychotic disorder involves the development of

acute psychotic symptoms that last at least 1 day but less than a month and
resolve spontaneously. The episode may be secondary to a trauma (stressor),
develop postpartum, or develop without an obvious precipitant. Patients return
to their previous level of functioning. The incidence of brief psychotic disorder
is unknown.3
852 JUNE 2018

SCHIZOPHRENIFORM DISORDER. In simple terms, schizophreniform disorder is KEY POINTS
similar to schizophrenia, except its duration from onset is less than 6 months.
● An important but subtle
In contrast to brief psychotic disorder, the symptoms must last at least 1 month. distinction in the cognitive
In one-third of cases, the illness resolves completely in less than 6 months, evaluation of the patient
with patients returning to their previous level of functioning. The remaining with psychosis is that the
two-thirds of patients usually progress to another psychotic disorder, most often patient’s ability to remain
oriented to his or her
schizophrenia or schizoaffective disorder.3
surroundings is not impaired
in primary psychosis.
SCHIZOPHRENIA. Schizophrenia is one of the most common severe mental A patient can be floridly
illnesses and is reported to have a lifetime incidence of 1%. Schizophrenia is psychotic and still remain
typically diagnosed before age 25 and is diagnosed equally in men and women. oriented to person, place,
and time.
When it is diagnosed after age 45, it is considered late onset. Schizophrenia is
diagnosed by the presence of at least two of the following five symptoms: ● Evaluating a patient’s
delusions, hallucinations, disorganized speech, grossly disorganized or catatonic cognitive status is an
behavior, and negative symptoms. At least one of the symptoms must be essential component in
delusions, hallucinations, or grossly disorganized behavior (CASE 9-1).3 differentiating primary
psychosis from secondary
psychosis.
SCHIZOAFFECTIVE DISORDER. Schizoaffective disorder is a combination of
schizophrenia and a mood disorder. Both disorders could be diagnosed ● The mental status
separately and are present in full in the same patient. Critically, the psychosis examination takes careful
must be present for at least 2 weeks when the mood disorder is not present. note of the patient’s physical
appearance, behavior,
Additionally, the mood disorder must be diagnostically present during a majority
mood, speech patterns,
of the active and residual phases of the illness.3 In other words, more than thought content, thought
50% of the time either depression or bipolar disorder must be evident. Major processes, cognition, insight,
depression with psychosis is different than schizoaffective disorder because the and judgment.
psychosis is only present when the patient is severely depressed. The incidence of
schizoaffective disorder is less than 1%.3
SUBSTANCE/MEDICATION-INDUCED DISORDER. Substance/medication-induced

disorder is diagnosed when a patient experiences psychosis in direct relationship
to ingestion of a substance or medication. If the substance or medication
is taken intentionally to achieve chemical alteration, it is termed
substance intoxication.
PSYCHOTIC DISORDER DUE TO ANOTHER MEDICAL CONDITION. Psychotic disorder

due to another medical condition is the diagnosis given for patients who experience
psychosis in the context of a medical condition (eg, lung neoplasm, MS,
epilepsy). This diagnosis is not given if the psychosis occurs exclusively during
the course of delirium.1
CATATONIA. Catatonia is diagnosed by the presence of three or more of the

following symptoms: stupor (no psychomotor activity [movement that is
impacted by thinking]), catalepsy (passive induction of a posture held against
gravity), waxy flexibility (slight, even resistance to positioning by examiner),
mutism (little or no verbal response), negativism (opposition or no response
to instructions or external stimuli), posturing (spontaneous and active
maintenance of posture against gravity), mannerism (odd, circumstantial
caricature of normal actions), stereotypy (repetitive, abnormally frequent,
non–goal-directed movements), agitation (not influenced by external stimuli),
grimacing, echolalia (mimicking another’s speech), and echopraxia (mimicking
another’s movements). The DSM-5 diagnoses for catatonia are catatonia

PSYCHOSIS
CASE 9-1 A 24-year-old man presented for a follow-up visit after a recent
psychiatric hospitalization. He had been seen in the clinic since age 18.
The recent hospitalization was for command auditory hallucinations
telling him to kill himself and persecutory delusions that his parents were
poisoning him. He had finished high school in the top 20% of his class and
was in his second year of college (at age 20) when he started experiencing
symptoms of psychosis. He had been hospitalized 5 times in the past
4 years for delusions that his parents were poisoning him and auditory
hallucinations telling him his neighbors were going to harm him. Initial
workup for this patient included a urine drug screen, comprehensive
metabolic profile, complete blood cell count, thyroid-stimulating
hormone (TSH), and brain CT. During each of his five hospitalizations, he
responded well to medication, and his symptoms improved, but when he
was released from the hospital, he stopped his medication and symptoms
recurred. He had to drop out of school after his second year because his
psychosis interfered with his ability to focus on his schoolwork.
He had a past history of treatment for attention deficit hyperactivity
disorder in late adolescence and an otherwise negative medical history.
His family history revealed a maternal aunt who had been in and out of the
hospital most of her life with psychotic symptoms. His parents were both
healthy, although his father, who was an engineer, had a history of
treatment for minor anxiety. The patient’s older brother was physically
and mentally healthy and attended law school. The patient was on
disability and unable to hold a part-time job when he was not on
his medication.
At the follow-up visit, the patient was slightly disheveled and had not
bathed in a week. He made a moderate amount of eye contact during the
interview and did not appear to be responding to internal stimuli. He
stated that he did not believe anyone was poisoning him at the time and
that he was taking his medication as prescribed. During his most recent
hospitalization, he was placed on a long-acting injectable antipsychotic
because of his history of noncompliance.
COMMENT The most likely Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
diagnosis for this patient would be schizophrenia, with the specifier “multiple
episodes, currently in acute episode.” He has poor insight and medication
nonadherence, leading to frequent relapses. This patient shows a typical
course for the cognitive ramifications of schizophrenia. In the absence of a
diagnosis of schizophrenia, this patient could be expected to finish college
and hold a higher-level degree. However, due to his schizophrenia, this
patient has had significant cognitive decline and is unable to finish college or
hold a steady job.
854 JUNE 2018

associated with another mental disorder (catatonia specifier) or catatonic disorder KEY POINTS
due to another medical condition. Unspecified catatonia is used when the underlying
● Antipsychotic
disorder is not known.1 medications are the
mainstay of the treatment
OTHER SCHIZOPHRENIA SPECTRUM AND OTHER PSYCHOTIC DISORDERS. The for psychosis and should be
diagnosis other schizophrenia spectrum and other psychotic disorders is used when a started promptly after an
accurate diagnosis has
patient meets a significant level of schizophrenia spectrum or other psychotic
been established.
disorder symptoms, but a full diagnosis cannot be made. The diagnosis other
specified schizophrenia spectrum and other psychotic disorders is used when the ● The choice of an
clinician specifies the symptoms present, and the unspecified schizophrenia antipsychotic medication is
spectrum and other psychotic disorders diagnosis is given when the clinician does primarily based on
adverse effects and cost
not specify the symptoms present.1 considerations, as they do
not differ significantly as far
TREATMENT as efficacy is concerned
The first steps in the treatment of acute psychosis should be evaluation for (with the exception of
clozapine, which has
agitation and harm prevention. Patients who are at an increased risk of harm to consistently been shown to
themselves or others may need to be hospitalized. Long-term goals of treatment be more effective than other
include sustaining remission, reducing relapses, and improving the patient’s oral antipsychotics).
level of functioning and quality of life.23
● Clozapine is effective in
Antipsychotic medications are the mainstay of the treatment for psychosis and
reducing suicidal behaviors
should be started promptly after an accurate diagnosis has been established. in patients with schizophrenia
Antipsychotic medications have been extensively studied for the treatment of and is also effective for
schizophrenia24 and also appear to be effective for other types of psychosis. psychotic symptoms
associated with Parkinson
Studies have found antipsychotics to be effective for bipolar mania with psychosis,25
disease. Clozapine can
depression with psychotic features (combination therapy with antidepressants),26 cause granulocytopenia
Parkinson disease psychosis,27 and psychosis related to dementia.28 or agranulocytosis in
The choice of an antipsychotic is primarily based on adverse effects and cost approximately 1% of
considerations, as they do not differ significantly as far as efficacy is concerned patients, requiring regular
blood cell count monitoring.
(with the exception of clozapine).29 Clozapine has consistently been shown to be
more effective than other oral antipsychotics in patients for whom a number
of other antipsychotics have failed (ie, treatment-resistant psychosis) and
has also been shown to be effective in reducing suicidal behaviors in patients
with schizophrenia and schizoaffective disorder.30 Clozapine can cause
granulocytopenia or agranulocytosis in approximately 1% of patients, requiring
regular blood cell count monitoring. Clozapine has been associated with
excess risk of myocarditis and venous thromboembolic events, including fatal
pulmonary embolism. TABLE 9-3 lists the major adverse effects of all the
antipsychotics available in the United States.31
Long-acting injectable antipsychotic medications provide an alternative
pharmacologic strategy for the treatment of psychosis and can be administered
by injection at 2- to 12-week intervals. Long-acting injectable antipsychotic
medications are usually reserved for patients in whom noncompliance to oral
antipsychotics leads to frequent relapses, but more recently they also have
been studied in early phases of schizophrenia. A systematic review involving
10 studies concluded that the use of long-acting injectable antipsychotic
medications in early phases of schizophrenia may be more effective than other
forms of antipsychotic medications in controlling symptoms and
relapses.32
Electroconvulsive therapy should be considered for individuals who have
severe psychosis and for whom multiple antipsychotic trials (including

PSYCHOSIS
TABLE 9-3 Selected Adverse Effects of Antipsychotic Medications for Schizophreniaa,b
Extrapyramidal Symptoms/
Medication Weight Gain/Diabetes Mellitus Hypercholesterolemia Tardive Dyskinesia
First-generation agents
Chlorpromazine +++ +++ +
Fluphenazine + + +++
Haloperidol + + +++
Loxapine ++ ND ++
Perphenazine ++ ND ++
Pimozide + ND +++
c
Thioridazine ++ ND +
Thiothixene ++ ND +++
Trifluoperazine ++ ND +++
Second-generation agents
Aripiprazole + – +
Asenapine ++ – ++
Brexpiprazoled + + +
Cariprazine d
+ –/+ ++
Clozapinee ++++ ++++ –/+
Iloperidone ++ ++ –/+
Lurasidone –/+ –/+ ++
Olanzapine ++++ ++++ +
Paliperidone +++ + +++
Pimavanserin + – –/+
Quetiapine +++ +++ –/+
Risperidone +++ + +++
Ziprasidone –/+ –/+ +
ND = no data.
a
Reprinted with permission from Stroup TS, Marder S, UpToDate.31 © 2018 UpToDate, Inc.
b
Adverse effects may be dose dependent.
c
Thioridazine is also associated with dose-dependent retinitis pigmentosa.
d
Based upon limited experience.
e
Clozapine also causes granulocytopenia or agranulocytosis in approximately 1% of patients, requiring regular blood cell count monitoring.
Clozapine has been associated with excess risk of myocarditis and venous thromboembolic events, including fatal pulmonary embolism.
856 JUNE 2018

Prolactin Elevation Sedation Anticholinergic Side Effects Orthostatic Hypotension QTc Prolongation
++ +++ +++ +++ +
+++ + –/+ – ND
+++ ++ –/+ – +
++ ++ + + +
++ ++ + – ND
++ + + + ++
+++ +++ ++++ ++++ +++
++ + + + +
++ + + + ND
– + – – –/+
++ ++ – + +
–/+ + –/+ –/+ –/+
–/+ + –/+ –/+ –/+
–/+ +++ +++ +++ +
–/+ + + +++ ++
–/+ ++ – + –/+
+ ++ ++ + +
+++ + – ++ +
– + + ++ +
–/+ ++ ++ ++ +
+++ + + + +
+ + – + ++

PSYCHOSIS
KEY POINT clozapine) have failed or could not be tolerated. Electroconvulsive therapy
is also a treatment option for psychosis with prominent catatonic
● Although antipsychotic
medications remain the
features.23
mainstay of treatment for It is recommended that certain assessments be completed before the initiation
psychosis, most patients of antipsychotics and periodically throughout the course of the treatment. These
require one or more assessments include vital signs; body weight and height; complete blood cell
additional strategies,
count; blood electrolytes; glucose level; tests of liver, renal, and thyroid function;
such as providing education
and information about the screening for diabetes mellitus; hyperprolactinemia and hyperlipidemia; ECG;
disease, social skills and screening for a movement disorder, including extrapyramidal symptoms
training, cognitive- and tardive dyskinesia.23
behavioral therapy,
Although antipsychotic medications remain the mainstay of treatment for
assertive community
treatment, or problem- psychosis, most patients require one or more additional strategies, such as
solving family therapy. providing education and information about the disease, social skills training,
cognitive-behavioral therapy, assertive community treatment, or
problem-solving family therapy.23,33
Special Considerations
According to the practice guideline published by the American Psychiatric
Association, antipsychotic medication should only be used for dementia-related
psychosis when symptoms are severe or dangerous or cause significant distress to
the patient.34 An increased mortality risk is associated with the use of
antipsychotic medication in elderly patients with dementia.
Pimavanserin is a newer medication marketed for the treatment of
psychotic symptoms associated with Parkinson disease. It differs from other
antipsychotics as it has no measurable dopaminergic activity.35 Clozapine and
quetiapine should also be considered in this patient population.27
CONCLUSION
Psychosis as a primary mental health disorder is a diagnosis of exclusion. Many
different manifestations of psychotic symptoms are directly related to an
underlying medical or neurologic disorder. Delirium and dementia are the two
most important disorders to rule out and can present in a very subtle fashion. It is
hoped that this article will help practitioners be more prepared to assess the
patient with psychosis.
In a psychotic patient, it is important to establish a good therapeutic alliance.
Psychosis can be a major barrier to treatment that is managed very well by a good
therapeutic alliance with the patient. Once underlying medical or neurologic
disorders have been ruled out and an appropriate primary psychotic disorder
diagnosis is made, antipsychotic medication can be prescribed. Antipsychotic
medication may also be used as an adjuvant to the treatment of a primary medical
or neurologic disorder. With antipsychotic treatment, it is important to regularly
assess vital signs, body weight and height, appropriate laboratory tests, and ECG
and to screen for movement disorders such as extrapyramidal symptoms and
tardive dyskinesia.
Social cognition is a major determiner to the outcome for patients with
schizophrenia. Treatments such as psychoeducation, social skills training, and
various forms of therapy can be very beneficial to the recovery of patients
with psychosis.
858 JUNE 2018

USEFUL WEBSITES
HOSPITAL ELDER LIFE PROGRAM (HELP) FOR PREVENTION PSYCHIATRIC TIMES—BPRS BRIEF PSYCHIATRIC RATING
OF DELIRIUM SCALE
The Hospital Elder Life Program website provides The BPRS Brief Psychiatric Rating Scale page on the
information about delirium for patients, caregivers, Psychiatric Times website provides a link to
and clinicians. download the assessment.
hospitalelderlifeprogram.org psychiatrictimes.com/clinical-scales-schizophrenia/
clinical-scales-schizophrenia/bprs-brief-
MONTREAL COGNITIVE ASSESSMENT (MOCA) psychiatric-rating-scale
The Montreal Cognitive Assessment website is a
clinician-only website with free registration for
access to use the MoCA tools.
mocatest.org
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860 JUNE 2018

Conversion Disorder REVIEW ARTICLE

By Anthony Feinstein, MD, PhD C O N T I N U UM A U D I O
ONLINE
ABSTRACT
PURPOSE OF REVIEW: This article provides a broad overview of conversion
disorder, encompassing diagnostic criteria, epidemiology, etiologic
theories, functional neuroimaging findings, outcome data, prognostic
indicators, and treatment.
RECENT FINDINGS: Two important changes have been made to the recent
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
diagnostic criteria: the criteria that conversion symptoms must be shown
to be involuntary and occurring as the consequence of a recent stressor
have been dropped. Outcome studies show that the rate of misdiagnosis
has declined precipitously since the 1970s and is now around 4%.
Functional neuroimaging has revealed a fairly consistent pattern of CITE AS:
hypoactivation in brain regions linked to the specific conversion symptom, CONTINUUM (MINNEAP MINN)
accompanied by ancillary activations in limbic, paralimbic, and basal 2018;24(3, BEHAVIORAL NEUROLOGY
ganglia structures. Cognitive-behavioral therapy looks promising as the
psychological treatment of choice, although more definitive data are still Address correspondence to
awaited, while preliminary evidence indicates that repetitive transcranial Dr Anthony Feinstein,
magnetic stimulation could prove beneficial as well. Department of Psychiatry,
Sunnybrook Health Sciences
Centre and the University of
SUMMARY: Symptoms of conversion are common in neurologic and Toronto, 2075 Bayview Ave,
Toronto, ON M4N 3M5, Canada,
psychiatric settings, affecting up to 20% of patients. The full syndrome of ant.feinstein@utoronto.ca.
conversion disorder, while less prevalent, is associated with a guarded
prognosis and a troubled psychosocial outcome. Much remains uncertain RELATIONSHIP DISCLOSURE:
Dr Feinstein serves on the
with respect to etiology, although advances in neuroscience and editorial board of the Multiple
technology are providing reproducible findings and new insights. Given Sclerosis Journal and receives
the confidence with which the diagnosis can be made, treatment should personal compensation for
speaking engagements for EMD
not be delayed, as symptom longevity can influence outcome. Serono, Inc; F. Hoffman-La
Roche Ltd; Novartis AG; Sanofi
Genzyme; and Teva
Pharmaceutical Industries Ltd.
Dr Feinstein receives
INTRODUCTION research/grant support from
T
he challenges posed by medically unexplained symptoms can be the Multiple Sclerosis Society of
Canada and publishing royalties
traced back to the origins of Western medicine. The list of luminaries from Amadeus Press,
who have turned their attention to the vexing question of etiology is Cambridge University Press, and
long and distinguished and includes, among others, Hippocrates, Johns Hopkins University Press.
Galen, Paracelsus, Robert Burton, William Harvey, Thomas Willis, UNLABELED USE OF
Thomas Sydenham, William Cullen, Philippe Pinel, Franz Anton Mesmer, PRODUCTS/INVESTIGATIONAL
Jean-Martin Charcot, Pierre Janet, and Sigmund Freud.1 Such a prolonged hold USE DISCLOSURE:
Dr Feinstein reports no
over succeeding generations of physicians of diverse specialties hints at the disclosure.
complexity of the disorder. This is reflected in the uncertainty of how best to
label these disorders and where they fit in the classification of mental illness. The © 2018 American Academy
term hysteria disappeared from the Diagnostic and Statistical Manual of Mental of Neurology.

CONVERSION DISORDER
KEY POINTS Disorders, Third Edition (DSM-III)2 in 1968 because of a pejorative association
with the wandering womb hypothesis, and a new set of disorders was created
● The diagnosis of
conversion disorder
to replace it. The 2013 Diagnostic and Statistical Manual of Mental Disorders,
depends on the presence of Fifth Edition (DSM-5) radically overhauled the nomenclature yet again,
atypical neurologic-type discarding somatization disorder, undifferentiated somatoform disorder, and
symptoms that do not hypochondriasis.3 Notwithstanding this periodic shuffling of the diagnostic
conform to the known
deck, the DSM-5 and International Classification of Diseases, Tenth Revision
anatomic and physiologic
constructs that support (ICD-10) continue to differ in their approach to taxonomy.4
neurologic diagnoses. One island of relative stability amid all this semantic flux is the condition of
conversion disorder, which was retained in DSM-5, although even here the
● The diagnostic criteria for authors added an alternative terminology in parentheses, namely functional
conversion disorder have
been revised recently to neurological symptom disorder. In conversion disorder, the focus is purely on
reflect two significant atypical neurologic symptoms that do not conform to any neurologic disorder.
conceptual shifts. It is no This article discusses the clinical signs, epidemiology, etiology, diagnostic
longer necessary to assert accuracy, functional brain imaging findings, and treatment of conversion
that the symptoms are not
intentionally produced or
disorder, interspersed with case reports to illustrate salient points.
linked to recent stressors.
CLINICAL SIGNS
The DSM-5 diagnostic criteria for conversion disorder appear in TABLE 10-1. One
notable change from the earlier Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) criteria has been to drop the assertion that the
symptom or deficit is not intentionally produced or feigned.5 This change is to
be welcomed, for it is frequently impossible to discern these factors during the
clinical interview. This does not, however, imply that conversion symptoms are
willfully produced, and it remains a tacit assumption when it comes to therapy
that involuntary factors underpin the etiology. A second conceptual change in
the DSM-5 is that the criterion invoking psychological stressors is no longer
considered mandatory; instead, one has the option of coding separately for it.
This change is once again welcomed, for symptom onset is not invariably
preceded by conflict.
In the DSM-5 criteria, the disorder is coded according to symptom type. A
significant omission from the list is cognitive impairment, most typically memory.
To the authors of the DSM-5, memory impairment in the absence of an underlying
dementia is better explained by the concept of dissociation (dissociative amnesia),
placing the classification at odds with the ICD-10 approach.
EPIDEMIOLOGY
The data here are mixed for methodologic reasons. Some studies report the
frequency of individual conversion symptoms, whereas others refer to the full
diagnosis. It is estimated that up to one-fourth of all patients in a general hospital
setting have individual symptoms of conversion,6 with 5% of these meeting the
full diagnostic criteria.7 These figures increase in neurologic populations, in
which it is estimated that 20% of patients attending a neurologic outpatient clinic
will have symptoms of conversion.8 Large-scale population-based studies show
a good degree of concordance, with incidence rates falling in the 4 per 100,000 to
12 per 100,000 range.9 Not surprisingly, the incidence rises to 11 per 100,000
to 22 per 100,000 in a primarily psychiatric setting.10
Conversion disorder can occur across the lifespan and is more common in
women11 and in those who have a history of abuse, not necessarily sexual, during
childhood (CASE 10-1).12 In keeping with the revised DSM-5 criteria, an
862 JUNE 2018

association exists with stressful life events around the time of symptom onset,
although here one must be mindful of retrospective bias in the reporting of
these events.
ETIOLOGY
The DSM approach to the diagnosis and classification of mental illness is essentially
descriptive and shies away from etiologic assumptions given the many
uncertainties surrounding causality. One exception is conversion disorder, for
which the role of stressors is still acknowledged, even if now not considered
obligatory. While it is recognized that precipitating stressors are not always present,
the freudian idea of unresolved psychological conflicts manifesting as physical
symptoms still persists and is not without validity, as CASE 10-1 illustrates.
DSM-5 Criteria for Conversion Disorder (Functional Neurological Symptom TABLE 10-1
Disorder)a
A One or more symptoms of altered voluntary motor or sensory function

B Clinical findings provide evidence of incompatibility between the symptom and
recognized neurological or medical conditions
C The symptom or deficit is not better explained by another medical or mental disorder
D The symptom or deficit causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning or warrants medical evaluation
Coding note: The ICD-9-CM code for conversion disorder is 300.11, which is assigned regardless
of the symptom type. The ICD-10-CM code depends on the symptom type (see below).
Specify symptom type:
(F44.4) With weakness or paralysis
(F44.4) With abnormal movement (eg, tremor, dystonic movement, myoclonus, gait disorder)
(F44.4) With swallowing symptoms
(F44.4) With speech symptom (eg, dysphonia, slurred speech)
(F44.5) With attacks or seizures
(F44.6) With anesthesia or sensory loss
(F44.6) With special sensory symptom (eg, visual, olfactory, or hearing disturbance)
(F44.7) With mixed symptoms
Specify if:
Acute episode: Symptoms present for less than 6 months
Persistent: Symptoms occurring for 6 months or more
Specify if:
With psychological stressor (specify stressor)
Without psychological stressor
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; ICD-9-CM = International
Classification of Diseases, Ninth Revision, Clinical Modification; ICD-10-CM = International Classification of
Diseases, Tenth Revision, Clinical Modification.
a

CONVERSION DISORDER
Implicit in our understanding of conversion disorder is that symptoms are not

deliberately, or consciously, produced. With this construct immutable, it is
necessary to look beyond psychoanalytic theories for clues as to etiology.
Cognitive models have posited that a faulty executive system could channel
misperceptions into conscious awareness.13 Attentional deficits14 and problems
with working memory15 have been found but not replicated. Impulsivity linked
to the processing of novel sensory data, thereby introducing interpretation bias,
has been implicated too.16 While all are of interest, the cognitive data are few and
fragmented and have yet to provide a coherent overall theory accounting for
symptom misattribution. More research is clearly needed here, but in a disorder
CASE 10-1 A 25-year-old woman was admitted to a neuropsychiatric unit because

of sudden unexplained left-sided weakness and sensory loss in the
presence of atypical neurologic findings and a normal CT brain scan.
She had previously been physically and psychiatrically well.
Neurologic examination revealed a flaccid left arm and leg, dense
anesthesia in the affected limbs, and midline truncal anesthesia. Muscle
stretch reflexes were normal and Babinski signs were absent. Her mental
state examination revealed distress and bemusement at her condition
and resentment that she had been admitted to a psychiatric unit rather
than a neurology unit. Her paralysis and sensory loss made it very difficult
for her to manage her activities of daily living, including her hygiene, and
her inability to walk meant she was reliant on a wheelchair to get around.
She denied a history of recent stressors, and her family confirmed this.
She was reluctant to talk about herself or divulge details of her personal
history other than to confirm that she lived alone, earned a good wage,
enjoyed her work, and had a good circle of friends.
Two weeks into her admission and faced with no symptom improvement
and ongoing recalcitrance to self-revelation, a sodium amytal interview
was undertaken with her permission. Under light sedation from the IV
barbiturate, the patient was encouraged to open up and be more
forthcoming. Suitably relaxed, she revealed that she had been raped
5 years earlier, had become pregnant, and had an abortion. She had never
previously divulged this to family or friends because of an intense feeling
of shame. For 5 years, she had lived with this secret and gotten on with
her life until 1 month previously, when she had fallen in love with a
coworker who had not reciprocated her affections. Soon thereafter, the
loss of sensation had begun, quickly followed by paralysis. The abreaction
(ie, release of emotional tension after her recall of the traumatic event)
induced by the amytal interview was the catalyst that opened the door to
psychotherapy and, in time, complete symptom resolution.
COMMENT This case provides compelling evidence of emotional upset, involuntarily

suppressed, that underlies the quasineurologic difficulties of an individual
with conversion disorder. It also demonstrates how recovery can take
place when these suppressed feelings are revealed and then addressed.
864 JUNE 2018

with protean manifestations, it remains unclear whether a central unifying KEY POINTS
cognitive theory exists for conversion disorder as a whole or whether specific
● While it is accepted that
theories are needed for each type of symptom. Furthermore, it is uncertain symptoms of conversion
whether cognitive deficits will mesh with the physiologic findings that are disorder are involuntary and
symptom specific, such as those pertaining to premovement EEG potentials not simulated, their precise
noted in functional myoclonus,17 changes in the blink reflex recovery cycle in origins remain unclear.
atypical (psychogenic) blepharospasm,18 or abnormalities in neuroimaging
● Given the protean
(discussed later in this article). Which, in turn, begs the question: Is it important manifestations of
that they do? When searching for diagnostic construct validity, it is, of course, conversion, it remains
preferable for the data from multiple sources to align coherently, but conversion unclear from an etiologic
may be the outlier here. Perhaps this can account for why the psychological perspective whether a
single theory can explain the
concept of suppressed emotional problems finding an outlet by their conversion disorder or whether specific
into physical symptoms remains attractive as a general theory, even if it theories are required
superficially blurs the margins when it comes to explaining symptom specificity. according to symptom
presentation.
DIAGNOSTIC ACCURACY ● Rates of misdiagnosis of
Notwithstanding all the uncertainties surrounding the underpinnings of a neurologic disorder as a
conversion disorder, one indirect marker of diagnostic validity is the degree to conversion disorder have
which the diagnosis is made correctly. Here the data offer reassurance. A improved considerably over
the decades and are now
systematic review of 27 studies involving 1466 subjects with a median duration of
low. Current estimates are
5 years of follow-up revealed a consistent 4% rate of misdiagnosis (ie, the approximately 4%.
presence of a neurologic condition rather than a conversion disorder) from 1970
onward. Of note is that this represented a steep decline from misdiagnosis rates ● Conversion disorder can
of 29% and 17% in the 1950s and 1960s, respectively, with improvements in study still occur in the presence
of a confirmed neurologic
design rather than improved diagnostic accuracy in the post-CT era credited disorder as long as the signs
for this.19 Further support for diagnostic accuracy and consistency comes from a and symptoms remain
Scottish study of 1144 patients assessed at baseline by neurologists as having atypical and do not conform
symptoms “unexplained by organic disease.” At 18-month follow-up, only four to established anatomic
and physiologic constructs.
individuals (0.4%) had their diagnoses changed to a definite neurologic condition.20
It should be remembered that unexplained symptoms can also arise in the
context of a confirmed neurologic diagnosis, such as multiple sclerosis. Evidence
suggests that no one particular neurologic disease is more frequently implicated
here.21 Individuals who self-reported more unexplained neurologic symptoms
also endorsed more psychiatric symptoms. The complexities of presentations
such as these are illustrated in CASE 10-2.
BRAIN IMAGING
The results from a small, yet compelling, functional MRI (fMRI) task activation
literature show that in the presence of sensory and motor conversion symptoms,
activation in the respective motor and somatosensory cortices is either absent or
reduced. Concomitantly, activation is seen in limbic, paralimbic, and basal
ganglia regions, but only in the conversion subjects. From a methodologic
standpoint, it is more straightforward to undertake a fMRI study of sensory
conversion symptoms given that nothing is asked of the subject other than to lay
quietly in the scan while a sensory stimulus is applied. Early studies of sensory
conversion were confined to single case reports, but more recently a study of 10
people with unilateral sensory loss was undertaken.22 A vibrotactile stimulus was
applied separately to the anesthetic and sensate regions in a block design, which
entailed 4 seconds of stimulation followed by 26 seconds of no stimulation, the
latter required to negate habituation to the stimulus. This pattern was repeated

CONVERSION DISORDER
CASE 10-2 A 28-year-old woman began experiencing very brief losses of sensation
associated with transient weakness in all her limbs. At first, she tried
to ignore the phenomena, but as they became more persistent, she
discovered that vigorously rubbing the affected areas caused sensation
to return and the weakness to resolve. This “remedy” proved short-lived,
however, and soon the symptoms began affecting her gait, which became
labored, shuffling, and interspersed with knee-bending movements.
She consulted a neurologist and two physical medicine and rehabilitation
specialists before being referred to a neuropsychiatry clinic. She had no
history of prior medical or psychiatric illness. Her developmental history
was unremarkable, and detailed inquiry failed to reveal a history of recent
stressors or past adverse life events. These facts were confirmed in
interviews with her husband and sister.
Her neurologic examination was repeatedly normal. No brain imaging
had been completed before the referral, with all three of her earlier
physicians noting that the obviously atypical nature of her symptoms,
particularly her bizarre gait, left little doubt to them as to the psychiatric
origins of her symptoms. This conclusion, in their collective opinions,
negated the need for further investigation. Head CT was nevertheless
completed and revealed a large left frontal meningioma with considerable
edema and midline shift. Rather than express shock or surprise, her face
lit up with relief. She felt vindicated. She had always believed something
was physically wrong with her and had strongly (and silently) resented the
referral to a neuropsychiatrist.
The tumor was subsequently removed successfully, and her neurologic
symptoms resolved completely. While the neurologist, physical
medicine and rehabilitation specialists, neurosurgeon, and
neuropsychiatrist involved in her care had little doubt that the odd
gait was functional, less certainty was expressed on the role of
such a large brain tumor in her presentation.
COMMENT It is important to remember that conversion disorder can still be diagnosed

in the presence of a confirmed neurologic disorder when the symptoms
are grossly atypical, as they were in this patient. In ruling out a possible
causative effect from the tumor, no suitable alternative explanation was
put forward. As in many patients with conversion disorder, the
presentation left the multidisciplinary treatment team with more questions
than answers. A final point of interest was the patient’s emotional reaction
to receiving the news from the neuropsychiatrist that she had a very large
brain tumor. The patient’s feelings of relief and vindication underscore the
importance of physicians validating the symptoms displayed by a person
with conversion disorder. To those with atypical weakness, loss of
sensation, aphonia, or blindness, the difficulties are all too real and
profoundly disabling, even if their disorder is classified as psychiatric and
the etiology occasionally linked to emotional factors. It is now known that
conversion disorder results from a disturbance in brain function. Conveying
this to patients is not only validating but, for many, reassuring too.
866 JUNE 2018

10 times. The results revealed KEY POINT
decreased activation of the
● Findings on functional
somatosensory cortex MRI in patients with
contralateral to the anesthetic conversion disorder are
region relative to the sensate side. specific to symptom type.
In addition, significantly greater Depending on the
presenting symptom, the
ancillary activation was seen in
data are consistent in
10 areas when the stimulus was showing hypoactivation of
applied to anesthetic compared to cortical (somatosensory)
the contralateral sensate regions regions coupled with
ancillary activation of limbic
(FIGURE 10-1). The areas involved
and basal ganglia structures.
were the right paralimbic cortices
(anterior cingulate and insula),
right temporoparietal junction
(angular gyrus and inferior
parietal lobe), bilateral
dorsolateral prefrontal cortex
(middle frontal gyri), right
orbital frontal cortex (superior
frontal gyrus), right caudate,
right ventral-anterior thalamus,
and left angular gyrus. These
findings were interpreted as
evidence of abnormal cerebral
activation of networks involved
in emotional processing and
sensory integration.
FIGURE 10-1
The question of whether these Event-related group averages of the blood oxygen
abnormal changes in brain level dependent (BOLD) response time-locked to
activation improve on symptom the onset of somatosensory stimulation in a
study of 10 patients with unilateral sensory loss
resolution was addressed in a due to conversion disorder. A–F, Ancillary brain
single-photon emission computed regions. A, Right anterior cingulate cortex
tomography (SPECT) study of (R ACC); B, right insula (R insula); C, right ventral
seven patients with unilateral anterior nucleus of the thalamus (R Va Tha); D,
right caudate (R caudate); E, right angular gyrus
sensorimotor loss using passive (R BA40); and F, right dorsolateral prefrontal
vibratory stimulation to both cortex (R BA9). Stimulation was applied for a
hands.23 All the subjects were duration of 4 seconds. The green line represents
tested when symptomatic and 2 stimulation applied to the symptomatic body
part and the white line to the asymptomatic body
to 4 months after recovery. part. Error bars represent the standard error.
The results revealed a consistent Reprinted with permission from Burke M, et al,
decrease of regional cerebral Neuroimage Clin.22 © 2014 The Authors.
blood flow in the thalamus
and basal ganglia contralateral to
the neurologic deficit. The
authors showed that these findings were present in each patient and
resolved with symptom resolution. Significantly, poorer recovery was
predicted by the degree of hypoactivation in the contralateral caudate when
symptoms were present. The conclusion derived from these data was that
conversion symptoms arose from a dysfunction in striato-thalamo-cortical
circuits involved in sensorimotor function. Of note, however, was that

CONVERSION DISORDER
no hypoactivation was detected in primary sensory or motor areas, unlike

the findings from the fMRI literature. The same inconsistencies pertain to
regions of ancillary activation for the SPECT data, which did not include
the orbitofrontal cortex and anterior cingulate that generally activate in
fMRI studies. The reasons for these discrepancies remain unclear; they are
unlikely to be due to different imaging modalities but suggest, as do the
variable cognitive and physiologic data, that conversion disorder may
arise from a composite of interconnected etiologic factors that vary
across subjects.
Imaging only the motor system presents additional challenges, because it
comes with uncertainty as to the subject’s volition in relation to the abnormal
movements. Is the flaccid limb an involuntary manifestation of conversion
or a conscious willed refusal to move, as in feigning? In patients deemed
to have conversion paralysis, the findings mirror the data from sensory
conversion, albeit with a different region of localization, namely the
hypoactivation is now seen in the motor cortex. The pattern of ancillary
activations remains fairly consistent,24 but when it comes to feigning motor
symptoms, fMRI studies have demonstrated differences in cerebral activation
between patients deemed to have conversion and healthy control subjects
who were instructed to simulate paralysis. The imaging findings, however,
lack consistency.25–27
Finally, a novel fMRI study that looked at how people with conversion
disorder process affective stimuli revealed increased connectivity between the
right amygdala and right supplementary motor cortex, hinting at a mechanism
that could explain how environmental stressors trigger conversion symptoms in
some individuals.28
PROGNOSIS
A number of methodologic limitations should be kept in mind when
assessing how outcome is determined. The conclusion, nevertheless, is that
the outcome is generally unfavorable. Symptoms frequently remain the
same or worsen with time. Early diagnosis and young age are the two bright
prognostic lights.29 Symptom longevity is considered an ominous sign.30 The
12-month follow-up data on 717 of 1144 people with “neurologic symptoms
unexplained by disease” showed that two-thirds of the sample were unchanged,
worse, or much worse.31 Predictors of poor outcome were patients’ beliefs
(expectations of nonrecovery), attribution of symptoms to physical rather than
psychiatric factors, and the receipt of illness-related financial benefits.
Collectively, these three variables could only explain 13% of the variance
in outcome.
Adding weight to this unfortunate outcome is the presence of significant
psychiatric comorbidity. A 3-year follow-up (standard deviation 2.2; range 1 to
7 years) of 88 patients with motor conversion symptoms revealed a lifetime
prevalence of 43% and 62% for major depression and anxiety disorders,
respectively, with an additional 27% displaying comorbid depression and anxiety
added to these percentages.30 Almost half the group had personality disorders,
although their prognostic role has been questioned by others.29 The psychosocial
impact of all this psychopathology can be considerable too, as revealed in the
Scottish Neurological Symptoms Study.32 A comparison of people with
unexplained versus confirmed “organic disease” revealed that the former were
868 JUNE 2018

more likely to have stopped work for medical reasons and were consequently KEY POINTS
in receipt of more disability-related financial benefits.
● Favorable prognostic
Some cause for greater optimism has, however, emerged from a recent signs are early diagnosis and
meta-analysis of treatment outcomes in people with psychogenic nonepileptic younger age, whereas poor
seizures. Results from a pooled sample of 228 participants who had received prognostic signs include
diverse forms of psychological interventions (cognitive-behavioral therapy, symptom longevity,
attribution of symptoms to
psychodynamic therapy, paradoxical intention therapy, and mindfulness, among
physical rather than
others) revealed that almost half the sample were seizure free on completion psychological beliefs,
of treatment. Whether this improvement is maintained over time, however, expectations of
remains unclear.33 nonrecovery, and the
receipt of illness-related
financial benefits.
TREATMENT
Given the somber prognostic data, it should come as no surprise that treatment of ● Limited treatment data
conversion disorder can prove challenging. Probably the best evidence comes suggest that cognitive-
from cognitive-behavioral therapy. A pilot randomized controlled study of 66 behavioral therapy can be
effective, although findings
people with nonepileptic seizures found that cognitive-behavioral therapy was from a proposed large
superior to standard medical care given over a 4-month period.34 Encouraged by multicenter randomized
these results, the authors proposed embarking on a multicenter randomized controlled trial are still
controlled trial and published their proposed protocol, which included enrolling a awaited.
sample of close to 300 people with nonepileptic seizures and randomly assigning
them to cognitive-behavioral therapy plus standard medical care or standard
medical care alone.35 The results are awaited. The rationale for a more definitive
cognitive-behavioral therapy trial is supported by a review of treatment options
for the somatoform disorders, a broad spectrum of somaticizing conditions
that includes conversion.36 The study identified 34 randomized controlled trials,
13 of which involved cognitive-behavioral therapy, with efficacy reported in nine
of these.
Variants of cognitive-behavioral therapy have been tried in different settings.
For example, an innovative study with an eye on the practicalities of
administering therapy with limited resources provides additional, albeit indirect,
evidence of cognitive-behavioral therapy efficacy. Here the focus fell on
cognitive-behavioral therapy–guided self-help, which was conveyed to
participants in a manual and four half-hour education sessions. When this
intervention was compared to usual care in a randomized controlled trial design,
it was found to be more effective in reducing subjective health concerns.37
Another approach has been to focus on training primary care providers in how
best to manage the patient with unexplained medical symptoms. The rationale
for this is twofold: patients with these disorders often present first to their
primary care providers, who may find it frustrating to deal with them, thereby
potentially missing the diagnosis or providing ineffective treatment. To assess
whether this proved effective, a study was devised using a cognitive-oriented
educational program for assessment, treatment, and management of patients
with these unexplained symptoms. The primary outcome measure was the
degree to which doctors changed their attitudes toward their patients. The
intervention proved effective: 12 months after training, the general practitioners
felt less anxious and more comfortable in their patient interactions.38 However, a
subsequent randomized controlled trial failed to demonstrate that the training
translated into benefits for the somaticizing patients across an array of outcome
measures that included quality of life, disability days, and patient satisfaction.39
On the other hand, a different approach with family doctors that incorporated

CONVERSION DISORDER
KEY POINTS reattribution training produced some modest benefits. Based on a core principle
that somaticizing behavior, which includes conversion disorder, entails
● Training geared toward
improving the attitude of
misattribution of symptoms, an 8-hour skill-based training offered to primary
primary care providers to care providers was geared toward helping patients correct their faulty
patients with conversion belief systems. When applied by primary care providers, the results led to
disorder may improve positive shifts in patients’ thinking but, interestingly, did not change the
outcomes.
incidence of investigations recommended by the primary care providers,
● Much remains unknown their drug prescriptions for the disorder, and their referrals for
about conversion disorder, specialist consultation.40
but advances in neuroscience A miscellany of other approaches has been tried as well, with varied effects.
are starting to provide key While individualized tailored psychotherapy offered some cost-effective
insights into the functional
neuroanatomy of the benefits,41 perhaps the most promising intervention is repetitive transcranial
condition and which magnetic stimulation. This proved effective in 89% of 70 participants with
therapies work best. psychogenic paralysis, although it should be noted that the study had no placebo
arm.42 A single case study of psychogenic aphonia did, however, have a built-in
placebo. Stimulation of the left dorsolateral prefrontal cortex had no therapeutic
effect, whereas shifting the stimulus to the right motor cortex produced symptom
resolution within days.43
Irrespective of which treatment modality is chosen, some basic management
principles should be observed. When a neurologist suspects the diagnosis is
conversion, the first step in managing the problem is not to lose the patient’s
trust. Therefore, validating the patient’s symptoms is important. The next
step will depend on a number of factors, including the relative acuity of the
symptoms and the comfort of the neurologist in treating them. If the symptoms
are no more than a few months old, are not incapacitating, and are clearly
linked to an identifiable, potentially modifiable stressor, and the patient
seems psychologically aware and open to reassurance that the symptoms can
resolve, then the neurologist may proceed by recommending practical steps
to deal with the stressor while emphasizing the importance of remaining
physically and socially active. In more complex situations, a speedy referral
to a psychiatrist or psychologist is recommended; however, when doing so,
the neurologist must endeavor to retain the confidence of the patient in
the medical system. A hasty cavalier referral to a mental health specialist
without adequate explanation of why the referral is being made (including
a discussion with the patient of conversion disorder as a brain disorder,
albeit one best managed by a psychiatrist) runs the risk of alienating the patient
from the medical system and complicating the work of the psychiatrist to come.
CONCLUSION
Conversion disorder remains a challenge for the medical profession. While
diagnostic accuracy and consistency are reassuring, much remains to be clarified.
Future research geared toward a better understanding of a complex etiology will
undoubtedly benefit from advances in technology and neuroscience, but as
knowledge inches forward, the most pressing issue remains treatment. The
results of the proposed multicenter randomized controlled trial are eagerly
awaited, while the full therapeutic potential of repetitive transcranial magnetic
stimulation has yet to be realized. From this perspective, the future
looks optimistic.
870 JUNE 2018

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28 Voon V, Brezing C, Gallea C, et al. Emotional stimuli self-help for functional (psychogenic)
and motor conversion disorder. Brain 2010;133(pt 5): symptoms: a randomized controlled efficacy
1526–1536. doi:10.1093/brain/awq054. trial. Neurology 2011;77(6):564–572. doi:10.1212/
WNL.0b013e318228c0c7.
29 Gelauff J, Stone J. Prognosis of functional
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139:523–541. doi:10.1016/B978-0-12-801772-2. randomized controlled trial of brief training in
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30 Feinstein A, Stergiopoulos V, Fine J, Lang AE.
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Psychiatric outcome in patients with a
psychogenic movement disorder: a prospective 39 Rosendal M, Olesen F, Fink P, et al. A randomized
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Neurol 2001;14(3):169–176. and treatment of somatization in primary care:
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31 Sharpe M, Stone J, Hibberd C, et al. Neurology
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689–698. doi:10.1017/S0033291709990717. with somatized mental disorder: effects of
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32 Carson A, Stone J, Hibberd C, et al. Disability,
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doi:10.1176/appi.psy.43.5.394.
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2011;82(7):810–813. doi:10.1136/jnnp.2010.220640. 41 Reuber M, Burness C, Howlett S, et al. Tailored
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33 Carlson P, Nicholson Perry K. Psychological
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872 JUNE 2018

Assessment REVIEW ARTICLE

and Management of C O N T I N U UM A U D I O
ONLINE
Posttraumatic Stress 
Disorder S U P P L E M E N T A L D I G I T AL
C O N T E NT ( S D C )
A V AI L A B L E O N L I N E
By Janet Ellis, MBBChir, MD, FRCPC; Ari Zaretsky, MD, FRCPC
ABSTRACT
PURPOSE: The goal of this article is to increase clinicians’ understanding of
posttraumatic stress disorder (PTSD) and improve skills in assessing risk for
and diagnosing PTSD. The importance and sequelae of lifetime trauma
burden are discussed, with reference to trends in prevention, early
intervention, and treatment.
RECENT FINDINGS: PTSD has different clinical phenotypes, which are

reflected in the changes in Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition (DSM-5) criteria. PTSD is almost always
complicated by comorbidity. Treatment requires a multimodal approach,
usually including medication, different therapeutic techniques, and
management of comorbidity. Interest is growing in the neurobiology of
childhood survivors of trauma, intergenerational transmission of trauma,
and long-term impact of trauma on physical health. Mitigation of the risk of
PTSD pretrauma in the military and first responders is gaining momentum,
given concerns about the cost and disability associated with PTSD. Interest
is also growing in screening for PTSD in medical populations, with evidence
of improved clinical outcomes. Preliminary research supports the
treatment of PTSD with repetitive transcranial magnetic stimulation. CITE AS:
SUMMARY: PTSD is a trauma-related disorder with features of fear and 2018;24(3, BEHAVIORAL NEUROLOGY
negative thinking about the trauma and the future. Untreated, it leads to
ongoing disruption of life due to avoidance, impaired vocational and social Address correspondence to
functioning, and other symptoms, depending on the phenotype. Despite a Dr Janet Ellis, 2075 Bayview Ave,
theoretical understanding of underlying mechanisms, PTSD remains Toronto, Ontario M4N 3M5,
Canada, janet.ellis@
challenging to treat, although evidence exists for benefit of pharmacologic sunnybrook.ca.
agents and trauma-focused therapies. A need still remains for treatments
that are more effective and efficient, with faster onset. RELATIONSHIP DISCLOSURE:
Drs Ellis and Zaretsky report no
disclosures.
INTRODUCTION UNLABELED USE OF
W
itnessed or experienced traumatic events may include war, USE DISCLOSURE:
violence, natural disaster, acute physical trauma, unexpected Drs Ellis and Zaretsky report
or unnatural death of a loved one, bullying, and physical no disclosures.
illness. Most people will have some symptoms of acute stress © 2018 American Academy
disorder after a traumatic event, but most will recover. of Neurology.

POSTTRAUMATIC STRESS DISORDER
Posttraumatic stress disorder (PTSD) is a trauma-related syndrome of chronic

distress, with dissociative features, including reexperiencing of the trauma, mood
and cognitive changes, hyperarousal, and avoidance.1 It is associated with personal
chaos; an impaired sense of cohesion; distress; withdrawal from hobbies, work,
and social activities; a poor quality of life; and increased health care utilization.
EPIDEMIOLOGY
Between 10% and 50% of people who have had exposure to a life-threatening
trauma will develop persisting symptoms of PTSD.2,3 The lifetime prevalence of
PTSD varies by the diagnostic system used, gender, country, culture, values, and
exposure to war or crime-related trauma.4 While more exposure to trauma occurs
in lower-income countries compared to higher-income countries, the prevalence
of PTSD is fairly consistent, possibly implying a capacity to adapt to a level of
expected trauma. The exception to this is in postconflict zones, where the prevalence
of PTSD is highest,5 highlighting the increased risk of PTSD with interpersonal
violence. A 2013 study found that 89.7% of 2953 US adults had exposure to at least one
traumatic event and that exposure to multiple traumatic events was the norm.6 A
2017 systematic review of over 7 million primary care patients found a median
point prevalence of PTSD of 12.5% and of 24.5% across studies in veterans.7
Wittchen and colleagues8 found a range of lifetime prevalence of 0.56% to 6.67%
across European countries, with the highest prevalence in Croatia.
CONSEQUENCES OF POSTTRAUMATIC STRESS DISORDER

Exposure to a traumatic event and the duration of PTSD increase the risk
of developing chronic physical conditions, emphasizing the importance of
prevention and intervention.9 An increased risk of hypertension, ischemic heart
disease, obesity, and dementia has been found in those with a high lifetime
burden of trauma.10 Some emerging evidence indicates that overall trauma load
and PTSD increase the risk of later-life cognitive decline.11 PTSD and depression
are strongly associated, and both should be treated to improve outcome. Eating
disorders are another common comorbidity, with reported trauma rates and
PTSD varying from 12% to 45%.12,13
DIAGNOSIS
Since some of the symptoms of PTSD are outside usual experience and,
furthermore, patients are generally not forthcoming about their symptoms
owing to avoidance, it is especially important for clinicians to become familiar
with and understand the diagnostic criteria and experience of PTSD. The
overriding experience of PTSD is that of living in fear and avoidance of
trauma-related triggers.
It is vital to recognize PTSD symptoms before planning treatment for any
mental health issue after a traumatic event. It is important to assess for PTSD
without inadvertently causing repeated trauma. Simply asking the patient to
recount the trauma may lead to a dissociative flashback, distress, shutdown of
any further history, a rupture in the therapeutic relationship, and possibly refusal
to return to treatment. A traumatic event should lead a clinician to conduct a
focused screen for further vulnerability and relevant diagnostic criteria in a
deliberate probe for symptoms rather than asking the patient to recount the trauma.
Patients may require stabilization; out-of-control substance use, unstable
living situation, and untreated comorbidity should all be addressed as much as
874 JUNE 2018

possible before starting active trauma therapy. The patient needs to develop KEY POINTS
skills in self-calming (breathing, visualization, or relaxation exercises when
● Posttraumatic stress
dysregulated) and grounding (the ability to reconnect with the present by disorder is a trauma-related
refocusing on sensory information in the present). After stabilization, specialized syndrome of chronic
parallel treatments for both PTSD and comorbid conditions (eg, depression, distress, reexperiencing the
anxiety, substance use) should be undertaken. trauma, dissociative
features with mood and
Pitfalls for clinicians when assessing patients with PTSD include
cognitive changes,
underestimating the distress or impact of the traumatic event (eg, the meaning or hyperarousal, and
subjective experience of a migraine14 or intensive care unit admission); failing avoidance.
to recognize the hidden face of PTSD in a complicated comorbid clinical picture;
and feeling frustrated with such patients as they are prone to unreliable ● Between 10% and 50%
of people who have
follow-up because of avoidance: “I’ll talk about anything else!” had exposure to a life-
PTSD is extremely disruptive to patients, who may not identify the problem as threatening trauma will
PTSD, simply believing that they are not coping. Patients with PTSD often say: develop persistent
“I do not know what this is, but I am not myself.” Many patients immediately symptoms of posttraumatic
stress disorder.
recognize the phrase “living in fear” as descriptive of how they feel, but they
generally do not put this into words themselves. The profound avoidance ● A traumatic event should
associated with PTSD can impact the therapeutic alliance, causing impatience in lead a clinician to conduct a
the clinician who may be faced with the paradox of a patient who is desperately focused screen for further
vulnerability and relevant
seeking help, yet misses appointments and does not follow through on taking
symptoms.
medications or doing homework.
● Pitfalls for clinicians
Identifying Those at Risk in the Clinical Environment when diagnosing patients
Health professionals often fail to recognize illness-related PTSD, apart from in with posttraumatic stress
disorder include
patients who have experienced acute physical trauma or burns. An increasing misdiagnosing the trauma
literature exists on the prevalence and impact of PTSD in patients with human (eg, underestimating the
immunodeficiency (HIV) and cancer and in patients who have experienced impact of an experience of a
childbirth or a stroke, been in intensive care, received an organ transplant, or had migraine or intensive care
unit admission) and failing to
cardiac surgery. recognize the hidden face of
PTSD is more likely to result from interpersonal violence than a natural posttraumatic stress
disaster.15 A higher risk of PTSD occurs with extended exposure to danger, disorder in a complicated
serious injury, dissociation during the event, or the loss of a loved one during the comorbid clinical picture.
traumatic event. The latter, if combined with PTSD, may result in an inability to
● Individual vulnerability to
grieve as the death is a reminder of the trauma.16 These survivors remain in posttraumatic stress
limbo, living in a hypervigilant fearful state with PTSD and without the capacity disorder includes a past
to deal with their complicated (avoided) grief, sometimes for years. Individual history of trauma, any
psychiatric disorder, and
vulnerability to PTSD includes a past history of trauma, any psychiatric disorder,
low social support.
and low social support. The way patients construe the cause of the trauma and
their posttrauma worldview should be carefully ascertained, since self-blame
(eg, “I should not have been walking in the dark”) and blanket negative
assumptions (eg, “I cannot keep myself safe,” “My life has been ruined by this
event”) predict and maintain PTSD.
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition

Diagnostic Criteria
According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5),17 a diagnosis of PTSD can only be made 1 month after exposure
to at least one traumatic event. PTSD may also have a delayed onset of 6 months
or more after the event. DSM-5 changed the classification of acute stress disorder
and PTSD from anxiety disorders to trauma-related disorders, reflecting that an

KEY POINTS external traumatic event is required for the illness to develop. A DSM-5 diagnosis
of PTSD includes seven specific criteria, including duration of at least 1 month
● When obtaining the
history, patients with
and functional impairment, an initial traumatic event, intrusive reexperiencing,
possible posttraumatic avoidance, numbing or negative alterations in cognition and mood, and
stress disorder should be alterations in arousal and reactivity (SDC 11-1; links.lww.com/CONT/A252).
asked about reexperiencing When obtaining the history, clinicians should ask the patient about the
the trauma through
following symptoms: reexperiencing (the trauma) through associated thoughts,
associated thoughts,
physiologic response, physiologic response, flashbacks, or nightmares; avoidance of trauma reminders;
flashbacks, or nightmares; loss of enjoyment; negative feelings or thinking; a sense of blame and isolation;
avoidance of trauma hyperarousal; irritability; poor sleep; tension; hypervigilance; and reactivity (more
reminders; loss of
highly emotional, less control of anger, possible self-destructive or aggressive
enjoyment; negative
feelings or thinking, a sense behavior). Avoidance can exhibit as an inability to leave the house for fear of
of blame and isolation; another assault or accident, not speaking with friends in case they ask about the
hyperarousal; irritability; traumatic event, or not being able to watch TV in case there is a trigger such as a
poor sleep; tension; motor vehicle accident. Common physiologic responses to trauma reminders
hypervigilance; and
reactivity. include increased heart and respiratory rate, sweating, nausea, and flushing. Patients
may also have significant features of dissociation, including feeling like an outside
● The different phenotypes observer or feeling detachment from self (depersonalization), or experiencing a
of posttraumatic stress sense of unreality, distance, or distortion of the external world (derealization). The
disorder make it more
difficult to recognize, and
addition of the dissociation subtype in DSM-5 describes acute PTSD and allows
symptoms may be masked what was previously informally called complex PTSD, a phenotype of PTSD
by comorbid substance use, from childhood trauma, to be diagnosed using the same criteria (SDC 11-1;
brain injury, depression, or links.lww.com/CONT/A252).18
anxiety disorder.
A flashback (as compared to the experience of a normal memory) is an
● Two phenotypes of involuntary dissociative episode. The patient temporarily involuntarily
posttraumatic stress reexperiences an aspect of the past traumatic event as if it were happening in the
disorder have been present (eg, smelling or tasting blood after being shot in the jaw or feeling
described, dysphoria and breathless with pain in the sternum after a steering wheel/airbag/seat-belt injury
emotional numbing, both
with reexperiencing, from a multivehicle accident). Once initiated, a flashback often continues
avoidance, and intrusively, as if the play button has been pressed for a horror movie.19 This
hyperarousal but differing in experience is cognitively disorganizing, often terrifying, and highly distressing.
sleep, irritability, and The clinical assessment of PTSD includes identifying events as traumatic and
concentration symptoms.
eliciting their significance, identifying the individual’s risk factors, and detecting
the signs of failure of recovery from the trauma. The different phenotypes of
PTSD make it more difficult to recognize, and symptoms may be masked by
comorbid substance use, brain injury, depression, or anxiety disorder.
PHENOTYPES OF POSTTRAUMATIC STRESS DISORDER

Two main phenotypes of PTSD have been described: dysphoria PTSD with
disrupted sleep and more dysphoric irritability, which often occurs after an acute
traumatic event as an adult (CASE 11-1), and complex PTSD from repeated
childhood trauma, often with an “emotionally numbed” presentation of PTSD
(CASE 11-2).21,22 Both phenotypes have reexperiencing, avoidance, and hyperarousal,
but they differ in sleep, irritability, and concentration symptoms (FIGURE 11-123).
QUESTIONNAIRES AND SCREENING TOOLS

A diagnosis of PTSD should not be made by self-report tools alone; clinical
assessment or clinician-administered semistructured interviews are needed to
confirm the diagnosis, such as the Structured Clinical Interview for DSM-5
(SCID-5)24 and the Clinician Administered PTSD Scale (CAPS).25 A 2005 review
876 JUNE 2018

A 22-year-old woman presented for a new episode of psychiatric CASE 11-1
assessment and care with severe depression and posttraumatic stress
disorder (PTSD). Two years earlier, while walking home after an evening
lecture, she was sexually assaulted by a stranger, who held a knife to her
throat. A passerby took her to a police station, and a rape procedure was
conducted. The woman was in a shocked state and felt emotionally
numb. The next day, she began to experience intense fear and startle
reactions to loud sounds. She was unable to watch the news on television
or walk outside unaccompanied without fear, even during the day. She
experienced severe insomnia, nightmares of the rape, and daily flashbacks.
She became suicidally depressed, despite seeing a psychiatrist for
supportive psychotherapy and receiving an antidepressant over a 2-year
period. She was hospitalized twice and received 12 courses of bilateral
electroconvulsive therapy but remained depressed, with profound PTSD.
The patient began trauma-focused therapy with the psychiatrist in this
new episode of care. She was provided with psychoeducation about
trauma, PTSD and avoidance, and the rationale for imaginal and behavioral
exposure to feared memories and situations. She was treated with sertraline
150 mg once daily and risperidone 1 mg at night. Prazosin was carefully
titrated up to 2 mg to treat nightmares.20
The patient wrote out the major “chapters” of the rape memory narrative
to address them, with gradually increasing exposure to distressing details of
the rape both in her journal as well as in sessions. She was asked to recall
the experience as if it were happening in 90-minute taped imaginal exposure
sessions, in which she was asked to recount the trauma in sequence from
start to finish in as much detail as possible, in the present tense, while the
therapist aimed to keep her engaged within a moderate range of anxiety and
distress. This exposure therapy helped her to form a narrative and process
thoughts and emotions surrounding the event. She listened to the tapes
daily between sessions and recorded her subjective units of distress. In
parallel, she listed the things she avoided and began to deliberately expose
herself to these (objectively safe) situations, first accompanied, then alone.
After 6 months, the patient’s overt PTSD symptoms went into remission,
except for brief periods of high stress, and after 1 year, the prazosin was
discontinued. The patient was able to speak about the rape and reestablish
intimate relationships in her social and interpersonal life, but she was unable
to reestablish her chosen career track.
This case exemplifies the dysphoric, fear-based, hyperaroused adult after COMMENT
a single traumatic event, who also developed a severe depression
comorbid with the PTSD. Left untreated, most people with severe PTSD
will develop another psychiatric disorder. Like this woman, these patients
will mostly not recover until their PTSD is recognized and treated by
someone with PTSD expertise.

CASE 11-2 A 24-year-old man from Bosnia was referred for psychiatric assessment
while undergoing treatment for sarcoma, as he was missing oncology
appointments and had difficulty coping with his treatment because of
extreme anxiety and difficulty surrounding treatment decisions and side
effects. His childhood experience included an absent father, a mother
with an alcohol use disorder, and little routine. At age 12, he witnessed his
mother, two siblings, and others being killed outside their family home,
while he managed to keep hidden. He spontaneously recounted this story
during the consultation with a flat, disengaged affect.
His main symptoms were flat mood (with a loss of meaning in life and
little joy or positive emotion but no feelings of guilt or worthlessness),
decreased energy, and sense of hopelessness. He reported feeling
numb, shut down, and internally dysphoric. He did not startle easily and
reported good sleep but did not wake refreshed. He was not especially
irritable. He experienced flashbacks and nightmares, and he avoided
Bosnians and reminders of genocide. He did not seek psychiatric help
after he immigrated, because he could not bear to “open up” the
memories. He did not have hypervigilance but was disoriented and dazed
during flashbacks and for some of the day, especially after his cancer
diagnosis. Overall, his flat, dysphoric state could have been mistaken for
a sole diagnosis of depression but without a feeling of heaviness or guilt
to account for his lack of functioning. However, this was a shut-down,
flat, numbed presentation of comorbid depression and complex
posttraumatic stress disorder; he was difficult to access/engage,
preoccupied, and slow, with derealization.
Venlafaxine XR was begun and titrated up to 150 mg, and he was given
support with the logistics of making appointments and treatment
decisions. He was referred to a local specialized center for victims of
torture for trauma-focused therapy, processing, and eye movement
desensitization and reprocessing therapy to help with recovery from his
childhood trauma. He was seen for existential concerns at the cancer
center; he struggled to accept that something else had gone wrong in his
life, as if he were cursed. He completed treatment and eventually
returned to school. One year later, he was noted to be more animated and
engaged in conversation, able to withstand direct gaze, and present in the
moment. He said he felt better than he ever remembered feeling in his life.
COMMENT This case exemplifies the difficulty of adapting to new trauma in those with
complex posttraumatic stress disorder (PTSD) or childhood trauma. It also
demonstrates how easy it can be to misdiagnose PTSD as depression in this
type of shut-down, numbed presentation. All patients with significant
complex trauma will be at risk of an increase in symptoms or new
symptoms of PTSD when faced with serious medical illness or acute
physical trauma.
878 JUNE 2018

concluded that the mean KEY POINTS
diagnostic efficiency of screening
● Patients having four or
tools was over 85% and that more categories of
using a small number of core childhood trauma had a 4 to
symptoms of PTSD was effective 12 times greater increased
across trauma populations.26 risk for substance abuse,
depression, and suicide
Four validated self-report scales
attempts; a 2 to 4 times
are commonly used: the Impact greater risk of smoking, 50
of Event Scale–Revised (IES-R),27 or more sexual partners, and
the PTSD Checklist–Civilian sexually transmitted
disease; and a 1.4 to 1.6 times
Version (PCL-C),28 the PTSD
greater risk of physical
Symptom Scale-Self-Report inactivity and morbid
Version (PSS-SR),29 and the FIGURE 11-1 obesity.
Davidson Trauma Scale (DTS).30 Posttraumatic stress disorder (PTSD) and
complex PTSD in classification hierarchy. This ● Of deployed US military
figure demonstrates the underlying similarity in personnel, 14% to 16% were
IMPACT ON LONG-TERM found to have posttraumatic
symptom clusters in both PTSD and complex
PHYSICAL AND PTSD. Since complex PTSD usually results from stress disorder, which was
MENTAL HEALTH repeated trauma in childhood, thus impacting prospectively associated
The physical and mental health development, personality traits often include with early-age heart disease
difficulties with sense of self/self-esteem mortality among those free
correlates of a lifetime trauma of heart disease at baseline.
(self-organization), intense uncontrolled
load are consistent with an emotions (affect dysregulation), and trust of
epigenetic understanding of the others, as well as attachment difficulties
etiology and comorbidity of (leading to difficulties in relationships).
PTSD.31–33 One mechanism Consequently, both groups need treatment for
PTSD. In addition, patients with complex PTSD
involves repeated states of require longer-term attachment-informed
physiologic stress response and psychological work to change the way they cope
loss of regulation, with increased and experience the world and themselves.
Modified from Cloitre M, et al, Eur J Psychotraumatol.23
risk of psychiatric and physical © 2013 The Authors.
disorders. In a landmark paper,
Felitti and colleagues34 reported a
strong relationship between abuse
or childhood family dysfunction and increased adult health risk behaviors and
mortality, including mortality from cancer and heart, liver, lung, and skeletal
disease. Patients having four or more categories of childhood trauma had
a 4 to 12 times greater risk for substance abuse, depression, and suicide
attempts; a 2 to 4 times greater risk for smoking, 50 or more sexual partners,
and sexually transmitted disease; and a 1.4 to 1.6 times greater risk of
physical inactivity and morbid obesity compared to patients with no
childhood trauma.34
Literature examining the mental and behavioral health in armed forces deployed
in Iraq and Afghanistan suggests that depression is more common in women and
substance use is more common among men.35 Of deployed US military personnel,
14% to 16% were found to have PTSD, which was prospectively associated with
early-age heart disease mortality among those free of heart disease at baseline.36
This finding suggests that early-age heart disease may be an outcome after
military service in veterans with PTSD.37
PTSD is associated with smoking, drug and alcohol abuse, and obesity in
military veterans and civilian trauma survivors.38 This may be due to maladaptive
coping with distress with habitual use of substance or food. Alcohol and nicotine
use is high in PTSD; the odds of alcohol use disorders increase with the number

of PTSD criteria the patient meets. Research on comorbid PTSD and substance use
disorder supports parallel treatment to reduce PTSD severity and drug/alcohol
use posttreatment and improve subsequent follow-up.39
POSTTRAUMATIC STRESS DISORDER AND NEUROLOGIC DISORDERS

Stroke-related PTSD is common, with 25% of patients developing PTSD in the
first year after stroke and over 10% having chronic PTSD 1 year later,40 which
can be an important factor in secondary prevention with medication adherence.
Patients with respiratory failure due to Guillain-Barré syndrome should also be
screened for PTSD afterward.41 In one study, 5.17% (12) of 232 patients with
multiple sclerosis developed PTSD.42
It used to be assumed that people with traumatic brain injury (TBI) had
decreased risk for PTSD, as they could not remember the trauma,43 and
TBI-related amnesia may be confused with traumatic dissociative amnesia, which
results in the patient being unable to recall some parts of the trauma without
evidence of a significant TBI. However, mild TBI confers extra risk of PTSD, and
the combination is synergistic, with increased symptoms, cognitive impairment,
and difficulty in treatment.44
Migraine may predispose patients to PTSD and headache-related disability,14
especially in male patients.45,46
DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER

Learning and evolutionary theory add to our theoretical understanding of two main
experiences of PTSD: (1) extreme distress when faced with any trauma-associated
cues due to fear conditioning (the learned association of all trauma-related
experience to fear/distress, such as an assault by a tall bald man may generalize
to fear of all tall or all bald men, as tallness or baldness becomes associated
with fear) and (2) avoidance
behavior, which is reinforced by
immediate relief when a trauma
cue is removed or avoided (this is
called negative reinforcement, as it
is relief on removal of aversive
cue).47 During exposure therapy,
the patient is guided to engage
with a fear memory repeatedly
while feeling safe in the here and
now (in the therapist’s office)
and to discuss and process the
thoughts and emotions of this
“silent horror movie” memory
FIGURE 11-2 cognitively with the therapist,
Fear consolidation. Individuals with posttraumatic thus disrupting and altering the
stress disorder show increased sensitization to memory by extinguishing fear
stress, overgeneralization of fear, and impaired
extinction of fear memories. Individuals who recover
and enabling a different way of
from stress appropriately demonstrate an ability thinking about it. This is
to discriminate between fear-inducing and normal followed by reconsolidation of
stimuli as well as normal extinction of fear the less distressing, more
memories.
Reprinted with permission from Mahan AL, Ressler KJ,
processed memory
Trends in Neurosciences.48 © 2012 The Authors. (FIGURE 11-248).
880 JUNE 2018

Understanding Posttraumatic Stress Disorder Using Cognitive and KEY POINTS
Learning Theory
● Mild traumatic brain injury
Classic fear conditioning involves the pairing of an innate fear reaction confers extra risk of
(adrenergic response: startle, increased heart rate) to an unconditioned stimulus posttraumatic stress
(eg, stabbing) with a previously neutral valence (conditioned) stimulus (eg, disorder, and the
sound of ambulance, sight of blood). If PTSD ensues, the sound of a siren or the combination is synergistic,
with evidence of increased
sight of spilled ketchup may induce a fear response and flashbacks. Avoidance
symptoms, cognitive
symptoms are negatively reinforced by operant conditioning, as avoidance of impairment, and difficulty
triggers reduces distress and leads to reinforced learning that avoidance is the in treatment.
best action. Failure to recover from a trauma results in continued maladaptive
avoidance, repeatedly reinforced. ● Learning theory, along
with memory engagement,
disruption, alteration, and
Neurobiology, Neuroendocrinology, and Neurocircuitry reconsolidation, underpins
Animal models of PTSD have elucidated neurobiological underpinnings in the use of prolonged
humans. PTSD-like effects have been induced in rats, with anxiety behaviors of exposure therapy for
posttraumatic stress
avoidance, reduced concentration and sleep, decreased hippocampal volume, disorder.
physiologic changes in the hypothalamic-pituitary-adrenal (HPA) axis, and
amygdala hyperactivity.49 Traumatic events interfere with the memory function ● Animal models of
of the hippocampus and increase the plasticity processes in the amygdala.50 posttraumatic stress
disorder have elucidated
Physiologic changes have been reproduced, including decreased growth rate and
neurobiological
thymus weight and increased adrenal weight, anxiety and startle response, underpinnings in humans.
cardiovascular reactivity, and hormonal reactivity, while fear stimuli result in
freezing and avoidance. Zoladz and colleagues49 also found that predator ● Three main brain
exposure alone did not cause persistent PTSD-like behavior, so a social instability structures involved in
appraising threat and
model was introduced by randomly changing the rat roommate combinations, regulating fear have been
which successfully produced PTSD-like symptoms with predator exposure, studied in posttraumatic
replicating findings in humans that insufficient social support and instability are stress disorder: the
associated with increased risk of PTSD. prefrontal cortex, the
hippocampus, and
Neurobiological correlates support the learning hypothesis of PTSD and explain the amygdala.
its symptoms. Three main brain structures involved in appraising threat and
regulating fear have been studied in PTSD: the prefrontal cortex, the hippocampus, ● In posttraumatic stress
and the amygdala.51 disorder, the amygdala is
mostly hyperactive,
The amygdala plays a pivotal role in the brain circuit regulating fear
promoting an abnormal fear
conditioning.52 The central amygdala is responsible for sending fear signals to response of hypervigilant
the hypothalamus and brainstem. The medial prefrontal cortex is able to inhibit and hyperaroused behavior.
the amygdala in a top-down manner and reduces subjective distress. The
hippocampus codes fear memories and appraises and interprets the context and
threat of memories evoked. Together with the medial prefrontal cortex, the
hippocampus modulates fear, regulating the amygdala’s output to subcortical
brain regions that activate the fear response.
In PTSD, the amygdala is mostly hyperactive, promoting an abnormal fear
response of hypervigilant and hyperaroused behavior.53 PTSD results from an
acquired impaired capacity for fear extinction, possibly mediated by less activity
in the medial prefrontal cortex. Stress causes limbic activation, which inhibits
prefrontal cortex functioning, reducing inhibition of the amygdala and resulting in a
further fear response (FIGURE 11-3).
Neuroanatomic changes have been found in PTSD, including a decreased volume
of the prefrontal cortex, with decreased activation on exposure to traumatic
events.54 This loss of cortical reappraisal and ability to reduce the heightened
amygdala response allows repeated activation of the amygdala and dysregulated

FIGURE 11-3
Limbic system of the brain and its involvement in posttraumatic stress disorder (PTSD). The
prefrontal cortex is responsible for reactivating past emotional association and emotional
regulation. The hippocampus allows for conditioned fear of traumatic events and learned
responses to contextual cues. Both the hippocampus and the prefrontal cortex have altered
responsiveness in patients with PTSD. The top-down control of the amygdala by the
hippocampus and prefrontal cortex could play a role in the hyperactivity of the amygdala
seen in patients with PTSD who are hypervigilant. The ultimate effects of PTSD include
increased stress reactivity, generalized fear responses, and impaired extinction. Other
affected regions of the brain include the anterior cingulate cortex, the orbitofrontal
cortex, the parahippocampal gyrus, the thalamus, and the sensorimotor cortex, which
contributes to fear regulation and PTSD.
Reprinted with permission from Mahan AL, Ressler KJ, Trends in Neurosciences.48 © 2012 The Authors.
circuits between the prefrontal cortex and the limbic system. Reconsolidation of
unstable fear memories can lead to ongoing distressing flashbacks that feed into
further activation of the amygdala, with reduced prefrontal cortex inhibition. This
leads to the trauma memories becoming more intrusive over time, with persistent
hyperarousal and distress. Unstable trauma memories also provide an opportunity
for exposure therapy and thus extinction of fear from the memory before
reconsolidation of a more stable and less fear-linked memory.
Reduced prefrontal cortex function may also explain the impaired executive
function seen in PTSD as well as cognitive deficits due to decreased volume and
dysfunction in the hippocampus, with specific deficits in hippocampal-dependent
learning and memory.55 PTSD leads to changes in the HPA axis stress response
(with possible epigenetic changes) and the sympathetic nervous system, with
increased arousal, skin conductance, adrenaline and noradrenaline levels, blood
pressure, and anxiety behavior (FIGURE 11-456).57
Lifetime trauma burden increases the risk for developing acute disabling
symptoms of PTSD in those who have experienced previous trauma or have
882 JUNE 2018

KEY POINTS
● Reconsolidation of
unstable fear memories can
lead to ongoing distressing
flashbacks that feed into
further activation of the
amygdala, with reduced
prefrontal cortex inhibition.
This leads to the trauma
memories becoming more
intrusive over time, with
persistent hyperarousal
and distress.
● Lifetime trauma burden

increases the risk for
developing acute disabling
symptoms of posttraumatic
stress disorder in those who
have experienced previous
trauma or have chronic
complex posttraumatic
stress disorder.
FIGURE 11-4
Stress response. Normal responses to stress (A), stress response in a patient with major
depressive disorder (B), and stress response in a patient with posttraumatic stress disorder
(PTSD) (C). In each panel, arrow thickness denotes the magnitude of biological response.
In healthy subjects and those with depression, periods of stress are associated with
increased cortisol and corticotropin-releasing factor. Corticotropin-releasing factor acts
on the anterior pituitary to stimulate corticotropin, which, in turn, stimulates cortisol
production by the adrenal cortex. Cortisol inhibits the release of both corticotropin and
corticotropin-releasing factor while also inhibiting many other stress-related biological
reactions. In patients with PTSD, cortisol levels are low, which allows for increased levels
of corticotropin-releasing factors. Additionally, the negative-feedback system of the
hypothalamic-pituitary-adrenal axis is more sensitive in patients with PTSD, contributing to
altered stress regulation in PTSD.
Reprinted with permission from Yehuda R, N Engl J Med.56 © 2002 Massachusetts Medical Society.
chronic complex PTSD. A longer and stronger physiologic reaction occurs

on anticipation or exposure to stress in those previously traumatized (due to the
initial increased secretion of cortisol and receptor density) compared to those
who have not experienced trauma, although enhanced negative feedback
follows, with an ongoing lower baseline cortisol.58 This phenomenon provides
the neurobiological explanation of why those with past trauma might be more
likely to develop PTSD with subsequent trauma.
Recent Trends in the Neurobiology of Posttraumatic Stress Disorder

An important area of recent research in PTSD is the study of genetic and
epigenetic phenomena with increasing trauma load. Epigenetic alteration of
the BDNF gene has been linked with brain function, memory, stress, and
neuropsychological changes.59 Using the psychosocial predator stress model,
Zoladz and colleagues demonstrated hypermethylation of the BDNF gene in the
dorsal hippocampus in mice.49 Changes in brain structures and pathways have
been explored in those with childhood trauma.60

Interventional research with the aim of regulating the HPA-prefrontal

cortex-amygdala circuitry includes electroconvulsive therapy, deep brain
stimulation, vagus nerve stimulation, repetitive transcranial magnetic
stimulation (rTMS), and transcranial direct current stimulation.
Neurotransmitters involved in control of thinking (such as g-aminobutyric acid
[GABA]) could be a target of treatment for PTSD. The current understanding
of the neurobiology of PTSD may explain the efficacy of selective serotonin
reuptake inhibitors (SSRIs) as a partial treatment for PTSD, as they increase
plasticity and learning capacity so that memories and danger assessment
of trauma-related cues can be altered more easily and sympathetic overdrive
is lessened.
TREATMENT OF POSTTRAUMATIC STRESS DISORDER

A broad, evidence-based approach is often needed in the treatment of PTSD,
including managing comorbid psychiatric illness, brain injury, and chronic pain;
medication; and using different therapeutic techniques, including prolonged
exposure therapy, cognitive processing therapy, and eye movement
desensitization and reprocessing therapy.
Early evidence supports new treatments for PTSD, such as rTMS, and
preliminary effectiveness has been shown for virtual reality exposure therapy,
Internet-based cognitive therapy, mindfulness-based cognitive therapy,
brainspotting, and yoga.61,62
A systematic review and meta-analysis of psychological treatments for
adults with PTSD demonstrated the efficacy of exposure therapy, including
prolonged exposure therapy, cognitive therapy, cognitive-behavioral
therapy mixed therapies, cognitive processing therapy, eye-movement
desensitization and reprocessing therapy, and narrative exposure therapy, in
improving PTSD symptoms.63 However, evidence is limited on whether any
one treatment or approach is more effective for particular symptoms or
patients. The tolerability and potential adverse effects of a particular
psychotherapy intervention over medication have also not yet been
fully explored.
In February 2017, the American Psychological Association published a
guideline for the treatment of PTSD in adults.64 The recommendations
were based on the strength of the evidence, outcomes, patient-reported
preference, balance of benefits, and applicability to the treatment population.
Cognitive-behavioral therapy, cognitive processing therapy, cognitive therapy,
and prolonged exposure therapy received strong recommendations. Other
suggested treatments included brief eclectic psychotherapy, eye movement
desensitization and reprocessing therapy, and narrative exposure therapy.
Recommended medications included fluoxetine, paroxetine, sertraline,
and venlafaxine, while insufficient evidence was found for risperidone
and topiramate.
Prolonged exposure therapy uses learning theory to extinguish fear from the
trauma memory by repeatedly engaging in the memories in a safe environment
without a feared outcome.65 Grounding and distraction may be needed in a
patient who quickly dissociates (the patient is physically present in the room but
increasingly goes back to the traumatic event in his/her mind, to the extent of
smelling smoke, coughing, feeling hot and terrified, as if back in the fire). In
prolonged exposure therapy, the memory is associated with less and less fear
884 JUNE 2018

each time it is engaged, processed, and consolidated, gradually reversing the KEY POINTS
classic conditioned response. The patient listens to a tape of the session daily,
● The current
while also gradually reducing avoidance behavior (eg, leaving the house, walking understanding of the
down a street, crossing the street, being a passenger in a car, driving), which neurobiology of
reverses the operant negative reinforcement, and the patient’s world gradually posttraumatic stress
opens up again. disorder may explain the
efficacy of selective
Cognitive theory provides a model of PTSD as a failure to accept and integrate
serotonin reuptake
a trauma and explains symptoms of avoidance.66 Cognitive processing therapy inhibitors as a partial
addresses the distressing thoughts (eg, “it was my fault”) and associated feelings treatment for posttraumatic
(eg, guilt) that people may have in response to trauma.67 Self-blame and guilt stress disorder as they
increase plasticity and
will make patients avoid trauma-associated cues, and, depending on how they
learning capacity so that
think about the future, they may become extremely avoidant and limited in their memories and danger
daily life (eg, thinking that the world is a dangerous place and they cannot assessment of trauma-related
keep themselves safe). cues can be altered more
Eye movement desensitization and reprocessing therapy is a therapy easily and sympathetic
overdrive is lessened.
developed in 1987 for the treatment of PTSD.68,69 A good evidence base exists
for eye movement desensitization and reprocessing therapy, although ● A broad, evidence-based
controversy exists over whether the mechanism of eye movement approach is often needed in
desensitization and reprocessing therapy is distinct from prolonged exposure the treatment of
therapy and whether it offers a treatment that is any more effective. In eye disorder, including
movement desensitization and reprocessing therapy, the patient is asked to allow managing comorbid
distressing trauma images to emerge while remaining aware of associated psychiatric illness, brain
thoughts, emotions, and bodily sensations and using side-to-side eye movements injury, and chronic pain;
medication; and using
or bilateral stimulation such as hand tapping.68,69 This is thought to allow
different therapeutic
processing of the trauma memory. techniques, including
prolonged exposure
Brief Eclectic Psychotherapy therapy, cognitive
Brief eclectic psychotherapy combines and integrates elements from processing therapy and eye
psychodynamic therapy, cognitive-behavioral therapy, and directive movement desensitization
and reprocessing therapy.
psychotherapy.70 Psychoeducation and exposure occur jointly with the patient
and therapist; a structured writing task and memorabilia are used to help ● The 2017 American
the patient access, feel, and express his or her trauma-related emotions. Psychological Association
This combination could be argued to effectively target social connection and guideline for the treatment
of posttraumatic stress
prefrontal cortex emotional regulation, correct cognitive distortions, and
disorder in adults gives
allow habituation. strong recommendation for
cognitive-behavioral
Recent Trends in the Treatment of Posttraumatic Stress Disorder therapy, cognitive
A recent consensus statement called for more research into novel pharmacologic processing therapy,
agents, therapeutic strategies, and targets based on our current understanding cognitive therapy, and
prolonged exposure
of PTSD neurocircuitry and mechanisms.71 Two reviews confirm new evidence
therapy.
for the use of rTMS based on interrupting the brain circuitry of PTSD (including
reducing hyperactivity of the amygdala), facilitating fear extinction capacity ● Prolonged exposure
and increasing cognitive control in the salience network (a network of brain therapy uses learning theory
regions of the brain that discriminate between stimuli, deciding how to allocate to extinguish fear from the
trauma memory by
attention to new stimuli and coordinating the brain's responses).72,73 Combining repeatedly engaging in the
brief script-driven exposure with deep transcranial magnetic stimulation was memories in a safe
found to reduce PTSD in patients who were treatment resistant.74 environment without a
feared outcome.
ONLINE THERAPY/VIRTUAL REALITY. In the past decade, e–mental health has been
shown to be a viable treatment for PTSD through virtual platforms in the form of
individual online psychotherapy, virtual reality programs, and Internet-based

self-help programs as the accessible first step of care.75 Internet-based

cognitive-behavioral therapy using video, audio, and virtual reality has
evidence as a preventive intervention early in the posttrauma period.76
TREATMENT OF COMPLEX TRAUMA

The picture and experience of complex trauma is different from acute
adult-onset PTSD after a single traumatic event. Some authors make the
argument that short-term, non–attachment-attuned treatment (treatment that is
not predicated on the therapeutic relationship being part of the treatment) for
single-trauma PTSD should not be assumed to be effective in those with complex
trauma.77,78 Little robust literature exists on effective treatment for complex
PTSD resulting from repeated trauma, including trauma in childhood. Some
Level 2 and Level 3 evidence exists for sensorimotor therapy and brainspotting
in the treatment of complex trauma. In brainspotting, the patient is guided
in a state of “focused activation” to correlate neurologic stimulation and
internal experience and allow for processing.61 It is posited that holding attention
on that “brainspot” allows processing of the traumatic event to continue
until activation has cleared. Significant controversy remains regarding the
mechanism of action of brainspotting, and strong evidence for its effectiveness
is lacking, partly because of the difficulty of manualizing this therapy into a
semistructured model of exact replicable steps.
PREVENTION OF AND EARLY INTERVENTION FOR POSTTRAUMATIC

STRESS DISORDER
Mitigation of the risk of PTSD pretrauma in the military and first responders is
gaining momentum, given concerns about the cost and disability associated with
PTSD. Interest is also growing in screening for PTSD in medical populations,
with evidence of improved clinical outcomes with secondary prevention and
early treatment.
Primary Prevention
Currently, a strong literature on successful primary prevention is lacking. Various
strategies have been used, such as pharmacologic intervention, pre–military
deployment screening for risk factors or stress, promotion of resilience, and
immediate postdeployment individual exposure therapy. Two recent studies
showed some promise for hydrocortisone in pretraumatic injury,79 and four
sessions of computerized attention bias modification training, thought to
disrupt threat monitoring and anticipatory stress response, reduced the risk
for PTSD.80
Secondary Prevention
Early posttrauma intervention, such as early brief exposure starting in the
emergency department to disrupt memory consolidation by habituating and
reducing the fear associated with the trauma memory, has had some success.81
Other early interventions to attempt to disrupt fear conditioning by reducing the
level of fear and arousal using propranolol or opioids have mixed evidence;
previous trials with clonidine and prazosin were not effective in reducing PTSD,
although prazosin has some evidence for reducing nightmares and improving
sleep in established PTSD (via a1 receptor antagonism).20
886 JUNE 2018

Recent Trends in the Prevention of Posttraumatic Stress Disorder KEY POINTS
Interest in how PTSD impacts the brain in the neurobiology of childhood
● Cognitive processing
survivors of trauma and in understanding and preventing intergenerational therapy addresses the
transmission of trauma is growing. Intergenerational transmission of trauma distressing thoughts and
may involve epigenetic phenomena and can also be understood in terms of associated feelings that
attachment and the impact of unprocessed trauma on the parent’s capacity to people may have in
response to trauma.
nurture his or her children (as illustrated in the Still Face Experiment82).83
PTSD in medical populations is the subject of ongoing program development ● Emerging evidence exists
and research, including patients in the intensive care unit; patients with HIV, for the use of repetitive
cancer, or stroke; patients who have had cardiac surgery or an organ transplant; transcranial magnetic
or patients who have given birth. Identifying those at particular risk and screening stimulation for
for symptoms allows for sustainable stepped care, timely interventions, and disorder based on
judicious use of limited resources.84 interrupting the brain
Screening and early intervention in medical populations is an area of current circuitry of posttraumatic
research. Zatzick and colleagues84 conducted a trial in 207 acute physical stress disorder (including
reducing hyperactivity of
trauma survivors, screening for PTSD symptoms and then randomly the amygdala), facilitating
assigning to a stepped-care combined intervention (psychopharmacology and fear extinction capacity, and
cognitive-behavioral therapy, n = 104) or control (usual care, n = 103). At increasing cognitive control
6, 9, and 12 months postinjury, intervention participants had significantly in the salience network.
reduced PTSD symptoms compared to controls; they also showed improved
● Internet-based
physical function 1 year after hospitalization. Similarly, a stepped-care cognitive-behavioral
cognitive-behavioral therapy model of intervention in those who have had therapy using video, audio,
myocardial infarctions was found to improve outcomes.85 and virtual reality has
evidence as a preventive
A 2017 review demonstrated evidence that trauma-focused cognitive-behavioral
intervention early in the
therapy and modified prolonged exposure therapy delivered within weeks posttrauma period.
for individuals showing signs of distress due to a potential traumatic event
are effective to treat acute stress and early PTSD symptoms as well as to prevent ● Early posttrauma
PTSD.86 Posttrauma escitalopram improved sleep quality and had a signal intervention, such as early
brief exposure starting in
for secondary prevention in a subgroup of participants, and peritrauma the emergency department
intranasal oxytocin showed reduced PTSD symptoms after 1 month in those to disrupt memory
with high PTSD symptoms at baseline.87,88 Early intervention using video consolidation by habituating
games in the emergency department showed some success. This distracted and reducing the fear
associated with the trauma
patients, reduced further distressing activation of the fear memory, and was memory, has had some
associated with physiologic calming before memory consolidation in the success.
immediate posttraumatic period. Some research supports the use of agents
such as D-cycloserine (partial agonist of the N-methyl-D-aspartate [NMDA] ● Interest in how
receptor) to augment the effects of learning.89
disorder impacts the brain
in the neurobiology of
EXISTENTIAL DISTRESS IN TRAUMA AND POSTTRAUMATIC GROWTH childhood survivors of
Apart from biological factors (eg, family history, past personal history of trauma and in understanding
psychiatric illness, TBI), psychological factors (eg, early loss, past trauma, low and preventing
intergenerational
self-esteem), and social factors (eg, low social support, financial difficulty), transmission of trauma
existential factors (finding meaning in an altered existence/life posttrauma, is growing.
coping with a threat to survival) can also play a part in trauma recovery.
Existential distress may result from a sense of demoralization, the inability to
accept the trauma, uncertainty about safety, death anxiety, and lost faith, and
they can all interfere with recovery.
In contrast, posttraumatic growth describes a philosophical change in
worldview after trauma, including increased gratitude to be alive, a sense of
connection to others, greater sense of meaning, spiritual well-being, and a sense

KEY POINTS of clear priority, with constructs of openness, optimism, and social support.90 A
2015 meta-analysis suggested active psychological intervention facilitates
● Identifying those at
particular risk for
posttraumatic growth and can help people make the most of adversity.91
disorder and screening for
symptoms allows for CONCLUSION
sustainable stepped care,
Untreated PTSD is associated with a sense of personal chaos and distress.
timely interventions, and
judicious use of limited Patients cannot live normal lives, fully connect in relationships, or function at
resources. work and are highly avoidant of internal or external trauma-related cues; their
lives become painfully restricted. Since PTSD can easily be misdiagnosed, a
● Posttraumatic growth clear understanding and knowledge of the different presentations of PTSD
describes a philosophical
change in worldview after and patterns of functional impairment are important to prevent and mitigate
trauma, including increased PTSD-associated distress, adverse health consequences, and comorbidity.
gratitude to be alive, a sense The downstream health costs, suffering, and disability associated with PTSD
of connection to others, make it imperative to continue to research feasible, acceptable, effective,
spiritual well-being, and a
sense of clear priority, with
efficient, and accessible treatments for PTSD from single events as well as
constructs of openness, repeated childhood trauma. Ideally, primary and secondary prevention will
optimism, and social reduce the incidence and severity of PTSD. A failure to address acute or
support. lifelong PTSD can lead to epigenetic and attachment-based intergenerational
transmission of trauma.
● Untreated posttraumatic
stress disorder is associated It is hoped that understanding the neurobiological correlates of PTSD
with a sense of personal (hyperaroused amygdala and fear network and inhibition of the prefrontal
chaos and distress. Patients cortex salience network, with consequent emotional dysregulation) will combat
cannot live normal lives,
vestiges of internalized stigma or doubt by the general public in the existence of
fully connect in
relationships, or function at PTSD. This may reduce the associated shame of trauma vulnerability and
work and are highly avoidant increase the recognition of PTSD as a war wound or civilian trauma-related
of internal or external disorder that requires specialized multimodal treatment.
trauma-related cues; their The link between the mind and the body is a hot topic in medicine; PTSD
lives become painfully
restricted. provides the ideal paradigm for biopsychosocial research in biomarkers,
pharmacologic interventions, rTMS, sensorimotor psychotherapy, and
● The downstream health existential and trauma-focused cognitive therapies.
costs, suffering, and
disability associated with
PTSD make it imperative to
continue to research ACKNOWLEDGMENTS
feasible, acceptable, The authors would like to thank Saurav Barua, MPH, for his assistance with
effective, efficient, and references and literature review; Andrew Irwin, BSc, for his assistance with the
accessible treatments for
figures; and Clare Pain, MD, and Anthony Feinstein, MD, for their expert advice
disorder from single events and comments.
as well as repeated
childhood trauma.
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892 JUNE 2018

Diagnosis and REVIEW ARTICLE

Management of C O N T I N U UM A U D I O
ONLINE
Anxiety Disorders
By Peter Giacobbe, MD, MSc, FRCPC; Alastair Flint, MD, FRCPC, FRANZCP
ABSTRACT
PURPOSE OF REVIEW: This article provides a synopsis of the current
understanding of the pathophysiology of anxiety disorders, the biological CITE AS:
and environmental risk factors that contribute to their development and CONTINUUM (MINNEAP MINN)
maintenance, a review of the Diagnostic and Statistical Manual of Mental AND PSYCHIATRY):893–919.
Disorders, Fifth Edition (DSM-5) diagnostic criteria, and a practical
approach to the treatment of anxiety disorders in adults. Address correspondence to
Dr Peter Giacobbe, Toronto
Western Hospital, 399 Bathurst
RECENT FINDINGS: Despite the ubiquity of anxiety, the evidence is that most St, Room 7M-415, Toronto, ON
individuals with an anxiety disorder are not identified and do not receive M5T 2S8, Canada, peter.
giacobbe@uhn.ca.
guideline-level care. In part, this may be because of the manifold clinical
presentations of anxiety disorders and clinicians’ lack of confidence in RELATIONSHIP DISCLOSURE:
accurately diagnosing and treating these conditions, especially in Dr Giacobbe serves on the
nonpsychiatric settings. Anxiety disorders represent the complex interplay advisory board of Janssen
Canada and receives
between biological, psychological, temperamental, and environmental research/grant support from
factors. Converging lines of evidence point to dysfunction in regulating the Canadian Institutes of
activity in the “threat circuit” in the brain as a putative common Health Research (MOP 125880,
MOP 326627) and the National
pathophysiology underlying anxiety disorders. Evidence-based treatments Institutes of Health
for anxiety disorders, such as cognitive-behavioral therapy and (1R01AG042165-O1A1,
2U01MH062446-O6A2). Dr Flint
antidepressant medications, have been shown to regulate activity in this receives research/grant
circuit, which consists of reciprocal connections between the dorsomedial support from the Alzheimer’s
prefrontal cortex, insula, and amygdala. Association, Brain Canada
Foundation, Canadian Frailty
Network, Canadian Institutes of
SUMMARY: Anxiety disorders are the most common class of emotional Health Research, Centre for
disorders and a leading cause of disability worldwide. A variety of Aging & Brain Health Innovation,
National Institute of Mental
effective treatment strategies are available, which may exert their Health, Ontario Brain Institute,
therapeutic benefits from top-down or bottom-up modulation of the and Patient-Centered
Outcomes Research Institute.
dysfunctional brain activity associated with anxiety disorders.
UNLABELED USE OF
USE DISCLOSURE:
INTRODUCTION Drs Giacobbe and Flint discuss
F
ear is a fundamental emotion expressed in all mammals and is necessary the unlabeled/investigational
for survival. Fear refers to the coordinated emotional, behavioral, and use of D-cycloserine,
gabapentin, pregabalin,
biological response invoked by an immediate threat detected in the propranolol, and quetiapine for
environment, allowing organisms to protect themselves through a the treatment of anxiety
“fight, freeze, or flight” response. In contrast, anxiety is a disorders.
future-oriented affective state in which the individual prepares to cope with an © 2018 American Academy
uncertain but possible negative event in the absence of a triggering stimulus. of Neurology.

ANXIETY DISORDERS
Although fear and anxiety are separate constructs, they share common neural
substrates, as demonstrated by neuroimaging studies.1 Anxiety responses can
be adaptive by orienting the individual toward the detection of a possible threat
and coordinating a set of psychological, behavioral, and biological reactions to
prepare a response to it. Although the transient experience of anxiety is a core
component of the human experience, when this process becomes more context
independent, prolonged, excessive, and more difficult to regulate, it can become
a pathologic state.
As a group, anxiety disorders are the most common class of disorders listed in
the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5).
Anxiety disorders are chronic and disabling conditions; they have been estimated
to be the sixth leading cause of disability worldwide, surpassing that associated
with diabetes mellitus, chronic obstructive pulmonary disease, and
osteoarthritis.2 This article provides a synopsis of the current understanding of
the pathophysiology of anxiety disorders, the biological and environmental risk
factors that contribute to their development and maintenance, and a practical
approach to the diagnosis and treatment of anxiety disorders in adults.
PATHOPHYSIOLOGY AND RISK FACTORS

Anxiety disorders represent the complex interplay between biological,
psychological, temperamental, and environmental factors. Recent computational
studies of highly anxious people found evidence for processing deficits in
decision-making situations that result in an increased propensity to make
spurious connections between unrelated events.3,4 Clinically, this may result in
overestimation of risk in situations and inappropriate pairing of neutral stimuli to
danger, leading to increased levels of activation of fear-related circuits in the
brain and the related behavioral responses seen in the anxiety disorders.5
Common neurocircuit abnormalities across the anxiety disorders, as well as
disorder-specific dysfunctions, may underlie these observations. Converging
lines of evidence have identified that the perception of noxious stimuli elicits
activation of a “threat circuit” in the brain, consisting of the reciprocal
connections between the dorsomedial prefrontal cortex, insula, and amygdala.1
Threatening stimuli have been shown to activate this circuit in healthy
individuals,6,7 and increased activation of this circuit is positively correlated to
state and trait levels of anxiety in individuals with anxiety disorders.8 Somatic
preoccupation, a common theme across the anxiety disorders, may represent
biases in interpreting interoceptive bodily cues as dangerous, thereby leading to
excessive cognitive elaboration and inappropriate threat-related processing to
benign internal cues, resulting in the trait of anxiety sensitivity. Fonzo and
colleagues9 reported that those with generalized anxiety disorder, social anxiety
disorder, and panic disorder share a pattern of greater amygdala activation when
processing fearful facial expressions compared to happy facial expressions, which
was correlated to levels of anxious traits. Those with panic disorder also uniquely
demonstrated increased activation of the insula during this task, consistent with a
pattern of hypersensitivity to both external and interoceptive threat cues seen in
panic disorder.9 Based on these data, anxiety disorders can then be characterized
by increased vigilance to situations that are perceived as threatening, with
concomitant maladaptive and prolonged activation of the threat circuit.
Several factors have been shown to regulate activity in this circuit. The threat
circuit has been shown to be inhibited by serotonin. Selective serotonin reuptake
894 JUNE 2018

inhibitors (SSRIs), first-line treatments for a variety of anxiety disorders, have KEY POINTS
been demonstrated to reduce neurobiological activity in the dorsomedial
● Anxiety disorders are the
prefrontal cortex–amygdala circuit to aversive stimuli.10 The dorsolateral most common class of
prefrontal cortex is thought to play a key role in emotional regulation through emotional disorders and
exerting top-down cognitive control on limbic structures, especially via an important cause of
attentional processes.1 Psychotherapies for anxiety, such as cognitive-behavioral disability worldwide.
therapy, are felt to exert their effects biologically through enhanced cortical
● The prefrontal cortex,
modulation of amygdala activity.11 Therefore, pathologic anxiety states can be insula, and amygdala are
conceptualized as due to excessive bottom-up automatic processing of threat key structures in the
stimuli, impaired top-down attentional control, or both. It is hypothesized that pathophysiology of anxiety.
the various evidence-based treatments for anxiety may exert their effects as
● Reduction in the
either dampening bottom-up processing (antidepressant medications) or activation of the prefrontal
enhancing top-down control (cognitive-behavioral therapy). Additionally, a cortex–amygdala circuit to
variety of genetic and environmental factors have been shown to increase the aversive stimuli may be a
risk of anxiety disorders, with their effects being mediated, in part, through the common neurobiological
mechanism underlying
excessive activation of the dorsomedial prefrontal cortex–amygdala circuit.1,8 effective treatments for
Anxiety disorders tend to run in families, with the likelihood of a first-degree anxiety.
relative of an affected proband having an anxiety disorder being 4 to 6 times
higher than relatives of unaffected probands.12 However, it also appears that a ● First-degree relatives of
those with anxiety disorders
general risk for psychopathology is conferred, since children of a parent with an
have an increased risk of
anxiety disorder are at increased risk of developing major depressive disorder13 or developing any anxiety
any of the anxiety disorders, not solely the anxiety disorder affecting their disorder or major depressive
parent. Genetic heritability estimates for anxiety disorders have been estimated disorder.
as 30% to 50%, comparable to those reported for cancer (heritability of 33%; 95%
● Anxiety disorders are
confidence interval, 30% to 37%)14 and major depressive disorder (heritability of polygenic, with estimated
37%; 95% confidence interval, 31% to 42%),15 suggesting that both genetics and genetic heritability
environmental factors play prominent roles in the genesis of anxiety disorders. estimates of between 30%
Although anxiety disorders are likely to be polygenic, representing the effect of a and 50%.
multitude of genetic variants, each conferring individually small risk effects, one
● Most anxiety disorders
of the most widely studied risk polymorphisms has been 5-hydroxytryptamine have their onset in
(serotonin) transporter gene-linked polymorphic region (5-HTTLPR) in the childhood, and cases of
serotonin-transporter gene promoter. Individuals who are homozygous or atypical “late-onset”
anxiety should be
heterozygous for the short allele of 5-HTTLPR have increased amygdala
considered as due to
reactivity to emotional and threatening stimuli,16 predisposing them to the medical, substance, or
development of anxiety and mood disorders. A temperament of behavioral mood disorder factors until
inhibition, characterized by fearfulness, avoidance, and autonomic proven otherwise.
hyperreactivity in unfamiliar situations, has been linked to an increased lifetime
risk of developing an anxiety disorder.17
Anxiety disorders typically have their onset in childhood,18 suggesting that
this is an important developmental period for the genesis of anxiety disorders.
Indeed, childhood adversities such as abuse and neglect have been linked to
increased vulnerability to the development of anxiety disorders. Some studies
have found that extreme forms of adversity are associated with alterations in the
neurocircuitry involved in fear and emotional processing. Children who
experienced institutionalization in an orphanage exhibited elevated reactivity in
the amygdala to faces,19 more typical of adultlike patterns of brain activation,
than children who did not experience childhood adversity.20 These findings may
indicate that early adverse experiences in childhood may alter the developmental
trajectory of the nascent emotion regulation circuits, thereby enhancing the
biological reaction to fearful stimuli and impairing the fear extinction system in

ANXIETY DISORDERS
KEY POINTS the brain. Parental factors associated with anxiety disorders in childhood include
overprotectiveness; interparental conflict; perfectionism; and modeling of
● Environmental factors
involving danger or threat,
reactions to fearful, stressful, or unpredictable situations.21
such as abuse or parental Stressful life events may play a role in precipitating emotional disorders, with
loss, increase the risk of stressors involving loss more typically related to the development of depression,
developing an anxiety whereas those signaling danger or threat have been specifically associated with
disorder later in life.
the onset of anxiety disorders,5 perhaps through excessive or maladaptive
● Females are twice as activation of the threat neurocircuitry. The distal environmental risk factor that
likely to manifest anxiety has the most profound effect on the development of a subsequent anxiety
disorders compared to disorder is childhood sexual abuse, which increases the risk of developing an
males. anxiety disorder by over threefold (odds ratio 3.09; 95% confidence interval, 2.43
to 3.94).22 Early parental loss through death or separation is associated with an
increased risk of subsequent anxiety disorders in offspring, with odds ratios of 1.2
for specific phobia and up to 2.4 for generalized anxiety disorder. A synergistic
relationship appears to exist between previous childhood adversity and the
impact of current stressful life events, whereby greater childhood adversity
produces larger effects of stressful life events on current psychopathology,
supportive of a stress-sensitization model.23 Female gender is a known risk factor
for developing an anxiety disorder, with the rate twice as high in females
compared to males, although it is not clear if this is caused by biological factors or
secondary to the higher rates of stressful life events experienced by women. In
summary, it appears likely that both genetic and environmental factors can
contribute to the development of anxiety disorders, mediated by inherited and
acquired patterns of maladaptive processing of emotional stimuli in the brain.
CLINICAL PRESENTATIONS
This article is confined to the DSM-5 anxiety disorders: panic disorder,
agoraphobia, generalized anxiety disorder, social anxiety disorder, specific
phobia, selective mutism, separation anxiety disorder, substance/medication-
induced anxiety disorder, and anxiety disorder due to another medical condition.
For information on obsessive-compulsive disorder, refer to the article
“Obsessive-Compulsive Disorder” by Peggy M. A. Richter, MD, FRCPC, and
Renato T. Ramos, MD,24 and for information on posttraumatic stress disorder,
refer to the article “Assessment and Management of Posttraumatic Stress
Disorder” by Janet Ellis, MBBChir, MD, FRCPC, and Ari Zaretsky, MD,
FRCPC,25 in this issue of Continuum.
Panic Attacks and Panic Disorder

The DSM-5 defines a panic attack as a discrete period of intense fear or
discomfort that reaches a peak within minutes, during which a number of
somatic and cognitive symptoms of anxiety occur (TABLE 12-1).26 Panic attacks
are not specific to panic disorder and can occur in other psychiatric and physical
conditions (CASE 12-1). As a result, panic attacks in isolation are not diagnostic.
Given the paroxysmal nature of panic attacks and the intensity of the sensations
that accompany them, patients experiencing panic attacks seek care from
emergency medical services more frequently than patients with major depressive
disorder and bipolar disorder.27 Despite the perception of imminent danger
that is experienced during a panic attack, ambulatory monitoring of vital signs
has revealed that only modest changes in heart rate (an average increase of
7 beats/min to a heart rate of 90 beats/min) typically occur during these
896 JUNE 2018

DSM-5 Diagnostic Criteria for Panic Disordera,b TABLE 12-1
A Recurrent unexpected panic attacks. A panic attack is an abrupt surge of intense fear or
intense discomfort that reaches a peak within minutes, and during which time four (or
more) of the following symptoms occur:
Note: The abrupt surge can occur from a calm state or an anxious state.
1 Palpitations, pounding heart, or accelerated heart rate
2 Sweating
3 Trembling or shaking
4 Sensations of shortness of breath or smothering
5 Feelings of choking
6 Chest pain or discomfort
7 Nausea or abdominal distress
8 Feeling dizzy, unsteady, light-headed, or faint
9 Chills or heat sensations
10 Paresthesias (numbness or tingling sensations)
11 Derealization (feelings of unreality) or depersonalization (being detached from oneself )
12 Fear of losing control or “going crazy”
13 Fear of dying
Note: Culture-specific symptoms (eg, tinnitus, neck soreness, headache, uncontrollable
screaming or crying) may be seen. Such symptoms should not count as one of the four
required symptoms.
B At least one of the attacks has been followed by 1 month (or more) of one or both of the
following:
1 Persistent concern or worry about additional panic attacks or their consequences
(eg, losing control, having a heart attack, “going crazy”)
2 A significant maladaptive change in behavior related to the attacks (eg, behaviors designed
to avoid having panic attacks, such as avoidance of exercise or unfamiliar situations)
C The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication) or another medical condition (eg, hyperthyroidism, cardiopulmonary
disorders)
D The disturbance is not better explained by another mental disorder (eg, the panic attacks
do not occur only in response to feared social situations, as in social anxiety disorder;
in response to circumscribed phobic objects or situations, as in specific phobia; in
response to obsessions, as in obsessive-compulsive disorder; in response to reminders
of traumatic events, as in posttraumatic stress disorder; or in response to separation from
attachment figures, as in separation anxiety disorder)

a
Reprinted with permission from American Psychiatric Association.26 © 2013 American Psychiatric
Association.
b
All the features listed must be present to make a diagnosis of panic disorder.

ANXIETY DISORDERS
episodes.28 Therefore, evidence of abnormal vital signs is not necessary nor

pathognomonic for a panic attack. The majority of panic attacks occur during the
daytime, but nocturnal panic attacks can occur and are associated with greater
resultant distress and functional impairment.29 For a diagnosis of panic disorder
to be made, the individual must experience recurrent and unexpected panic
attacks not due to medical conditions or substances that are followed by at least
1 month of persistent concern or worry about additional panic attacks or an
increase in maladaptive avoidance behaviors related to the attacks (TABLE 12-1).
The lifetime prevalence of panic disorder worldwide has been estimated to be
2% to 5%.30 A bimodal distribution in the age at onset has been observed, with
peaks of onset in late adolescence and again in the midthirties. Risk factors for
panic disorder include female gender, a history of separation anxiety in
childhood, a behaviorally inhibited temperament, and a history of sexual or
physical abuse. The majority of people with panic disorder report co-occurring
stressful life events in the year preceding the onset of their disorder, often with
themes of danger or threat (eg, physical assault, news of a medical diagnosis).
Most individuals with panic disorder will have comorbid psychiatric conditions,
in particular, major depressive disorder, substance misuse, or other
anxiety disorders.31
CASE 12-1 A 75-year-old woman was referred to a psychiatrist for management of

panic attacks. She described a 3-month history of episodes
characterized by pounding in the chest, racing heart, sweating, and
dizziness that lasted for hours. She had no identified psychological
triggers or personal or family history of psychiatric illness. Her medical
history was significant for hyperlipidemia, hypertension, and, most
recently, hypothyroidism in the past year. She was on a statin, an
angiotensin-converting enzyme inhibitor, a diuretic, and thyroid
replacement. The only change in her medications had been the addition
of the thyroid replacement pill, with the dosage increased twice in the
past 6 months. A recent ECG and echocardiogram were normal.
Laboratory testing showed a thyroid-stimulating hormone (TSH) level of
0.01, suggesting an excessive dose of thyroid replacement.
COMMENT This patient’s episodes, although resembling panic attacks, were related to
thyroid hormone excess. Late-onset anxiety disorders should prompt a
search for other psychiatric or medical conditions that may be contributing
to, or mimicking, anxiety (eg mood disorders, medical conditions, and the
physiologic effects of substance use or medication). Elderly patients who
present with panic attacks require a medical workup to rule out a
concurrent medical condition. Red flags for a possible medical etiology for
panic attacks in the elderly include an absence of a personal and family
history of panic disorder; the presence of neurologic symptoms during a
panic attack, such as loss of consciousness, loss of bladder or bowel
control, or syncope; and somatic symptoms without the psychological
symptoms of panic.
898 JUNE 2018

Panic disorder in late life is usually the continuation of an illness that began KEY POINTS
earlier in life; it is rare for panic disorder to start for the first time in late life.
● Panic attacks typically
Therefore, it is important to assess the age of onset of panic disorder (and other present as the perception of
anxiety disorders) to determine if the onset of the condition is atypical. frightening physical
Late-onset anxiety disorders should prompt a search for other psychiatric or symptoms, such as racing
medical conditions that may be contributing to, or mimicking, anxiety (eg, mood heart, shortness of breath,
and sweating, in the
disorders, medical conditions, and the physiologic effects of substance use or
presence of normal vital
medication). Elderly patients who present with panic attacks require a medical signs and medical
workup to rule out a concurrent medical condition. Red flags for a possible investigations.
medical etiology for panic attacks in the elderly include an absence of a personal
and family history of panic disorder; the presence of neurologic symptoms ● A pattern of recurrent and
uncued panic attacks is
during a panic attack, such as loss of consciousness, loss of bladder or bowel necessary for a diagnosis of
control, or syncope; and somatic symptoms without the psychological symptoms panic disorder.
of panic.
Both psychological therapies and medications have been shown to be effective ● In the Diagnostic and
Statistical Manual of Mental
for panic disorder. Robust evidence exists for cognitive-behavioral therapy as a Disorders, Fifth Edition
first-line option. Interestingly, in studies of cognitive-behavioral therapy (DSM-5), the presence of
compared to medication or the combination of cognitive-behavioral therapy and panic disorder is no longer
medication, combination therapy has not emerged to be clearly more efficacious required to make a diagnosis
of agoraphobia.
to cognitive-behavioral therapy alone.32 Most clinical guidelines do not
recommend the routine use of cognitive-behavioral therapy together with
antidepressant medication because of the lack of demonstrated superiority of
this strategy compared to the use of cognitive-behavioral therapy or medication
alone.33 US Food and Drug Administration (FDA)-approved medications for
panic disorder include SSRIs (eg, fluoxetine, paroxetine, and sertraline),
serotonin norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine XR), and
benzodiazepines (eg, alprazolam and clonazepam) (TABLE 12-2). Data from
long-term studies suggest that panic disorder has a fluctuating course, with high
rates of symptom improvement (75%) but lower rates of complete functional
recovery (12%) over a 3-year-period.34
Agoraphobia
Agoraphobia was previously designated as a subtype classifier of panic disorder,
but DSM-5 divides agoraphobia and panic disorder into separate diagnostic
entities. Agoraphobia is characterized by marked fear or anxiety about actual or
anticipated exposure within public spaces that lasts at least 6 months, with the
symptoms of fear or anxiety occurring most of the time in more than one setting
(TABLE 12-3). As a result, individuals with agoraphobia fear and avoid these
situations because of worry about developing paniclike symptoms or the belief
that escape might be difficult. Importantly, the feared situations should not be
realistically threatening (eg, walking alone in a dangerous part of town). Those
patients who meet criteria for both disorders would be diagnosed with panic
disorder and agoraphobia.
The lifetime prevalence of agoraphobia has been estimated to be 2%.30 The
relationship between panic disorder and agoraphobia changes across the lifespan.
That is, most older persons with agoraphobia do not have a history of panic attacks35
and develop agoraphobia following the onset of a physical illness or after a traumatic
experience, such as a fall.36 The ability of the clinician to make the diagnostic
distinction between panic disorder with comorbid agoraphobia and agoraphobia
alone has important implications for management, as no robust evidence exists

ANXIETY DISORDERS
that pharmacotherapy is effective in treating agoraphobia without a history of

panic disorder; the treatment of choice in this situation is in vivo exposure.
Generalized Anxiety Disorder

Generalized anxiety disorder is characterized by a pattern of excessive anxiety
and worry about multiple themes that lasts 6 months or more, is difficult for the
individual to control, and is accompanied by a number of physical symptoms
(TABLE 12-4). Clinically, individuals with generalized anxiety disorder exhibit a
pattern of excessive worry about minor matters and intolerance of uncertainty,
which in experimental paradigms manifests as automatic or unconscious
attentional bias toward potentially threatening stimuli in the environment.37 In
addition to worry, DSM-5 requires the presence of somatic symptoms consistent
with hyperarousal (eg, irritability, muscle tension, insomnia, feeling keyed up)
and excessive fatigue. An epidemiologic survey found that only approximately
one-third of those in the community who met criteria for generalized anxiety
TABLE 12-2 Medications With US Food and Drug Administration–Approved Indications

for Anxiety Disorders
Panic Generalized Social Anxiety

Medication Disorder Anxiety Disorder Disorder
Selective serotonin reuptake

inhibitors (SSRIs)
Escitalopram X
Fluvoxamine XR X
Fluoxetine X
Paroxetine X X X
Paroxetine CR X
Sertraline X X
Serotonin norepinephrine
reuptake inhibitors (SNRIs)
Duloxetine X
Venlafaxine XR X X X
Azapirones
Buspirone X
Benzodiazepines
Alprazolam X
Clonazepam X
CR = controlled release; XR = extended release.
900 JUNE 2018

disorder had ever sought help specifically for this condition27; this may be
because, in nonpsychiatric settings, patients with generalized anxiety disorder
rarely identify chronic worry as their primary symptom. Rather, patients with
generalized anxiety disorder often develop physical symptoms, such as
headaches, back pain, insomnia, and gastrointestinal distress, which bring them
to seek care in primary care and medical settings.38
The lifetime prevalence of generalized anxiety disorder worldwide has been
estimated to be 3% to 5%.30 A trimodal distribution in the age at onset has been
observed, with peaks of onset in childhood and early adulthood, followed by a
later peak in the fifth and sixth decades of life, perhaps due to the development of
chronic health conditions. Identified risk factors for generalized anxiety disorder
DSM-5 Diagnostic Criteria for Agoraphobiaa,b TABLE 12-3
A Marked fear or anxiety about two (or more) of the following five situations:
1 Using public transportation (eg, automobiles, buses, trains, ships, planes)
2 Being in open spaces (eg, parking lots, marketplaces, bridges)
3 Being in enclosed places (eg, shops, theaters, cinemas)
4 Standing in line or being in a crowd
5 Being outside of the home alone
B The individual fears or avoids these situations because of thoughts that escape might
be difficult or help might not be available in the event of developing paniclike symptoms
or other incapacitating or embarrassing symptoms (eg, fear of falling in the elderly; fear
of incontinence)
C The agoraphobic situations almost always provoke fear or anxiety
D The agoraphobic situations are actively avoided, require the presence of a companion, or
are endured with intense fear or anxiety
E The fear or anxiety is out of proportion to the actual danger posed by the agoraphobic
situations and to the sociocultural context
F The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more
G The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning
H If another medical condition (eg, inflammatory bowel disease, Parkinson disease) is
present, the fear, anxiety, or avoidance is clearly excessive
I The fear, anxiety, or avoidance is not better explained by the symptoms of another mental
disorder—for example, the symptoms are not confined to specific phobia, situational type;
do not involve only social situations (as in social anxiety disorder); and are not related
exclusively to obsessions (as in obsessive-compulsive disorder), perceived defects or flaws in
physical appearance (as in body dysmorphic disorder), reminders of traumatic events (as in
posttraumatic stress disorder), or fear of separation (as in separation anxiety disorder).
Note: Agoraphobia is diagnosed irrespective of the presence of panic disorder. If an
individual’s presentation meets criteria for panic disorder and agoraphobia, both diagnoses
should be assigned.

a
Association.
b
All the features listed must be present to make a diagnosis of agoraphobia.

ANXIETY DISORDERS
include female gender, childhood adversity, and lower socioeconomic status. A

high rate of comorbid physical and mental health conditions is seen, and those
with generalized anxiety disorder should be screened for substance abuse
and mood disorders.5 Those with co-occurring depression often describe a
long-standing history of worry that became more difficult to control
following the onset of the mood disorder. The presence of both generalized
anxiety disorder and a mood disorder renders both conditions more difficult
to treat.
Generalized anxiety disorder is a chronic condition that may require
long-term treatment. It is responsive to both psychological treatments and
pharmacotherapy, with response rates in the 30% to 50% range for both
modalities.38 Cognitive-behavioral therapy is considered a first-line option.
Cognitive-behavioral therapy protocols for generalized anxiety disorder typically
involve both remediation of the typical cognitive biases of overestimation of
TABLE 12-4 DSM-5 Diagnostic Criteria for Generalized Anxiety Disordera,b
A Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at
least 6 months, about a number of events or activities (such as work or school performance)
B The individual finds it difficult to control the worry
C The anxiety and worry are associated with three (or more) of the following six symptoms
(with at least some symptoms having been present for more days than not for the past
6 months):
Note: Only one symptom is required in children.
1 Restlessness or feeling keyed up or on edge
2 Being easily fatigued
3 Difficulty concentrating or mind going blank
4 Irritability
5 Muscle tension
6 Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep
D The anxiety, worry, or physical symptoms cause clinically significant distress or
impairment in social, occupational, or other important areas of functioning
E The disturbance is not attributable to the physiologic effects of a substance (eg, a drug of
abuse, a medication) or another medical condition (eg, hyperthyroidism)
F The disturbance is not better explained by another mental disorder (eg, anxiety or worry
about having panic attacks in panic disorder, negative evaluation in social anxiety disorder
[social phobia], contamination or other obsessions in obsessive-compulsive disorder,
separation from attachment figures in separation anxiety disorder, reminders of traumatic
events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physical
complaints in somatic symptom disorder, perceived appearance flaws in body
dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of
delusional beliefs in schizophrenia or delusional disorder)

a
Association.
b
All the features listed must be present to make a diagnosis of generalized anxiety disorder.
902 JUNE 2018

danger and underestimation of resiliency factors and relaxation techniques to KEY POINTS
decrease symptoms of bodily tension. FDA-approved medications for
● Generalized anxiety
generalized anxiety disorder include SSRIs (escitalopram and paroxetine), SNRIs disorder is associated with
(duloxetine and venlafaxine XR), and azapirones (buspirone) (TABLE 12-2). high rates of comorbid
Most experts suggest that benzodiazepines may have an adjunctive role when conditions, such as physical
used on a short-term basis (3 to 6 months).5,33,38 However, this class of medications health issues, substance
abuse, and mood disorders.
should be avoided in those with substance abuse. The recommended minimum
duration of medication treatment for generalized anxiety disorder is 1 year. ● Social anxiety disorder is
a chronic condition
Social Anxiety Disorder associated with fear of
The lifetime prevalence of social anxiety disorder has been estimated to be up to negative appraisal by
others, excessive or
10% worldwide,30 with one-third having the performance-only subtype.39 unrealistic fear of social or
Approximately two-thirds of individuals with social anxiety disorder are female. performance situations, and
The typical age of onset is midadolescence, with de novo emergence in the fourth intolerance of the possibility
decade of life and after being very uncommon; such later-onset cases should of embarrassment or
scrutiny by others in social
prompt a search for other comorbid psychiatric, medical, or substance-related situations.
etiologies. Only a small minority of patients with social anxiety disorder seek
treatment. Data from a community sample of US residents found that less
than 10% of people who meet the criteria for social anxiety disorder had ever
seen a clinician for social anxiety.27 Social anxiety disorder is often a chronic
condition, with a 5-year recovery rate for those seeking treatment in the range
of 25%.40
The core feature of social anxiety disorder is fear of negative appraisal by
others in social or performance situations (TABLE 12-5 and CASE 12-2). For
example, patients with social anxiety disorder may have excessive or unrealistic
fear of social or performance situations and intolerance of the possibility of
embarrassment or scrutiny by others. Common situations that may be difficult
for those with social anxiety disorder include public speaking and attending
social functions where there are others who are unknown to the individual.
Individuals with social anxiety disorder may overestimate the likelihood of
a negative event occurring (eg, “no one will like me at the party”), leading to
activation of a threat-related circuit in the brain that can produce a dysphoric
physical state (eg, rapid heartbeat, sweaty palms) via an autonomic arousal
response mediated by the sympathetic nervous system. Withdrawal from
such events where negative appraisal is anticipated will produce a rapid
cessation of the negative emotional and physical state, reinforcing the
avoidance behavior. Ultimately, through repetition of avoidance behavior,
individuals with social anxiety disorder do not provide themselves with
opportunities where they can potentially disconfirm their assumptions of
having negative social interactions with others, thereby strengthening the
fear-avoidance cycle and leading to impaired interpersonal and vocational
functioning. Avoidance of a feared social situation can also lead to negative
self-appraisal in those with social anxiety disorder, including ruminations
about the event and a reinforcing cycle of embarrassment, self-loathing,
depression, and further withdrawal. Randomized controlled trials have shown
strong evidence for the efficacy of cognitive-behavioral therapy and
short-term psychodynamic therapy in the treatment of social anxiety
disorder.39 FDA-approved medications for social anxiety disorder include
the SSRIs fluvoxamine XR, paroxetine, paroxetine CR, and sertraline and
the SNRI venlafaxine XR (TABLE 12-2). If fear or anxiety is restricted to

ANXIETY DISORDERS
speaking or performing in public, the performance anxiety only subtype

would apply. Evidence exists for the off-label use of beta-blockers for
performance anxiety.
Specific Phobia
The cross-national lifetime prevalence of specific phobia has been estimated to
be 7.4%.43 Natural environment phobias (eg, fear of bodies of water or heights)
are the most common subtype, followed by situational phobias (eg, flying),
animal phobias (eg, spiders or dogs), and blood-injury phobias (eg, fear of
needles). In contrast to other anxiety disorders, the blood-injury subtype of
specific phobia involves decreased rather than increased sympathetic nervous
system activity, leading to syncope and vasovagal-type reactions.44
Approximately 75% of cases of specific phobia will have their onset within
the first decade of life.45 Having multiple specific phobias is the rule rather
TABLE 12-5 DSM-5 Diagnostic Criteria for Social Anxiety Disordera–c
A Marked fear or anxiety related to one or more social situations in which the individual is
exposed to scrutiny by others. Examples include social interactions (eg, having a
conversation, meeting unfamiliar people), being observed (eg, eating or drinking), and
performing in front of others (eg, giving a speech).
Note: In children, the anxiety must occur in peer setting and not just during interactions with
adults.
B The individual fears that he or she will act in a way or show anxiety symptoms that will be
negatively evaluated (ie, will be humiliating or embarrassing; will lead to rejection or
offend others).
C The social situations almost always provoke fear or anxiety.
Note: In children, the fear or anxiety may be expressed by crying, tantrums, freezing,
clinging, shrinking, or failing to speak in social situations.
D The social situations are avoided or endured with intense fear or anxiety.
E The fear or anxiety is out of proportion to the actual threat posed by the social situation
and to sociocultural context.
F The fear, anxiety, or avoidance is persistent, typically lasting for 6 months or more.
G The fear, anxiety, or avoidance causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
H The fear, anxiety, or avoidance is not attributable to the physiologic effects of a substance
(eg, a drug of abuse, a medication) or another medical condition.
I The fear, anxiety, or avoidance is not better explained by the symptoms of another mental
disorder, such as panic disorder, body dysmorphic disorder, or autism spectrum disorder).
J If another medical condition (eg, Parkinson disease, obesity, disfigurement from burns or
injury), is present, the fear, anxiety, or avoidance is clearly unrelated or is excessive.

a
Association.
b
If fear or anxiety is restricted to speaking or performing in public, social anxiety disorder should be
specified as performance anxiety only.
c
All the features listed must be present to make a diagnosis of social anxiety disorder.
904 JUNE 2018

than the exception, with most patients with specific phobia having three or
more sources of phobias in their lifetime. Similar to most anxiety disorders,
approximately two-thirds of individuals with specific phobia are female.
Specific phobias can be transient in childhood, with some affected individuals
growing out of their fears through the processes of developmental maturation
and naturalistic exposure to fearful stimuli over time. However, in other
cases, specific phobias are chronic, persisting into and throughout the
adult years.46
A 21-year-old woman presented with a history of anxiety in social CASE 12-2

situations dating back to adolescence, which resulted in her feeling
negatively appraised by others in her college classes when doing group
assignments. She was reluctant to speak in class, but when she did, her
comments were valued by others. She recognized that the anxiety was
out of proportion to the actual threat of the situations. She had no other
psychiatric, medical, or substance-use problems.
Social anxiety disorder was diagnosed. The severity of her symptoms
was deemed to be mild based on her score of 8 on the Generalized
Anxiety Disorder 7-Item Scale (GAD-7) self-report questionnaire.41 She
was provided with reassurance and education about the nature of anxiety
and recommended to engage in healthy coping strategies, such as
aerobic exercise, relaxation, and mindfulness techniques, and to avoid
excessive use of caffeine and other substances. She was also provided
with information about online educational resources on anxiety
disorders, and a follow-up appointment was arranged for 1 month later.
At the follow-up appointment, she reported that the symptoms of
social anxiety had worsened, and she was missing half of her classes and
avoiding some friends. Her GAD-7 score was now 14. She reported
following the advice and accessing the resources that had been provided
at her last visit. She asked about what to do next, and psychotherapy
and medication options were discussed.
A stepped-care approach to the selection of treatment modalities for COMMENT

anxiety disorders has been advocated based on symptom severity.42
Quantification of the severity of anxiety symptoms can be aided by the use
of patient-rated questionnaires. The GAD-7 is a validated seven-item
self-report measure applicable to multiple anxiety disorders.41 Scores in
the range of 5 to 9 are consistent with mild anxiety, 10 to 14 with moderate
anxiety, and 15 or more with severe anxiety. For mild anxiety, the treatment
recommendation is for psychoeducation, support, and watchful waiting.
Cognitive-behavioral therapy (including Internet- or computer-based
cognitive-behavioral therapy), pharmacotherapy, or both, is recommended
for those with moderate anxiety. Severe or treatment-resistant anxiety
symptoms warrant cognitive-behavioral therapy concurrently with
pharmacotherapy.42

ANXIETY DISORDERS
The primary treatment approach for specific phobia is psychological

treatment, such as cognitive-behavioral therapy and exposure-based
therapies. No medications are FDA approved for specific phobia, although
off-label use of benzodiazepines for short-term anxiolysis when the
individual is unavoidably faced with confronting the phobic situation (eg,
flying) or the beta-blocker propranolol for performance anxiety is
not uncommon.
Selective Mutism
Selective mutism is characterized by an individual’s failure to speak in certain
social situations, with the presence of normal ability to speak in other settings.
The prevalence rates of selective mutism have been estimated to range from
0.11% to 2.2% in children, with an average age of onset of 2 to 5 years. The most
common presentation is failure to speak in school, resulting in significant
adaptation difficulties in social and academic spheres.47
Identified risk factors for selective mutism include a temperament of
behavioral inhibition, communication delays, bilingualism, immigration, and a
history of parental social anxiety disorder or selective mutism. Although the
majority of children with selective mutism have a complete remission of their
symptoms in adolescence, rates of mood and anxiety disorders are high in
adulthood, with 58% having a psychiatric disorder, most commonly social
anxiety disorder.48
Treatment approaches consist of psychoeducation, cognitive-behavioral
therapy, and graduated exposure to situations requiring verbal communication.
No medications are FDA approved for selective mutism; limited literature exists
for the use of SSRIs.49
Separation Anxiety Disorder

Separation anxiety disorder is characterized by excessive fear or anxiety
regarding separation from attachment figures that is developmentally
inappropriate and present for at least 4 weeks in a child or adolescent and for at
least 6 months in an adult. Separation anxiety disorder is a new addition to the
group of anxiety disorders in DSM-5. Changes to the diagnostic criteria for
separation anxiety disorder no longer require an onset of symptoms before the
age of 18 years. Typical presentations in adulthood may include fears that their
attachment figure, such as a spouse or child, will come to harm, resulting in
extreme efforts to remain in close contact with them.50 The prevalence of
separation anxiety disorder in adults has been estimated to be 4.8% worldwide,
with adult onset in 43.1% of cases.51
Identified risk factors for separation anxiety disorder include female gender,
childhood parental loss, and lifetime trauma. The presence of separation anxiety
disorder is generally associated with a worse prognosis for mood and other
anxiety disorders when those disorders are comorbid with separation anxiety
disorder.52 Childhood onset of separation anxiety disorder has been linked to an
increased risk specifically for panic disorder in adulthood, and these two
conditions may share a common neurobiology as evidenced by hypersensitivity
to symptom provocation with a 35% carbon dioxide challenge.53 Treatment
approaches consist primarily of psychological treatments, including
cognitive-behavioral therapy and psychodynamic-informed approaches.52 No
medications are FDA approved for separation anxiety disorder, although SSRIs
906 JUNE 2018

have been used given the symptom overlap of separation anxiety disorder with KEY POINTS
other anxiety disorders.
● Phobias in childhood may
be transient, but those that
MANAGEMENT OF ANXIETY DISORDERS persist into adulthood will
A variety of effective treatment strategies for anxiety are available, including typically remain chronic.
both psychosocial and biological interventions. The following section provides a
● Separation anxiety
proposed general clinical approach to the evaluation and treatment of anxiety
disorder, which is
disorders, augmenting the management discussions in the previous sections characterized by excessive
about the specific forms of anxiety disorders. fear or anxiety regarding
separation from
General Approach to Evaluating Anxiety attachment figures, has
pathophysiologic links to
The most important step in the treatment of anxiety is to establish the cause, panic disorder and is a new
triggers, and duration of the symptoms. This is achieved through the exploration addition to the group of
of the nature of the symptoms (eg, worries, somatic symptoms, and avoidance anxiety disorders in DSM-5.
behaviors), proximal triggers for the anxiety (eg, stressful life events, medical
● The most important step
illnesses, substance abuse, and change in medications), and the patient’s in the treatment of anxiety is
thoughts and beliefs regarding his or her anxiety. For example, anxiety and the establishment of the
avoidance about attending a social engagement may be due to low mood and a diagnosis, which includes an
lack of interest (major depressive disorder) or due to the fear of being negatively exploration of the nature of
the symptoms and an
scrutinized by others (social anxiety disorder), of having panic attacks (panic
assessment of comorbid
disorder and agoraphobia), of being separated from a loved one (separation medical and psychiatric
anxiety disorder), of the need to travel via airplane (specific phobia), or of the factors such as mood
need to give a speech (social anxiety disorder, performance subtype), to name a disorders, suicidality, and
substance use.
few possible causes. Short-term anxiety can be treated symptomatically with
support, reassurance, and, if needed, a time-limited course of a benzodiazepine. ● Anxiety disorders are
Given that anxiety disorders are diagnoses of exclusion, it is important to rule chronic but treatable
out the contribution of concurrent medical illnesses and medications. A conditions.
symptom-targeted physical examination should be performed to rule out an
● Selection of the
underlying medical condition. Factors increasing the possibility of a medical or appropriate treatment
substance etiology for an anxiety disorder include no previous history of an modality for anxiety
anxiety disorder; an onset of an anxiety disorder later in the lifespan than the disorders may, in part, be
usual natural history; a recent change in medical health, prescribed medication, guided by symptom severity
and by patient-rated
or substance use pattern; and the presence of atypical symptoms, such as loss of
questionnaires, such as the
consciousness, loss of bladder or bowel control, or syncope during a presumed Generalized Anxiety
panic attack. Recommended screening investigations for those presenting with Disorder 7-Item Scale.
de novo anxiety symptoms or an exacerbation of an existing anxiety condition
may include a complete blood count, electrolytes, fasting glucose, thyroid-
stimulating hormone (TSH), urine toxicology for substance use, and an ECG.5,33
Further investigations and a more focused physical examination are dictated by
the presentation.
Clinical experience and guidelines support that anxiety disorders can be
treated with either psychotherapy or pharmacotherapy,5,33,42 with short-term
response rates up to 50% to 60% with either approach. Often, the choice of
treatment depends on patient preference, the availability of treatments, and
clinical factors. A stepped-care approach to the selection of treatment modalities
for anxiety disorders has been advocated based on symptom severity.42
Quantification of the severity of anxiety symptoms can be aided by the use of
patient-rated questionnaires. Studies have validated the psychometric properties
of the Generalized Anxiety Disorder 7-Item Scale (GAD-7), a self-report measure
applicable to multiple anxiety disorders in primary care and medical settings.41

ANXIETY DISORDERS
KEY POINTS The GAD-7 is a seven-item questionnaire with total scores ranging from 0 to 21.
A total score in the range of 5 to 9 is consistent with mild anxiety, 10 to 14 with
● Education about the
nature of anxiety disorders,
moderate anxiety, and 15 or more with severe anxiety. For those with mild
avoidance of known anxiety, the treatment recommendation is for psychoeducation, support, and
exacerbating factors, the watchful waiting; if symptoms worsen, cognitive-behavioral therapy may be
promotion of healthy coping added (including Internet- or computer-based cognitive-behavioral therapy).
strategies, and emotional
Cognitive-behavioral therapy, pharmacotherapy, or both are recommended for
support should be provided
to all patients. those with moderate anxiety. Severe or treatment-resistant anxiety symptoms
warrant cognitive-behavioral therapy concurrently with pharmacotherapy.42
● A stepped-care approach
for those with moderate or Treatment Approach for Mild Symptoms
severe anxiety has been
recommended.
Patients and their families should be given education about the nature of anxiety,
including both psychological and physical symptoms; the known clinical course
● The routine of the specific anxiety disorder(s) affecting them; and the treatment options
coadministration of available. Clinical experience suggests that patients greatly benefit from
psychotherapy and
discussions emphasizing the common frequency of anxiety conditions, the
medications has not been
shown to be superior to biological and genetic component of anxiety, and the good recovery rates with
either approach alone. treatment. Patients should also be educated to avoid possible common
exacerbating factors for anxiety, such as excessive use of caffeine or alcohol, and
● Robust data exist to to potentially reduce medications with stimulating properties. Medications and
support cognitive-
behavioral therapy in the
substances with sedating effects, such as alcohol or marijuana, may be commonly
treatment of anxiety used by people to try to alleviate anxiety; however, they can potentially
disorders, whether precipitate panic and anxiety in the withdrawal phase (CASE 12-3). Patients
administered directly by a should be encouraged to get regular aerobic exercise and to practice
therapist or via the Internet.
relaxation techniques.
Treatment Approach for Moderate Symptoms

The stepped-care approach to anxiety disorder recommends cognitive-behavioral
therapy, pharmacotherapy, or both for those with moderate anxiety.42
Currently, biomarker data to predict preferential response to psychotherapy or
medications is lacking, although neuroimaging data suggest that similar
neurobiological correlates to response are seen for both modalities.54 In
long-term studies, administering cognitive-behavioral therapy and an SSRI
together has not routinely been found to be superior to cognitive-behavioral
therapy alone,33,55 although this combination may have a role to play in those
with severe or treatment-resistant anxiety.5 Before initiating treatment, patients
should be made aware that anxiety may worsen in the early stages of treatment
with antidepressant medication as well as in psychotherapy when individuals
begin to confront fear-provoking stimuli and attempt to alter their pattern of
phobic avoidance.
PSYCHOTHERAPY. Cognitive-behavioral therapy is a type of psychotherapy that

attempts to change the thoughts and behaviors that are fundamental to
maintaining the anxiety disorder. Given the evidence that people with anxiety
disorders tend to overestimate the risk of a situation and underestimate their
ability to manage the risk, the goals of cognitive-behavioral therapy include
identifying and challenging cognitive biases that contribute to this misappraisal
and minimizing avoidant behavior that perpetuates the anxiety. This is
accomplished through a time-limited collaborative relationship between
patient and therapist that is focused on problem solving. The efficacy of
908 JUNE 2018

cognitive-behavioral therapy in the treatment of anxiety disorders is well
established, and it is considered a first-line therapy for anxiety disorders.5,33,38,39
A 2016 meta-analysis found large to very large treatment effect sizes associated
with cognitive-behavioral therapy, with numbers needed to treat of 1.42, 2.54.
and 2.54 for panic disorder, generalized anxiety disorder, and social anxiety
disorder, respectively.56
Components of cognitive-behavioral therapy interventions include cognitive
restructuring through the evaluation of automatic thoughts and the provision of
homework assignments that provide patients the opportunity for experiential
learning to modify the nature of their beliefs regarding anxiety triggers.
A 43-year-old man presented to the emergency department reporting CASE 12-3

symptoms of sudden-onset chest tightness, dyspnea, sweating, and
anxiety. The symptoms occurred while the patient was sitting in his
backyard reading. He reported a long-standing history of such episodes
over the past 15 years, which occurred both when he was under extreme
stress and unprovoked. He described using increasing amounts of alcohol
over the past year to manage his sense of anxiety and worry about another
episode occurring. In a typical week, he consumed more than 20 alcoholic
drinks. He had no signs or symptoms of acute alcohol intoxication or
withdrawal or other comorbid medical or psychiatric issues.
His vital signs were normal, and general physical and neurologic
examinations were normal. Laboratory investigations were normal,
including troponins, and ECG and other investigations were normal. Urine
toxicology was positive only for alcohol. He was diagnosed with panic
disorder and alcohol dependence and provided with psychoeducation
about the nature of anxiety and the role that his alcohol use may have
played in perpetuating his anxiety difficulties. He was also provided with
information on relaxation techniques and given a referral to psychiatric
urgent care to be seen the following week. He was relieved to hear that he
was not having a heart attack but asked if he could receive a prescription
for a medication to help his anxiety in the future.
In patients who present with anxiety disorders, it is essential to assess for COMMENT
the presence of alcohol and substance abuse. Benzodiazepines should be
avoided in patients with a history of substance abuse because of the
potential for dependence and the ability of benzodiazepines to potentiate
the effects of alcohol and opioids, which can increase the likelihood of death
in overdose. In cases where pharmacologic interventions are deemed
necessary, priority should be given to selective serotonin reuptake inhibitors
(SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and buspirone,
although it may take weeks to months to see the full effects of these
medications. Pregabalin, a medication that does not bind to benzodiazepine
receptors and has reduced addiction potential, was given to provide more
immediate anxiolysis given this patient’s history of substance abuse.

ANXIETY DISORDERS
Graduated exposure to fearful stimuli involves helping patients to systematically

confront feared but otherwise safe stimuli in a manner that promotes extinction
of the feared stimuli through corrective learning experiences. Other common
elements of cognitive-behavioral therapy for anxiety include relaxation and
breathing techniques to decrease physiologic arousal. Psychological therapies are
the mainstay of treatment for specific phobia, agoraphobia, separation anxiety
disorder, and selective mutism.
A number of anxiety disorder–specific cognitive-behavioral therapy protocols
have been developed based on the presumptive core cognitive components of
each disorder. A 2017 randomized controlled trial aimed to elucidate the active
elements of cognitive-behavioral therapy for anxiety disorders.57 Patients were
randomly assigned to receive either a disorder-specific cognitive-behavioral
therapy protocol or a transdiagnostic unified protocol for all anxiety disorders,
which prioritized the reactions to the emotional experience, such as autonomic
arousal, rather than its situational precipitants. The transdiagnostic unified
protocol consisted of five core treatment modules: (1) mindful emotion
awareness, (2) cognitive flexibility, (3) identifying and preventing patterns of
emotion avoidance, (4) increasing awareness and tolerance of emotion-related
physical sensations, and (5) interoceptive and situational emotion-focused
exposures. While the disorder-specific and transdiagnostic protocols each
produced reductions in anxiety compared to wait-list controls, with large effect
sizes for improvement, those who were randomly assigned to the transdiagnostic
protocol were more likely to complete treatment.57 Therefore, it appears that a
focus on the common emotional experiences across the anxiety disorders is
effective in treating anxiety disorders.
Although the evidence base for cognitive-behavioral therapy in anxiety
disorders is strong, the majority of persons with an anxiety disorder do not
receive this treatment, despite patients’ preference for psychotherapy rather
than pharmacotherapy.58 Data from a community-based survey revealed that
only 1 in 10 people with social anxiety disorder, 1 in 3 people with a diagnosis
of generalized anxiety disorder, and just under 1 in 2 with panic disorder had
ever seen a therapist or doctor for their condition.27 Barriers include the
limited number of available therapists trained in cognitive-behavioral therapy,
the time and costs associated with the treatment, and stigma or fear of
self-disclosure to another person.59 These constraints have prompted
investigation of alternative means of delivering cognitive-behavioral therapy,
including Internet-based cognitive-behavioral therapy. Randomized controlled
trials have demonstrated that Internet-based cognitive-behavioral therapy is
equally effective as face-to-face cognitive-behavioral therapy for social anxiety
disorder, panic disorder, and generalized anxiety disorder, with durable
effects lasting months after completion.60 Therefore, Internet-based
cognitive-behavioral therapy may be an important option for people who
experience difficulties traveling to appointments with a therapist because
of the fear and avoidance inherent in anxiety disorders. Mindfulness meditation
has been found to regulate anxiety states, with reductions in anxiety associated
with increased activation of the anterior cingulate cortex, ventromedial
prefrontal cortex, and anterior insula following this treatment.61 For social
anxiety disorder, evidence exists from randomized trials for manual-based
short-term psychodynamic therapy with short- and long-term results
comparable to cognitive-behavioral therapy and superior to wait-list controls.39,62
910 JUNE 2018

Other types of psychotherapy have also been used to treat anxiety disorders, KEY POINTS
but, in general, the support for these therapies is based on fewer or
● US Food and Drug
lower-quality studies. Administration–approved
medications for the
MEDICATIONS. Four classes of medications have received FDA approval for the treatment of anxiety
treatment of anxiety disorders: SSRIs, SNRIs, azapirones, and benzodiazepines. disorders are from four
Multiple meta-analyses and clinical guidelines recommend either SSRIs or SNRIs pharmacologic classes:
selective serotonin reuptake
as a first-line choice for the treatment of anxiety disorders.33,55 FDA-approved
inhibitors, serotonin
medications are listed in TABLE 12-2. It is important to note that evidence exists norepinephrine reuptake
for the efficacy of SSRIs and SNRIs beyond those with an FDA indication for an inhibitors, azapirones, and
anxiety disorder,33 suggesting that this may be a class effect rather than restricted benzodiazepines.
to certain compounds. The effective dosages of these medications are similar to
● To minimize the risk of
those used for major depressive disorder (TABLE 12-6 63–66). Because patients premature discontinuation
with anxiety may have increased sensitivity to medication side effects or of medication, start at a low
misattribute physical symptoms of anxiety to the medication, it is recommended dose and slowly increase
to start at a low dosage and slowly increase the dosage every 2 to 4 weeks, as the dose every 2 to 4 weeks
up to the therapeutic range.
tolerated, to achieve dosages in the therapeutic range.
● The azapirone medication
SELECTING A MEDICATION. In the absence of biomarkers to guide decision making, buspirone has antianxiety
effects limited to reduction
several factors may aid clinicians in choosing a medication and longitudinally
of worry. As such, it has
monitoring its effects. The first is the specific diagnosis. As previously noted, limited effects for other
several anxiety disorders respond to antidepressants. In contrast, buspirone is indications beyond
limited to the treatment of generalized anxiety disorder. Buspirone, an azapirone generalized anxiety
disorder, although it may be
with no effects on g-aminobutyric acid (GABA), works as a 5-hydroxytryptamine
a helpful option when the
1A (5-HT1A) partial agonist. Similar to an antidepressant, buspirone takes 3 to use of a benzodiazepine is
4 weeks to start exerting its effects and may have a limited role in treating acute contraindicated.
anxiety. The efficacy of beta-blockers, such as propranolol, appears to be
restricted to those with the performance subtype of social anxiety disorder. ● The beta-blocker
propranolol may be
Propranolol is effective in doses between 20 mg and 40 mg when taken effective for peripheral
30 minutes before a predictable performance-related anxiety, such as giving a manifestations of anxiety
presentation. This medication may be preferentially effective in minimizing (eg, tremor) in those with the
peripheral manifestations of anxiety, such as tremor. Heart block, chronic performance subtype of
social anxiety disorder.
obstructive pulmonary disease, asthma, and bronchospasm are considered
contraindications to propranolol, and monitoring of vital signs is essential
when using this medication.
Assessing for comorbid depressive symptoms may also help in choosing a
medication. Given that little evidence exists for the antidepressant properties of
benzodiazepines, those with anxiety and major depressive disorder should be
treated with an SSRI or SNRI. Since response rates seen across the different
antidepressants are deemed to be roughly equivalent, the selection of an
antidepressant medication may, in part, be based on its side effect profile,
understanding that both efficacy and acceptability ultimately contribute to its
clinical effectiveness (TABLE 12-7). Common side effects of SSRIs include
gastrointestinal upset, sedation, insomnia, and sexual dysfunction. The presence
of certain side effects, such as erectile dysfunction, may be deal breakers for
some, but not all, patients. It is important to discuss potential side effects with
patients before starting a medication to determine if they would prove to be
barriers to adherence. Paroxetine has more anticholinergic activity than other
SSRIs. Anticholinergic effects can cause cognitive impairment, especially in older
individuals and those with preexisting brain disease. The tertiary amine tricyclic

ANXIETY DISORDERS
TABLE 12-6 Commonly Prescribed Medications for Anxiety Disorders
Initial Total Target Total Daily

Class/Medication Daily Dosage (mg) Dosage (mg)a Frequency of Use Common Side Effects
}
Selective serotonin reuptake inhibitors (SSRIs)b
Citalopramc 10 20–40 Daily
c,d
Escitalopram 5 10–20 Daily
Fluvoxamine XRd 50 100–300 Daily

Nausea, somnolence, insomnia,
d sexual dysfunction, loose stools,
Fluoxetine 5–10 20–80 Daily
sweating, headache
Paroxetined 10 20–60 Daily
d
Paroxetine CR 12.5 25–75 Daily
Sertralined 25 50–200 Daily
Serotonin norepinephrine reuptake inhibitors (SNRIs)b

Duloxetined
Venlafaxine XRd
30
37.5
60–90
75–225
Daily in the morning
Daily in the morning

} SSRI side effects, hypertension
Azapirones
Buspironed 10 20–60 Daily Dizziness, nausea, insomnia,
headache
}
Benzodiazepines
Alprazolamd 0.5–1.0 2–6 3 times a day
d Sedation, psychomotor
Clonazepam 0.25–0.50 1–2 Daily or 2 times a day
impairment, dependence,
Diazepam 2.5–5.0 10–40 Daily tolerance
Lorazepam 0.5–1.0 1–4 2 times a day
Other
Gabapentin 100–200 100–1800 2 or 3 times a day Sedation
Pregabalin 150 150–600 2 or 3 times a day Sedation, weight gain, peripheral

edema
Propranolol 10 10–40 As needed 30–60 Bradycardia, hypotension
minutes before
situation
Quetiapine 25 50–200 Daily at bedtime Sedation, weight gain, metabolic
effects
a
Lower dosages are recommended for the elderly.
b
Evidence exists for the efficacy of SSRIs and SNRIs beyond those with a US Food and Drug Administration (FDA) indication for an anxiety disorder,
suggesting that this may be a class effect rather than restricted to certain compounds.
c
A warning exists of increased risk of the QT prolongation at doses of citalopram greater than 40 mg (greater than 20 mg in those older than 60 years
of age) and escitalopram greater than 20 mg. In those age 65 years and older, the maximum recommended dose of citalopram is 20 mg/d63 and
the maximum recommended dose of escitalopram is 10 mg/d64 (Health Canada). The FDA recommends a maximum dose of 20 mg/d for citalopram in
those older than age 60.65 For escitalopram, the maximum recommended dose is 10 mg/d in the elderly.66
d
FDA indication for an anxiety disorder.
912 JUNE 2018

antidepressants have been found to be effective in treating anxiety but are
generally not recommended as a first- or second-line choice because of their
potential for causing orthostatic hypotension, cardiotoxicity, and anticholinergic
side effects. First-generation monamine oxidase inhibitors (MAOIs), such as
phenelzine, also are not considered first-line therapies for the treatment of
anxiety disorders because of their potential for orthostatic hypotension and
peripheral edema and the need to avoid tyramine-containing foods and certain
medications to prevent development of a hypertensive crisis.
When choosing a medication, it is important to assess the patient for
suicidality. In a systematic review and meta-analysis, anxiety disorders apart
from obsessive-compulsive disorder were associated with an increased risk of
suicidal thoughts (odds ratio 2.89; 95% confidence interval, 2.09 to 4.00),
attempted suicides (odds ratio 2.47; 95% confidence interval, 1.96 to 3.10), and
completed suicides (odds ratio 3.34; 95% confidence interval, 2.13 to 5.25).67 In
patients with an anxiety disorder, a comorbid mood disorder may have a
synergistic effect, as the risk of suicidal behavior in this group appears to be
greater than in those with either an anxiety or mood disorder alone, perhaps
because of anxiety facilitating the transition from suicidal thoughts to behaviors.68
In those with anxiety and suicidality, caution should be exerted to provide
smaller quantities of medication to minimize the risk of a fatal overdose. More
frequent appointments to assess the effects of treatment and safety are prudent.
It is also important to assess for alcohol and substance abuse when selecting a
medication. Because of the potential for dependence and the ability to potentiate
the effects of alcohol and opioids, benzodiazepines should be avoided in patients
with a history of substance abuse. Although concerns exist about the increased
Rates of Side Effects of US Food and Drug Administration–Approved TABLE 12-7

Antidepressants for Anxiety Disordersa
Class/ Dry Sexual

Medication Constipation Diarrhea Mouth Fatigue Headache Insomnia Nausea Sedation Dysfunction
Selective serotonin reuptake inhibitors (SSRIs)
Escitalopram 0–9% 0–9% 0–9% 0–9% 0–9% 0–9% 10–29% 0–9% 10–29%
Fluvoxamine 10–29% 0–9% 10–29% 0–9% >30% 10–29% >30% >30% >30%
Fluoxetine 0–9% 0–9% 10–29% 0–9% 0–9% 10–29% 10–29% 10–29% 10–29%
Paroxetine 10–29% 10–29% 10–29% 0–9% 10–29% 10–29% 10–29% 10–29% >30%
Sertraline 0–9% 10–29% 10–29% 10–29% >30% 10–29% >30% 10–29% >30%
Serotonin norepinephrine reuptake inhibitors (SNRIs)
Duloxetine 10–29% 0–9% 10–29% 0–9% 0–9% 10–29% >30% 0–9% 10–29%
Venlafaxine 10–29% 0–9% 10–29% 0–9% 10–29% 10–29% >30% 10–29% 10–29%
a
Based on unadjusted rates from product monographs.

ANXIETY DISORDERS
use of benzodiazepines in recent years,69 they continue to have a role in selected

patients with anxiety without substance abuse when used judiciously. Long-term
use of benzodiazepines has been shown to increase with age, with 14.7% of those
between 18 and 35 years of age receiving a prescription for benzodiazepines in
the United States during the year, compared to 31.4% of those 65 to 80 years of
age.69 Despite the increased use of this class of medications in the elderly,
benzodiazepines should be used with caution in this age group because of
concerns about falls, sedation, and cognitive impairment. Strategies to decrease
the likelihood of long-term benzodiazepine use and dependence include the use
of shorter-acting benzodiazepines in small supplies and with frequent
reassessment of the ongoing need for them.70
Approach to Severe Anxiety Disorders or Treatment Nonresponse

Anxiety disorders are considered chronic conditions with relapsing-remitting
courses. Several factors have been associated with treatment resistance,
including illness characteristics (younger age of onset, longer course of illness,
greater severity and frequency of symptoms, persistent anticipatory anxiety and
avoidance, substance abuse, a history of childhood abuse, a family history of
psychiatric disorders, and psychiatric and medical comorbidities),
sociodemographic factors (male sex, low socioeconomic status, poor social
supports), and possible biological factors (S allele of 5-HTTLPR, lower serum
brain-derived neurotrophic factor [BDNF] level).71
In cases of an incomplete response, an important initial step is to determine if
the lack of response is because of medication factors such as inadequate dose and
duration of treatment. Pseudoresistance factors include nonadherence to
treatment and inaccurate or concurrent diagnoses. A review of the literature
estimated that approximately half of patients with an anxiety disorder
prematurely discontinue their treatment sessions, and this may reach up to 85%
of those with social phobia.72 Group therapies are more likely to be declined than
individual therapy.73 Rates of nonadherence to prescribed medications are
similar. In an analysis of a large managed care database, Stein and colleagues74
estimated that 57% of patients diagnosed with an anxiety disorder had
discontinued their SSRI or SNRI medication at 6 months. Illness comorbidity has
not been consistently identified as contributing to nonadherence in anxiety
disorders, and, in fact, investigators have proposed a bimodal relationship with
higher rates of premature discontinuation of treatment in those at the mildest
and most severe ends of the severity perspective because of lack of investment in
ongoing treatment and extreme functional impairment, respectively.75 Given
that fear and avoidance are key components in the genesis and perpetuation of
anxiety disorders, it is prudent to explore patients’ beliefs regarding illness and
the proposed treatments.
Nonresponse to an initial course of cognitive-behavioral therapy or
medication should also prompt a reexamination of the diagnosis to explore
whether factors such as latent substance abuse or mood disorder may be
contributory. Following the confirmation of an accurate diagnosis and lack of
nonadherence to treatment, the next step is to determine whether a therapeutic
dose of treatment has been obtained. Typical medication dose ranges are shown
in TABLE 12-6. The following step is to determine whether the dose of treatment
has been in place for an adequate duration of time. It is recommended that a trial
of an antidepressant should be for a minimum of 8 to 10 weeks, including 2 weeks
914 JUNE 2018

or more at the highest tolerated dose. If effective, the antidepressant should be KEY POINTS
maintained at the highest tolerated dose for 9 to 12 months to minimize the risk of
● The risk of suicide is
relapse.5 A typical course of cognitive-behavioral therapy would be 12 to increased in those with
16 sessions. anxiety disorders, especially
A lack of consensus exists regarding the definitive next steps following a lack in cases of a comorbid mood
of response to an adequate trial of treatment.33,76 Options include switching from disorder or substance
abuse.
one first-line treatment modality to the other (ie, from cognitive-behavioral
therapy to antidepressant medication or vice versa). For those who have failed a ● Benzodiazepines should
trial of an SSRI, it has been suggested that an alternative SSRI be tried.42 If the be avoided in those with
patient still has no response, switching to an SNRI, such as duloxetine or alcohol or substance abuse
venlafaxine, has been recommended. An alternative option is to combine and should be used with
caution in the elderly.
cognitive-behavioral therapy and antidepressant medication. A third option is to
augment psychotherapy or pharmacotherapy with other strategies not felt to ● A lack of response to an
have strong anxiolytic properties on their own. adequate course of either
The paucity of evidence-based treatments has led investigators to explore the psychotherapy or
medication should prompt a
efficacy of novel strategies for those with difficult-to-treat anxiety disorders. reexamination of the
Medication strategies for treatment-resistant generalized anxiety disorder or for diagnosis, confirmation of
when a benzodiazepine should be avoided include pregabalin and buspirone. treatment adherence, and
Pregabalin, an established treatment for fibromyalgia, epilepsy, and neuropathic ruling out of latent comorbid
factors.
pain, has efficacy in generalized anxiety disorder.5 Pharmacologically, pregabalin
is a GABA analogue that does not bind to benzodiazepine receptors; it has ● Options for those with a
clinically demonstrated anxiolytic effects, with a decreased risk of dependence. lack of response to
Given that both pregabalin and buspirone do not bind to benzodiazepine treatment for an anxiety
receptors, both compounds have reduced addiction potential and may be disorder may include
(1) switching from
preferred treatments for those with a history of alcohol abuse. However, medication to
prescribers of pregabalin (and gabapentin) should pay attention to signs of psychotherapy or vice versa,
abuse, especially in those patients with a history of substance use disorders. (2) combining medication
Limited evidence exists for the efficacy of atypical antipsychotics, such as and psychotherapy,
(3) switching between
quetiapine, in panic disorder or generalized anxiety disorder.76 When antidepressant medication
augmentation with an atypical antipsychotic is used, the potential risks of weight classes, or (4) adding a
gain, extrapyramidal symptoms, and metabolic syndrome should be actively medication to an
monitored in patients. Another putative augmentation strategy for anxiety is antidepressant or
psychotherapy to augment
D-cycloserine, an antibiotic traditionally used to treat tuberculosis. D-Cycloserine
its effects.
acts as a partial N-methyl-D-aspartate (NMDA) agonist in the brain. Preclinical
studies have indicated that D-cycloserine is able to enhance the resolution of fear
memories when administered concurrently during extinction learning
paradigms, suggesting that it may play a role in augmenting the effects of
cognitive-behavioral therapy.77 In a 2017 meta-analysis of the efficacy of
D-cycloserine in augmentation of cognitive-behavioral therapy with or without
an SSRI, it was found that doses of D-cycloserine between 50 mg/d and 250 mg/d
were associated with a small antianxiety effect compared to placebo.78
Interestingly, the effect of D-cycloserine was not moderated by the dose or the
concurrent use of SSRIs, suggesting it may play a specific role in enhancing
psychotherapy for those with anxiety disorders. Further research is needed to
determine the proper sequence of treatments beyond first-line options.
CONCLUSION
Anxiety is often a transient response to perceived threats, which coordinates a
set of psychological, behavioral, and biological reactions to prepare the individual

ANXIETY DISORDERS
to mount an adaptive response to a stressor. However, if this process becomes

more context-independent, prolonged, excessive, and more difficult to regulate,
it can become an anxiety disorder. DSM-5 recognizes nine distinct anxiety
disorder diagnoses, which share the common elements of acute distress, physical
manifestations of fear, anticipatory worry, and avoidance of the anxiety-
provoking stimuli. Anxiety disorders often manifest early in life and are chronic
but treatable conditions, amenable to both psychological and biological
approaches. Evidence-based treatments for anxiety disorders include
cognitive-behavioral therapy and medications (SSRIs, SNRIs, benzodiazepines,
and azapirones), which may exert their effects either through enhanced
top-down cortical modulation of amygdala activity or via decreased bottom-up
automatic negative reactivity to threat stimuli. Initial treatment selection may be
guided by the severity of anxiety symptoms, the presence of comorbidities, and
an individualized risk-benefit consideration of potential side effects of
medications. A lack of consensus exists regarding next steps for treatment-
resistant anxiety disorders, but therapeutic options include combining
cognitive-behavioral therapy and antidepressant medication and add-on
augmentation strategies, such as pregabalin, gabapentin, and quetiapine. More
research in anxiety disorders is needed to address the unmet needs of biological
tests to aid in diagnosis and treatment selection and the development of novel
anxiolytic treatments and to further refine our knowledge on the optimal means
of combining and sequencing existing treatments.
USEFUL WEBSITES
ANXIETY AND DEPRESSION ASSOCIATION OF AMERICA NATIONAL INSTITUTE OF MENTAL HEALTH
The Anxiety and Depression Association of America The National Institute of Mental Health webpage on
website provides resources for understanding anxiety disorders provides educational resources,
depression, anxiety, and stress; information about including signs and symptoms, risk factors, and
suicide prevention; and links for treatment and treatments and therapies. It also includes
support. information on how to join a clinical trial for anxiety
adaa.org disorders.
nimh.nih.gov/health/topics/anxiety-disorders/
MOODGYM index.shtml
MoodGym is a free online cognitive-behavioral
therapy resource.
moodgym.com.au
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ETHICAL AND
MEDICOLEGAL ISSUES Assessment of Medical

Decision-making
Capacity in Patients
ONLINE
With Dementia
By Joshua J. Rodgers, MD; Joseph S. Kass, MD, JD, FAAN
ABSTRACT
Medical decision-making capacity, the patient’s ability to exercise
autonomy reasonably, is an essential component of both informed consent
and informed refusal. The assessment of medical decision-making
capacity is thus fundamental to the ethical practice of medicine. Medical
decision-making capacity is not all or nothing but rather exists on a
continuum and should be assessed on a decision-by-decision basis.
Alzheimer disease and other neurocognitive disorders can affect a
CITE AS:
patient’s medical decision-making capacity and may pose special
2018;24(3, BEHAVIORAL NEUROLOGY challenges to capacity assessment. To illustrate some of these challenges,
AND PSYCHIATRY):920–925. this article presents a case of a patient with Alzheimer disease who refused
a recommended operation and discusses the components of capacity, a
Dr Joshua J. Rodgers, 12301 S Main useful mnemonic and tools, the variability of state laws, and the roles
St, Houston, TX 77479, Joshua. neurologists and psychiatrists play in the assessment of capacity.
Rodgers@bcm.edu.
Dr Rodgers reports no CASE
disclosure. Dr Kass serves as Note: This is a hypothetical case.
associate editor of ethical and
medicolegal issues for A 75-year-old retired woman neurologist with a diagnosis of early
Continuum, as an associate dementia due to Alzheimer disease was brought to the emergency
editor for Continuum Audio, as a department of a university hospital by her daughter and husband because
neurology section editor of
Ferri’s Clinical Advisor for of the patient’s report of worsening abdominal pain. Aside from
Elsevier, and as co-editor of well-controlled hypertension and a cholecystectomy 30 years earlier, she
Neurology Secrets, Sixth Edition.
Dr Kass has received personal
had no other significant past medical or psychiatric history. She asked her
compensation for CME lectures family to take her to the emergency department because she thought she
from Pri-Med Medical Group and might have an incarcerated hernia. The emergency department physician
has received personal
compensation as a medicolegal
concurred with her assessment of her symptoms but was unable to
consultant in legal cases completely reduce the hernia and recommended that she be admitted for
involving criminal cases, additional workup and surgical evaluation. The patient reluctantly agreed to
malpractice, and personal injury.
the admission but stated emphatically that she did not want surgical repair.
UNLABELED USE OF She was compliant with all evaluations and initial interventions, including
placement of an IV for hydration. The evaluation determined that the hernia
USE DISCLOSURE:
Drs Rodgers and Kass report no was likely strangulated, and emergent surgery was recommended. The
disclosures. patient refused surgery for unclear reasons and was agitated with the
surgeon. The surgeon then requested a psychiatry consultation to evaluate
of Neurology. the patient’s capacity to refuse this urgently needed procedure.
920 JUNE 2018

The consulting psychiatrist found the patient to be alert and oriented,
with intact nonfluctuating attention and awareness; thus, she was not
delirious. She was calm and cooperative with the assessment. She was able
to communicate a thorough understanding of her condition, including the
high risk of bowel necrosis and possible death. She was also able to
communicate an adequate understanding of the proposed intervention but
claimed not to have been educated on any alternatives. She stated that
she desired to live, did not want the hernia to cause bowel necrosis, and
certainly did not want to die. She emphasized that she had always valued
being in good health, exercised regularly, and maintained a healthy diet
so she could live into her nineties as her mother did. She recalled having
undergone general anesthesia and abdominal surgery previously without
complication. However, she remained adamant in her refusal of the surgery
and insisted another solution be found. She then confided that she was
sure her husband was engaged in multiple extramarital affairs and
expressed the concern that if she were to undergo surgery, she would not
be able to “keep an eye on him.” She was convinced he would be unfaithful
the moment she was under general anesthesia. She was unable to
provide any objective evidence to support her belief.
The patient’s husband and daughter were interviewed separately.
Her husband, who was older than the patient, exhibited evidence of
cognitive decline himself and required a walker for ambulation; he said
that he had not been sexually active in years. Their daughter reported
that her mother had experienced delusions of infidelity and jealousy
for some time. The delusions had not abated in response to treatments
suggested by the patient’s neurologist. Her husband and daughter
both stated that her decision to refuse the surgery was not in line with
either her values or her previous decisions regarding medical care. Her
daughter informed the team that the patient had recently granted her
durable medical power of attorney, and she was very willing to produce
the necessary documents.
The psychiatry team then spoke with the patient and her daughter
together. With her daughter’s reassurance and promise that she would
keep an eye on her father, the patient agreed to defer to her daughter’s
judgment. The primary team met with the patient’s daughter to explain the
indications, risk, benefits, and alternatives so she could provide informed
consent for the surgery.
INTRODUCTION TO MEDICAL DECISION-MAKING CAPACITY
I
n the clinical setting, capacity refers to patients’ ability to make informed
decisions regarding their care. The exercise of this autonomy is a pillar of
ethical medical practice and critical to both informed consent and informed
refusal; it is, therefore, a cornerstone of the patient-clinician relationship.1–3
In addition to requiring that the patient have decision-making capacity,
autonomous medical decision making (and therefore proper informed consent or
refusal) requires that the clinician disclose the risks and benefits of the proposed
intervention and any alternatives to the recommended intervention with their
attendant risks and benefits. The patient must then be allowed to make a choice
free from undue influence or coercion.1,4 Whereas medical decision-making

DECISION-MAKING CAPACITY IN DEMENTIA
capacity is a medical judgment made by physicians, competency is a legal term

referring to a person’s ability to participate in legal proceedings (eg, to stand
trial) as determined by a judge, sometimes based on physicians’ evaluations.2,5
Neurologists may be called upon to assess other domains of capacity aside from
medical decision-making capacity, including the patient’s capacity to drive,
manage finances, engage in advanced care planning, or vote, but these and other
types of capacity assessments are beyond the scope of this article.
According to Appelbaum and colleagues,1 to possess medical decision-making
capacity, a patient must demonstrate four abilities: (1) the ability to
communicate a consistent choice, (2) the ability to demonstrate adequate
understanding of relevant information the clinician has provided, (3) the ability
to appreciate how the information applies to the particular situation, and (4) the
ability to reason through the choices to make a decision. Based on this
formulation, Chow and colleagues6 proposed the mnemonic CURVES as a way to
remember the four elements of medical decision-making capacity:
u C: Choose and Communicate. The patient must be able to communicate a consistent choice.
u U: Understand. The patient must be able to express an adequate
understanding of the risks, benefits, alternatives, and consequences.
u R: Reason. The choice must logically follow from this understanding (ie, be reasonable).
u V: Value. The choice must follow the patient’s expressed value system.
u E/S: Emergency/Surrogate. In emergency situations when no surrogate decision maker is
available, lifesaving or limb-saving interventions may be performed for a patient who
lacks capacity.
While no agreed-upon consensus exists for how these abilities should be

assessed,4 several standardized clinical rating scales are used regularly in both
clinical practice and research settings, including the MacArthur Competence
Assessment Tool for Treatment (MacCAT-T), the Capacity to Consent to
Treatment Instrument (CCTI), and the Hopemont Capacity Assessment
Interview (HCAI).7 The use of a structured instrument can reduce interrater
inconsistencies in medical decision-making capacity evaluations of patients
with Alzheimer disease (AD).8 For patients with mild or moderate AD, the
MacCAT for Clinical Research (MacCAT-CR) was found to adequately assess
capacity to enroll in early-stage AD research.9 Even in more advanced AD states,
patients may maintain the capacity to appoint a proxy for research decisions,
potentially enabling them to engage in studies.10 General day-to-day medical
decision-making capacity in the elderly with cognitive impairment may be
assessed via use of the Assessment of Capacity for Everyday Decision-Making
(ACED).11
Assessment of a patient’s capacity is implicitly part of every informed consent
process, ie, every decision regarding either medical treatment or participation
in research is, to varying degrees, based on the complexity and potential
consequences of the decision.5,12 For example, the decision to agree to a course of
physical therapy requires an assessment of capacity but requires less discussion
and assessment than the decision to agree to brain surgery. Likewise, the patient
may retain medical decision-making capacity for some simple, less intrusive
interventions but lack medical decision-making capacity for more complex or
more high-risk interventions. Additionally, capacity may change over time. A
922 JUNE 2018

patient may lack all decision-making capacity when delirious but regain capacity
when the condition resolves.13 Thus, a patient’s medical decision-making
capacity should not be conceived as all or nothing but rather as existing on a
continuum that should be assessed on a decision-by-decision basis.5 The personal
experience of the authors is that too often patients’ capacity to consent is not
seriously questioned until the patient disagrees with the recommendation of the
treating clinician.
It is the duty of the treating clinician—the clinician interacting with the
patient and ordering, overseeing, and performing the intervention (including
ordering a medication, not just performing an invasive procedure)—to inform
the patient about the condition, the risks and benefits, and alternatives to the
proposed intervention and to evaluate the patient’s capacity to consent to
treatment.12 State law determines the amount of information required according
to standards of “reasonable professional” (what information a reasonable
professional would provide based on standard of care), “reasonable patient”
(what information an average reasonable patient would want to know), or
“particular patient” (what information this particular patient would want to
know based on his or her expressed values), or some hybrid of the three.3 Since
treating clinicians are the most informed regarding the indications, risks,
benefits, and alternatives to a proposed intervention, they are the most
appropriate providers to perform this assessment.
Often, psychiatrists or psychiatry consult liaison services are called upon to
assess a patient’s capacity. Psychiatric consultation is generally not obligatory
and is only appropriate after the primary clinician has attempted to make this
assessment and is seeking a second opinion to ensure best care for the patient.
Relying solely on a psychiatrist for the assessment of capacity is inappropriate,
since a psychiatrist would not have the specialty training to fully discuss all
interventions or assess if the patient’s understanding of the intervention, its
risks and benefits, and the possible alternatives is adequate.
If the patient is found to lack medical decision-making capacity, efforts should
be made to determine if an advance directive document (eg, living will, health
care power of attorney, physician orders for life-sustaining treatment, or legal
guardianship) outlining the patient’s wishes for care or selection of a surrogate
decision maker is available. If such a document is not available, then the duty of
surrogate decision maker generally defaults to the next of kin in a hierarchy
that varies somewhat by state but typically has the patient’s spouse at the top,
followed by adult children, then parents, siblings, and other family members.14
In some states, the hierarchy for medical decision making varies slightly from the
hierarchy for end-of-life decision making, so clinicians should be aware of the
laws in their own states.
Neurologists encounter many conditions that can be reasonably expected to
affect a patient’s medical decision-making capacity. Focal lesions (eg, strokes)
or neurodegenerative disorders (eg, primary progressive aphasia) affecting
language networks can limit the patient’s ability to communicate or understand
information. In these situations, multiple communication approaches should
be tried. For example, a patient in a locked-in state may still maintain medical
decision-making capacity if a reliable communication approach is developed
through the patient’s blinking. Anosognosia, a consequence of a variety of
conditions, may limit patients’ understanding or ability to appreciate how the
information provided applies to them. Lack of reality testing, seen in patients

DECISION-MAKING CAPACITY IN DEMENTIA
with delusions, may impair the patient’s ability to understand how the
medical facts apply to his or her current circumstances and logically reason in
a manner consistent with previously expressed values. Finally, a patient’s ability
to reason may also be limited by any number of neuropsychiatric disorders
affecting frontal or cerebellar networks and associated cortical-subcortical
circuits.
CASE DISCUSSION
Neurocognitive disorders inherently jeopardize medical decision-making
capacity, and neurodegenerative diseases, including AD, inevitably reduce the
patient’s medical decision-making capacity over time by eroding the rational
autonomous self.2 In one study, 60% of patients with mild to moderate AD were
found to lack medical decision-making capacity regarding AD treatment.15
Nevertheless, no diagnosis is, in itself, a determination of capacity. Likewise,
performance on a cognitive screening test such as the Mini-Mental State
Examination (MMSE) is not, in itself, a determination of capacity. In AD,
capacity can be gradually affected by the progressive amnesia characteristic of
the disorder. If a patient is unable to remember the necessary details of the
proposed intervention, the patient will be unable to demonstrate adequate
understanding of these details. Additionally, the neuropsychiatric symptoms that
commonly complicate AD (eg, apathy, anxiety, depression, delusions) may
intrude on the patient’s decision making.16 Indeed, as in this case, delusions of
infidelity and emotional distress were presenting features of Dr Alois
Alzheimer’s seminal case for the disorder that bears his name.16
In the case presented, the patient was able to communicate a consistent choice,
demonstrate adequate understanding of the relevant information provided by
her surgeon, and demonstrate an appreciation of how the information applied to
her in her situation. Despite these abilities, the primary treating team believed
that she lacked medical decision-making capacity because she refused a
life-sustaining intervention. The psychiatry consultant agreed that she lacked
capacity for this decision because the patient’s decision was not reasonable as it
did not logically follow from an integration of the clinical information and her
stated values. The psychiatry consultant felt that delusions of infidelity unduly
influenced the patient’s decision, and therefore she lacked capacity to make this
decision. This determination of the reasonableness of the decision is up to the
clinical judgment of the clinician. Up until this point (the point at which she
refused treatment), her decision-making capacity had neither been seriously
questioned nor rigorously assessed. Indeed, in this case, the primary team never
discovered the delusional thought process; the critical failing on the patient’s
part, from their point of view, was that she refused the surgeon’s proposed
intervention. (It should be noted that agreeing with the clinician is not a required
component of capacity.)
All patients should be educated regarding the importance of having a living
will (an advance directive to physicians) and appointing surrogate decision
makers in the event of incapacity, and clinicians should encourage patients to
update these documents regularly. In neurodegenerative diseases, completion of
these documents early in the disease course is especially important. Additionally,
formally granting medical power of attorney (which is distinct from power of
attorney for finances and often mental health power of attorney) to a trusted
person while capacity is intact is extremely prudent in these disorders.
924 JUNE 2018

CONCLUSION
The assessment of medical decision-making capacity is an essential component of
ethical medical practice and should be part of every medical decision to varying
degrees, based on the complexity and potential consequences of the decision.
Capacity exists on a spectrum, and neurocognitive disorders can affect medical
decision-making capacity and pose special challenges to its assessment. Capacity
assessment is within the scope of practice of all physicians, although many
physicians are not adequately trained to assess capacity and are poorly versed in
the relevant laws regarding this assessment in their state. Neurologists, however,
routinely care for patients with neurocognitive disorders and must consider
capacity assessment a routine facet of care for cognitively impaired patients.
Psychiatry consultation for medical decision-making capacity assessment can be
helpful in challenging situations, especially when the patient exhibits psychiatric
symptoms that may influence decision-making capacity, but need not be relied
upon as the sole determinant of decision-making capacity.
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429–501. doi:10.1177/009885880603200401. decision-making ability in older persons with
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4 Siegel AM, Barnwell AS, Sisti DA. Assessing
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decision-making capacity: a primer for the
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s10730-014-9234-8. theory and clinical practice. 2nd ed. New York,
NY: Oxford University Press, 2001.
5 Ganzini L, Volicer L, Nelson WA, et al. Ten myths
about decision-making capacity. J Am Med Dir 13 Auerswald KB, Charpentier PA, Inouye SK. The
Assoc 2004;5(4):263–267. doi:10.1097/01. informed consent process in older patients who
JAM.0000129821.34622.A2. developed delirium: a clinical epidemiologic
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doi:10.1016/j.jalz.2012.12.001.

PRACTICE ISSUES
Coding for Behavioral
Neurology and Psychiatry
By Raissa Villanueva, MD, MPH, FAAN; Bruce H. Cohen, MD, FAAN
ABSTRACT
Medical coding is highly technical, and proper use of both Current
Procedural Terminology (CPT) and the International Classification of
Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) is difficult
because of the considerable detail of the code definitions, the changes
implemented yearly, and the vast change a few years ago with the
transition to ICD-10-CM. Although basic office visit and hospital visit
Evaluation and Management (E/M) codes have not changed in decades,
CITE AS: new cognitive care codes have been added to the cognitive codes that fall
under E/M. Accuracy in documentation is essential as the basis for
AND PSYCHIATRY):926–935. precision in coding, which will result in both best practice and proper
payment from payers.
Dr Raissa Villanueva, University of
Rochester Medical Center
Neurology, Westfall Road
Building C, Suite 220, Rochester, INTRODUCTION
C
NY 14618, Raissa_Villanueva@ urrent Procedural Terminology (CPT) codes are published annually
URMC.Rochester.edu.
and maintained by the American Medical Association’s CPT
RELATIONSHIP DISCLOSURE: Editorial Panel.1 The CPT code set describes all tests, surgeries,
Dr Villanueva reports no evaluations, and procedures that may be performed on a patient
disclosure. Dr Cohen serves on
the board of directors of the
by a health care provider. It is an integral part of billing because it
Mitochondrial Medicine Society, tells the insurance payer what is to be reimbursed. The International Classification
on the board of trustees of the of Diseases, Tenth Revision (ICD-10) is written and maintained by the World
United Mitochondrial Disease
Foundation, and on the editorial Health Organization2; the expanded version of this code set used in the
boards of Mitochondrion, Brain & United States is called the International Classification of Diseases, Tenth Revision,
Life, and Pediatric Neurology. Clinical Modification (ICD-10-CM).3 On October 1, 2015, ICD-10-CM became
Dr Cohen serves as a consultant
for Stealth BioTherapeutics Inc effective for all Health Insurance Portability and Accountability Act
and receives research/grant (HIPAA)–covered entities, and, although it has been 3 years since the
support from BioElectron
Technology Corporation;
introduction of ICD-10-CM, clinicians are still becoming acquainted with the
Horizon Pharma plc; the elements of proper use.
National Institutes of Health The two components of the coding process are the selection of diagnosis codes
(subaward 8; GG006326-03);
Reata Pharmaceuticals, Inc; and
from ICD-10-CM and the selection of the proper CPT codes. Although neurologists
Stealth BioTherapeutics Inc. perform some procedural coding, most of the care delivered for cognitive
Dr Cohen receives publishing conditions is represented by the CPT Evaluation and Management (E/M) codes.
royalties from Elsevier.
The three types of codes in CPT have different uses and payment rules.
UNLABELED USE OF Category I codes are the most common type of code and can be thought of as
the codes representing standard and well-accepted medical interventions. The
USE DISCLOSURE:
Drs Villanueva and Cohen report Category I codes do not change year to year and are considered permanent codes,
no disclosures. although even these codes must be rewritten when technology and medical
practice change. For approval, Category I codes require widespread use, US Food
of Neurology. and Drug Administration (FDA) approval for a device if the code requires a
926 JUNE 2018

device, and US or other high-quality evidence, published in peer-reviewed
literature. Almost all Category I codes are reimbursed by insurance companies,
although two main exceptions to this statement exist: cosmetic surgeries and
consultation codes not reimbursed by Medicare. Category I codes used by
neurologists include inpatient and outpatient office and hospital services (E/M)
as well as procedural codes for EEG, EMG, and injections. Category II codes
are supplemental tracking codes that are used to look at performance measures
and management. Category III codes are temporary codes that describe emerging
and experimental technologies, services, and procedures. For procedures and
devices, the technology must be FDA approved (as with Category I codes) but
may not be widely available to US physicians, may lack adequate literature, or
may be considered too new for a permanent code. Category III codes have a
5-year time limit; after 5 years, they will be replaced by a Category I code or
removed from the CPT book.
The “G” codes represent a different code set known as the Healthcare
Common Procedure Coding System (HCPCS), which is maintained by the Center
for Medicare & Medicaid Services (CMS).4 This is a separate code set that
includes services not in CPT, such as medical supplies and durable medical
equipment when used outside of a hospital or physician’s office. It is important
to understand that HCPCS G codes are not diagnostic ICD-10-CM codes
beginning with the letter G; they are two very different code sets. The HCPCS G
codes are E/M or procedural codes, similar to CPT codes. They are generally
thought of as temporary codes that are not available in CPT. Reimbursement
decisions and the level of reimbursement for G code services are the decision of
the carrier. The CPT panel has a goal to eventually create a code to replace each
G code for services relevant to CPT. One such recent G code was G0505,
Cognition and functional assessment using standardized instruments with
development of recorded care plan for the patient with cognitive impairment,
history obtained from the patient and/or caregiver, in office or other outpatient
setting or home or domiciliary or rest home. G0505 code was replaced at the
beginning of 2018 with CPT code 99483. The full description of code 99483 is
as follows:
u Assessment of and care planning for a patient with cognitive impairment, requiring an
independent historian, in the office or other outpatient, home or domiciliary or rest home,
with all of the following required elements:
⋄Cognition-focused evaluation, including a pertinent history and examination

⋄Medical decision making of moderate or high complexity
⋄Functional assessment (eg, basic and instrumental activities of daily living) including
decision-making capacity
⋄Use of standardized instruments to stage dementia (eg, functional assessment staging

test [FAST], clinical dementia rating [CDR])
⋄Medication reconciliation and review for high-risk medications

⋄Evaluation for neuropsychiatric and behavioral symptoms, including depression,
including use of standardized screening instrument(s)
⋄Evaluation of safety (eg, home), including motor vehicle operation

⋄Identification of caregiver(s), caregiver knowledge, caregiver needs, social supports,
and the willingness of caregiver to take on caregiving tasks
⋄Development, updating or revision, or review of an Advance Care Plan

CODING FOR BEHAVIORAL NEUROLOGY AND PSYCHIATRY
⋄Creation of a written care plan, including initial plans to address any neuropsychiatric
symptoms, neurocognitive symptoms, functional limitations, and referral to community
resources as needed (eg, rehabilitation services, adult day programs, support groups)
shared with the patient and/or caregiver with initial education and support
⋄The service period for G0505 is not stated and is, therefore, a carrier-based decision.
G0505 should be used only as a stand-alone code, meaning the visit would result only in
generating this one code. This service cannot be reported along with the following
codes: 90785, 90791, 90792, 92610, 96103, 96120, 96127, 99201–99215, 99324–99337,
99341–99350, 99366–99368, 99497, 99498, 99374, G0181, G0182, and GPPP7
ICD-10-CM CODING FOR DEMENTIA

ICD-10-CM coding for dementia is complex. The first code that must be listed
is considered the etiology code, the second is the manifestation code, and the
third describes sequelae, if applicable.
The etiology code is the best estimate of the underlying physiologic
condition. In ICD-10-CM, etiology codes fall under the rule of “code first,” and
include (but are not limited to) disorders such as G30, Alzheimer’s disease, and
G31.83, Dementia with Lewy bodies. However, sometimes the etiology is not
known, in which case the less-specific manifestation codes listed in the code
section F03, Unspecified dementia, would be acceptable for the etiology code.
Manifestation codes consist of the following:
u F01, Vascular dementia: The first etiology code includes the underlying physiologic
condition or sequelae of cerebrovascular disease
u F02, Dementia in other diseases classified elsewhere: The first etiology code could include
Alzheimer’s, Creutzfeldt-Jakob disease, dementia with Lewy Bodies, frontotemporal
dementia, or others
u F03, Unspecified dementia: This code is unique, because it can be a stand-alone code
without having an associated etiology code listed first
If the dementia has an identified cause, such as could occur in long-standing

untreated vitamin B12 deficiency or thiamine deficiency, it is proper to list the
etiology code first, for example, E53.8, Deficiency of other specified B group
vitamins, before the dementia code F02.80, Dementia in other diseases classified
elsewhere without behavioral disturbance, or F02.81, Dementia in other diseases
classified elsewhere with behavioral disturbance.
One major challenge for neurologists and other physicians practicing in the
area of cognitive diseases is coding for all services rendered. Although codes for
ambulatory visits cover face-to-face services, behavioral neurologists perform
tasks that are beyond the scope of typical E/M code structure. Financial
reimbursement for patients with behavioral conditions is dependent on E/M
services, which, in general, are reimbursed at a lower rate per time spent
delivering the service compared with procedural codes. Visits with patients with
behavioral conditions may require more time than the typical E/M services
provided for some other neurologic conditions because of complicated comorbid
diseases, the need for standardized instruments for cognitive testing, functional
assessment, and the caregiver’s own cognitive or medical impairment that
may impact on their ability to be an active participant in the treatment.
Decision-making capacity and end-of-life issues may be pertinent. Evaluation
of behavioral and neuropsychiatric symptoms, safety in the home, and social
support issues can dominate the patient visits. Although these issues alone can
take the required time to increase the level of service to any level 5 ambulatory
928 JUNE 2018

visit based on the counseling and coordination of care billing requirements, the
time generally will go beyond the time allotment for the total duration of visit
(40 minutes for 99215 or 60 minutes for 99205, the CPT codes for established
[also referred to as follow-up] and new patient level 5 visits).
In 2017, the current three chronic care management codes were introduced
(CODING TABLE 1) and, as noted previously, CMS introduced code G0505,
which was replaced in 2018 with CPT code 99483. These codes are specifically
for behavioral/cognitive visits where the requirements for using the code are
essential but fall outside that of typical office E/M.
CASE
A 74-year-old woman with Parkinson disease returned for a scheduled
6-month established-patient neurologic visit accompanied by her husband.
She denied any specific issues during the visit, but her husband reported
new cognitive changes. He had noticed her becoming forgetful about what
was said during recent conversations and repeating questions often. She
also repeated stories to the same person on the same day. Her self-care had
also started to deteriorate. She used to be well dressed and took time to put
on makeup and dress up, but she no longer took the time to do this. She had
lost interest in hobbies such as knitting and playing mah-jongg. She had a
history of hypertension, hyperlipidemia, and prior myocardial infarction,
with stents placed. She did not smoke, drink alcohol, or use illegal drugs.
She was taking rosuvastatin, aspirin, metoprolol, and carbidopa/levodopa
two tablets 3 times a day and had no medication allergies.
Her physical examination was normal, with a normal heart rate and
rhythm and no carotid bruits. Her Montreal Cognitive Assessment (MoCA)
score was 20/30, with points lost for trail making, cube drawing, clock
drawing (she did not draw the numbers on the clock correctly), recall of
five objects, and inability to state month and date. The 25-point
single-system neurologic examination (1997 version) was completed and
demonstrated normal cranial nerves, motor strength, sensation,
coordination, and reflexes. She had a pill-rolling tremor in the right hand
with decreased arm swing on the right with casual gait and decreased
finger tapping on the right. She had some rigidity in the right arm only.
The patient was diagnosed with a dementia. Brain MRI and routine
laboratory studies were ordered, including vitamin B12 and thyroid-stimulating
hormone (TSH) levels and Venereal Disease Research Laboratory (VDRL)
test. No change was made in her medication for Parkinson disease at this
follow-up visit.
DISCUSSION
Although this patient presented with a new neurologic problem, she was known
to the physician and, despite the complexity of the visit, must be coded as an
established patient. The E/M code choices for such a patient would include the
CPT codes 99211 to 99215. For such a complex visit, the code choice of 99215
(high complexity established patient visit) may be the best choice given the
nature of the primary symptom, which is a significant change necessitating
a comprehensive history and comprehensive neurologic single-system

examination, with the medical decision likely qualifying as high complexity. The
full description of code 99215 is as follows:
u 99215, Office or other outpatient visit for the evaluation and management of an established
patient, which requires at least 2 of these 3 components:
⋄A comprehensive history;
⋄A comprehensive examination;
⋄Medical decision making of high complexity.
u Counseling and/or coordination of care with other physicians, other qualified health care
professionals, or agencies are provided consistent with the nature of the problem(s) and
the patient’s and/or family’s needs.
u Usually the presenting problem(s) are of moderate to high severity. Typically, 40 minutes are
spent face-to-face with the patient and/or family.
Because the primary symptom reported in this follow-up appointment is new

cognitive symptoms, one could decide not to use the 9921x code choices but
instead use the new 99483 code for billing, as long as documentation of the
required elements is completed.
Alternatively, because the time required to complete the elements of 99483
is substantial and may exceed what the physician’s schedule allows that day,
another visit could be made in the near future to perform the elements of
99483. In the case presented, the physician decided to complete the elements
necessary for a 99215 visit; because only 30 minutes of time was available, a
comprehensive history was taken, and comprehensive examination
CODING TABLE 1 Current Procedural Terminology Chronic Care Management Codes
Code Description Required Elements

99490 Chronic care management services, Multiple (two or more) chronic conditions
at least 20 minutes of clinical staff expected to last at least 12 months or until
time directed by a physician or other qualified the death of the patient
health care professional per calendar month
Chronic conditions place the patient at
significant risk or death, acute
exacerbation/decompensation, or
functional decline
Comprehensive care plan established,

implemented, revised, or monitored
99487 Complex chronic care management See 99490, except time spent must be at
services of at least 60 minutes of clinical least 60 minutes in a month; medical
staff time directed by a physician or other decision making must be of moderate to
qualified health care professional, per high complexity
calendar month
99489 Each additional 30 minutes of clinical staff NA

time directed by a physician or other qualified
health care professional per calendar month
NA = Not applicable.
CPT © 2017 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
930 JUNE 2018

completed, which are the elements necessary to submit a level 5 established patient
code (CPT code 99215). The physician did not feel there were elements necessary
for a determination of high-complexity medical decision making because there
were simply not enough diagnostic or management options, or a high level of
complexity of data review that would support a level 5 E/M code, despite the
devastating nature of the suspected illness. Because established patients require
the highest level of only two of the three elements (history, examination, and
medical decision making), the 99215 code was justified because of the
comprehensive history collected and examination performed.
The ICD-10-CM code choices for this visit included F03.90, Unspecified
dementia without behavioral disturbance, and G20, Parkinson’s disease. When
dementia is known but the etiology is not, the ICD-10-CM code best used is
F03.90, Unspecified dementia without behavioral disturbance; at the time of this
initial visit for this new symptom, the data to further classify the dementia were
not available. G20, Parkinson’s disease, was chosen because that condition was
also part of the total medical decision making.
CASE CONTINUED
The patient was scheduled for follow-up to review the test results and
further discuss her diagnosis and also to include further dementia
assessment and care planning. Her husband and other family members
were present at the follow-up visit. Given the time needed to further
evaluate her cognitive symptoms in this visit, additional time
was scheduled.
The laboratory results from the previous visit were discussed with the
patient; complete blood cell count, complete metabolic panel, vitamin B12
level, TSH, lipid panel, and VDRL test were all normal. The results were not
diagnostic of any medical illness that would explain the dementia. The MRI,
which showed generalized atrophy, multiple chronic infarctions, and
moderate small vessel disease, was also reviewed with the patient and
her family.
DISCUSSION CONTINUED
Given the patient’s history of cardiac stent placement and vascular risk factors of
hypertension and hyperlipidemia, a vascular etiology for her dementia
could be assumed. Therefore, when choosing the diagnosis codes for the second
follow-up visit, the etiology code would be related to the multiple strokes that
were found on MRI, and the manifestation code would be F01.50, Vascular
dementia without behavioral disturbance. CODING TABLE 2 lists ICD-10-CM
codes for vascular dementia and dementia in other diseases, and CODING TABLE 3
lists ICD-10-CM codes for other common cognitive dementia syndromes. The
purpose of this follow-up visit was to perform the elements necessary to develop
a better idea of the nature of her disability and develop a care plan, as specified
in the 99483 code requirements. The following elements were performed
and documented.
Moderate or High Complexity in Medical Decision Making

Complexity of medical decision making is the driving factor when deciding on
the complexity of the visit. Three components contribute to establishing the level

of complexity of medical decision making as straightforward, low complexity,

moderate complexity, or high complexity: the number of diagnosis or management
options; the amount or complexity of data to be reviewed; and the risk of
complications, morbidity, or mortality. In this case, the patient had vascular
risk factors for stroke in addition to Parkinson disease and the new diagnosis
of dementia; therefore, this case easily falls into the category of high complexity
based on satisfying two out of three of the components: the number of diagnoses/
management options and risk of complications/morbidity/mortality. A functional
assessment of the patient, including decision-making capacity, should be
performed, including asking about activities of daily living and instrumental
activities of daily living.
Use of Standardized Instruments to Stage Dementia

In this case, the Montreal Cognitive Assessment (MoCA) was used at the
follow-up visit, and the patient’s score of 20/30 was the same as when she
first presented with cognitive symptoms, which indicates dementia rather than
just mild cognitive impairment.
Medication Reconciliation/Review
A review of the patient’s current medications and possible medication
interactions or contributors to cognitive impairment was performed. The
medications available to treat this form of dementia were discussed with the family;
several experimental protocols family members found online were also
discussed. In the end, the decision was made to start rivastigmine, with the most
common side effects and benefits discussed.
Evaluation of Neuropsychiatric and Behavioral Symptoms

Providers should ask about depression, anxiety, and mood changes during
the initial visit for cognitive deficits and follow-up visits. For example, the
Generalized Anxiety Disorder Scale (GAD-7) is a seven-item questionnaire that
screens for anxiety, and the Beck Depression Inventory (BDI) can be used as a
screening tool for depression. Both these questionnaires are self-reported and can
CODING TABLE 2 ICD-10-CM Codes for Vascular Dementia and Dementia in Other Diseasesa
Code Description
F01.50 Vascular dementia without behavioral disturbance
F01.51 Vascular dementia with behavioral disturbance
F02.80 Dementia in other diseases classified elsewhere without behavioral disturbance
F02.81 Dementia in other diseases classified elsewhere with behavioral disturbance
F03.90 Unspecified dementia without behavioral disturbance
F03.91 Unspecified dementia with behavioral disturbance
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

a
The codes F01, F02, and F03 are not billable codes; digits to the right of the decimal must be included as indicated.
932 JUNE 2018

be completed by the patient during the follow-up visit to screen for anxiety
(GAD-7) and depression (BDI).
Safety Evaluation
Driving and safety issues in the home should be assessed, and caregiver input
or collateral history may be needed for this assessment. In this case, the
patient’s husband felt that he could handle all her safety issues, and when
he needed to be away from home, his children could stay with the patient to
ensure safety. The patient quit driving 4 years ago after a friend was involved
in a tragic accident.
Caregiver Needs
The ability of the caregiver to address ongoing and future needs of the patient
based on the patient’s current activities of daily living, instrumental activities
of daily living, and overall level of functioning and stage of dementia should
be assessed. In this case, time was spent with the family addressing these
issues and providing resources for additional support to the family to deal with
the impairment of activities of daily living and instrumental activities of
daily living.
ICD-10-CM Codes for Alzheimer Disease, Frontotemporal Dementia, CODING TABLE 3

Dementia With Lewy Bodies, Primary Progressive Aphasia, Corticobasal
Degeneration, and Mild Cognitive Impairment
Code Description
G30.0 Alzheimer’s disease with early onset
G30.1 Alzheimer’s disease with late onset
G30.8 Other Alzheimer’s disease
G30.9 Alzheimer’s disease, unspecified
G31.0 Frontotemporal dementia
G31.01 Pick’s disease

Primary progressive aphasia
Progressive isolated aphasia
G31.09 Other frontotemporal dementia

Frontal dementia
G31.1 Senile degeneration of brain, not elsewhere classified

G31.83 Dementia with Lewy bodies
Dementia with Parkinsonism
Lewy body dementia
Lewy body disease
G31.84 Mild cognitive impairment, so stated

G31.85 Corticobasal degeneration
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

Palliative Care Needs

Discussions around end-of-life issues, advance directives, and wishes of patients
should occur before the later stages of dementia affect their capacity to make
these decisions. This patient had already signed health care proxy and living will
statements, which the husband brought to the visit so they could be placed in
her electronic medical record.
Care Plan
A care plan that includes community resources, education, and caregiver and
patient support resources should be put into place. In this case, the physician
gave the family a list of these resources and the phone number of the social
worker who supported the practice.
Coding for Second Visit

The coding for this follow-up visit would include code 99483 when all the
eight elements above were documented in the visit and the following
ICD-10-CM codes:
u F01.50, Vascular dementia without behavioral disturbance

u I69.310, Attention and concentration deficit following cerebral infarction
u I69.311, Memory deficit following cerebral infarction
u I69.312, Visuospatial deficit and spatial neglect following cerebral infarction
Since Parkinson disease management, hypertension, and hyperlipidemia were

not specifically addressed in the follow-up visit, it is not listed in the ICD-10-CM
coding for this visit.
CONCLUSION
The historical limitations of the available CPT codes that define the services
rendered by neurologists for patients with dementia has created an economic
barrier for caring for these vulnerable patients. The addition of the 99483 code
has created a reimbursement model that accounts for the work performed by the
neurologist in developing the data set to assist in the diagnosis and management
plan for patients with dementia. This code and the subsequent development of
other CPT codes help define the complexity and comprehensive work performed
by neurologists on behalf of their patients. The old concept that E/M is only
face-to-face work is being replaced so that other value-added work performed by
clinicians can be accounted for and reimbursed. As the etiology of a patient’s
dementia is identified, the choice of ICD-10-CM codes may change between
visits. The underlying cause of the dementia (or other associated conditions),
once identified, should be listed first, with the manifestations, including
dementia, as necessary secondary codes. If the underlying etiology is not known
or cannot be determined, codes from the F03 set are acceptable as a primary
ICD-10-CM code.
934 JUNE 2018

REFERENCES
1 American Medical Association. Current 4 Centers for Medicare & Medicaid Services.
procedural terminology (CPT) 2017. Chicago, IL: HCPCS Level II Coding Process & Criteria. cms.
American Medical Association Press, 2017. gov/Medicare/Coding/MedHCPCSGenInfo/
HCPCSCODINGPROCESS.html. Updated
2 World Health Organization. ICD-10 Version. 2016.
September 30, 2013. Accessed March 29, 2018.
apps.who.int/classifications/icd10/browse/
2016/en. Accessed March 29, 2018.
3 Centers for Disease Control and Prevention.
National Center for Health Statistics.
International classification of diseases, tenth
revision, clinical modification (ICD-10-CM). cdc.
gov/nchs/icd/icd10cm.htm#FY%202018%
20release%20of%20ICD-10-CM. Updated
August 18, 2017. Accessed March 29, 2018.

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(Section 3) as defined by the Maintenance of Certification 15 A B C D E 35 A B C D E
Program of the Royal College of Physicians and Surgeons
of Canada and approved by the Office of Continuing 16 A B C D E 36 A B C D E
Medical Education and Professional Development,
University of Calgary, on April 1, 2017. Refer to the CME 17 A B C D E 37 A B C D E
tab on ContinuumJournal.com for dates of accreditation.
Canadian participants should visit MAINPORT 18 A B C D E 38 A B C D E
(www.mainport.org) to record learning and outcomes.
Canadian participants can claim a maximum of 20 hours
(credits are automatically calculated).
For all questions regarding Continuum CME, email
ContinuumCME@aan.com or call (612) 928-6161.

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment
and CME Test
By James W. M. Owens Jr, MD, PhD; Allison L. Weathers, MD, FAAN
BEHAVIORAL NEUROLOGY AND PSYCHIATRY

The Continuum Postreading Self-Assessment and CME Test is an integral
part of the issue that is intended to stimulate thought and help participants
assess general understanding of the material presented in this issue. The
Postreading Self-Assessment and CME Test is also approved by the
American Board of Psychiatry and Neurology (ABPN) to meet the Lifelong
Learning (CME), Self-Assessment (SA) (part 2) component for Maintenance
of Certification.
For each item, select the single best response. A tally sheet is provided
with this issue to allow the option of marking answers before entering them
online at continpub.com/CME. Nonsubscribers who have purchased single
back issues should email ContinuumCME@aan.com for instructions to
complete this test online.
Upon the completion of the Postreading Self-Assessment

US PARTICIPANTS:
and CME Test and issue evaluation online at continpub.com/CME,
participants may earn up to 20 AMA PRA Category 1 CreditsTM toward
SA-CME. US participants have up to 3 years from the date of publication
to earn SA-CME credits. No SA-CME will be awarded for this issue after
June 30, 2021.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

Program (Section 3) as defined by the Maintenance of Certification
Program of the Royal College of Physicians and Surgeons of Canada and
approved by the Office of Continuing Medical Education and Professional
Development, University of Calgary, on April 1, 2017. Refer to the CME
tab on ContinuumJournal.com for dates of accreditation. Canadian
participants should visit MAINPORT (mainport.org) to record learning
and outcomes. Canadian participants can claim a maximum of 20 hours
(credits are automatically calculated).

POSTREADING TEST
ARTICLE 1: BEDSIDE APPROACH TO THE MENTAL STATUS ASSESSMENT
1 The family of a 62-year-old man being evaluated for memory problems

reports that his first noted symptom was an inability to recognize
familiar people at church. Which of the following disorders is most
suggested by this historical feature?
A Alzheimer disease
B corticobasal syndrome
C dementia with Lewy bodies
D semantic dementia variant of frontotemporal dementia
E vascular cognitive impairment
2 A patient with damage to the dominant inferior parietal lobule would be

expected to have difficulty with which of the following cognitive domains?
A attention
B calculations
C episodic memory
D semantic knowledge
E task setting
3 A 50-year-old right-handed man is being evaluated for the recent onset

of difficulty in “making sense of what he sees.” For the past month,
his family has noted that he tends to see only one object at a time (eg,
seeing the spoon but not the knife or the plate next to it). This symptom
started fairly suddenly but has not changed significantly over time and
does not wax and wane. On examination, the patient is unable to discern
numbers in any Ishihara plates, although he sees individual dots of
different colors. His visual acuity and visual fields appear normal. He is
unable to shift his gaze to objects of interest in the environment and has
difficulties initiating saccades to command. Instead, he has to turn his
head in the direction the examiner instructed. In contrast, the
oculocephalic reflex is intact. He also has impaired visually guided
hand movements as demonstrated by misreaching for objects. His
language function and memory appear to be normal by bedside
screening. He has no weakness or abnormalities of tone, and no
abnormal movements are noted. Which of the following underlying
processes most likely explains this patient’s cognitive dysfunction?
A corticobasal syndrome
B dementia with Lewy bodies
C left middle cerebral artery infarction
D progressive supranuclear palsy
E watershed infarctions
940 JUNE 2018

ARTICLE 2: CLINICAL ASSESSMENT OF PREFRONTAL LOBE FUNCTIONS
4 A 75-year-old man is brought by his family for evaluation because of

changes in his overall demeanor. The patient had always been socially
active and energetic but over the past year has seemed increasingly
apathetic and withdrawn. He spends his days just sitting in a reclining
chair in the living room and will not engage in anything unless directly
invited. However, when he does participate in his former favorite
activities, he seems to enjoy them. On examination, he is slow but
accurate in his responses to mental status questions. Despite 6 years of
post–high school education, he is unable to generate more than 5 words
that begin with the letter F in 1 minute. His motor strength and tone are
normal, as are his reflexes and sensation. Which of the following
prefrontal regions is predominantly implicated in this patient’s clinical
decline?
A frontopolar cortex
B left lateral prefrontal cortex
C orbitofrontal cortex
D right lateral prefrontal cortex
E superior medial prefrontal cortex
5 A 50-year-old physician is referred by his state’s licensing board for a

fitness for duty evaluation given increasing disruptive behavior. He had
no history of prior concerns about his professionalism. Over the past
year, multiple complaints had been lodged against him because of
sexually inappropriate behavior toward patients and staff. Previously
described as an even-tempered man, he now frequently flies into a rage
when faced with even minor inconveniences. On examination, he scores
30/30 on the Montreal Cognitive Assessment (MoCA) and his
neurologic examination is notable only for frequent sarcastic remarks
and sexually charged humor. Brain MRI reveals a frontal brain tumor.
Given his constellation of symptoms, what region of the frontal lobe is
most likely compromised by this mass?

POSTREADING TEST
6 A 74-year-old woman with dementia presents in follow-up with her

husband, who has been particularly bothered by the patient’s loss of
sympathy. She was once very sensitive to the emotions of others, often
noted to shed tears when a friend relayed a sad story or during especially
affecting movies. She now seems emotionally oblivious to those around
her. Recently she found her husband upset after the death of a close
friend and asked him why he was crying despite knowing about the loss.
Which of the following prefrontal regions is predominantly implicated
in these symptoms?
ARTICLE 3: MEMORY DYSFUNCTION
7 Which of the following types of memory refers to general knowledge of

people, objects, words, and concepts?
A autobiographical
B episodic
C nondeclarative
D semantic
E working
8 Which of the following processes is characteristic of consolidation?
A lists of items often being recalled in groups categorized by

similarity
B memories becoming less dependent on medial temporal lobe
structures over time
C pairing of an unconditioned stimulus with a conditioned stimulus
producing a conditioned response
D prior exposure to a stimulus altering later responses
E repeated nonreinforcement of a response leading to decreased
response strength
942 JUNE 2018

9 A 65-year-old man being evaluated for memory concerns is given the
Three Words-Three Shapes Test. On his fourth trial, he is only able to
correctly reproduce three of the six items, and this does not improve
with three additional presentations. After 15 minutes, he is able to recall
two of the six items. He correctly recounts autobiographical historical
information from several years ago. He is able to produce a normal
number of animal names in 1 minute. He also performs normally on
Serial 7s subtractions. He is alert and is oriented to person, place, and
time. Which of the following memory processes is most clearly
dysfunctional in this patient?
A attention
B consolidation
C encoding
D retrieval
E storage
10 A 37-year-old man with a long history of an alcohol use disorder is

brought to the emergency department after being found in his home
confused and unsteady. He was last seen 3 days ago. On examination, he
is afebrile and disorientated with ophthalmoparesis, nystagmus, and
severe gait ataxia. Brain CT is normal, and serum alcohol level is 0.
Thiamine supplementation leads to some improvement in his
neurologic function. However, the patient has persistent severe
anterograde and retrograde amnesia with confabulation. Damage to
which of the following neuroanatomic structures is most likely
involved in the patient’s amnestic syndrome?
A amygdala
B lateral temporal cortex
C mammillary bodies
D orbitofrontal cortex
E pulvinar
ARTICLE 4: PRIMARY PROGRESSIVE APHASIA AND STROKE APHASIA
11 Which of the following aphasia features is commonly seen in semantic

variant primary progressive aphasia?
A difficulty with repetition

B greater difficulty with concrete than abstract nouns
C no difficulty naming pictured objects
D particularly severe difficulty with number concepts
E profound agrammatism

POSTREADING TEST
12 A 67-year-old woman who lives alone is brought by her niece for

evaluation of difficulty speaking. She had no difficulty with speech
when her niece last saw her 1 week ago. On examination, her speech is
fluent with an impoverished vocabulary. She has particular difficulty
with confrontation naming of objects but relative preservation of
knowledge of what the object would be used for. Repetition is
significantly impaired. Her oral reading is relatively preserved, but she
is not able to express full understanding of what she reads. What
aphasia syndrome best fits this constellation of findings?
A conduction aphasia
B logopenic variant primary progressive aphasia
C nonfluent/agrammatic primary progressive aphasia
D semantic variant primary progressive aphasia
E Wernicke aphasia
13 A 68-year-old man with progressive difficulty in producing speech

sounds and who inserts oddly placed pauses into his speech stream
most likely has which of the following aphasia syndromes?
E Wernicke aphasia
14 A 55-year-old man is being evaluated for progressive difficulty with his

speech. His family describes his speech as slowed and hesitant, with
increasing problems finding the right word. On examination, his speech
output is around 90 words per minute, at times with significant pauses
and with speech sound substitutions. His repetition is severely
impaired, and he often engages in circumlocutions. He has severe
word-finding difficulties but improves with cueing. He does not have
difficulty with understanding single words. What aphasia syndrome
best fits this constellation of findings?
E Wernicke aphasia
944 JUNE 2018

15 A 62-year old woman has the acute onset of a speech disorder
characterized by omitting small morphemes such as was and a as well
as inflected endings such as -ed from both her speech and her writing.
This finding would best fit with which of the following aphasia
syndromes?
A Broca aphasia
B conduction aphasia
C logopenic variant primary progressive aphasia
E Wernicke aphasia
ARTICLE 5: APRAXIA, NEGLECT, AND AGNOSIA
16 Which of the following is the most appropriate first step in assessing a

patient for apraxia?
A ask the patient to assume a static body position

B ask the patient to pantomime a familiar movement by voice
command only
C demonstrate that the patient has intact comprehension
D have the patient copy a meaningless gesture
E perform a gesture and ask the patient to pantomime it
17 The phenomenon of allesthesia is best defined by which of the

following responses when a patient with neglect is asked to touch his or
her neglected limb?
A the patient will be able to follow the command only with his or her
eyes open, but not with them closed
B the patient will deny ownership of the affected limb
C the patient will report sudden pain in the affected limb
D the patient will touch the examiner’s limb rather than their own
E the patient will touch the stimulated location on the contralateral
side
18 Which of the following cortical regions supports the integration of

visual information to form an internal representation of an object?
A inferior occipitoparietal
B inferior occipitotemporal
C primary visual cortex
D superior calcarine fissure
E superior occipitoparietal

POSTREADING TEST
19 A 78-year-old man is brought to the emergency department by his

family because he has been unable to hear his family talking to him
since awakening this morning. He has a history of hypertension and
diabetes mellitus. He appears quite frightened. He can easily identify
and is bothered by the noises in the emergency department (eg, alarms
going off, telephones ringing, IV pole beeping) but is not able to
understand speech, despite being able to speak, read, and write when
asked. MRI of the brain is most likely to show restricted diffusion in
which of the following locations?
A left anterior temporal lobe

B left inferior temporal gyrus
C left superior temporal gyrus
D right inferior temporal gyrus
E right superior temporal gyrus
ARTICLE 6: AGGRESSION AND AGITATION IN DEMENTIA
20 A 78-year-old woman with Parkinson disease dementia is seen in

consultation for aggressive behavior. Over the past 2 months, she has
increasingly and unpredictably acted out against the staff of her
chronic care facility with biting, kicking, and scratching during routine
care. Recently, an attendant required stitches when the patient
lacerated her arm with a fork. The staff has introduced calming music
and differential reinforcement with only modest improvement. No
clear trigger has been elucidated. Which of the following medications
would be the most appropriate first choice pharmacologic treatment
of this patient’s aggression?
A fluoxetine
B lamotrigine
C olanzapine
D risperidone
E trazodone
946 JUNE 2018

21 A 74-year-old woman with Alzheimer disease is refusing meals with
increasing frequency. Her weight has begun to decline, although it
remains in an acceptable range for her height. The meals she refuses
are characterized by foods of a variety of types and textures and include
items known, in the past, to be her favorites. No clear diurnal pattern
is noted, with refusal of meals at different times of the day. Her only
medications at present are donepezil, memantine, furosemide, and
propranolol. Which of the following strategies would be best to
employ first?
A add lamotrigine
B add sertraline
C evaluate her swallowing
D increase her donepezil dose
E place a nasogastric tube
22 An 82-year-old man with Alzheimer disease has developed a delusion

that he is the head of a research lab in which the staff of his residential
facility are employed. He frequently demands status reports from his
caregivers regarding their experiments and resists any direction, given
that he is “in charge.” He has had no significant change in his general
medical condition. He is taking citalopram and donepezil. Which of
the following strategies would be recommended to deal with this
patient’s delusions?
A accept the delusion as the patient’s reality

B add gabapentin
C mild sensory deprivation
D stop citalopram
E stop donepezil
ARTICLE 7: MOOD DISORDERS
23 Which of the following proposed mechanisms of the pathophysiology

of mood disorders is unique to bipolar disorder?
A decreased hippocampal neurogenesis

B diversion of tryptophan metabolism toward the production of
quinolinic acid
C genetic polymorphisms on the GSK-3B gene
D reduced brain-derived neurotrophic factor (BDNF)
E reduced glucocorticoid receptor sensitivity

POSTREADING TEST
24 Polysomnography performed on a patient during a bipolar episode

would most likely reveal which of the following findings?
A average rapid eye movement (REM) density

B average sleep efficiency
C decreased rapid eye movement (REM) density
D prolonged rapid eye movement (REM) latency
E reduced rapid eye movement (REM) latency
25 Which of the following neurologic diseases has been associated with an

increase in suicidal ideation but not suicide attempts?
A epilepsy
B Huntington disease
C migraine with aura
D multiple sclerosis
E Parkinson disease
ARTICLE 8: OBSESSIVE-COMPULSIVE DISORDER
26 A 34-year-old man with a past medical history of generalized anxiety

disorder diagnosed at the age of 17 presents with a 9-year history of
thoughts of inadvertently hitting pedestrians while driving. Initially,
these thoughts only occurred as he was arriving to work in the morning
and back home in the evening, lasted only a few minutes, and were
associated with a compulsion to drive around his apartment and work
parking lot before parking and entering the buildings. Over the years,
his preoccupation with these thoughts has increased. He gets up hours
earlier to get to work on time and, with the exception of driving to
work and back home, he avoids leaving his house. He realizes his
concerns are irrational, but he is unable to stop himself from having
these thoughts or performing these behaviors. He is diagnosed with
obsessive-compulsive disorder. Which of the following characteristics
of this patient’s presentation is required for this diagnosis to be made?
A at least 5 years of symptoms prior to diagnosis

B existing diagnosis of generalized anxiety disorder
C insight into the irrational nature of his thoughts
D more than 1 hour spent per day on his obsessions and compulsions
E onset of his symptoms prior to the age of 25
948 JUNE 2018

27 A 27-year old-woman with no history of mood disorders has been on
sertraline for newly diagnosed obsessive-compulsive disorder for
6 weeks. Her dose was titrated over the 6 weeks to 200 mg/d. She
showed little motivation to participate in cognitive-behavioral
therapy; therefore, it was stopped after 2 weeks. She is not
experiencing any benefit from sertraline and asks to be switched to
clomipramine because it helped a friend of hers in her online
obsessive-compulsive disorder support group. What is the most likely
cause of this patient’s inadequate therapeutic response?
A absence of comorbid mood disorder

B early cessation of cognitive-behavioral therapy
C inadequate dosing
D inadequate length of treatment time
E lack of coadministration of an atypical antipsychotic
ARTICLE 9: PSYCHOSIS
28 A 35-year old-man with a 10-year history of schizophrenia has just

started a job training and placement program. His current symptoms
include believing that he is best friends with God and that he receives
messages directly from God through his microwave. He believes that
God appears and speaks directly to him when he is alone at night. He is
unable to express emotions and has poverty of speech. He also reports
poor memory, and, on limited formal neuropsychiatric testing, he
has moderate deficits in interpreting and remembering information.
Which of his symptoms is most likely to prevent him from successfully
completing the job program?
A auditory hallucinations
B delusions
C diminished emotional expression
D memory deficits
E poverty of speech
29 A patient with schizophrenia would be expected to be unimpaired on

which component of a mental status examination?
A attention
B episodic memory
C fine motor dexterity
D orientation
E problem solving

POSTREADING TEST
30 An 82-year-old woman with a 60-year history of schizoaffective

disorder presents with a several-month history of worsening
symptoms of psychosis, including new paranoid delusions, auditory
hallucinations, and decrease in spontaneous speech. She has not
changed her antipsychotic medication regimen in several years, and
her family assists her with her medications to ensure strict compliance.
Head CT and basic laboratory workup, including complete metabolic
profile, complete blood cell count, and urinalysis, are all nonrevealing.
Which of the following validated scales would be most helpful in
determining whether this patient’s worsening is due to a developing
dementia?
A Family Confusion Assessment Method

B Functional Assessment Staging Tool
C Global Deterioration Scale
D Mini-Mental State Examination (MMSE)
E Montreal Cognitive Assessment (MoCA)
31 A 34-year-old man with a 12-year history of schizophrenia has not

experienced a therapeutic benefit with multiple agents, including
haloperidol, olanzapine, and quetiapine, despite his family ensuring
that he is strictly adherent to his treatment schedule. He has no other
significant medical history, including no history of obesity, diabetes
mellitus, hypercholesterolemia, or hematologic disease. Which of the
following antipsychotic agents should be tried next in this patient?
A aripiprazole
B clozapine
C pimozide
D risperidone
E thioridazine
950 JUNE 2018

ARTICLE 10: CONVERSION DISORDER
32 A 30-year-old woman with no significant past medical history presents

to the emergency department in significant emotional distress,
reporting several weeks of progressive right arm and leg weakness and
numbness of her entire right side, including her face. She has also
developed severely slurred and stuttering speech and reports profound
memory loss. While initially episodic, her symptoms are now constant,
and she has become bedbound and fully reliant on her husband. On
neurologic examination, she is unable to register or recall any words at
5 minutes; the remainder of mental status testing is normal. Her speech
is intermittently severely dysarthric, hypophonic, and stuttering, but
when she is distracted, it is normal. She has a flaccid right arm and
leg but is noted to move her right side when positioning herself in bed.
She has loss of sensation to all modalities in the affected limbs and
midline truncal and facial anesthesia. Reflexes are normal. She declines
gait testing. Which of the following characteristics of the patient’s
presentation is not part of the Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition (DSM-5) criteria for conversion
disorder?
A hemiplegia
B hemisensory loss
C initial transient nature of her symptoms
D memory loss
E speech abnormalities
33 A 16-year-old girl presents for a fourth subspecialist movement disorder

opinion for intermittent symptoms, including severe bilateral action
and resting tremor, dystonic movements that migrate from limb to limb,
and a shuffling gait. Her symptoms began 6 months after she was sexually
assaulted by a relative and have persisted for over 3 years. She was
initially diagnosed with dopamine-responsive dystonia and treated with
carbidopa/levodopa; however, this was stopped after a year as she had no
improvement. Due to her disability, the patient is now homeschooled,
and as her parents do not feel she will ever be able to hold down a job,
they have already made plans to support her financially for the rest of her
life. They acknowledge that the previous two neurologists she saw
diagnosed her with a conversion disorder but state that they know her
symptoms are due to a physical issue. As no one will believe them, they
have lost hope of her ever recovering. Which of the following
characteristics of her presentation is associated with a good prognosis?
A attribution of her symptoms to a physical issue

B expectation that she will never work
C her current age
D loss of hope of recovery
E 3-year duration of her symptoms

POSTREADING TEST
34 Reattribution training geared toward primary care providers has been

shown to have which outcome with regard to the care of patients
with conversion disorder?
A decreased drug prescriptions

B decreased patient visits to the primary care provider
C decreased referrals for specialist consultations
D fifty percent reduction in symptoms by 6 months posttraining
E positive shift in patients’ thinking
ARTICLE 11: ASSESSMENT AND MANAGEMENT OF POSTTRAUMATIC

STRESS DISORDER
35 When assessing for posttraumatic stress disorder, asking patients to

just recount the trauma may result in them experiencing which of
the following?
A dissociative flashback
B eagerness to pursue the role of posttraumatic stress disorder in
their neurologic symptoms
C psychogenic hemiparesis
D strengthening of the provider-patient relationship
E therapeutic breakthrough
36 Which of the following structures involved in the pathophysiology

of posttraumatic stress disorder is involved in the reduction of
subjective distress?
A amygdala
B hippocampus
C hypothalamus
D medial prefrontal cortex
E pituitary gland
ARTICLE 12: DIAGNOSIS AND MANAGEMENT OF ANXIETY DISORDERS
37 Which of the following childhood factors is most highly associated

with the development of an anxiety disorder in adulthood?
A childhood sexual abuse

B early parental loss
C interparental conflict
D overprotective parenting style
E parental perfectionism
952 JUNE 2018

38 A 42-year-old woman reports significantly worsening headaches,
nausea, and abdominal pain over the past year. Her primary care
doctor diagnosed her with migraines and then referred her to
neurology when treatment with sumatriptan was ineffective. The
patient has a long history of headaches, but they have become much
worse since her daughter began applying to colleges in the past year.
The patient describes always having been “very close” to her daughter
and indicates that they have never spent a night apart. She would
always accompany her on overnight school trips, and sleepovers were
always at her house rather than at the house of her daughter’s friends.
She reports being terrified that her daughter will become seriously ill
or be kidnapped from her dorm room if she is not there, and she has
frequent nightmares centered on such scenarios. She is currently
planning to sell her house and rent an apartment near campus
wherever her daughter attends school. At her last performance review
at work, her boss indicated that she needed to pay attention to her job
or would be at risk of being fired. Other than a history of headaches,
the only other significant historical factor is having lost both of her
parents in a plane crash when she was 6 years old. She has never
demonstrated symptoms of posttraumatic stress disorder. Which of
the following diagnoses best fits this patient’s presentation?
A agoraphobia
B generalized anxiety disorder
C separation anxiety disorder
D social anxiety disorder
E specific phobia
39 A 35-year-old man with generalized anxiety disorder has persistent

disabling symptoms despite 20 sessions of cognitive-behavioral
therapy and concurrent treatment with a selective serotonin reuptake
inhibitor (SSRI). In addition to the anxiety disorder, he has a long
history of polysubstance abuse, including alcohol and oxycodone,
although he has been abstinent for the past 6 months. Which of the
following medications would be the best next choice as an adjunct in
treating this patient’s anxiety disorder?
A alprazolam
B levetiracetam
C lorazepam
D pregabalin
E propranolol

POSTREADING TEST
40 A 26-year-old man seeks care for anxiety that has been very distressing
for the past year. He feels anxious and cannot control his worrying on
more than half of the days of the week, although not every day. Less
frequently, he will be noticeably irritable or easily annoyed and have
trouble relaxing, with difficulty falling asleep. He does not feel afraid
that something awful might happen. He has no other medical
problems, and no significant life stressors were associated with the
onset of the anxiety. He takes no medications, drinks no more than
three drinks per week, and does not use recreational drugs. His score
on the Generalized Anxiety Disorder 7-Item Scale (GAD-7) is
approximately 6. Which of the following treatments is indicated for
this patient?
A cognitive-behavioral therapy
B psychoeducation and support
C treatment with a selective serotonin reuptake inhibitor (SSRI)
D treatment with an SSRI plus a benzodiazepine
E treatment with an SSRI plus cognitive-behavioral therapy
954 JUNE 2018

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JUNE 2018

VOL. 24 NO. 3 Behavioral Neurology

668 Editor’s Preface

672 Bedside Approach to the Mental Status Assessment

704 Clinical Assessment of Prefrontal Lobe Functions

727 Memory Dysfunction

745 Primary Progressive Aphasia and Stroke Aphasia

768 Apraxia, Neglect, and Agnosia

783 Aggression and Agitation in Dementia

804 Mood Disorders

828 Obsessive-Compulsive Disorder

DENOTES SUPPLEMENTAL 845 Psychosis

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

873 Assessment and Management of Posttraumatic Stress Disorder

893 Diagnosis and Management of Anxiety Disorders

ETHICAL AND MEDICOLEGAL ISSUES

920 Assessment of Medical Decision-making Capacity in Patients

926 Coding for Behavioral Neurology and Psychiatry

SELF-ASSESSMENT AND CME

658 Learning Objectives and Core Competencies

937 Instructions for Completing Postreading Self-Assessment and CME Test

939 Postreading Self-Assessment and CME Test

955 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

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

Morris Freedman, MD, Bruce H. Cohen, MD, FAAN

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660 JUNE 2018

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Ontario, Canada Unlabeled Use of Products/Investigational

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Yael Goldberg, PhD, CPsych Alexandre Henri-Bhargava,

MDCM, FAAN Unlabeled Use of Products/Investigational

662 JUNE 2018

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

Mark Rapaport, MD Peggy M. A. Richter, MD, FRCPC

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664 JUNE 2018

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Unlabeled Use of Products/Investigational Relationship Disclosure: Dr Villanueva

Ari Zaretsky, MD, FRCPC

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James W. M. Owens Jr, Allison L. Weathers, MD, FAAN

666 JUNE 2018

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Reversing Neglect and Amnesia

668 JUNE 2018

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and cognition in our patients. © 2018 American Academy of Neurology.

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672 JUNE 2018

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(ACE)/Addenbrooke’s Cognitive Examination Revised (ACE-R).17,18,22 Most of ● It is important to obtain

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Importance of a Collateral History

First Symptom Noticed Affected Cognitive Domain Disorders to Consider

674 JUNE 2018