Continuum: Lifelong Learning in Neurology—Dementia, Volume 22, Issue 2, April 2016

Issue Overview

Dementia April 2016;22(2)

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

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

skills.

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

► Perform a cognitive examination of patients suspected of having a neurodegenerative

condition and develop a framework for the clinical evaluation and ancillary testing of patients at
risk for a neurodegenerative dementia
► Diagnose and counsel patients with mild cognitive impairment

► Discuss the clinical diagnosis, neuroimaging features, genetic and pathologic aspects, and
management of Alzheimer disease
► Discuss the unifying and differentiating features of dementia with Lewy bodies and Parkinson
disease dementia, distinguish these entities from other parkinsonian dementias and Alzheimer
disease, and review their current management
► Discuss the clinical, neuroimaging, genetic, and pathologic features of frontotemporal
dementia and related disorders to aid in the evidence-based diagnosis and management of
patients presenting with these conditions
► Define vascular cognitive impairment and describe strategies for diagnostic investigation and
management
► Evaluate and manage patients with rapidly progressive dementias

► Discuss methods to appropriately evaluate and treat patients with autoimmune

encephalopathies and dementias
► Discuss the clinical, genetic, and radiographic features of adult-onset inherited
leukoencephalopathies that may present with cognitive decline
► Discuss the approach to the diagnosis and treatment of idiopathic normal pressure
hydrocephalus

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

► Discuss the association of psychiatric disorders with dementia, and describe the diagnostic
and therapeutic implications of psychiatric symptoms in patients with dementia
► Discuss contributors to caregiver stress and employ strategies to reduce caregiver burden

► Discuss the ethical framework for addressing patient and family member requests for future
novel pharmacologic interventions to treat dementia

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

► Patient Care and Procedural Skills

► Medical Knowledge

► Practice-Based Learning and Improvement

► Interpersonal and Communication Skills

► Professionalism

► Systems-Based Practice

Disclosures
CONTRIBUTORS

Elizabeth C. Finger, MD, FRCPC, Guest Editor

Associate Professor, Department of Clinical Neurological Sciences, Schulich School of Medicine
and Dentistry, Western University, London, Ontario, Canada; Scientist, Lawson Health Research
Institute, London, Ontario, Canada
a
Dr Finger has received personal compensation as a speaker for Western University and receives grant support
from the Canadian Institutes of Health Research for this work as well as grant funding from the Alzheimer Society
of Canada, the Ministry of Research and Innovation, Ontario Brain Institute, and the Weston Foundation. Dr Finger
has provided expert legal testimony for the Ontario Court of Justice.
b
Dr Finger discusses the unlabeled/investigational use of disease-modifying therapies in development, dopaminergic
medications, neuroleptic medications, oxytocin, and selective serotonin reuptake inhibitors for the treatment of
frontotemporal dementias as discussed in the article “Frontotemporal Dementias.” In the Patient Management
Problem, Dr Finger discusses the unlabeled/investigational use of antipsychotic medications for behavioral
management in dementia.

Liana G. Apostolova, MD, MS, FAAN

Professor of Neurology, Radiology, and Medical and Molecular Genetics, Barbara and Peer
Baekgaard Professor in Alzheimer’s Disease Research, Indiana University School of Medicine,
Indianapolis, Indiana
a
Dr Apostolova serves as senior associate editor of Alzheimer’s & Dementia: Diagnosis, Assessment & Disease
Monitoring and receives personal compensation for serving on the speaker’s bureau of Eli Lilly and Company and

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

GE Healthcare Worldwide. Dr Apostolova receives grant support from the Jim Easton Consortium for Alzheimer’s
Drug Discovery and Biomarker Development and the National Institute on Aging.
b
Dr Apostolova discusses the unlabeled/investigational use of antidepressant and antipsychotic medications for
behavioral management as well as antidementia therapy in mild cognitive impairment.

Bruce H. Cohen, MD, FAAN

Professor of Pediatrics, Northeast Ohio Medical University, Rootstown, Ohio; Director,
NeuroDevelopmental Science Center, Department of Pediatrics, Children’s Hospital Medical
Center of Akron, Akron, Ohio
a
Dr Cohen has received personal compensation from the American Academy of Neurology for educational speaking
engagements, has served as an expert consultant for the Division of Vaccine Compensation and the United States
Department of Justice and Health & Human Services, and serves on the speakers bureau of the United
Mitochondrial Disease Foundation. Dr Cohen serves on the editorial boards of Mitochondrian and Pediatric
Neurology, serves as content editor for Motive Medical Intelligence, and has received personal compensation and
travel expenses as a consultant for Stealth BioTherapeutics. Dr Cohen receives research funding from the National
Institutes of Health (GG006326-03), and Dr Cohen’s institution has received compensation for his lectures at
Courtagen Life Sciences, Inc, and Transgenomic, Inc, and for his expert witness testimony in various court cases.
Dr Cohen’s institution has also received research support from Edison Pharmaceuticals, Inc, Raptor
Pharmaceuticals, Reata Pharmaceuticals, Inc, and Stealth BioTherapeutics, and Dr Cohen has also received travel
expense reimbursement from these entities.
b
Dr Cohen reports no disclosure.

Peter D. Donofrio, MD, FAAN

Professor of Neurology, Vanderbilt University, Nashville, Tennessee
a
Dr Donofrio has served on the scientific advisory board of and as a consultant for Baxter,CSL Behring, and UCB,
Inc, and has served on the editorial board of Muscle & Nerve.
b
Dr Donofrio reports no disclosure.

Serge Gauthier, CM, MD, FRCPC

Professor, Departments of Neurology, Neurosurgery, and Psychiatry, Director, Alzheimer
Disease Research Unit, McGill University Research Centre for Studies in Aging, McGill
University, Montreal, Quebec, Canada
a
Dr Gauthier receives personal compensation for serving on the scientific advisory boards of AFFiRiS, Eli Lilly and
Company, and Hoffmann-La Roche Ltd; for serving as chair of the scientific advisory board of TauRx Therapeutics;
and as a lecturer for Ever Pharma and Schwabe, Williamson & Wyatt. Dr Gauthier serves as an editorial board
member of Alzheimer’s & Dementia: The Journal of The Alzheimer’s Association, Current Medical Research &
Opinion, Dementia and Geriatric Cognitive Disorders, Eurasian Journal of Medicine, European Neurology, and the
World Journal of Biological Psychiatry. Dr Gauthier receives research funding as site principal investigator of the
Eli Lilly and Company and Hoffmann-La Roche Ltd, and receives funding for this work from the Canadian Institutes
of Health Research and the Canadian Consortium on Neurodegeneration in Aging as chair of the Ethical, Legal,
and Social Issues advisory committee. Dr Gauthier receives book royalties from Cambridge University Press.
b
Dr Gauthier reports no disclosure.

Michael D. Geschwind, MD, PhD

Professor of Neurology, Michael J. Homer Chair in Neurology, Memory and Aging Center,
University of California, San Francisco, San Francisco, California
a
Dr Geschwind serves on the board of directors for San Francisco Bay Area Physicians for Social Responsibility
and serves as a consultant for Advance Medical, Best Doctors, Inc, the Franciscan Physician Network, the Gerson
Lehrman Group, Inc, Lewis Brisbois Bisgaard & Smith LLP, MEDACorp, and Quest Diagnostics. Dr Geschwind
receives personal compensation as a speaker for grand rounds lectures and receives research/grant support
from Cure PSP, the Michael J. Homer Family Fund, the National Institute on Aging, Quest Diagnostics, and the
Tau Consortium.
b
Dr Geschwind reports no disclosure.

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

Stephen N. Gomperts, MD, PhD
Assistant Professor, Harvard Medical School, Boston, Massachusetts; Assistant in Neurology,
Massachusetts General Hospital, Boston, Massachusetts
a
Dr Gomperts receives grant support from the National Institutes of Health as principal investigator of study 1-R21-
NS-090243-01 and receives research support as principle investigator from the National Parkinson Foundation.
b
Dr Gomperts reports no disclosure.

Murray Grossman, MD, FAAN

Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
a
Dr Grossman receives personal compensation for serving as a consultant for C 2N Diagnostics, as a lecturer for the
Lundbeck Institute, for serving on the international scientific advisory board of the Max Planck Institutes, and for
serving as associate editor of Neurology. Dr Grossman’s institution has received grant support from the National
Institutes of Health (AG017586, AG038490, NS044266, and NS053488), and Dr Grossman has received research
support from the Arkin Family Foundation, the Samuel I. Newhouse Foundation, Inc, and the Wyncote Foundation.
b
Dr Grossman reports no disclosure.

David J. Irwin, MD
Assistant Professor of Neurology, University of Pennsylvania Perelman School of Medicine,
Philadelphia, Pennsylvania
a
Dr Irwin’s institution receives grant support from the National Institutes of Health and the National Institute of
Neurological Disorders and Stroke (K23NS088341-01).
b
Dr Irwin reports no disclosure.

Joseph S. Kass, MD, JD, FAAN

Associate Professor of Neurology, Psychiatry, and Medical Ethics, Director, Neurology
Residency Program, Chief of Neurology Service, Ben Taub General Hospital, Baylor College of
Medicine, Houston, Texas
a
Dr Kass has received personal compensation for expert testimony in legal cases involving personal injury,
defamation, and malpractice.
b
Dr Kass reports no disclosure.

Jan Malm, MD, PhD

Professor, Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå,
Sweden
a
Professor Malm receives royalty payments from Likvor AB, where he holds patents related to the CELDA infusion
device, which is approved within the European Union, but not in the United States, and receives payments for a
patent of a new CSF shunt design created with Medtronic, Inc. Professor Malm receives research support as
principal investigator for studies from the Swedish Heart-Lung Foundation and the Swedish National Space Board.
b
Professor Malm reports no disclosure.

Andrew McKeon, MD
Associate Professor of Neurology and Laboratory Medicine and Pathology, Mayo Clinic College
of Medicine, Rochester, Minnesota
a
Dr McKeon receives research funding from MedImmune.
b
Dr McKeon discusses the unlabeled/investigational treatments for autoimmune encephalopathies and dementias,
none of which have been approved by the US Food and Drug Administration for these indications.

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

Chiadi U. Onyike, MD, MHS
Associate Professor of Psychiatry and Behavioral Sciences, Johns Hopkins University School of
Medicine, Baltimore, Maryland
a
Dr Onyike has received personal compensation as special issue editor for the International Review of Psychiatry
and the Psychiatric Clinics of North America and has given expert legal testimony for the Paley Rothman law firm
on disabilities related to frontotemporal dementia. Dr Onyike receives research funding from the Jane Tanger Black
Fund forYoung-Onset Dementia Research, the National Institute of Neurological Disorders and Stroke, the National
Institute on Aging, the National Institutes of Health, the Robert and Nancy Hall family, and Tau Therapeutics.
b
Dr Onyike discusses the unlabeled/investigational indications and evidence for efficacy and risks of prescribing
antidepressants, antipsychotics, and other psychotropic agents for treating psychiatric aspects of dementia, as well
as the alternatives to making these prescriptions, which include behavioral interventions, care programs, caregiver
support and training, environment modulation, and structured recreation.

Ronald C. Petersen, PhD, MD

Professor of Neurology, Cora Kanow Professor of Alzheimer’s Disease Research, Director of
Mayo Alzheimer’s Disease Research Center, Director of Mayo Clinic Study of Aging, Mayo
Clinic College of Medicine, Rochester, Minnesota
a
Dr Petersen serves on the board of directors for the Alzheimer’s Association and receives personal compensation
for serving as chair of the data monitoring committees for Janssen Alzheimer Immunotherapy and Pfizer Inc. Dr
Petersen receives personal compensation as a consultant for Biogen, Eli Lilly and Company, the Federal Trade
Commission, Genentech, Inc,Hoffmann la Roche, Inc, and Merck & Company, Inc. Dr Petersen receives grant and
funding support from the Mayo Foundation for Education and Research, the National Institute on Aging, and the
Patient Centered Outcomes Research Institute (PAT 206548). Dr Petersen receives royalties from Oxford University
Press.
b
Dr Petersen discusses the unlabeled/investigational clinical trial results for mild cognitive impairment.

Deborah L. Renaud, MD
Associate Professor of Neurology and Pediatrics, Mayo Clinic College of Medicine, Rochester,
Minnesota
a
Dr Renaud serves on the editorial boards of the Journal of Child Neurology and Pediatric Neurology.
b
Dr Renaud reports no disclosure.

Pedro Rosa-Neto, MD, PhD

Associate Professor, Douglas Research Institute, Department of Neurology, Neurosurgery, and
Psychiatry, Alzheimer Disease Research Unit, McGill University Research Centre for Studies in
Aging, McGill University, Montreal, Quebec, Canada
a
Dr Rosa-Neto receives grant support from the Alzheimer’s Association.
b
Dr Rosa-Neto reports no disclosure.

Amy E. Sanders, MD, MS, FAAN

Assistant Professor and Director of Cognitive and Behavioral Neurology, State University of
New York Upstate Medical University, Syracuse, New York
a
Dr Sanders served as an expert medical witness for Gilreath Law Firm.
b
Dr Sanders reports no disclosure.

Eric Smith, MD, MPH

Associate Professor of Neurology and Katthy Taylor Chair in Vascular Dementia, University of
Calgary, Calgary, Alberta, Canada
a
Dr Smith serves as a board member of the Quality Oversight Committee of the American Heart Association and as
an assistant editor for Stroke. Dr Smith receives grant support from the Alzheimer Society of Canada, the Canadian

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

Institutes of Health Research, the Canadian Partnership Against Cancer, and the Heart and Stroke Foundation of
Canada and receives research support from McMaster University.
b
Dr Smith discusses the unlabeled/investigational use of cholinesterase inhibitors for the treatment of vascular
dementia.

Michael A. Williams, MD, FAAN

Professor of Neurology and Neurological Surgery, University of Washington School of
Medicine, Seattle, Washington
a
Dr Williams serves on the technical advisory board for and holds stock options in Aqueduct Critical Care, Inc, and
has received personal compensation and travel expenses as a lecturer for Codman Neuro, Canada. Dr Williams has
received research support from the National Space Biomedical Research Institute as principle investigator of study
SMST02801, comparing the continuous noninvasive and invasive intracranial pressure management therapies, and
as co-investigator of study CA02801, investigating the effects of microgravity on intracranial pressure. Dr Williams
has received research support from NeuroDx Development for research funded by the National Institutes of Health.
b
Dr Williams reports no disclosure.

Douglas J. Gelb, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
a
Dr Gelb receives royalties from Oxford University Press and UpToDate, Inc.
b
Dr Gelb reports no disclosure.

Joseph E. Safdieh, MD, FAAN

Vice Chairman for Education, Associate Professor, Department of Neurology, Weill Cornell
Medical Center/New York–Presbyterian Hospital, New York, New York
a
Dr Safdieh receives personal compensation for providing expert legal testimony and for the development of
educational presentations from Elsevier.
b
Dr Safdieh reports no disclosure.
a
Relationship Disclosure
b
Unlabeled Use of Products/Investigational Use Disclosure

Methods of Participation and Instructions for Use

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

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

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

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

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

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

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

care.

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

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

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

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

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

pretest, multiple-choice questions with preferred responses, and a patient management problem.

For detailed instructions regarding Continuum self-assessment and CME activities, visit

aan.com/continuum/cme.

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

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

issue topic accompanies issues when applicable.

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

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

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

can be met.

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

 LIFELONG LEARNING IN NEUROLOGY ®

Dementia
Volume 22 Number 2 April 2016

CONTRIBUTORS
Elizabeth C. Finger, MD, FRCPC, Guest Editor
Associate Professor, Department of Clinical Neurological Sciences,
Schulich School of Medicine and Dentistry, Western University, London,
Ontario, Canada; Scientist, Lawson Health Research Institute, London,
Ontario, Canada
aDr Finger has received personal compensation as a speaker for Western University and
receives grant support from the Canadian Institutes of Health Research for this work as well as
grant funding from the Alzheimer Society of Canada, the Ministry of Research and Innovation,
Ontario Brain Institute, and the Weston Foundation. Dr Finger has provided expert legal
testimony for the Ontario Court of Justice.
bDr Finger discusses the unlabeled/investigational use of disease-modifying therapies in
development, dopaminergic medications, neuroleptic medications, oxytocin, and selective
serotonin reuptake inhibitors for the treatment of frontotemporal dementias as discussed in
the article “Frontotemporal Dementias.” In the Patient Management Problem, Dr Finger
discusses the unlabeled/investigational use of antipsychotic medications for behavioral
management in dementia.

Liana G. Apostolova, MD, MS, FAAN

Professor of Neurology, Radiology, and Medical and Molecular Genetics,
Barbara and Peer Baekgaard Professor in Alzheimer’s Disease Research,
Indiana University School of Medicine, Indianapolis, Indiana
aDr Apostolova serves as senior associate editor of Alzheimer’s & Dementia: Diagnosis,
Assessment & Disease Monitoring and receives personal compensation for serving on the
speaker’s bureau of Eli Lilly and Company and GE Healthcare Worldwide. Dr Apostolova
receives grant support from the Jim Easton Consortium for Alzheimer’s Drug Discovery
and Biomarker Development and the National Institute on Aging.
bDr Apostolova discusses the unlabeled/investigational use of antidepressant and
antipsychotic medications for behavioral management as well as antidementia therapy
in mild cognitive impairment.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(2) www.ContinuumJournal.com

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Bruce H. Cohen, MD, FAAN
Professor of Pediatrics, Northeast Ohio Medical University, Rootstown, Ohio;
Director, NeuroDevelopmental Science Center, Department of Pediatrics,
Children’s Hospital Medical Center of Akron, Akron, Ohio
aDr Cohen has received personal compensation from the American Academy of Neurology for
educational speaking engagements, has served as an expert consultant for the Division of
Vaccine Compensation and the United States Department of Justice and Health & Human
Services, and serves on the speakers bureau of the United Mitochondrial Disease Foundation.
Dr Cohen serves on the editorial boards of Mitochondrian and Pediatric Neurology, serves as
content editor for Motive Medical Intelligence, and has received personal compensation and
travel expenses as a consultant for Stealth BioTherapeutics. Dr Cohen receives research funding
from the National Institutes of Health (GG006326-03), and Dr Cohen’s institution has received
compensation for his lectures at Courtagen Life Sciences, Inc, and Transgenomic, Inc, and for
his expert witness testimony in various court cases. Dr Cohen’s institution has also received
research support from Edison Pharmaceuticals, Inc, Raptor Pharmaceuticals, Reata
Pharmaceuticals, Inc, and Stealth BioTherapeutics, and Dr Cohen has also received travel
expense reimbursement from these entities.
bDr Cohen reports no disclosure.

Peter D. Donofrio, MD, FAAN

Professor of Neurology, Vanderbilt University, Nashville, Tennessee
aDr Donofrio has served on the scientific advisory board of and as a consultant for Baxter,
CSL Behring, and UCB, Inc, and has served on the editorial board of Muscle & Nerve.
bDr Donofrio reports no disclosure.

Serge Gauthier, CM, MD, FRCPC

Professor, Departments of Neurology, Neurosurgery, and Psychiatry,
Director, Alzheimer Disease Research Unit, McGill University Research Centre
for Studies in Aging, McGill University, Montreal, Quebec, Canada
aDr Gauthier receives personal compensation for serving on the scientific advisory boards of
AFFiRiS, Eli Lilly and Company, and Hoffmann-La Roche Ltd; for serving as chair of the
scientific advisory board of TauRx Therapeutics; and as a lecturer for Ever Pharma and
Schwabe, Williamson & Wyatt. Dr Gauthier serves as an editorial board member of
Alzheimer’s & Dementia: The Journal of The Alzheimer’s Association, Current Medical
Research & Opinion, Dementia and Geriatric Cognitive Disorders, Eurasian Journal of
Medicine, European Neurology, and the World Journal of Biological Psychiatry. Dr Gauthier
receives research funding as site principal investigator of the Eli Lilly and Company and
Hoffmann-La Roche Ltd, and receives funding for this work from the Canadian Institutes of
Health Research and the Canadian Consortium on Neurodegeneration in Aging as chair of
the Ethical, Legal, and Social Issues advisory committee. Dr Gauthier receives book royalties
from Cambridge University Press.
bDr Gauthier reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

www.ContinuumJournal.com April 2016

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Michael D. Geschwind, MD, PhD
Professor of Neurology, Michael J. Homer Chair in Neurology,
Memory and Aging Center, University of California, San Francisco,
San Francisco, California
aDr Geschwind serves on the board of directors for San Francisco Bay Area Physicians for
Social Responsibility and serves as a consultant for Advance Medical, Best Doctors, Inc, the
Franciscan Physician Network, the Gerson Lehrman Group, Inc, Lewis Brisbois Bisgaard &
Smith LLP, MEDACorp, and Quest Diagnostics. Dr Geschwind receives personal
compensation as a speaker for grand rounds lectures and receives research/grant support
from Cure PSP, the Michael J. Homer Family Fund, the National Institute on Aging, Quest
Diagnostics, and the Tau Consortium.
bDr Geschwind reports no disclosure.

Stephen N. Gomperts, MD, PhD

Assistant Professor, Harvard Medical School, Boston, Massachusetts;
Assistant in Neurology, Massachusetts General Hospital, Boston, Massachusetts
aDr Gomperts receives grant support from the National Institutes of Health as principal
investigator of study 1-R21-NS-090243-01 and receives research support as principle
investigator from the National Parkinson Foundation.
bDr Gomperts reports no disclosure.

Murray Grossman, MD, FAAN

Professor of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania
aDr Grossman receives personal compensation for serving as a consultant for C N
2
Diagnostics, as a lecturer for the Lundbeck Institute, for serving on the international
scientific advisory board of the Max Planck Institutes, and for serving as associate editor of
Neurology. Dr Grossman’s institution has received grant support from the National Institutes
of Health (AG017586, AG038490, NS044266, and NS053488), and Dr Grossman has received
research support from the Arkin Family Foundation, the Samuel I. Newhouse Foundation,
Inc, and the Wyncote Foundation.
bDr Grossman reports no disclosure.

David J. Irwin, MD
Assistant Professor of Neurology, University of Pennsylvania Perelman
School of Medicine, Philadelphia, Pennsylvania
aDr Irwin’s institution receives grant support from the National Institutes of Health
and the National Institute of Neurological Disorders and Stroke (K23NS088341-01).
bDr Irwin reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(2) www.ContinuumJournal.com

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Joseph S. Kass, MD, JD, FAAN
Associate Professor of Neurology, Psychiatry, and Medical Ethics,
Director, Neurology Residency Program, Chief of Neurology Service,
Ben Taub General Hospital, Baylor College of Medicine, Houston, Texas
aDr Kass has received personal compensation for expert testimony in legal cases involving
personal injury, defamation, and malpractice.
bDr Kass reports no disclosure.

Jan Malm, MD, PhD

Professor, Department of Pharmacology and Clinical Neuroscience, Umeå
University, Umeå, Sweden
aProfessor Malm receives royalty payments from Likvor AB, where he holds patents related
to the CELDA infusion device, which is approved within the European Union, but not in the
United States, and receives payments for a patent of a new CSF shunt design created with
Medtronic, Inc. Professor Malm receives research support as principal investigator for studies
from the Swedish Heart-Lung Foundation and the Swedish National Space Board.
bProfessor Malm reports no disclosure.

Andrew McKeon, MD
Associate Professor of Neurology and Laboratory Medicine and Pathology,
Mayo Clinic College of Medicine, Rochester, Minnesota
aDr McKeon receives research funding from MedImmune.
bDr McKeon discusses the unlabeled/investigational treatments for autoimmune
encephalopathies and dementias, none of which have been approved by the US Food
and Drug Administration for these indications.

Chiadi U. Onyike, MD, MHS

Associate Professor of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, Baltimore, Maryland
aDr Onyike has received personal compensation as special issue editor for the International
Review of Psychiatry and the Psychiatric Clinics of North America and has given expert
legal testimony for the Paley Rothman law firm on disabilities related to frontotemporal
dementia. Dr Onyike receives research funding from the Jane Tanger Black Fund for
Young-Onset Dementia Research, the National Institute of Neurological Disorders and
Stroke, the National Institute on Aging, the National Institutes of Health, the Robert and
Nancy Hall family, and Tau Therapeutics.
bDr Onyike discusses the unlabeled/investigational indications and evidence for efficacy and
risks of prescribing antidepressants, antipsychotics, and other psychotropic agents for
treating psychiatric aspects of dementia, as well as the alternatives to making these
prescriptions, which include behavioral interventions, care programs, caregiver support
and training, environment modulation, and structured recreation.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

www.ContinuumJournal.com April 2016

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Ronald C. Petersen, PhD, MD
Professor of Neurology, Cora Kanow Professor of Alzheimer’s Disease Research,
Director of Mayo Alzheimer’s Disease Research Center, Director of Mayo Clinic
Study of Aging, Mayo Clinic College of Medicine, Rochester, Minnesota
aDr Petersen serves on the board of directors for the Alzheimer’s Association and receives
personal compensation for serving as chair of the data monitoring committees for Janssen
Alzheimer Immunotherapy and Pfizer Inc. Dr Petersen receives personal compensation as a
consultant for Biogen, Eli Lilly and Company, the Federal Trade Commission, Genentech, Inc,
Hoffmann la Roche, Inc, and Merck & Company, Inc. Dr Petersen receives grant and funding
support from the Mayo Foundation for Education and Research, the National Institute on
Aging, and the Patient Centered Outcomes Research Institute (PAT 206548). Dr Petersen
receives royalties from Oxford University Press.
bDr Petersen discusses the unlabeled/investigational clinical trial results for mild
cognitive impairment.

Deborah L. Renaud, MD
Associate Professor of Neurology and Pediatrics, Mayo Clinic
College of Medicine, Rochester, Minnesota
aDr Renaud serves on the editorial boards of the Journal of Child Neurology
and Pediatric Neurology.
bDr Renaud reports no disclosure.

Pedro Rosa-Neto, MD, PhD

Associate Professor, Douglas Research Institute, Department of Neurology,
Neurosurgery, and Psychiatry, Alzheimer Disease Research Unit, McGill
University Research Centre for Studies in Aging, McGill University, Montreal,
Quebec, Canada
aDr Rosa-Neto receives grant support from the Alzheimer’s Association.
bDr Rosa-Neto reports no disclosure.

Amy E. Sanders, MD, MS, FAAN

Assistant Professor and Director of Cognitive and Behavioral Neurology,
State University of New York Upstate Medical University, Syracuse, New York
aDr Sanders served as an expert medical witness for Gilreath Law Firm.
bDr Sanders reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2016;22(2) www.ContinuumJournal.com

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Eric Smith, MD, MPH
Associate Professor of Neurology and Katthy Taylor Chair in Vascular Dementia,
University of Calgary, Calgary, Alberta, Canada
aDr Smith serves as a board member of the Quality Oversight Committee of the American
Heart Association and as an assistant editor for Stroke. Dr Smith receives grant support from
the Alzheimer Society of Canada, the Canadian Institutes of Health Research, the Canadian
Partnership Against Cancer, and the Heart and Stroke Foundation of Canada and receives
research support from McMaster University.
bDr Smith discusses the unlabeled/investigational use of cholinesterase inhibitors for the
treatment of vascular dementia.

Michael A. Williams, MD, FAAN

Professor of Neurology and Neurological Surgery, University of Washington
School of Medicine, Seattle, Washington
aDr Williams serves on the technical advisory board for and holds stock options in Aqueduct
Critical Care, Inc, and has received personal compensation and travel expenses as a lecturer
for Codman Neuro, Canada. Dr Williams has received research support from the National
Space Biomedical Research Institute as principle investigator of study SMST02801,
comparing the continuous noninvasive and invasive intracranial pressure management
therapies, and as co-investigator of study CA02801, investigating the effects of microgravity
on intracranial pressure. Dr Williams has received research support from NeuroDx
Development for research funded by the National Institutes of Health.
bDr Williams reports no disclosure.

SELF-ASSESSMENT AND CME TEST WRITERS

Douglas J. Gelb, MD, PhD, FAAN
Professor of Neurology, University of Michigan, Ann Arbor, Michigan
aDr Gelb receives royalties from Oxford University Press and UpToDate, Inc.
bDr Gelb reports no disclosure.

Joseph E. Safdieh, MD, FAAN

Vice Chairman for Education, Associate Professor, Department of Neurology,
Weill Cornell Medical Center/New York–Presbyterian Hospital, New York,
New York
aDr Safdieh receives personal compensation for providing expert legal testimony and for the
development of educational presentations from Elsevier.
bDr Safdieh reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

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 Volume 22 n Number 2 n April 2016

LIFELONG LEARNING IN NEUROLOGY ®

www.ContinuumJournal.com

Dementia Denotes Supplemental Digital Content

Guest Editor: Elizabeth C. Finger, MD, FRCPC

Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 383

REVIEW ARTICLES
The Mental Status Examination in Patients With Suspected Dementia. . . . . . . . . 385
Murray Grossman, MD, FAAN; David J. Irwin, MD
Mild Cognitive Impairment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404
Ronald C. Petersen, PhD, MD
Alzheimer Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 419
Liana G. Apostolova, MD, MS, FAAN
Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson
Disease Dementia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435
Stephen N. Gomperts, MD, PhD
Frontotemporal Dementias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
Elizabeth C. Finger, MD, FRCPC
Vascular Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Eric Smith, MD, MPH
Rapidly Progressive Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
Michael D. Geschwind, MD, PhD
Autoimmune Encephalopathies and Dementias. . . . . . . . . . . . . . . . . . . . . . . . . . 538
Andrew McKeon, MD
Adult-Onset Leukoencephalopathies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 559
Deborah L. Renaud, MD
Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus. . . 579
Michael A. Williams, MD, FAAN; Jan Malm, MD, PhD
Psychiatric Aspects of Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600
Chiadi U. Onyike, MD, MHS

Volume 22 n Number 2 www.ContinuumJournal.com 379

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 LIFELONG LEARNING IN NEUROLOGY ®

ETHICAL ISSUES
Ethical Considerations for the Use of Next-Generation Alzheimer Drugs in
Symptomatic and At-Risk Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615
Serge Gauthier, CM, MD, FRCPC; Pedro Rosa-Neto, MD, PhD;
Joseph S. Kass, MD, JD, FAAN

PRACTICE ISSUES
Caregiver Stress and the Patient With Dementia . . . . . . . . . . . . . . . . . . . . . . . . . 619
Amy E. Sanders, MD, MS, FAAN
Coding for Dementia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626
Bruce H. Cohen, MD, FAAN; Peter D. Donofrio, MD, FAAN

SELF-ASSESSMENT AND CME

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 381
Instructions for Completing Postreading Self-Assessment and CME Test
and Tally Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639
Postreading Self-Assessment and CME Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 641
Postreading Self-Assessment and CME Test—Preferred Responses . . . . . . . 652
Douglas J. Gelb, MD, PhD, FAAN; Joseph E. Safdieh, MD, FAAN
Patient Management Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
Patient Management Problem—Preferred Responses . . . . . . . . . . . . . . . . . . . . 679
Elizabeth C. Finger, MD, FRCPC

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover

380 www.ContinuumJournal.com April 2016

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

s Perform a cognitive examination of patients suspected of having a neurodegenerative

condition and develop a framework for the clinical evaluation and ancillary testing
of patients at risk for a neurodegenerative dementia
Diagnose and counsel patients with mild cognitive impairment
s

Discuss the clinical diagnosis, neuroimaging features, genetic and pathologic

s

aspects, and management of Alzheimer disease

Discuss the unifying and differentiating features of dementia with Lewy bodies
s

and Parkinson disease dementia, distinguish these entities from other parkinsonian
dementias and Alzheimer disease, and review their current management
Discuss the clinical, neuroimaging, genetic, and pathologic features of frontotemporal
s

dementia and related disorders to aid in the evidence-based diagnosis and management
of patients presenting with these conditions
Define vascular cognitive impairment and describe strategies for diagnostic
s

investigation and management

Evaluate and manage patients with rapidly progressive dementias
s

Discuss methods to appropriately evaluate and treat patients with autoimmune

s

encephalopathies and dementias

Discuss the clinical, genetic, and radiographic features of adult-onset inherited
s

leukoencephalopathies that may present with cognitive decline

Discuss the approach to the diagnosis and treatment of idiopathic normal
s

pressure hydrocephalus
Discuss the association of psychiatric disorders with dementia, and describe
s

the diagnostic and therapeutic implications of psychiatric symptoms in patients

with dementia
Discuss contributors to caregiver stress and employ strategies to reduce
s

caregiver burden
Discuss the ethical framework for addressing patient and family member
s

requests for future novel pharmacologic interventions to treat dementia

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

Patient Care and Procedural Skills

s

Medical Knowledge
s

Practice-Based Learning and Improvement

s

Interpersonal and Communication Skills

s

Professionalism
s

Systems-Based Practice
s

Continuum (Minneap Minn) 2016;22(2) www.ContinuumJournal.com

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 Editor’s Preface

AD or Not AD? That

* 2016 American Academy
of Neurology.

Is Just One of the

Questions
This issue of Continuum agement of dementia
is devoted to the diagnosis with Lewy bodies and
and management of our Parkinson disease de-
patients with dementia. mentia, which together
To accomplish this goal, form the Lewy body de-
Dr Elizabeth C. Finger has mentias. The diagnosis
brought together a re- and management of
markable group of world- frontotemporal demen-
class experts to help each tia is the focus of the
of us answer the many clin- subsequent article by
ically relevant questions Dr Finger, who, simi-
that arise daily in our as- larly to each of the
sessment and care of pa- other authors in this
tients with these illnesses. Dr Elizabeth C. Finger issue, addresses the
The issue begins with has brought together a questions that many of
the article by Drs Murray remarkable group of us have as we encoun-
Grossman and David J. world-class experts to help ter patients who may
Irwin, who provide their each of us answer the many have these disorders,
comprehensive approach clinically relevant questions especially as we attempt
that arise daily in our
to the examination and to differentiate the var-
assessment and care of
assessment of patients patients with [dementia]. ious forms of fronto-
with a suspected neuro- temporal dementia from
degenerative dementiaVan approach the other dementing disorders. Dr
we can all emulate in our practices. Eric Smith next reviews vascular cog-
Dr Ronald C. Petersen discusses mild nitive impairment, a common and
cognitive impairment, including the potentially treatable cause (or con-
evolution and continued relevance of tributor) to cognitive impairment, and
this diagnostic construct and the im- emphasizes that the condition often
portance of its clinical recognition as a coexists with other pathologic causes
predementia state of neurodegenera- of dementia.
tive disorders (not just Alzheimer Dr Michael D. Geschwind next re-
disease [AD]) as well as treatable non- views the state of the art in the diag-
degenerative conditions. Dr Liana G. nosis and management of the many
Apostolova next reviews the cur- causes of rapidly progressive demen-
rent state of the art in diagnosis and tias in an article that serves as a com-
management of our patients with AD. panion to his recent contribution to
Dr Stephen N. Gomperts reviews the Neuroinfectious Disease issue of
the most current diagnostic and patho- Continuum that focused on Jakob-
physiologic considerations in the man- Creutzfeldt disease. Fittingly, the next

Continuum (Minneap Minn) 2016;22(2):383–384 www.ContinuumJournal.com 383

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

 Editor’s Preface

article by Dr Andrew McKeon focuses with regard to diagnosis and Evaluation

on the diagnosis and management and Management coding when seeing
of the remarkably quickly evolving patients with dementia.
spectrum of autoimmune encephalop- As with all issues of Continuum, a
athies and dementias. number of opportunities exist for
Dr Deborah L. Renaud reviews the CME. By taking the Postreading Self-
clinical, genetic, and imaging char- Assessment and CME Test, written by
acteristics of the adult-onset leuko- Drs Douglas J. Gelb and Joseph E.
encephalopathies, which, although Safdieh, after reading the issue, you
individually rare, are conditions that may earn up to 12 AMA PRA Category 1
need to be considered by adult neu- CreditsTM toward self-assessment and
rologists in the appropriate clinical and CME. The Patient Management Prob-
imaging context and are important to lem, written by Dr Finger, describes
include in our Continuum curriculum the case of a 57-year-old man who
(so that we will recognize them when presents with progressive memory
they do walk into our offices). problems, executive dysfunction, and
Drs Michael A. Williams and Jan navigational difficulty. By following
Malm provide their modern approach this case and answering multiple-
to the diagnosis and treatment of choice questions corresponding to
idiopathic normal pressure hydroceph- diagnostic and management decision
alus and the important role neurolo- points along the course of his disor-
gists play in diagnosis and follow-up der, you will have the opportunity
of this treatable cause of cognitive (and to earn up to 2 AMA PRA Category 1
gait and urinary) dysfunction. In the CME Credits.
final review article in this issue, Dr I want to thank Dr Finger for all of
Chiadi U. Onyike discusses the complex the work she put into the creation of
interface between the psychiatric and this expertly written and organized is-
neurologic aspects of dementia. sue of Continuum and for her remark-
In the Ethical Issues article, Drs able devotion and responsiveness to all
Serge Gauthier, Pedro Rosa-Neto, and of the critical details that arise from the
Joseph S. Kass discuss the ethical con- conception of an issue until its publi-
siderations that may arise in the use of cation. I would also like to thank each
(theoretical) next-generation AD of our internationally expert authors
drugs in symptomatic and at-risk pa- for providing state-of-the art in-
tients. In the Practice Issues article, Dr formation to help us answer the im-
Amy E. Sanders discusses the impor- portant clinical questions that arise in
tant issue of caregiver stress and the our encounters with patients with
patient with a dementing disorder. Drs dementing illnesses.
Bruce H. Cohen and Peter D. Donofrio
then review the many considerations VSteven L. Lewis, MD, FAAN
that neurologists need to be aware of Editor-in-Chief

384 www.ContinuumJournal.com April 2016

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 Review Article

The Mental Status

Address correspondence to
Dr Murray Grossman,
Department of Neurology,

Examination in Patients
2 Gibson, University of
Pennsylvania, 3400 Spruce St,
Philadelphia, PA 19104-4283,
[email protected].

With Suspected Relationship Disclosure:

Dr Grossman receives personal
compensation for serving as a

Dementia consultant for C2N Diagnostics,

as a lecturer for the Lundbeck
Institute, for serving on the
international scientific advisory
Murray Grossman, MD, FAAN; David J. Irwin, MD board of the Max Planck
Institutes, and for serving as
associate editor of Neurology.
Dr Grossman’s institution has
ABSTRACT received grant support from
Purpose of Review: This article describes a comprehensive approach to the mental the National Institutes of
Health (AG017586, AG038490,
status examination and diagnostic workup of patients suspected of having an NS044266, and NS053488),
emerging neurodegenerative dementia. Key strategies for obtaining a history and and Dr Grossman has received
bedside examination techniques are highlighted. research support from the
Arkin Family Foundation, the
Recent Findings: Classic descriptions of behavioral neurology syndromes were Samuel I. Newhouse
largely based on clinicopathologic correlations of strategic lesions in stroke patients. Foundation, Inc, and the
While still very important, advances in neuroimaging have expanded our armamen- Wyncote Foundation.
Dr Irwin’s institution receives
tarium of cognitive evaluations to include assessments of findings in nonstroke grant support from the National
anatomic distributions of disease. These efforts support comprehensive assessments Institutes of Health and the
of large-scale cerebral networks in cognitive neurology. National Institute of Neurological
Disorders and Stroke
Summary: A thorough and focused mental status examination is essential for the (K23NS088341-01).
evaluation of patients with cognitive symptoms. Selective use of laboratory testing and Unlabeled Use of
neuroimaging can aid in the diagnosis of dementia by excluding non-neurodegenerative Products/Investigational
Use Disclosure:
etiologies. Neurodegenerative diseaseYspecific tests are in development and will Drs Grossman and Irwin
enhance diagnosis and efforts for disease-modifying therapy development. report no disclosures.
* 2016 American Academy
Continuum (Minneap Minn) 2016;22(2):385–403. of Neurology.

INTRODUCTION not easily localized to a single ana-

The mental status examination is a key tomic structure. Rather than localizing
component of a complete neurologic an impairment to a specific anatomic
examination. The neurologic exami- locus, our perspective on brain-behavior
nation is structured to assess different relationships is more consistent with
elements of the neuraxis, and the men- an approach focusing on the disruption
tal status examination largely targets the of a large-scale neural network or con-
cerebrum. Like the elemental neurolog- nectome.1Y7 In this approach, each net-
ic examination, the mental status exam- work is composed of multiple gray
ination is organized into subsections to matter nodes that are interconnected
assess each major domain of cognition. by projections within the white mat-
Cognitive processes and behaviors like ter, and these white matter tracts serve
memory, language, visual-perceptual- to integrate the functioning of the gray
spatial functioning, and executive func- matter nodes. From this perspective,
tioning are targeted. These processes disease disrupting some of the nodes
are very complex. Therefore, the cog- or projections of a cerebral network
nitive functions that are interrogated may compromise a complex cogni-
by the mental status examination are tive function. The quality of cognitive

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 Mental Status Examination

KEY POINTS
h The mental status disruption depends, in part, on the tive impairment of specific components
examination is structured component (or components) of the of the mental status examination, it is
to probe each major network that are disrupted. Indeed, often the overall pattern of cognitive
cognitive domain any gray matter node may contribute performance across multiple compo-
(attention, memory, to multiple networks. While the as- nents that is most informative. For ex-
language, visuospatial sessment of a patient can reveal selec- ample, in Case 1-1 there is a relatively
perception, executive
functioning, and
social comportment).
Case 1-1
h Cognitive function is A 67-year-old woman, who worked as a lawyer, presented for a neurologic
mediated by large-scale evaluation accompanied by her son, who was concerned about slowly
networks or progressive problems with her memory. While she felt that nothing was
connectomes, where wrong, her son stated that she had been misplacing her keys and forgetting
gray matter nodes are the words she wanted to use in a sentence. She also had trouble remembering
interconnected by names of acquaintances. The son also stated that he was concerned that she
white matter tracts. was asking the same questions repeatedly during the course of a day, and she
h Any gray matter node had made some errors at work that had caught the attention of her coworkers.
may contribute to On her screening Mini-Mental State Examination (MMSE), the patient scored 27
multiple cognitive out of 30. Additional screening identified difficulty with a list-learning task,
networks. in which she learned 5 out of 6 words of a 6-word list in three trials, but
subsequently could not recall any words following a 1-minute delay. Presentation
h While the assessment of
of cues and semantic foils found poor recognition, with only 2 out of 6 words
a patient can reveal
recognized. Similarly, construction of a modified Rey-Osterrieth figure (Figure 1-1)
selective impairment of
showed poor organization with minor spatial displacement and omissions,
specific components
while reproduction of the figure 1 minute later revealed minimal recall. There
of the mental status
was mild difficulty in an oral trials test, and digits recited forward were seven
examination, it is
and backward were five. Her brain MRI showed moderate bilateral hippocampal
often the overall
volume loss. Despite her mild symptoms, her high level of education and
pattern of cognitive
premorbid functioning together with the relative predominance of memory
performance across
impairments raises the question that her diagnosis is suspicious for a mild
multiple components
stage of Alzheimer disease (mild cognitive impairment, amnestic type).
that is most informative.

FIGURE 1-1 Modified Rey-Osterrieth figure. Construction

of a modified Rey-Osterrieth figure by the
patient in Case 1-1 reveals some poor
organization with minor spatial displacement (arrow) and
omissions (asterisks).

Continued on page 387

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 KEY POINTS
Continued from page 386 h A single mental status
Comment. This case vignette illustrates several key points in the cognitive examination obtains only
examination of patients with neurodegenerative disease. First, the importance a cross-sectional
of the mental status history in helping to differentiate benign forgetfulness perspective of a patient’s
and more clinically worrisome symptoms is noted by the reports of work performance. A history
performance concerns based on memory symptoms. Next, there are relative of slow progression or
imbalances in this patient’s performance across tasks (ie, relative worse observed longitudinal
episodic memory performance compared to visuospatial and executive decline on serial cognitive
functioning, rather than isolated deficits in one cognitive domain), which is examination testing
a common occurrence. Finally, the patient’s high level of education may have is required to make
influenced her performance on bedside testing, which illustrates the need a diagnosis of
to account for patient factors in interpretation of cognitive evaluations. a neurodegenerative
dementia.

greater deficit for episodic memory guide cognitive functions that should h The neurologic history is
an important component
compared to other cognitive domains, be ascertained.
to determine the onset,
which suggests the diagnosis of mild It is also important to consider the
tempo, and associated
Alzheimer disease (AD). There are sev- mental status examination in the con- features of the cognitive
eral important caveats to consider when text of other medical and neurologic symptoms. These
administering a mental status examina- features. Attention to elementary neu- factors help direct the
tion. First, the mental status examina- rologic features that are not reflected specific features to focus
tion can be quite lengthy. Like other in the mental status examination will on during examination.
aspects of the neurologic examination, enhance the interpretation of cogni-
it is valuable to tailor the mental status tive findings. It is helpful for cognitive
examination to the most pertinent pos- neurologists to consider involuntary
itive findings and negative features. This movements, for example, in approach-
kind of editing process benefits enor- ing their mental status examination.
mously from a mental status history and Conversely, attention to the mental status
the larger medical history. Indeed, a examination by neurologists treating
single mental status examination ob- neuromuscular or movement disorders,
tains only a cross-sectional perspective such as amyotrophic lateral sclerosis
of a patient’s performance at a given (ALS) or Parkinson disease (PD), are
period of time, and longitudinal assess- important due to the high frequency of
ment is often very informative. cognitive difficulties in these patients.8,9
A detailed mental status history is Furthermore, the mental status exam-
important to determine onset, time ination may be significantly influenced
course, and progression of symptoms by demographic features of the patient.
that influences the differential diagno- Thus, factors such as education, age,
sis. For example, the pace of disease and cultural background can have an
progression may be characterized as important impact on cognitive and
an acute decline that can be seen fol- behavioral functioning. For example,
lowing a stroke or head injury, or sub- education may influence baseline vo-
acute decline that can be associated cabulary and other cognitive skills, age
with an infectious or neoplastic pro- may influence executive functioning,
cess, or a slow, insidious change that is and ethnicity may influence familiarity
most often associated with a neurode- with specific objects or social norms.
generative condition. Since each of these Consequently, performance expecta-
time courses may be associated with a tions should be adjusted to accom-
particular pattern of cognitive and be- modate individual differences, as
havioral impairment, the history can help illustrated by Case 1-1. In these

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 Mental Status Examination

KEY POINTS
h Each cognitive domain scenarios, formal neuropsychological NEUROLOGIC HISTORY
should be probed during testing using standardized examina- After obtaining a patient’s chief com-
the history, similar tions with normative scores scaled for plaint, reviewing the history of the in-
to a medical review age and education can be useful and dividual’s cognitive and behavioral
of symptoms. compliment observations from bed- symptoms is essential. In addition to
h Differentiating side evaluations. A number of comput- querying the nature of the onset and
age-associated memory erized cognitive test batteries are pace of cognitive change, each major
decline from pathologic available, but these are often limited in domain of cognition and behavior
etiologies is challenging. their scope and testing by computer should be probed, similar to a review
Mental status history often does not replicate the result of of systems. This is critical since an in-
should include details on testing administered by a human. Fi- dividual’s chief complaint may not re-
the functional impact nally, it is also important to be mind- flect the true nature of the disorder.
of problems associated ful of an individual’s current mental For example, a patient’s reported
with aging and state. Poor sleep, anxiety/depression, or memory difficulty may indicate prob-
recognition of a problem
side effects of a medication in the in- lems remembering words (ie, word-
by others.
dividual’s regimen may interfere with finding difficulty) rather than problems
remembering recent events (ie, epi-
concentration and level of functioning.
sodic memory difficulty). It is also
If there is suspicion of a neurode-
important to review reported cognitive
generative disease upon the conclusion
and behavioral symptoms with a family
of a detailed mental status examination,
member or close friend because there
it is important to judiciously consider is often limited insight in one’s own
ancillary laboratory and neuroimaging cognitive functioning.
studies to help support the diagnosis
and exclude non-neurodegenerative Memory
etiologies. Indeed, a range of toxic, Memory difficulties can be probed by
metabolic, inflammatory, neoplastic, asking about problems learning and
paraneoplastic, or infectious etiologies recalling new information, as well as
can mimic neurodegenerative diseases. forgetfulness. Individuals may forget
Diagnosis of these conditions is critical, conversations and repeat questions
as disease-specific treatments may need about recent activities. Forgetting to
to be implemented. Conversely, labora- pay bills or paying bills twice and going
tory and neuroimaging investigations to the store and purchasing the same
can be initially equivocal or normal in food items repeatedly represent worri-
early neurodegenerative disease; thus, some memory difficulties, as in Case 1-1.
a careful mental status examination is By comparison, minor memory prob-
the first line in detecting these condi- lems associated with aging, such as mis-
tions. This is of critical importance as placing keys and difficulty finding a car
earlier diagnosis and implementation of in a parking lot, are less concerning.
supportive care can improve quality of
life, prevent comorbidities, and reduce Language
caregiver distress. As disease-modifying Many patients may report a decline
treatments emerge, patients are likely in language production and may
to benefit from the earliest possible experience word-finding difficulty.
administration of these interventions. Sometimes this can take the form of
This article reviews the mental status trouble retrieving the name of a family
examination with exemplary case vig- member or familiar friend. At other
nettes and discusses the diagnostic times, patients may report difficulty re-
evaluation and emerging biomarkers trieving the names of objects. Some-
for neurodegenerative diseases. times individuals will report substituting

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one word for another or mispronounc- (eg, over the telephone), and reading
ing words. These are lifelong findings and writing difficulties. It is important
that increase in frequency as individuals to ascertain whether these symptoms
age, and, thus, symptoms of this sort are truly a disorder of language, such
are challenging to evaluate and should as spelling difficulty when writing, or
be investigated carefully since they reflect another source of difficulty, such
may represent an exaggeration of as motor weakness interfering with
otherwise healthy aging. Other com- mechanical aspects of writing. It is im-
monly reported symptoms include portant to consider other nonlanguage
effortful speech, as in Case 1-2, difficul- etiologies that contribute to these
ties with comprehension of speech symptoms, including reduced auditory

Case 1-2
A 62-year-old woman who worked as a phone operator reported difficulty
getting her words out. She stated that she worked at a busy switchboard
for a large building complex, and she had become easily overwhelmed
with complex tasks and had stopped working as a result. She stated that
she was aware of the words she would like to use but had difficulty
producing them, which caused her great frustration. Her daughter felt
impatient waiting for her mother to finish a sentence, which caused a
significant depressed mood for the patient, but she had no other behavioral
changes. She noticed that she had made more spelling errors lately.
Mental status examination found a Mini-Mental State Examination
(MMSE) score of 28 out of 30, with two points lost for difficulty spelling
‘‘world’’ backward (the patient spelled ‘‘D-L-O-R-W’’). She had significant
difficulty with executive functioning including oral alternation between
letter and number sequences and reciting digits backward. She also had
some minor difficulty with an alternating manual manipulation task (ie,
Luria three-step maneuver to pantomime an alternating sequence of hand
gestures), a measure of executive functioning. Her speech was slow and
hesitant. Sentence length was short with simplified grammatical structure
to her speech and rare frank agrammatisms. Verbal comprehension for
simple commands like ‘‘fold a paper in half and put it on your lap’’ was
preserved, but she had difficulty with the request to ‘‘point to the ceiling
after you point to the floor’’ due to grammatical comprehension difficulties.
She had preserved single word and object knowledge and could readily
identify and describe line drawings and objects. Reading and writing were
comparable to her oral language. The patient did not exhibit limb apraxia
but she had difficulty pantomiming how to ‘‘blow out a match’’ or ‘‘suck
in through a straw,’’ indicating orobuccal apraxia.
She was asked to describe a children’s photo book depicting a scene
where a boy’s pet frog sneaks out of his bedroom in the middle of the
night. The patient’s response was as follows: ‘‘And the dog and the boy
was oo- eh sleeping, on the baw- eh the- the, um, the uh, bed. And uh...
the uh, the- the frog (2.7 second pause) emptied- of the- move the- the
glass, ba- bottom... and go to... uh... uh, w- wo wook goo could do anything.’’
Comment. This patient was diagnosed with the nonfluent variant of
primary progressive aphasia due to her relatively isolated grammatical
comprehension and expression difficulties with executive limitations and
preserved single word/object comprehension.

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 Mental Status Examination

KEY POINTS
h Visual-perceptual-spatial acuity, visual acuity limitations, or other ning, as in Case 1-3. Individuals may
difficulties may be sensory-motor deficits. describe challenges executing previ-
difficult to elicit through ously familiar multistep activities such
history. Common Visual-Perceptual-Spatial as cooking a meal, organizing a trip, or
examples include Performance maintaining the household. Family
difficulty navigating a Visual-perceptual-spatial symptoms are members may have noticed a change
car, finding objects in often challenging for patients to report in the patient’s lifestyle, with the indi-
the home, recognizing because of problems articulating day- vidual no longer engaging in activities
faces or objects, or to-day examples. There may be diffi- outside of the home, requiring others
difficulty dressing. culty driving, such as frequent fender to initiate activities or talk the individ-
h Detecting social and benders or difficulty with parallel ual through the steps of the task. Indi-
personality changes parking. An individual may struggle viduals may have difficulty completing
associated with when trying to find an object in a tasks that have been started because
neurodegenerative complex visual scene, such as identify- of easy distractibility. Driving is a dual-
dementia often requires
ing a specific jar in a pantry. Patients tasking environment, and driving
a careful history from a
may have difficulty recognizing faces difficulty may be related to limited
reliable informant who
spends significant time
or objects and may find it necessary executive resources. The patient may
with the patient. to hear a person’s voice or an object’s exhibit limited attention or fluctuating
associated sound prior to recognition. levels of attention.
Difficulty dressing may reflect a visuo-
spatial symptom, and there may be Social and Personality Changes
difficulty negotiating space around the Family members may note a significant
home, and falls may occur because of change in the patient’s personality, while
lateralized neglect. It is important to patients with social difficulties often
rule out deficits of coordination or the have limited insight, as in Case 1-3. De-
extrapyramidal system that can influ- tecting social and personality changes
ence these symptoms. necessitates a careful mental status
history from a reliable companion.
Executive Functioning There may be some obvious
Dysexecutive symptoms often reflect changes suggesting disinhibition,
difficulty with organization and plan- which may take the form of frequent

Case 1-3
A 54-year-old man developed slowly progressive behavior and personality
changes. His wife reported that she first noticed a change when he became
less interested in socializing approximately 3 years earlier. He formerly would
be well dressed but had begun to wear the same ripped sweatpants daily.
He approached strangers to tell them his political views, which included racist
and sexist comments that most would find offensive, and his wife claimed
that these were not his previous beliefs. This behavior caused considerable
interpersonal relationship problems both at home and at his employment as a
salesman, although he questioned why his family found his behaviors to be
objectionable. He showed no concern for his brother’s recent cancer diagnosis.
After eating large amounts of food, he left his cousin’s wedding unexpectedly
and was found watching television in his hotel room. On one recent occasion he
sent large sums of money to a stranger over the Internet who claimed to
be a prince from another country. He demonstrated increasing difficulty
performing multistep activities at home, such as making a sandwich for lunch.
Continued on page 391

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Continued from page 390
Mental status examination revealed difficulty with attention and poor
social discourse (he interrupted the examiner on several occasions with
tangential comments). He could not perform a complex oral alternating
pattern (continuing an oral sequence that begins with A-1-B-2-C-3I) and
made several perseverative errors throughout testing, indicating poor
set-shifting ability. He inappropriately tapped his fingers on the desk and
whistled a repetitive song during the majority of the examination. A brain
MRI showed atrophy in the orbitofrontal and medial frontal lobe and the
insula on the right with similar but less pronounced change in the homologous
regions of the left hemisphere, consistent with the behavioral variant of
frontotemporal dementia (bvFTD) (Figure 1-2).

FIGURE 1-2 Knife-edge cortical atrophy in the behavioral

variant of frontotemporal dementia.
Parasagittal T1 MRI of the right
hemisphere of the patient in Case 1-3 displaying significant
dorsolateral, orbitofrontal, and perisylvian atrophy in the
frontal lobes and severe anterior and medial temporal
atrophy in the right hemisphere greater than the left
hemisphere (arrows). There is relative preservation of
posterior cortices, resulting in a dramatic knife-edge
appearance of the border between precentral gyri and
postcentral gyri.

Comment. This case illustrates the range of social and behavioral

impairments commonly seen in bvFTD. Furthermore, this patient exhibited
only mild executive impairments, which is common early in the course of
bvFTD as patients can have largely a social disorder with minimal cognitive
deficits. Finally, social cognition is difficult to assess without a reliable
informant due to the reduced insight in patients with bvFTD.

rude or inappropriate comments in- may exhibit hypersexuality in the

volving strangers, or engaging in form of sexual jokes, viewing pornog-
overly familiar behavior or sharing raphy on the Internet, or inappropriate
confidential information. The patient touching of strangers. Episodes of

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 Mental Status Examination

KEY POINTS
h Social comportment is explosive agitation and rage without harmful events for others, as evidenced
difficult to assess in apparent provocation may be seen. An by Case 1<3. There may be limited in-
the mental status individual may become apathetic and sight into the motivations of others,
examination and often have difficulty initiating activities. Flat- which can result in a range of behav-
requires a thorough tening of affect and a loss of the normal iors, such as investing in scams or fail-
history from a variety of emotions may be seen. Al- ing to acknowledge significant events
reliable informant to ternatively, the patient may exhibit ex- in the lives of others, such as the death
be detected. aggerated and childlike emotional of a spouse.
h It is important to inquire expressions. There may be ritualistic These behavioral changes are com-
about activities of daily behavior such as the development of monly associated with the behavioral
living to identify potential unusual and repetitive habits and col- variant of frontotemporal dementia
safety issues that could lections, and the emergence of novel (bvFTD) and forms of primary progres-
result in morbidity religious beliefs or political interests. sive aphasia, but can be also seen in
and mortality from Socially intrusive simple repetitive be- other neurodegenerative conditions.
cognitive impairment.
haviors also can be seen such as clap- Indeed, there is significant overlap of
ping, tapping, and humming. Hoarding frontotemporal dementia (FTD) symp-
of unusual collections of objects may toms with atypical parkinsonian disor-
occur. Hyperoral behavior may become ders (eg, corticobasal degeneration and
evident, such as shoveling food into the progressive supranuclear palsy) and
mouth, continuing to eat even though ALS.10,11 Furthermore, apathy and de-
the individual is sated, or oral explora- creased motivation are not uncommon
tion of nonedible substances. There in AD and PD. Impulse control disor-
may be a strong preference for sweets der seen in PD may also resemble fea-
or carbohydrates, and an individual tures of FTD.12
may gain substantial weight over a
very brief period of time. There may Activities of Daily Living
be shoplifting as the result of hyper- Safe execution of activities of daily living
oral behavior or attraction to shiny is essential for minimizing morbidity
objects. Utilization behavior involves and mortality in patients with cognitive
unavoidably using objects such as a impairment, so it is important to ask
patient picking up a pen on the desk about activities of daily living. Specific
and signing his or her name. Patients activities of daily living should be
may perseverate or exhibit echolalic or probed, including bathing, toileting,
echopractic behavior that mirrors the eating, and dressing, as difficulties could
behaviors of others. Frequently, the lead to falls, aspiration, or infection. It
patient may have limited insight into is also important to note if patients
these changes in behavior and may be have difficulty managing complex tasks
bewildered by the concerns of others that can have dangerous consequences
or may express childlike denial. Diffi- such as cooking and administering
culty with perspective taking also can medications. Access to finances and
interfere with social interactions, which the Internet or telephone should be
can be seen commonly in conversation- assessed to protect patients with frontal
al or behavioral exchanges where there disease and poor judgment from being
may be limited empathy for a conversa- financially exploited, as in Case 1<3.
tional partner. Frequent interruptions Finally, determining the level of super-
with tangential comments and poorly vision provided on an average day is
organized narrative speech (ie, poor important in more severely impaired
social discourse) may be seen. Likewise, patients in order to prevent wandering
there are inappropriate responses to or other dangerous events.

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 KEY POINTS
MENTAL STATUS EXAMINATION common method involves presenting h Screening cognitive
Several brief mental status assessment an individual with a list of words at a instruments provide a
tools have been developed for ease of pace of about one per second, and then brief sample of different
use in a busy clinical setting. These can asking the individual to repeat the cognitive domains that
be used at times to serve as screening words in order to confirm registration. can be useful to track
devices and may be useful for following The individual is asked to retain the patients longitudinally
an individual longitudinally. However, words in memory during the perfor- but do not substitute for
mance of another task in order to block a thorough examination.
these screening instruments should not
be considered a reasonable substitute subvocal repetition and to examine h Episodic memory is
for a comprehensive mental status exam- fading of the memory trace over time. often tested by using
ination. Examples of brief instruments Subsequently, recall is requested. There list-learning tasks where
are many variations of this basic format. a sequence of words is
include the Mini-Mental State Exam-
The number of words in the list may repeated after several
ination (MMSE),13 the Addenbrooke
vary from three up to 15, and the num- trials and then recalled
Cognitive Examination (ACE),14 and the after a brief delay.
Montreal Cognitive Assessment (MoCA).15 ber of repetitions requested may vary
Recognition is assessed
Each of these brief surveys covers slightly from one to five, depending on the
through use of cues or
different domains. There are also several level of difficulty that is sought and the semantic foils. Difficulty
more comprehensive but slightly longer desire to document a learning curve. can be adjusted
surveys that probe all of the major cog- The amount of time between presen- depending on length of
nitive domains. One example is the tation and recall may vary from list and delay time.
Philadelphia Brief Assessment of Cogni- 30 seconds to many minutes. In the
tion.16 A more comprehensive mental event of failure to recall some of the
status evaluation of each cognitive do- target words, prompts can be offered.
main is outlined in the following sections. These can include a superordinate cue
(eg, a kind of clothing) or a rhyming
Attention word (eg, sounds like ‘‘block’’). After
It is valuable to begin the mental status spontaneous recall and prompted re-
evaluation with a consideration of at- call, a recognition procedure may be
tention. This can be derived in part administered. During this phase, some
during the history by observing whether of the previously mentioned target
the individual is maintaining a reason- words are offered, intermixed among
able, sustained level of arousal or is foils that may be semantically similar
easily distracted. A more systematic to the target, phonologically similar to
approach is obtained by performing a the target, or random words. In the
simple assessment of vigilance. This authors’ screening mental status eval-
can involve asking an individual to lift a uation, we administer a six-word list
hand whenever a target letter (eg, A) is presented for three learning trials, use
heard in a string of random letters a 1 minuteYfilled interval, obtain free
delivered at a pace of about one per recall, and administer a yes-no recog-
second. Alternatively, repetition of a nition procedure for words that are
sequence of digits can be performed, not remembered during free recall. We
starting at two and gradually increas- monitor the number of words pro-
ing the digit length, delivering the digits duced during learning trials to see if
at a rate of one per second. Seven digits there is a learning curve, the number of
or more is considered normal. words freely recalled, and recognition
accuracy. Regardless of the examiner’s
Memory preferred form of episodic memory
There are several different ways to as- testing, it is important to document the
sess episodic memory. Perhaps the most parameters used to assess memory.

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 Mental Status Examination

KEY POINTS
h Nonverbal methods Other memory tasks can include ask- tation can be viewed as a test of
of testing memory, such ing an individual to listen to a sentence incidental memory. In the authors’ as-
as figure-recall tasks, are or a paragraph and then probing recall sessment of memory, we include eval-
useful in patients of the sentence or paragraph at a later uation of incidental recall of a visual
with significant time. A memory score is derived from geometric design. Other forms of mem-
left-hemispheric disease. the ability to recall critical key words ory that can be assessed include habit
h Language dysfunction from the sentence or paragraph. In ad- learning (ie, asking an individual to
can be detected during dition to verbal memory, assessing epi- repeat a sequence of novel hand ges-
the clinical examination sodic memory recall with another kind tures), semantic memory (ability to rec-
through identification of of material is often helpful as this mini- ognize familiar but infrequent objects
abnormal prosody,
mizes confounds associated with the [eg, a shoehorn] and to answer ques-
word-finding pauses, tions about these objects [eg, ‘‘Is it
specific learning material and depen-
circumlocutions, found in the kitchen?’’]), auditory-verbal
grammatical dence on left hemispheric function. One
method is to perform episodic mem- short-term memory (repetition of digits,
sophistication, and
ory testing using visual presentation of multisyllabic words, and sentences of
frank agrammatisms in
words or recall of a visual geometric various lengths), and working mem-
spontaneous speech.
ory (reproducing a list of digits in the
h Language comprehension design. Recall of a visual geometric de-
reverse order of presentation). Further
should be performed on sign often takes the form of copying a
details on object knowledge/semantics
the single-word and visual design, removing the target de-
and working memory are discussed in
sentence level. Single-word sign and its copy, engaging the individ-
comprehension can be
the sections on language and executive
ual in another visual-perceptual-spatial
assessed through word functioning that follow.
activity for a brief period of time, and
and object meaning and
then asking the patient to reproduce Language
sentence comprehension
through repetition and
the visual design. As with verbal episodic Language is a complex process that is
verbal commands of memory, visual episodic memory test- crucial for daily functioning. Several
sequenced tasks. ing can be manipulated by varying the components of language should be as-
complexity of the visual stimulus, the certained in a comprehensive mental
meaningfulness of the stimulus (eg, a status evaluation. We first evaluate
nameable design such as a clock face or single-word processing. During speech
a non-nameable multicomponent geo- production, listening for word-finding
metric design), and the amount of time pauses and circumlocutions is impor-
between presentation and recall (refer tant. An individual also may make
to Case 1<1 for an example). Recogni- frequent lexical substitutions or speech
tion for elements of a visual stimulus sound errors. Confrontation naming is a
(eg, the position of the clock hands) more formal way to assess single-word
can be tested as well. use and word finding and typically takes
These verbal and visual memory tests the form of asking an individual to
involve an explicit request to learn, name a pictured object or a real object.
remember, and then recall specific The frequency of the word’s occur-
information (ie, intentional memory). rence and familiarity of the target object
In our daily lives, we often also learn can be manipulated. Confrontation nam-
and retain information without con- ing also can be assessed using other
scious effort (ie, incidental memory), nonvisual modalities. Thus, naming can
and it is not unreasonable to assess be performed in response to a sound or
incidental memory by asking an indi- the feel of a target object. This is im-
vidual to recall words or designs when portant for an individual who has
there is no explicit request to remem- difficulty with visual-perceptual-spatial
ber at the time of presentation. Orien- functioning. Some patients may have a

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 KEY POINTS
modality-specific naming problem in- quality of speech, in which prosodic h Lexical comprehension
terfering with interpretation of a visual difficulty may be reflected in a limited should be assessed in
stimulus such as visual agnosia, while a or exaggerated range of pitch. Disrup- parallel with assessment
more general deficit in semantic mem- tion of the coordination of the motor of object meaning in
ory interferes with interpretation of an speech apparatus may occur, such as semantic memory. This
object in any modality. apraxia of speech, where the timing of can be done by asking
Comprehension can be assessed for speech is irregular and speech sound for the definition of a
a word, paralleling the assessment of errors are produced that consist of single word or asking to
the representation of object meaning sounds that are not from the native name attributes of a
in semantic memory. Lexical compre- speaker’s lexicon. This should be dis- word’s referent.
hension can be assessed by asking an tinguished from dysarthria, which is a h Apraxia of speech refers
individual to provide a definition of a dysfunction of the muscles involved in to disruption of
word. Word meaning can be assessed speech. Sentence comprehension can coordination of the
in a multiple-choice manner as well. be assessed by asking an individual to motor speech apparatus
and should be
Specific attributes of a word’s referent perform a brief series of simple tasks
distinguished from
can be assessed as well, such as asking in the mentioned order. Sentence com-
dysarthria, which is a
whether a camel lives in the ocean or prehension also involves a uniquely dysfunction of the muscles
whether asparagus is red in color. An language component, namely, grammar. involved in speech.
individual also can be asked whether An individual can be asked to point to
h Grammatical
two words are from the same category, objects in an order that differs from the
comprehension can be
such as deciding whether a lemon and order of mention through the use of a assessed through use of
an apple are both fruit. preposition, as in Case 1<2. Also, an simple questions of
Language comprehension should individual can be asked to choose the ‘‘who did what to
also be assessed at a multiword or sen- agent of an action in a simple, brief whom’’ in sentences
tence level. Sentence processing is a sentence such as ‘‘It was the boy that with increasing
complex process. Since words in a sen- the girl chased. Who did the chasing?’’18 grammatical complexity
tence emerge over time, it is valuable to It is also important to assess written (ie, ‘‘The car that hit the
assess repetition, a form of auditory- communication such as reading and truck was green. Who
verbal short-term memory. Repetition writing. Letter-by-letter reading involves was hit?’’).
can be assessed by asking an individual slowed interpretation of the geometric h Surface dyslexia is the
to repeat a monosyllabic word, a mul- shapes that constitute a written word, reading of a sight
tisyllabic word, a multisyllabic phrase, and, thus, the amount of time needed (orthographically irregular)
and sentences of various lengths. In to read a word is directly proportional word that requires
sentence expression, pathologic speech to its length. Single-word reading also semantic knowledge
rather than phonetics for
is often characterized as effortful. The assesses the spelling system. In English,
proper pronunciation,
rate of nonfluent speech production is many words involve letter-sound corre-
examples of which include
about 45 words per minute (refer to spondence rules, and this can be as- cough, choir, and pint.
Case 1<2 for an example), much slower sessed by asking an individual to read a
than the normal adult speech rate of pseudoword such as ‘‘tig.’’ English also
more than 140 words per minute.17 contains sight vocabulary words, and an
There may be omissions of bound or individual with surface dyslexia who
free grammatical morphemes (ie, cannot correctly pronounce sight words
words, prefixes, or suffixes with gram- (ie, orthographically irregular) like
matical function), giving speech a dough, choir, or pint will often attempt
telegraphic quality. It is important to to pronounce them using letter-sound
listen for the variety of grammatical correspondence rules. Reading compre-
forms used in conversational speech. hension can be assessed by asking an
Other errors in speech include dis- individual to perform a simple written
orders of prosody, or the sing-song act, such as ‘‘Close your eyes.’’ Spatial
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 Mental Status Examination

KEY POINTS
h Executive impairment neglect can interfere with reading, and tion). Perhaps the simplest assessment
can cause impairments this can be demonstrated by asking an of visuospatial functioning involves the
in construction tasks individual to read a compound word location of an object in space, which
through poor such as cowboy. Writing can be as- can be tested by asking an individual to
organization and sessed by asking an individual to write reach for an object. An individual also
omission of elements. In to dictation, including both words that can be asked to imitate a meaningless
contrast, visuospatial obey letter-sound correspondence gesture, such as placing the dorsum of
impairments manifest in rules and orthographically irregular one hand against the contralateral
spatial displacements words. A motor coordination disorder cheek. A more formal assessment of
and distortions on known as apractic agraphia results spatial relationships includes the judg-
construction tasks.
in difficulty with the automatic me- ment of line orientation, where an
h Visuospatial function chanical formation of letters, which individual is asked to evaluate whether
can be assessed through will significantly slow writing. It is a pair of lines is parallel. An element of
construction of figures important to keep in mind that liter- visuospatial functioning may involve
with varying familiarity
acy is highly variable, and reading and part-whole discrimination, also known
and complexity.
writing abilities will vary depending as simultagnosia. One task frequently
h Ideomotor apraxia is on experience. used to assess this involves using many
difficulty in small letter A characters to form a
demonstrating learned Visual-Perceptual-Spatial shape that looks like a large letter E
gestures. Transitive Functioning (ie, Navon figure)21 and asking an
gestures involve use of
tools while intransitive
Visual-perceptual-spatial functioning is individual to name the letter. Individ-
gestures do not involve an important aspect of the bedside uals with difficulty involving whole-part
an implement. mental status examination that is fre- discrimination name the small letter and
quently neglected. Perhaps the most do not recognize that these are in a
common assessment involves copying configuration forming a large letter.
a visual geometric design. The design Another visual-perceptual-spatial task
itself may vary in complexity, from a involves face processing. An individual
simple nameable geometric form to a can be asked to recognize a photo-
nameable object or a more complex graph of a famous face. It is also pos-
non-nameable geometric design. Ex- sible to use the examiner’s face as a
amples include overlapping pentagons stimulus and query whether there are
and the more complex designs devel- features such as a full head of hair or a
oped by Rey and Osterrieth or Benson beard. Visual agnosia may manifest
(refer to Case 1<1 for an example).19,20 itself as difficulty recognizing the visu-
These designs should be scored for al presentation of an object, although
accuracy as well as the manner in which the object can be recognized from its
they were executed. This includes poor sound or feel. Color processing can be
organization and the omission of ele- assessed by asking an individual to
ments, which may reflect executive name or recognize a color and asking
impairment and spatial displacements, whether two colors match.
such as the placement of an individual There are a variety of other disor-
component in an inappropriate spatial ders associated with diseases of the
location relative to other elements of parietal lobe that can be assessed as
the design. Sometimes one-half of a well. Apraxia is difficulty demonstrat-
figure can be impoverished or ne- ing learned gestures, which involves
glected. Spatial difficulty can interfere transitive gestures that use an imple-
with reading (eg, difficulty finding a ment such as demonstrating the use of
line on a printed page) and writing (eg, a hammer, or intransitive gestures that
spatially disordered written produc- do not involve an implement such
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 KEY POINTS
as waving good-bye.22 These gestures Executive Functioning h Higher-order parietal
can be elicited in response to a verbal Executive functioning is a complex lobe functions include
request or with imitation. Imitation domain that involves the efficient exe- calculations, cortical
(pantomiming) can help dissociate a cution of tasks. Perhaps the most com- sensation, left-right
disorder of verbal comprehension from mon assessment of executive functioning discrimination,
true apraxia. Oral praxis also can be as- is category naming fluency. This can somatosensory maps
sessed as well (eg, ‘‘blow out a match’’), involve naming words beginning with (ie, limb position),
and this does not necessarily track a target letter (eg, F) or naming words and apraxia.
apraxia of speech or limb apraxia, as from a target semantic category (eg, h Executive functioning
in Case 1<2. animals). Task performance is evalu- involves mental
Calculations and other assessments ated by counting the number of manipulation of
of number knowledge also are associ- words produced during a period of information and shifting
ated with the integrity of the parietal time, such as 60 seconds. Category between tasks. These
lobe.23 This can be assessed by asking functions can be tested
naming fluency in response to a target
through an alternating
an individual to select the one of two letter is a more challenging measure of
sequence of written,
numbers that is larger, to perform executive functioning, while the seman- oral, or manual tasks.
simple calculations orally or in writing tic guidance provided by a meaningful
(eg, 7 + 9 =___), or to solve a simple category like animals generally facili-
day-to-day problem that depends on tates category naming fluency. It can
calculations (eg, ‘‘How much change be informative to monitor whether
from a dollar should you receive after production is organized, such as nam-
buying a 65-cent candy?’’). Like spatial ing farm animals, then jungle animals,
aspects of reading and writing, spatial then varieties of fish. Another sign of
difficulties can interfere with the align- executive dysfunction is perseveration
ment of numbers in a multidigit cal- or difficulty shifting set between tasks.
culation and consequently result in a One sign of this is frequent repetition of
calculation error. Higher-order parie- words in category naming fluency. A
tal lobe sensory integration can be as- visual analogue of category naming
sessed by cortical sensation; a letter or fluency involves design fluency. The
a number can be written in the palm most common form of this measure
of the hand and named by the patient involves connecting a number of dots,
(testing for graphesthesia), or an ob- such as nine dots, to form different
ject can be placed in the hand and designs.
named (testing for stereognosis). Body Another common executive mea-
part localization can be assessed by sure involves alternating patterns. This
touching a body part of an individual entails performing a task, and then
with his or her eyes closed, and asking inhibiting that performance to perform
the individual to indicate the part of a second task. The material can be quite
the body that was touched. Left-right simple or more complex. Simple ver-
discrimination can be assessed by iden- sions of this kind of alternating task
tifying a body part bilaterally on an in- involve a simple rule such as tapping
dividual (eg, ears) and asking the once on a table when the examiner taps
individual to identify the right one or twice and not tapping when the exam-
the left one of the pair. A more difficult iner taps once. The examiner provides
assessment of left-right orientation a random sequence of single or double
asks an individual to identify the left tapping. Another variety of alternat-
or right body part on the examiner. ing pattern involves the examiner
Finger agnosia also may be evident in touching an individual’s right hand or
an individual with parietal disease. left hand in a random order with the

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 Mental Status Examination

KEY POINTS
h Working memory is the eyes closed, and the individual responds page and asking an individual to point
ability to hold and by lifting the touched hand. After this to these in an order reversing the
manipulate data. task has been well learned, the examiner order of demonstration.
Assessment of the reverses the association and asks the
number of digits individual to lift the right hand when Social Functioning and Behavior
recalled in reverse can the left hand is touched, and lift the Examination of social comportment is
be useful to test left hand when the right hand is challenging and often requires infor-
working memory. touched. More complex versions of mation from a reliable caregiver, as pa-
h Social functioning and alternating patterns involve reproduc- tients with ventral frontal disease often
behavior difficulties ing two intermixed, overlearned se- have little insight or concern into their
should be considered in quences, such as alternating production difficulties. There are several valuable
any patient who has of a letter and a number in ascending social questionnaires that can be com-
difficulties with social order, such as A, 1, B, 2, C, 3. This can be pleted by spouses, family members, or
discourse, simple performed orally or as a written trails close friends concerning changes in
repetitive motor rituals,
procedure, where letters and numbers personality, behavior, and social func-
or inappropriate behavior
are randomly distributed on a page tioning. Examples include the Neuro-
during the interview. A
reliable informant should
and an individual is asked to draw a psychiatric Inventory and the Frontal
be obtained to gather line between a letter and a number in Behavioral Inventory, which probe day-
additional history. ascending sequence. to-day functioning, looking for changes
Two related components include in personality and behavior compared
h A major limitation in
the development of
parsing a sequence into smaller, re- to baseline.24,25 The previous section
meaningful treatment peated units and inhibitory control. A on history details specific domains of
for neurodegenerative repeated series of three hand gestures social comportment that are affected
diseases is that is demonstrated to the patient three by frontal lobe disease. Observation
definitive diagnosis is times, and then the patient is asked to of patient interactions in clinic are
obtained only at autopsy. demonstrate the hand gestures. A mea- also important as detection of be-
sure intended to assess inhibitory con- havioral disinhibition, simple repet-
trol is a Stroop test, where words are itive motor rituals, and poor social
written in a colored font that differs discourse (Case 1<3) should prompt a
from the color name, and an individual more thorough examination for evi-
is asked to name the color of the font dence of social comportment disorder
and not read the printed word. When and executive limitations. Other be-
seeing the word ‘‘blue’’ printed in a red havioral and emotional changes that
font, for example, the individual is should be noted include depression
asked to respond ‘‘red.’’ and anxiety since these can be signif-
Working memory is often thought icant and can also interfere with the
to be a component of executive func- mental status examination.
tioning and involves the ability to main-
tain some material in an active form
and do some work on this material. DIFFERENTIAL DIAGNOSIS AND
Common tests of working memory ANCILLARY TESTING FOR
involve reproducing a list of numbers NEURODEGENERATIVE DISEASE
in the reverse order or reordering a A major limitation in the development
random sequence of letters and num- of meaningful treatment for neurode-
bers into their ascending orders, using generative diseases is that definitive
progressively longer sequences. A sim- diagnosis is obtained only at autopsy.
ilar kind of assessment can be per- Furthermore, significant clinicopatho-
formed in the visual domain by pointing logic overlap exists between neuro-
to randomly distributed circles on a degenerative diseases, and clinically

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

 KEY POINT
defined phenotypes of AD, PD, FTD, neurodegenerative condition. EEGs can h Careful selection of
and ALS often vary in the ability to be helpful to identify partial status ancillary laboratory and
accurately predict underlying neuro- epilepticus, or periodic discharges as- neuroimaging studies
pathology. This is of significance as sociated with prion disease, some can be useful to rule
emerging therapies are targeting steroid-responsive encephalopathies, out common
disease-specific misfolded proteins and other rapidly progressive demen- non-neurodegenerative
(eg, tau, amyloid-" [A"], synuclein). A tias. EEG recordings in neurodegenera- etiologies of cognitive
focus of current neurodegenerative tive disease usually show nonspecific impairment.
disease research includes early diag- slowing, although DLB may have fluc-
nosis as patients may potentially show tuations in slowing.33 CSF analysis can
a greater benefit from emerging be particularly useful to evaluate vascu-
disease-modifying therapies earlier in litides or other inflammatory conditions
the disease course.11,26Y28 This includes that can mimic neurologic conditions
focus on mild cognitive impairment that may not be evident in blood se-
(MCI) or prodromal states for AD, PD, rologic testing.34 The authors routinely
dementia with Lewy bodies (DLB), and check CSF protein, cell count, IgG
ALS.27,29Y32 Additionally, patients with levels, cytology, cryptococcus antigen,
FTD may often present with minimal and cultures in all patients with
cognitive dysfunction and feature def- suspected FTD, ALS, and atypical
icits that are largely restricted to social AD to rule out alternative non-
functioning.11 Moreover, many of the neurodegenerative etiologies.
cognitive and social deficits seen in Current biomarker research is aimed
neurodegenerative diseases also can at developing neurodegenerative
be manifested in non-neurodegenerative diseaseYspecific tests,11,27,28 and, cur-
disorders of the cerebrum. Thus, a rently, the only biomarker test ap-
detailed evaluation, including ancillary proved by the US Food and Drug
laboratory and neuroimaging studies, is Administration (FDA) is in vivo amy-
necessary to rule out common meta- loid imaging for AD using positron
bolic, toxic, inflammatory, or infectious emission tomography (PET) with
mimics of a neurodegenerative disease. amyloid-specific radiotracers. However,
In individuals without prior testing, due to clinicopathologic complexities in
it is often valuable to have additional aging and cognitive impairment, scan-
laboratory studies to supplement the ning is currently recommended only for
mental status examination and screen younger patients with a progressive
for common etiologies that can con- dementia, those with atypical AD clin-
tribute to cognitive impairment. Among ical symptoms, or unexplained pro-
these are a complete blood count, longed MCI.35 CSF measurements of
electrolyte panel, liver and kidney func- tau and A" can also be a potentially
tion tests, thyroid-stimulating hormone useful biomarker for AD neuropathol-
(TSH), vitamin B12 level, and sedimen- ogy. Indeed, an AD CSF signature of
tation rate. These may be supple- elevated total tau (t-tau) and phosphory-
mented depending on the specific lated tau (p-tau) with lower A"1-42 is
medical history and mental status highly consistent with AD and MCI at
examination findings. risk for progression to AD compared
Structural brain MRI images can help with cognitively normal controls, and
exclude cerebrovascular disease, neu- correlates well with AD neuropathology
roinflammatory conditions, or other at autopsy.36Y38 Lab-to-lab variation cur-
structural lesions such as hydroceph- rently precludes this test from being
alus or malignancy that can mimic a clinically available, but international
Continuum (Minneap Minn) 2016;22(2):385–403 www.ContinuumJournal.com 399

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

 Mental Status Examination

efforts to standardize detection assays if there is hypometabolism in fron-

will likely lead to clinical availability totemporal regions suggestive of FTD
in the near future. 39,40 AD CSF bio- in the absence of cortical atrophy. Fi-
markers also may have value in nally, FTD syndromes may be difficult
other neurodegenerative diseases. In- to differentiate from AD if episodic
deed, many patients with PD have memory or visuospatial difficulties are
considerable plaque and tangle pa- prominent. FDG-PET can identify pa-
thology at autopsy associated with de- tients likely to have AD neuropathology,
mentia, and low CSF A"1-42 may predict with posterior parietal and medial tem-
cognitive decline in PD.8,41 Additionally, poral hypometabolism, or DLB, which
lower CSF !-synuclein may differentiate may be characterized by parietal-
PD from normal control patients.42 Fi- occipital hypometabolism. The authors
nally, since half of all FTD cases and have also found high diagnostic accu-
virtually all ALS cases have a TDP-43 racy to differentiate atypical AD from
proteinopathy, CSF p-tau levels appear FTD in autopsy-confirmed CSF cases
to be lower than seen in tauopathies using the t-tau to A"1-42 ratio.46 Future
and healthy controls.43,44 Thus, CSF is a FTD-specific biomarkers will be useful
promising modality for neurodegener- to improve antemortem diagnosis, and
ative disease biomarker discovery. a combination of clinical, biofluid, and
The clinical diagnosis of FTD and neuroimaging modalities may be
primary progressive aphasia syn- most effective.11
dromes can be especially difficult as
these patients are usually younger, CONCLUSION
and some patients may have a non- The mental status examination has sev-
progressive neuropsychiatric condition eral components focused on each cog-
that resembles bvFTD (ie, phenocopy nitive domain (ie, attention, memory,
syndrome, which is a recently described language, visuospatial perception, ex-
clinical syndrome of nonprogressive ecutive functioning, and social com-
social comportment disorder that is portment). A thorough mental status
not due to underlying frontotemporal examination includes a detailed med-
lobar degeneration or other neurode- ical and neurologic history with focus
generative disease. The etiology of these on features of each cognitive domain
cases is currently unclear, but many are to guide the examination and provide
thought to be due to decompensated details for onset and tempo of disease.
psychiatric disease later in life and, thus, Several bedside assessments are effec-
clinically mimic bvFTD initially).45 Due tive in probing these areas and pro-
to the lack of biomarkers or laboratory viding insight into the underlying
tests that are specific for frontotemporal neurologic condition, and formal neu-
lobar degeneration neuropathology,11 ropsychological testing with normative
excluding these alternative etiologies scores can be helpful to detect subtle
with ancillary testing is important. In deficits in highly educated patients.
Case 1<3, ‘‘knife-edge’’ frontal atrophy Longitudinal assessment in neurode-
associated with FTD can be seen clearly, generative conditions that are char-
but many patients may have equivocal acteristically progressive can be
or no signs of cortical atrophy at diag- particularly informative. Finally, history
nosis despite florid behavioral changes. taking should include a detailed ac-
In these circumstances, fluorodeoxy- count of events at home for activities
glucose positron emission tomography of daily living to prevent cognitive
(FDG-PET) can be helpful to determine impairmentYinduced morbidity and
400 www.ContinuumJournal.com April 2016

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

mortality. Since neurodegenerative 9. Evans J, Olm C, McCluskey L, et al. Impaired
cognitive flexibility in amyotrophic lateral
disease diagnosis is obtained at au- sclerosis. Cogn Behav Neurol 2015;28(1):
topsy, careful evaluation with laboratory 17Y26. doi:10.1097/WNN.0000000000000049.
and neuroimaging testing is neces- 10. Irwin D, Lippa CF, Swearer JM. Cognition and
sary to rule out non-neurodegenerative amyotrophic lateral sclerosis (ALS). Am J
mimics. Emerging biomarkers for AD, Alzheimers Dis Other Demen 2007;22(4):
300Y312. doi:10.1177/1533317507301613.
PD, DLB, ALS, and FTD will be helpful
to improve diagnosis, especially in 11. Irwin DJ, Cairns NJ, Grossman M, et al.
Frontotemporal lobar degeneration: defining
early-stage or prodromal cases, which phenotypic diversity through personalized
will enhance development of mean- medicine. Acta Neuropathol 2015;129(4):
ingful disease-modifying therapies for 469Y491. doi:10.1007/s00401-014-1380-1.
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control disorders in Parkinson’s disease.
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 Review Article

Mild Cognitive
Address correspondence to
Dr Ronald C. Petersen, Mayo
Clinic, Department of

Impairment
Neurology, 200 1st St SW,
Rochester, MN 55905-0001,
[email protected].
Relationship Disclosure:
Dr Petersen serves on the Ronald C. Petersen, PhD, MD
board of directors for the
Alzheimer’s Association and
receives personal compensation
for serving as chair of the ABSTRACT
data monitoring committees
for Janssen Alzheimer Purpose of Review: As individuals age, the quality of cognitive function becomes
Immunotherapy and Pfizer an increasingly important topic. The concept of mild cognitive impairment (MCI) has
Inc. Dr Petersen receives evolved over the past 2 decades to represent a state of cognitive function between
personal compensation as a
consultant for Biogen, Eli Lilly that seen in normal aging and dementia. As such, it is important for health care
and Company, the Federal providers to be aware of the condition and place it in the appropriate clinical context.
Trade Commission, Genentech, Recent Findings: Numerous international population-based studies have been con-
Inc, Hoffmann la Roche, Inc,
and Merck & Company, Inc. ducted to document the frequency of MCI, estimating its prevalence to be between
Dr Petersen receives grant and 15% and 20% in persons 60 years and older, making it a common condition en-
funding support from the Mayo countered by clinicians. The annual rate in which MCI progresses to dementia varies
Foundation for Education and
Research, the National Institute between 8% and 15% per year, implying that it is an important condition to identify
on Aging, and the Patient and treat. In those MCI cases destined to develop Alzheimer disease, biomarkers are
Centered Outcomes Research emerging to help identify etiology and predict progression. However, not all MCI is due
Institute (PAT 206548).
Dr Petersen receives royalties to Alzheimer disease, and identifying subtypes is important for possible treatment and
from Oxford University Press. counseling. If treatable causes are identified, the person with MCI might improve.
Unlabeled Use of Summary: MCI is an important clinical entity to identify, and while uncertainties per-
Products/Investigational
Use Disclosure:
sist, clinicians need to be aware of its diagnostic features to enable them to counsel
Dr Petersen discusses the patients. MCI remains an active area of research as numerous randomized controlled
unlabeled/investigational trials are being conducted to develop effective treatments.
clinical trial results for mild
cognitive impairment.
* 2016 American Academy Continuum (Minneap Minn) 2016;22(2):404–418.
of Neurology.

INTRODUCTION of detecting very early clinical features

Identifying pending cognitive impair- of incipient disease.
ment at an early stage has become an Central to this diagnostic scheme
increasingly important challenge to is the clinical construct of MCI.2,3 MCI
physicians. Decades ago, it was satis- is generally regarded as the border-
factory to distinguish dementia from land between the cognitive changes
typical cognitive aging, but in recent of aging and very early dementia, but
years, the desire to make a more fine- while conceptually reasonable, the con-
grained decision on incipient disease struct poses difficulties in clinical prac-
has become apparent. In evaluating tice (Case 2-1A).4
persons for suspected Alzheimer dis-
ease (AD), the clinical spectrum from HISTORICAL ASPECTS OF THE
dementia has extended back to mild CONCEPT OF MILD COGNITIVE
cognitive impairment (MCI) and ulti- IMPAIRMENT
mately to preclinical AD, at which point Historically, the term MCI has been in
people are cognitively normal but har- the literature for almost 4 decades,
bor the underlying biological features with the initial use coming from in-
of AD.1 This puts the clinician in the vestigators at New York University
challenging but opportunistic position who referred to Stage 3 on the Global

404 www.ContinuumJournal.com April 2016

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

 KEY POINT

Case 2-1A h The Key Symposium

criteria for mild
A 66-year-old retired high school teacher presented for symptoms of
cognitive impairment
increasing forgetfulness, which he had begun to experience in the past 1
accomplished two
to 2 years. His other cognitive functions, including language, attention,
goals: (1) to broaden the
executive function, problem solving, and visuospatial skills, were all intact.
classification scheme
He continued to drive without difficulty and handled the financial matters
beyond memory, and
for his family without a problem. His wife had noted a slight increase in
(2) to recognize that mild
forgetfulness, but this had not been of concern to her. The patient noted that
cognitive impairment
he had been taking more time to remember previously well-remembered
could result from a
events such as appointments with his doctor, scheduled meetings with friends,
variety of etiologies
and planned visits with the children. He was not particularly disturbed by
and not just
these symptoms, and he had not made any major social mistakes. His
Alzheimer disease.
behavior was otherwise intact, and his mood was stable. He generally slept
well and did not admit to any features of dream enactment behavior. He was
concerned, however, because his mother had developed dementia later in
life and died of what was probably Alzheimer disease at age 81, and the
patient wanted to be assessed for the disease.
Comment. This scenario represents a common presentation to clinicians
with an aging patient population. This patient is more forgetful than he
formerly was and is worried about the possibility of a problem beyond
aging. This patient appears to have had progressive memory difficulties in
recent months to years. It did not appear that he had other extant medical
comorbidities that were influencing his condition. Mental status testing is
indicated and may provide further useful information, as is discussed in the
continuation of this case later in the article.

Deterioration Scale as being MCI.5 In incipient AD nor did all patients have
1999, a group at the Mayo Clinic de- just a memory impairment. To address
scribed subjects in their community this situation, the Key Symposium was
aging study who had a memory con- held in Stockholm, Sweden, in 2003,
cern beyond what was expected for and criteria of a more broad scope were
age and who demonstrated a slight published in 2004.2,7 These criteria ac-
memory impairment yet did not meet complished two goals: (1) to broaden
criteria for dementia.6 The research the classification scheme beyond mem-
criteria used to characterize these sub- ory, and (2) to recognize that MCI could
jects were described, and the clinical result from a variety of etiologies and
outcomes were noted. not just AD. These criteria are outlined
in Figure 2-1,8 demonstrating the syn-
MULTIPLE TERMINOLOGIES dromic phenotypes and how they can
Over the years, several sets of termi- be paired with possible etiologies
nology for MCI and related conditions to assist the clinician in diagnosis. The
have evolved, many referring to similar Key Symposium characterization of
constructs in the general MCI range. MCI led to the distinction between the
The Mayo Clinic criteria previously noted amnestic form of MCI and the non-
focused on a memory disturbance and amnestic form of MCI, since these clin-
were developed to elucidate the earliest ical syndromes appeared to be aligned
symptomatic stages of AD. However, with etiologies in a differential fash-
it soon became apparent that not all ion and may have variable outcomes.
intermittent cognitive states represented Traditionally, amnestic MCI is the

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

 Mild Cognitive Impairment

FIGURE 2-1 Key Symposium criteria. First Key Symposium criteria demonstrating the syndromic phenotypes
and how they can be paired with possible etiologies to assist the clinician in making a diagnosis.
AD = Alzheimer disease; DLB = dementia with Lewy bodies; FTD = frontotemporal dementia;
MCI = mild cognitive impairment; VCI = vascular cognitive impairment.
Modified with permission from Petersen RC, Continuum (Minneap Minn).8 journals.lww.com/continuum/Fulltext/2004/02000/
MILD_COGNITIVE_IMPAIRMENT.3.aspx. B 2004, American Academy of Neurology.

KEY POINTS typical prodromal stage of dementia due posium criteria while making some of
h Traditionally, amnestic to AD, but other phenotypes can also the diagnostic features more explicit.
mild cognitive impairment lead to this type of dementia, such as These criteria also added biomarkers
is the typical prodromal
logopenic aphasia, posterior cortical at- for underlying AD pathophysiology in
stage of dementia due to
rophy (also known as the visual variant), an attempt to refine the underlying
Alzheimer disease, but
other phenotypes can
or a frontal lobeYdysexecutive presenta- etiology and, hence, predict outcome.
also lead to this type of tion of AD.9 The essential feature of this These criteria did not differentiate be-
dementia, such as portrayal is that not all MCI is early AD. tween amnestic and nonamnestic MCI.
logopenic aphasia, The Key Symposium criteria pre- At approximately the same time, the
posterior cortical atrophy vailed in the field and influenced the Diagnostic and Statistical Manual
(also known as the visual development of several randomized of Mental Disorders, Fifth Edition
variant), or a frontal controlled trials for possible interven- (DSM-5) was being developed.17 For
lobeYdysexecutive tion.10Y14 In 2011, the National Insti- the general category of neurocogni-
presentation of tute on Aging (NIA) and the Alzheimer’s tive disorders, the criteria now include
Alzheimer disease. Association convened workgroups to a predementia phase called mild
h Not all mild cognitive develop criteria for the entire AD spec- neurocognitive disorder. Once again,
impairment is early trum.1,9,15,16 The criteria for MCI due the construct is very similar to the
Alzheimer disease. to AD essentially adopted the Key Sym- Key Symposium criteria for MCI and

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 KEY POINTS
suggests that, in addition to the syn- the current sets of criteria, regardless h The criteria for mild
dromic classification, certain features of the terminologies, emanate from cognitive impairment due
would allow the subclassification of the Key Symposium criteria for MCI, to Alzheimer disease
the clinical presentation into patho- and most recent approaches embellish developed by the
logic etiologies. The category of mild these criteria with pathophysiologic National Institute on
neurocognitive disorder due to AD is biomarkers to lend specificity to the Aging and the Alzheimer’s
very similar to the classification of underlying diagnoses. The entire field Association essentially
MCI due to AD formulated by the NIA/ of aging and dementia is moving in adopted the Key
Alzheimer’s Association workgroups.17 this direction, and these criteria are Symposium criteria while
Finally, over the course of several likely to be important going forward. making some of the
diagnostic features more
years, the construct of prodromal AD
PREVALENCE explicit. These criteria
evolved.18Y20 This clinical condition
also added biomarkers
grew from the accumulating literature In the past decade, there have been for underlying Alzheimer
that had developed regarding the ob- numerous epidemiologic studies con- disease pathophysiology
servation that amnestic MCI, when ducted on the prevalence of MCI and in an attempt to
paired with certain biomarkers, approx- the incidence of cognitively normal refine the underlying
imated the condition of AD. In fact, the persons progressing to MCI.21Y29 There etiology and, hence,
proponents believed that a certain type has been a great deal of variability in predict outcome.
of amnestic MCI coupled with bio- the prevalence figures due to method- h In the Diagnostic and
markers for the presence of amyloid ological variation in the studies and Statistical Manual of
or amyloid and tau constituted the ear- the different implementations of the Mental Disorders, Fifth
liest symptomatic stages of the AD criteria.4 For example, some of the fac- Edition, for the
process.20 The temporal evolution of tors to be considered include the general category of
the criteria for MCI and prodromal AD breadth of the MCIVsuch as all MCI, neurocognitive disorders,
are presented in Figure 2-2. amnestic MCI, nonamnestic MCIVas the criteria now include
As is apparent, sufficient overlap well as the methods of data gathering. a predementia
phase called mild
exists among these various sets of In addition, factors such as the retro-
neurocognitive disorder.
terminologies, which may reflect the spective application of criteria to pre-
reality that the core features of MCI viously collected clinical data, versus h The construct of
correspond to the earliest symptom- prospective design using established prodromal Alzheimer
disease evolved from the
atic stages of a variety of cognitive criteria and applying them as subjects
accumulating literature
disorders.4 Figure 2-3 attempts to are enrolled in the study, can affect
that had developed
characterize the common features of prevalence figures. In general, the regarding the observation
these various sets of criteria. Most of prospectively designed studies that that amnestic mild
cognitive impairment,
when paired with certain
biomarkers, approximated
the condition of
Alzheimer disease. In fact,
the proponents believed
that a certain type of
amnestic mild cognitive
impairment coupled with
biomarkers for the
presence of amyloid or
amyloid and tau
FIGURE 2-2 Temporal evolution of criteria for mild cognitive impairment (MCI) and prodromal
Alzheimer disease (AD).
constituted the earliest
symptomatic stages
DSM-5 = Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; of the Alzheimer
NIA-AA = National Institute on AgingYAlzheimer’s Association.
disease process.

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 Mild Cognitive Impairment

KEY POINTS
h The multiple sets of
criteria referring to mild
cognitive impairment
actually contain many of
the same elements and
are quite similar to the
original Key
Symposium criteria.
h Numerous international
studies have been
completed involving
several thousand
subjects, and these
studies tend to estimate
the overall prevalence
of mild cognitive
impairment in the
12% to 18% range in
persons over the age
of 60 years.

FIGURE 2-3 Comparison of common criteria used to characterize mild cognitive impairment
(MCI) in various publications. The biomarkers for amyloid-" (A") or tau could
be derived from either positron emission tomography (PET) imaging or CSF to
accompany the clinical syndromes described above.
AD = Alzheimer disease; CSF = cerebrospinal fluid; DSM-5 = Diagnostic and Statistical Manual of
Mental Disorders, Fifth Edition; FDG-PET = fluorodeoxyglucose positron emission tomography;
MRI = magnetic resonance imaging.
Reprinted with permission from Petersen RC, et al, J Intern Med.4 onlinelibrary.wiley.com/doi/10.1111/j.1365-
2796.2004.01388.x/full#b36. B 2014 The Association for the Publication of the Journal of Internal Medicine.

establish criteria prior to labeling the in persons over the age of 60 years.21Y26
participants as having MCI are more The Mayo Clinic Study of Aging, which
reliable and valid. Studies that apply is a population-based study in Olmsted
MCI criteria to previously collected data County, Minnesota, found the overall
can generate a variety of figures based prevalence of MCI to be 16% in resi-
on the cutoff scores that are used to dents age 70 years and older.27 MCI is
define MCI. Therefore, since MCI is a clearly an age-related condition, and
clinical diagnosis informed by neuro- to the extent that the evaluation sug-
psychological data, a prospective study gests a degenerative etiology, AD is
is preferred when interpreting epide- most likely.30
miologic data. A similar situation pertains to the
Numerous international studies have normal cognition to MCI transition,
been completed involving several with certain methodological issues
thousand subjects, and these studies lending themselves to some of the
tend to estimate the overall preva- variation. Several longitudinal epidemi-
lence of MCI in the 12% to 18% range ologic studies have followed cognitively

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 KEY POINTS
normal subjects sufficiently long events, appointments, visits of friends, h The Mayo Clinic Study
enough to characterize the progression or conversations. If the patient is start- of Aging followed
rate, which also can be variable.28,31 ing to repeat himself or herself, then subjects 70 years and
The Mayo Clinic Study of Aging this is an index that some memory def- older for a median of
followed subjects 70 years and older icits are evolving. Again, the clinician 5 years and found the
for a median of 5 years and found the should focus on a change in memory progression rate of mild
progression rate to be in the 5% to 6% or cognitive function for that individual. cognitive impairment to
per year range.28 The rates are lower in Next, the clinician should explore be in the 5% to 6% per
younger subjects and rise considerably the breadth of the cognitive concern. year range.
with age. All these data speak to the Is the concern related to memory h Mild cognitive impairment
frequency of the condition of MCI alone, or does it involve memory and is not meant to reflect
and why it is important to recognize other cognitive domains such as at- lifelong low cognitive
in clinical practice. tention and concentration? Patients function; rather, it is
will often describe cognitive changes meant to reflect a change
CLINICAL EVALUATION for this individual person.
in the domain of memory when, in fact,
If a clinician adopts the flowchart they may mean attention or language h In mild cognitive
for fulfilling the criteria outlined in problems. The breadth of the cognitive impairment, the
Figure 2-1, the MCI diagnosis for a change is important to characterize. At patient’s daily function
is largely preserved.
patient can be approached as follows. this point, the clinician will need to do a
At the top of the figure, presuming the mental status examination and explore
patient presents with a cognitive con- the various cognitive domains. If time is
cern, the clinician is then faced with a limitation, a mental status assessment
the question of how to evaluate this involving an instrument such as the
symptom. Obtaining a history from Montreal Cognitive Assessment (MoCA)
the patient and confirming this history or the Short Test of Mental Status can
with someone who knows the patient be useful, but the clinician must be
well is critical. It is important that a mindful that these screening instru-
cognitive concern is elicited either on ments are insufficient to make the
the part of the patient, the patient’s diagnosis; nevertheless, they can be
informant, or the physician. The cog- important to isolate domains of impair-
nitive concern is important since it ment and advise the clinician on further
reflects a change in the person’s perfor- assessments.32,33 If the primary ques-
mance. That is, MCI is not meant to tion with the patient concerns the dif-
reflect lifelong low cognitive function; ferentiation between the patient’s
rather, it is meant to reflect a change symptoms and the changes in cognitive
for this individual person. As such, in function seen in normal aging, neuro-
the absence of formal longitudinal cog- psychological testing can be particularly
nitive data on an individual, the clinical helpful. The neuropsychologist can
history is critical. Here, the clinician characterize the profile of cognitive
should focus on the types of cognitive function and assess whether the level
changes the patient has noted. If the of function is appropriate for the pa-
primary concern is in the memory tient’s age, sex, and education. If this is
domain, the physician should focus on not available to the clinician, then the
instances of forgetfulness that are rela- clinician must make the best estimate
tively new (ie, appearing approximately of function possible.
in the last 6 months to a year). In Other elements in the history to
particular, the physician should be in- be assessed include functional per-
terested in instances of forgetful- formance, which, in a patient with
ness involving recently experienced MCI, should indicate that the patient’s
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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Mild Cognitive Impairment

daily function is largely preserved. The ease is a likely candidate. Alternatively,

patient may be inefficient at doing if the patient has a history of vascu-
certain tasks and may take more time lar risk factors and has experienced
but ultimately can do them without any cerebral ischemic events, a vascular
assistance. This type of assessment ful- contribution needs to be considered.
fills the preserved cognitive function In addition, some aspects of psychiat-
aspect of the criteria. This can be a very ric conditions such as major depres-
subjective assessment, and here, a re- sion or generalized anxiety disorder can
liable informant can be helpful. How- have cognitive components, and con-
ever, if the person is still functioning sequently, in the early stages of these
in daily life, driving, paying bills, doing disorders, cognition may be impaired.
taxes, and to the casual observer ap- The clinician must always consider
pears normal, generally speaking, func- other medical conditions such as un-
tion is preserved. Finally, given all of compensated heart failure, poorly con-
these considerations, the patient does trolled diabetes mellitus, or chronic
not meet criteria for dementia. That obstructive pulmonary disease as
is, the person’s cognitive impairments contributors to cognitive impairment.
are not of sufficient severity to compro- Some of these medical comorbidities
mise daily functioning. Hence, the chief may be treatable, and their medica-
criterion for dementia is not met. tions may play a role in the clinical
The clinician following the flow- syndrome as well.
chart in Figure 2-1 should determine If the clinician believes that a de-
whether the person has experienced a generative condition is most likely the
change in cognition, whether there is underlying explanation, then the clin-
some objective corroboration of this, ical syndromes can be useful in sug-
whether function is relatively well pre- gesting an underlying diagnosis. If
served, and whether the patient does the patient appears to have a typical
or does not meet criteria for dementia. amnestic syndrome leading to MCI and
If MCI is determined to be a reasonable is in the appropriate age range, AD is a
diagnosis, the clinician then needs to likely consideration. However, if the
determine if memory is a salient part of patient is experiencing attention, con-
the cognitive impairment, and if so, the centration, and visuospatial difficulties,
arm in the diagram in Figure 2-1 that a forme fruste of dementia with Lewy
outlines amnestic MCI would be ap- bodies might be considered, and if
propriate. If, however, the person is the person is experiencing behavioral
experiencing a cognitive decline but changes, inappropriate behavior, apa-
memory is relatively well preserved, thy, lack of insight, and attention and
then the nonamnestic arm of the dia- concentration are impaired, fronto-
gram would apply. temporal lobar degeneration may be
After the clinical syndrome has been possible. Of course, the most common
determined, as outlined above, then degenerative disease of aging, AD, can
the clinician needs to determine the have atypical presentations involving
cause or etiology of that syndrome. attention, concentration, and language.
Figure 2-1 characterizes possible ex- Based on the history and the exam-
planations of the various clinical syn- ination, the clinician may be able to
dromes and can help determine the make a likely supposition regarding
further diagnostic workup. If the his- the nature of the condition. At this
tory of the onset of the disorder is point, further testing such as an MRI
slow and gradual, a degenerative dis- scan, fluorodeoxyglucose positron
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 KEY POINT
emission tomography (FDG-PET) or gression, and many imaging and fluid h Several studies have
positron emission tomography (PET) biomarker studies.30,34 The Alzheimer’s indicated that individuals
for amyloid imaging along with a CSF Disease Neuroimaging Initiative with mild cognitive
analysis could be considered. These (ADNI) has been very active for the impairment who have a
further assessments may assist in past 10 years evaluating individuals positive amyloid positron
depicting the underlying etiology of with amnestic MCI who have been emission tomography
the clinical syndromes. While no phar- followed for several years. These data scan are more likely to
macologic therapies are currently ap- as well as others indicate that, in progress rapidly, which is
proved by the US Food and Drug general, medial temporal lobe atrophy confirmed by data from
Administration (FDA) for MCI due to on MRI tends to predict progres- the Alzheimer’s Disease
sion as does a hypometabolic pattern Neuroimaging Initiative.
AD, lifestyle modifications and cogni-
tive and behavioral therapies can be consistent with AD on FDG-PET.34Y37
useful. Also, counseling patients on Figure 2-4 shows individuals who are
expectations can be quite important. cognitively normal along with those
The contribution of medical comor- who have MCI and those who have
bidities, as outlined previously, in- dementia on MRI scans, FDG-PET,
cluding sleep disorders such as sleep amyloid PET, and the newest imaging
apnea, also need to be considered modality, tau PET. Several studies have
since some of these have treatable indicated that individuals with MCI
components (Case 2-1B). who have a positive amyloid PET scan
are more likely to progress rapidly and,
PREDICTORS OF PROGRESSION again, ADNI data confirm this.38,39
There has been a great deal of data For many years, it has been known
generated in recent years concern- that carriers of the apolipoprotein E4
ing the progression of persons diag- (APOE4) genotype are more likely to
nosed with MCI. In particular, there progress rapidly, and this has been
are clinical variables such as severity of borne out in numerous studies; how-
cognitive impairment that predict pro- ever, in clinical practice APOE testing

Case 2-1B
A mental status examination was performed on the 66-year-old patient
discussed in Case 2-1A, and while the patient did quite well, there was a
suggestion of memory impairment with impaired delayed recall of the
words. Neuropsychological testing was pursued, which showed a profile
that looked normal for his age, sex, and education in virtually all cognitive
domains except for memory. Here, his delayed recall of lists, paragraphs,
and nonverbal materials was mildly impaired.
Further interview of the patient and a family member revealed that
his function was largely preserved. In particular, he functioned in the
community quite well without difficulty, and while slightly more inefficient
at some tasks, he still completed everything quite well.
Comment. Based on examination findings, neuropsychological testing,
and discussions with the patient and his family member, he does not
appear to have dementia. A reasonable diagnosis at this point would be
amnestic mild cognitive impairment, but the etiology, given the patient’s
young age and negative family history, is uncertain. At this point, a
discussion with the patient might include possible etiologies and education
about lifestyle alterations, planning for the future, and consideration of
enrollment in randomized controlled trials.

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 Mild Cognitive Impairment

FIGURE 2-4 Progression of imaging features from cognitively

normal to mild cognitive impairment to dementia.
FDG-PET = fluorodeoxyglucose positron emission
tomography; MRI = magnetic resonance imaging;
PET = positron emission tomography.

does not add significantly to the diag- tia.42,43 The 2006 study by Hansson
nostic evaluation.34,40 and colleagues44 was most informative
The newest PET tracer that is emerg- with regard to these data and corrob-
ing allows investigators to evaluate the orates the suspicion that those indi-
role of tau in clinical progression, and viduals, particularly with amnestic
these data are evolving.41 It is quite MCI, who harbor low CSF levels of
likely that a tau PET scan that shows A"42 and elevated total tau and phos-
the spread of tau outside of the me- phorylated tau are at an increased risk
dial temporal lobe into lateral tempo- for progressing more rapidly than
ral lobe structures portends a poorer those subjects with the same clinical
prognosis and, more likely, a rapid phenotype but normal CSF biomarkers.
progression from MCI to AD demen- In general, these predictors all refer
tia, but these data need to be ampli- to individuals who are on the AD spec-
fied (Figure 2-4). trum. Biomarkers for other degenera-
Numerous studies have shown that tive disorders are less certain at this
the various CSF markers consistent with point and need to be fully evaluated.
AD predict progression to AD demen- As biomarkers for other disorders

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 KEY POINTS
evolve, it is likely that they will be the term neurocognitive disorder is h The National Institute
matched with a particular phenotype used for the syndromes of cognitive on Aging and the
of MCI and increase the ability to impairment irrespective of specific Alzheimer’s Association
predict the clinical outcome. etiology.17 The spectrum was divided divided the Alzheimer
into mild neurocognitive disorder, disease spectrum into
CRITERIA FOR MILD COGNITIVE which is very similar to MCI, and major three overlapping areas:
IMPAIRMENT DUE TO neurocognitive disorder, which is very preclinical Alzheimer
ALZHEIMER DISEASE similar to dementia. The criteria for disease in which
mild neurocognitive disorder essen- individuals are clinically
The NIA and the Alzheimer’s Associa-
tially incorporate the MCI criteria from normal but possess
tion convened groups of experts to
biomarker evidence for
revise the criteria for AD across the the Key Symposium in 2004 and sug-
the Alzheimer disease
spectrum.8 The groups divided the AD gest that, as data accumulate, speci-
process, mild cognitive
spectrum into three overlapping areas: ficity of etiology will be added through impairment due to
preclinical AD in which individuals are the use of biomarkers. After the syn- Alzheimer disease
clinically normal but possess biomarker drome of either mild or major neuro- whereby individuals meet
evidence for the AD process, MCI due cognitive disorder is made, DSM-5 then the clinical criteria for
to AD whereby individuals meet the gives recommendations as to how the mild cognitive impairment
clinical criteria for MCI and have varying clinician can determine the underlying and have varying levels

levels of biomarker specificity for AD, etiology of the syndrome.17 As such, of biomarker specificity
conditions such as AD, frontotemporal for Alzheimer disease,
and AD dementia in which individuals and AD dementia in
lobar degeneration, dementia with Lewy
meet clinical criteria for dementia and which individuals meet
bodies, vascular cognitive impairment,
similarly have varying degrees of bio- clinical criteria for
human immunodeficiency (HIV)-related
marker support.1 These criteria have dementia and similarly
disorders, alcohol and substance abuse,
proved useful in characterizing the en- have varying degrees of
Parkinson disease, and a variety of other biomarker support.
tire spectrum of AD and expanding it
possible etiologies are explicated. As
beyond the dementia phase. Prior sets h The spectrum of
noted above, the process of combining
of criteria had focused only on the de- the clinical syndrome with patient his-
neurocognitive disorder,
mentia phase, but it has become ap- as defined by the
tory, clinical examination findings, and, Diagnostic and Statistical
parent in recent years that the AD while still evolving, biomarker informa- Manual of Mental
process likely begins years and per- tion is used to specify the clinical syn- Disorders, Fifth Edition, is
haps decades before clinical symp- drome. As is seen in DSM-5, there are divided into mild
toms appear.45 As such, the use of often degrees of certainty added to the neurocognitive disorder,
biomarkers has afforded an important clinical diagnoses based on the pre- which is very similar
tool for specificity for the clinician. It ponderance of evidence for a specific to mild cognitive
must be emphasized, however, that underlying disorder.17 impairment, and major
these criteria involving biomarkers are In 2007 and updated in 2010 and neurocognitive disorder,
still in the research phase, and specific 2013, investigators have proposed the which is very similar
recommendations regarding their use to dementia.
term prodromal AD as an alternative
in clinical practice remain to be deter- for characterizing individuals along
mined. However, based on the litera- the AD spectrum.18Y20 The most re-
ture cited above, it is apparent that the cent version of these criteria embod-
use of biomarkers is working its way ies the notion of amnestic MCI and
into clinical practice. embellishes it with evidence for amy-
In addition, the American Psychiatric loid deposition via PET scanning or
Association has recently published the amyloid and tau information using
DSM-5, and this set of criteria gives CSF.20 These investigators contend
consideration to the diagnosis of mild that the combination of amnestic MCI
neurocognitive disorder. In general, with specific biomarkers is highly
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 Mild Cognitive Impairment

KEY POINTS
h Currently, there are no suggestive of the AD process and should ever, subsequent data suggest that
accepted pharmacologic be labeled as AD. These criteria have there may be some efficacy to be
treatments for mild been useful for randomized control gleaned from lifestyle modifications,
cognitive impairment trials for evaluation of pharmacologic and these need to be explored further.
approved by the US therapeutics intended to target under-
Food and Drug lying AD pathophysiology.46,47 CLINICAL ACCEPTANCE
Administration, the The construct of MCI has been in the
European Medicines TREATMENTS medical literature for many years and,
Agency, or the Currently, there are no accepted phar- over time, has been accepted in clin-
Pharmaceuticals and ical practice to certain degrees. The
macologic treatments for MCI ap-
Medical Devices Agency
proved by the FDA, the European American Academy of Neurology
in Japan.
Medicines Agency, or the Pharmaceu- (AAN) completed an evidence-based
h Lifestyle modifications ticals and Medical Devices Agency in medicine review of the literature and
and other
Japan. Numerous randomized control concluded that the construct of MCI is
nonpharmacologic
trials have been conducted in the MCI useful for clinicians to identify since
therapies have also
been investigated, and spectrum, but none has been success- the condition does lead to a higher
there is a suggestion ful at demonstrating effectiveness at risk of progression to dementia.50
that some of these delaying the progression from MCI to Numerous epidemiologic studies have
modifications or AD dementia.10Y14 One of the first been done around the world that have
therapies, such as trials, conducted by the Alzheimer’s suggested the utility of the identi-
aerobic exercise, may Disease Cooperative Study, evaluated fication of MCI as a clinical entity.
be effective at reducing donepezil and high-dose vitamin E in Roberts and colleagues51 evaluated
the rate of progression amnestic MCI.13 This study indicated members of the Behavioral Neurology
from mild cognitive that donepezil may be effective at section and the Geriatric Neurology
impairment to dementia. section of the AAN and documented
slowing the rate of progression in all
h Criticism has been subjects with amnestic MCI for the that MCI is used frequently in clinical
raised regarding the first year of the trial and perhaps up to practice and that practitioners find the
boundaries of the construct useful. There were concerns
2 years in subjects with amnestic MCI
condition of mild about its specificity and the lack of
who were positive for the APOE4 iso-
cognitive impairment treatments, but, nevertheless, it was
with respect to
form. However, since the study was
designed to continue for 36 months, believed to be useful.
differentiating it from
no treatments demonstrated effective- Recently, a similar exercise was done
changes of cognitive
aging and also ness at that time and, as such, the trial in Europe assessing the utility of the
differentiating it was negative. Other studies involving construct of MCI in clinical practice and
from dementia. cholinesterase inhibitors that have the outcome was quite similar to that
been used for the treatment of AD found in polling members of the AAN.
dementia were also unsuccessful.10,11,13 As such, it appears that the construct of
Lifestyle modifications and other MCI is accepted in clinical practice and
nonpharmacologic therapies have also serves a function for clinicians in com-
been investigated, and there is a municating clinical diagnoses to pa-
suggestion that some of these modifi- tients. It has also been a useful construct
cations or therapies, such as aerobic for research as literally thousands of
exercise, may be effective at reducing studies have been generated in the
the rate of progression from MCI to past decade assessing various aspects
dementia.48 However, a state-of-the- of the condition.
science report from the National Insti- This is not to say, however, that there
tutes of Health (NIH) in 2010 failed to is not controversy surrounding the con-
document any successful interventions struct. Criticism has been raised regard-
for progression to dementia.49 How- ing the boundaries of the condition

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with respect to differentiating MCI CONCLUSION
from changes of cognitive aging and MCI has become an important topic in
also from dementia. Since cognitive clinical practice and research. With the
changes with aging are believed to be emphasis on earlier identification of
common, it can be challenging to de- incipient forms of cognitive deficits,
termine whether a particular person is MCI put boundaries on this intermedi-
experiencing those changes or the ate state. Numerous randomized con-
forme fruste of MCI. A recent publica- trolled trials are underway for the MCI
tion from the Institute of Medicine has subtype due to AD, and clinicians need
characterized the expectations of cog- to be aware of these research opportu-
nitive aging, and a distinction is made nities for their patients. As treatable
between these changes and those that etiologies of MCI are identified (such
represent incipient MCI.52 However, as those due to psychiatric conditions,
there is a great deal of variability in medications, or medical comorbidities),
the literature regarding MCI, and many the cognitive deficits may be reversible.
of these features have been reviewed Biomarker development should pro-
recently.4 There have been controver- vide the clinician with new tools to
sies regarding the implementation of identify and hopefully treat MCI.
MCI criteria involving neuropsycho-
logical tests, cutoff scores, types of ACKNOWLEDGMENTS
measures, and cross-sectional versus
The author receives grant support
longitudinal assessment. There has
from the National Institute on Aging
been variability in methodology of
(P50 AG016574, U01 AG006786, U01
studies including the subjects sampled
AG024904, R01 AG011378, and R01
for the studies, how they were evalu-
AG041581).
ated (eg, prospectively or retrospec-
tively), and the availability of normative
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 Mild Cognitive Impairment

49. National Institute of Health Office of the Academy of Neurology. Neurology

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 Review Article

Alzheimer Disease
Address correspondence to
Dr Liana G. Apostolova,
Indiana Alzheimer’s Disease
Center, 355 W 16th St, Suite
Liana G. Apostolova, MD, MS, FAAN 4700, Indianapolis, IN 46202,
[email protected].
Relationship Disclosure:
Dr Apostolova serves as senior
ABSTRACT associate editor of Alzheimer’s
Purpose of Review: This article discusses the recent advances in the diagnosis and & Dementia: Diagnosis,
Assessment & Disease
treatment of Alzheimer disease (AD). Monitoring and receives
Recent Findings: In recent years, significant advances have been made in the fields personal compensation for
of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most serving on the speaker’s bureau
of Eli Lilly and Company and
important recent advances in AD is our ability to visualize amyloid pathology in the GE Healthcare Worldwide.
living human brain. The newly revised criteria for diagnosis of AD dementia embrace Dr Apostolova receives grant
the use for biomarkers as supportive evidence for the underlying pathology. Guide- support from the Jim Easton
Consortium for Alzheimer’s
lines for the responsible use of amyloid positron emission tomography (PET) have Drug Discovery and Biomarker
been developed, and the clinical and economic implications of amyloid PET imaging Development and the National
are actively being explored. Institute on Aging.
Unlabeled Use of
Summary: Our improved understanding of the clinical onset, progression, neuroim- Products/Investigational
aging, pathologic features, genetics, and other risk factors for AD impacts the Use Disclosure:
approaches to clinical diagnosis and future therapeutic interventions. Dr Apostolova discusses the
unlabeled/investigational use
of antidepressant and
Continuum (Minneap Minn) 2016;22(2):419–434. antipsychotic medications for
behavioral management as
well as antidementia therapy
in mild cognitive impairment.
INTRODUCTION United States.1 Although there is in- * 2016 American Academy
of Neurology.
Alzheimer disease (AD) is a neuro- creasing evidence that AD pathology
degenerative disorder featuring grad- starts depositing in the brain in midlife,
ually progressive cognitive and the first clinical symptoms usually occur
functional deficits as well as behavioral after the age of 65.2,3
changes and is associated with accu- AD prevalence is rapidly increasing
mulation of amyloid and tau deposi- in large part because the proportion
tions in the brain. Cognitive symptoms of people 65 years and older is grow-
of AD most commonly include deficits ing faster than any other age sector
in short-term memory, executive and of the population worldwide. Between
visuospatial dysfunction, and praxis. 1997 and 2050, the elderly popula-
Several rarer variants of AD with relative tion, defined as subjects 65 years of
preservation of memory have been age and older, will increase from 63 to
recognized. Clinical assessment, includ- 137 million in the Americas, from 18
ing cognitive testing, remains critical to 38 million in Africa, from 113 to
for the diagnosis and staging of AD, 170 million in Europe, and from 172
although recent advances in amyloid to 435 million in Asia.4 One nationally
imaging and genetics show great representative US data set, the Aging,
promise for facilitating early and Demographics, and Memory Study
presymptomatic diagnosis of AD and (ADAMS), estimated that in the
its discrimination from other neuro- United States, 14% of people 71 years
degenerative disorders. and older have dementia. AD demen-
tia accounted for 70% of the dementia
EPIDEMIOLOGY cases across the age spectrum in this
AD is the most common neurode- cohort.5 In a subsequent publication,
generative disorder and the sixth the ADAMS investigators reported that
most common cause of death in the an additional 22% (or 5.4 million

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 Alzheimer Disease

KEY POINTS
h Alzheimer disease Americans) 71 years or older have cog- to the clinical diagnosis and staging of
prevalence is nitive impairment in the absence of patients with AD.
rapidly increasing. overt dementia.6
Although age is the greatest risk Cognitive Decline
h Although age is the
greatest risk factor for
factor for the development of AD, in Memory impairment is the most per-
the development of and of itself, old age is not sufficient vasive feature of AD. Although non-
Alzheimer disease, old to cause AD. Other major risk factors memory cognitive deficits (eg, aphasia,
age is not sufficient, in include the presence of one or more executive dysfunction, apathy, or per-
and of itself, to cause apolipoprotein gene E4 alleles (APOE4), sonality change) can manifest early and
Alzheimer disease. low educational and occupational at- even be the presenting feature, in
h Memory impairment tainment, family history of AD, moder- general, memory decline is considered
is the most pervasive ate or severe traumatic brain injuries, the leading symptom. Early in the
feature of and cardiovascular risk factors. disease course, recent episodic mem-
Alzheimer disease. Gender modulates the prevalence ories are most affected, while memo-
of AD. Nearly two-thirds of all patients ries from the distant past are usually
diagnosed with AD are women.7 Ac- spared. As the disease progresses, all
cording to ADAMS, 16% of women, but aspects of episodic memory become
only 11% of men, live with dementia affected. In contrast to episodic mem-
after 71 years of age.5 While it is true ory, working memory and semantic
that women live longer than men, this memory are preserved until later in the
alone does not explain the discrepancy. disease course.
Genetic, hormonal, and societal factors Language disturbance, especially
(eg, lower education and occupational word-finding difficulties, is a com-
attainment among women currently in mon early symptom in AD but is
their 70s and 80s compared to men) generally mild. Subtle decline in visuo-
likely play a significant role as well. spatial skills likewise occurs in the
Racial disparities in AD prevalence mild dementia stages and progresses
have also been reported. Older African throughout the course of the disease.
Americans and Hispanics have a higher Executive dysfunction, on the other
prevalence of AD relative to older hand, begins even earlierVin the
Caucasians in part because of lower predementia stagesVand, similar to all
education levels and higher preva- other cognitive domains, worsens over
lence of cardiovascular comorbid- the disease course.
ities,8Y10 although other genetic and
societal factors likely play a role as well. Neuropsychiatric Symptoms
Patients with AD exhibit a variety of
CLINICAL PRESENTATION neuropsychiatric symptoms. Behavioral
Recognition of the clinical features and symptoms, once manifest, tend to
presenting symptoms of AD remains worsen over the course of the disease;
essential for the diagnosis and manage- however, these symptoms often fluctu-
ment of patients, even as biomarker ate and are not consistently present at
tests such as amyloid positron emis- each visit. Attention to these treatable
sion tomography (PET) imaging that components of excess morbidity is im-
detect the underlying neuropathology portant as they have a profound im-
of AD are increasingly available for pact on caregiver burden and are the
patient care. Ascertainment of symp- leading cause of institutionalization.11
toms of cognitive decline, behavioral The earliest AD-associated neuro-
symptoms, functional decline, and cog- psychiatric symptoms are apathy, anx-
nitive testing remain the cornerstones iety, and irritability. The latter two
420 www.ContinuumJournal.com April 2016

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

 KEY POINTS
symptoms are often provoked in situ- ATYPICAL ALZHEIMER DISEASE h Neuropsychiatric
ations that the patient finds challeng- VARIANTS comorbidities often
ing. Mild to moderate depressive In addition to the classic AD presen- present the most
symptoms are also frequently present tation, several less common AD variants pressing therapeutic
early on. Disturbances of appetite and should be recognized, which include needs due to the
sleep, disinhibition, and alterations in frontal variant of AD, posterior cortical psychological and
perception (hallucinations) or thought atrophy, and logopenic variant primary physical strain they
(delusions) commonly occur in the progressive aphasia due to AD. place on the family and
later stages of dementia. In addition to caregivers of patients
Frontal variant of AD is character-
the classic neuropsychiatric behaviors, with Alzheimer disease.
ized by substantial behavioral or per-
anosognosia (ie, lack of insight) often sonality changes that are out of h Several less common
manifests early on and poses another proportion to the observed short-term Alzheimer disease
difficult management problem. variants should be
memory loss. These patients are often
Of all AD neuropsychiatric comor- recognized, which
profoundly impatient, irritable, impul-
include frontal variant
bidities, irritability, agitation, sundown- sive, and disinhibited. On formal test- of Alzheimer disease,
ing, psychosis, and diminished insight ing, they invariably show significant posterior cortical atrophy,
often present the most pressing thera- executive disturbances.12 and logopenic variant
peutic needs due to the psychological Posterior cortical atrophy presents primary progressive
and physical strain they place on the with visuospatial dysfunction often aphasia due to
family and caregivers. in the form of partial or full Balint Alzheimer disease.
syndrome (simultanagnosia, ocular
Neurologic Examination apraxia, and ocular ataxia), partial or
Outside of the mental status examina- full Gerstmann syndrome (acalculia,
tion, findings on the neurologic exam- agraphia, right/left disorientation, and
ination are often normal in patients finger agnosia), apperceptive visual
with AD. Parkinsonian symptoms can agnosia, and environmental disorienta-
emerge in the later stages, but if tion. Patients often develop construc-
these symptoms are present early in tional, dressing, and ideomotor apraxia
the course of the disease (eg, within early on in the presence of relatively
1 year of onset of cognitive problems) preserved memory and insight.
and especially when accompanied by Finally, the occasional patient with
cognitive fluctuations and early-onset AD may also present with early pro-
psychosis, a diagnosis of dementia gressive language involvement, most
with Lewy bodies should be consid- often in the form of logopenic aphasia
ered. Later in the disease course, with pronounced anomic deficits and
pathologic reflexes such as grasp, impaired repetition but preserved
root, and suck reflexes may be found. grammar and syntax.
Patients become increasingly impaired
in the moderate and severe stages and DIAGNOSTIC CRITERIA
are ultimately mute, incontinent, and Currently, the diagnostic standard for
bedridden at the end stages of disease. dementia is the Diagnostic and Sta-
At this stage, multiple complications tistical Manual of Mental Disorders,
arise such as risk of aspiration with Fifth Edition (DSM-5).13 DSM-5 recog-
unsafe swallowing, malnutrition, im- nizes two cognitive syndromes: major
mobility with associated risks for bed- neurocognitive impairment and mild
sores, deep venous thrombosis, and neurocognitive impairment. The diag-
infections. Often, these complications nosis of major neurocognitive im-
are the direct cause of death in patients pairment requires objective cognitive
with AD. decline that is severe enough to
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 Alzheimer Disease

KEY POINTS
h The Diagnostic and interfere with activities of daily living ciation (AA).14Y16 Similarly to the DSM-5
Statistical Manual of and is not caused by delirium or criteria, the NIA-AA criteria for de-
Mental Disorders, Fifth another neurologic, medical, or psy- mentia of any cause no longer explicitly
Edition criteria no chiatric disorder. Patients with mild require memory impairment to be
longer require the neurocognitive impairment have present, but rather, for the diagnosis
presence of memory milder cognitive decline that does of dementia to be established, call for
impairment for the not yet deprive them of the ability to documentation of impairment in two
diagnosis of lead an independent lifestyle and cognitive domains or one cognitive
neurodegenerative perform complex daily activities such and one behavioral domain in addition
dementia to as managing finances or driving a car. to significant decline in day-to-day
be established.
It should be noted that the DSM-5 functioning (Table 3-2). For the first
h The National Institute introduces a major change in terms of time, the NIA-AA criteria for probable
on Aging and diagnostic criteria for cognitive disor- Alzheimer dementia as a subtype of
Alzheimer’s Association ders. The criteria no longer require the dementia recognized the diagnostic
criteria for probable
presence of memory impairment for utility of disease biomarkers that
Alzheimer dementia
the diagnosis of neurodegenerative de- have proven sensitivity, specificity,
recognize the
diagnostic utility of
mentia to be established, as was the and pathologic validity (Table 3-2).
disease biomarkers. case in all previous DSM editions. At the present time, two types of
DSM-5 thus recognizes that for some biomarkers meet these criteria. Two
dementing disorders such as vascular neurodegenerative biomarkersV
and frontotemporal dementia, for in- mesial temporal lobe atrophy on
stance, memory impairment is not an structural imaging (Figure 3-1) and
early symptom and may never mani- posterior predominant hypometabo-
fest (Table 3-1). lism with involvement of the posterior
Another set of diagnostic criteria cingulate gyrus on fluorodeoxyglu-
spanning all three major stages of AD cose positron emission tomography
(ie, the preclinical, the prodromal, and (FDG-PET) (Figure 3-2)Vhave already
the overt dementia stages) were recently received wide acceptance. However,
developed by the National Institute on neither of these are exclusively seen
Aging (NIA) and the Alzheimer’s Asso- in AD dementia. Hippocampal atrophy

TABLE 3-1 Summary of Diagnostic Criteria for Mild and Major

Neurocognitive Disordera

b Mild Neurocognitive Impairment

Cognitive decline one to two standard deviations from normal on formal
cognitive testing
Does not interfere with independence
Not due to delirium or other medical or psychiatric disorder
b Major Neurocognitive Impairment
Cognitive decline two standard deviations or more from normal on formal
cognitive testing
Interferes with independence
Not due to delirium or other medical or psychiatric disorder
a
Data from American Psychiatric Association.13

422 www.ContinuumJournal.com April 2016

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TABLE 3-2 Summary of Diagnostic Criteria for Dementia Syndrome
and Probable Alzheimer Disease from the National
Institute on Aging and the Alzheimer’s Associationa

b Dementia Syndrome
Objective cognitive or behavioral impairment in at least two of the following
Memory
Reasoning and handling complex tasks
Visuospatial abilities
Language functions
Personality, behavior, or comportment
Decline from previous level of functioning
Functional impairment
b Probable Alzheimer Disease Dementia
Criteria for dementia are met
Insidious onset
Gradual progression
Initial symptoms
Amnestic
Nonamnestic (language, executive)
No other neurologic, psychiatric, or general medical disorders of severity
that can interfere with cognition
Positive biomarkers (eg, CSF amyloid-" [A"]/tau, amyloid positron emission
tomography [PET], hippocampal atrophy on MRI) increase diagnostic certainty
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Data from McKhann GM, et al, Alzheimer Dement.15 www.alzheimersanddementia.com/
article/S1552-5260(11)00101-4/fulltext.

occurs in normal aging,17,18 and both played an important role in the workup
hippocampal atrophy and FDG-PET of patients with dementia. The American
abnormalities occur in other demen- Academy of Neurology (AAN) guidelines
ting conditions.19,20 On the other hand, for the diagnostic evaluation of de-
amyloid proteinYbased biomarkers such mentia require physicians to obtain
as a low CSF level of "-amyloid or a a structural imaging scan in every pa-
positive amyloid PET scan have been tient with objective cognitive decline.23
shown to be highly sensitive and spe- This recommendation follows the re-
cific in their ability to detect amyloid view of the evidence presented in a
pathology in the brain.21,22 Class II study showing that 5% of all
patients with cognitive complaints har-
Current Role of Biomarkers in bored a causative nondegenerative
Alzheimer Disease Diagnosis lesion, such as a slow-growing brain
In addition to supporting clinical diag- neoplasm (most commonly of the fron-
nosis, biomarkers have historically tal lobes), subdural hematoma, or

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

 Alzheimer Disease

ter quantification of cerebral structures

and better discrimination of normal
from mildly affected patients with AD
than is possible with CT. Some of the
findings suggestive of AD pathology
include mesial temporal atrophy25Y27
and, in the more advanced stages, global
brain atrophy with pronounced ven-
tricular enlargement (Figure 3-1).28,29
Cortico-subcortical microhemorrhages
are often found on gradient echo
MRI sequences and are suggestive of
the presence of vascular amyloidosis
(Figure 3-3).
Functional brain imaging using
single-photon emission computed to-
mography (SPECT) and PET technol-
ogies can be used to identify AD-specific
patterns such as temporoparietal
hypoperfusion/hypometabolism in pa-
tients with AD (Figure 3-2). More re-
FIGURE 3-1 Coronal T1-weighted MRI slices with findings
suggestive of Alzheimer disease (AD) pathology cently, arterial spin-labeling MRI
show mesial temporal atrophy (A, B, arrows) sequences have been shown to capture
and, in the more advanced stages, global brain atrophy with
pronounced ventricular enlargement. perfusion abnormalities.30 Validation
studies of SPECT and PET have gen-
erally shown high sensitivity yet rela-
normal pressure hydrocephalus.24 In tively lower specificity, hence the
addition to identifying a potentially increased risk for false-positive diagno-
treatable lesion, a brain CT or MRI scan ses.31,32 Currently, FDG-PET and SPECT
can uncover ischemic changes that use is only covered by Medicare for
would prompt further workup and differentiating AD from frontotem-
potential initiation of therapy aiming poral dementia.
to reduce vascular risk factors or intro- The recent discovery and validation
duce behavioral modifications. MRI, of amyloid PET imaging has the poten-
with its improved resolution, allows bet- tial to change the approach to clinical

FIGURE 3-2 Temporal (thick arrows) and parietal (thin arrows) hypometabolism on
fluorodeoxyglucose positron emission tomography (FDG-PET) is often seen in
patients with Alzheimer disease dementia.

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 KEY POINT
h Amyloid positron
emission tomography
imaging allows the
detection of moderate
to severe amyloid
deposition in the brain.

FIGURE 3-3 Cortico-subcortical microhemorrhages are often found on gradient echo MRI
sequences and are suggestive of the presence of vascular amyloidosis.

diagnosis of AD. This type of imaging which recommend employing amyloid

allows the detection of moderate to PET imaging in three specific clinical
severe amyloid deposition in the scenarios: (1) patients with amnestic
brain (Figure 3-4). Despite its well- mild cognitive impairment (ie, mild
documented sensitivity and specific- neurocognitive disorder), (2) patients
ity,22 this technology has not yet in the dementia stages with suspected
entered routine clinical practice, in atypical AD or etiologically mixed pre-
part because insurance companies do sentation, and (3) those with early
not provide coverage for it. The major disease onset (younger than 65 years
drawbacks among insurance carriers
are: (1) the unproven economic benefit
of using this relatively expensive PET
technology for diagnostic purposes
while disease-modifying therapies are
lacking and (2) the potential risk for it
to be used in cognitively normal in-
dividuals. Clearly, the latter scenario
(ie, detecting AD in the latent stages in
the form of asymptomatic brain amy-
loidosis) could inflict an insurmount-
able psychological burden given the
absence of effective therapeutic ap-
proaches to delay disease onset or
modify its course. In response to these Amyloid positron emission tomography
FIGURE 3-4
concerns, a group of imaging and de- (PET) imaging allows the detection of amyloid
pathology of the brain. A negative scan (A)
mentia experts convened to establish shows only nonspecific white matter binding and indicates
a set of recommendations of which no to sparse amyloid plaque deposition, while a positive
amyloid PET scan (B) shows significant uptake in multiple
patients should be imaged. These cortical areas and indicates the presence of moderate to
suggestions are the Appropriate Use severe amyloid pathology.
Criteria for amyloid PET imaging,33,34

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 Alzheimer Disease

KEY POINTS
h Amyloid positron of age). At present, the impact of in the brain tissue begins early in the
emission tomography amyloid PET imaging on clinical prac- disease course and is associated with
scans are only tice and health outcomes is not yet decline in CSF A".35 CSF total and
appropriate if the scan known. Given the lack of disease- phosphorylated tau levels rise in AD
results are expected to modifying drugs for AD, the rationale secondary to neurodegeneration of
alter clinical management. for the use of amyloid PET imaging in tau-containing neurons.36Y39 CSF tau
h The APOE4 genotype clinical practice includes: (1) helping changes occur later in the disease
should be considered a the practitioner to select appropriate course and are associated with cognitive
risk factor that is neither treatments and avoid unnecessary in- decline.40Y43 CSF A" and tau mea-
sufficient nor necessary terventions and to aid in accurate surements are covered by most insur-
for Alzheimer disease diagnosis, (2) improving diagnostic ac- ance companies in the United States
development. curacy, (3) advising patients and fami- as part of the workup for AD. Despite
lies on the clinical course and prognosis, this, they are not routinely used due
and (4) educating patients and families to relative invasiveness of the lumbar
on community services and resources puncture procedure and the risk for
for medical, financial, and legal plan- side effects such as back discomfort,
ing.34 Case 3-1 and Case 3-2 describe headache, and, in rare cases, iatrogenic
exemplary scenarios. meningitis. However, CSF A" and tau
The Appropriate Use Criteria also testing can be quite useful in diag-
define the inappropriate uses of amy- nostically challenging cases as well as
loid PET imaging. Patients who should in those with early disease onset or an
not be scanned include those lacking unusual clinical course. CSF A" level is
objective cognitive decline. Scanning highly correlated with the presence
solely on the basis of family history or of amyloid deposition in the cor-
APOE4 status was likewise determined tex. 44 Thus, CSF A" levels can be
to be inappropriate. Furthermore, amy- used in lieu of an amyloid PET scan
loid PET scans cannot be used for de- as a reliable proxy measure of the
termining dementia severity, as this is presence of brain amyloidosis.
not feasible with this technology.
Another important suggestion of the GENETICS OF ALZHEIMER
Appropriate Use Criteria for amyloid PET DISEASE
imaging is the recommendation that Although the APOE4 gene variant is
the responsibility for determining pa- the most established genetic risk fac-
tients’ eligibility (ie, appropriateness for tor for sporadic AD, screening for
imaging) should lie with medical pro- APOE4 is not recommended on a rou-
fessionals with significant expertise in tine basis. While it has been estimated
evaluating and treating patients with that one copy of this genetic variant
dementia (defined as 25% or greater increases the odds for developing
proportion of clinical practice devoted AD threefold and two copies increase
to cognitive disorders of the elderly).33 the odds 15-fold,45 a large multicenter
Last but not least, the committee rec- study demonstrated that the presence
ommended that amyloid PET scans of the APOE4 allele increased the
are only appropriate if the scan results positive predictive value of diagnos-
are expected to alter clinical manage- ing AD by only 4% over diagnoses made
ment (see Case 3-1 and Case 3-2 on clinical grounds alone (from 90%
for examples). to 94%).46 The APOE4 genotype should
CSF amyloid-" (A") and tau protein be considered a risk factor that is
levels are the most established AD fluid neither sufficient nor necessary for dis-
biomarkers. Pathologic A" deposition ease development.
426 www.ContinuumJournal.com April 2016

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 Case 3-1
A 78-year-old man with 12 years of education presented to the memory
disorder clinic reporting progressive memory difficulties for the past 1 to
2 years. His memory deficits were most noticeable when he recalled recent
events as opposed to events from the distant past. He had on two occasions
experienced mild spatial confusion when walking his dog but, in both
instances, he was eventually able to find his way. He had no problems with
attention, language skills, or judgment. He operated all appliances at home
and safely drove a car. His family noticed mild anxiety in challenging
situations and questioned whether he was a little depressed, as he had
become quieter. The patient had no significant comorbidities and no family
history of dementia. He had been prescribed memantine 10 mg once a
day by an outside physician.
The patient’s cognitive evaluation revealed a Mini-Mental State
Examination (MMSE) score of 25 out of 30, poor recollection of recent events,
lower than expected performance on category fluency (number of animals
produced in 1 minute), poor encoding and retention of verbal and
nonverbal information, mild anxiety, and minimal depression. His attention,
visuospatial skills, and abstract thinking were preserved. Formal
neuropsychological testing confirmed the above deficits and further
clarified his memory profile as most consistent with retrieval memory
loss, as he showed significant improvement on cued recall (ie, the
recognition portion of the memory tests). Review of an outside MRI
revealed age-appropriate atrophy.
The patient was given a diagnosis of mild neurocognitive disorder by
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5)13 criteria (ie, mild cognitive impairment), most likely due to a
neurodegenerative etiology. Although the leading consideration was
Alzheimer disease (AD), the observed significant improvement on cued
recall, suggestive of retrieval rather than encoding deficits, was considered
atypical. An amyloid positron emission tomography (PET) scan was ordered
and revealed diffuse amyloid tracer uptake in the cerebral cortical gray
matter with complete loss of the gray-white matter differentiation
consistent with the presence of moderate to severe amyloid pathology.
A diagnosis of mild neurocognitive disorder due to AD was made.
The patient was prescribed donepezil. He experienced significant
gastrointestinal side effects as the dose was increased from 5 mg/d to
10 mg/d. A slower escalation regimen (introducing an additional titration
step of 7.5 mg/d for 1 month before introducing 10 mg/d) was effective. Two
years later, his MMSE score had declined to 19 out of 30. His family reported
difficulties with managing finances, shopping, navigation, and cooking.
Comment. This patient presented with atypical amnestic mild cognitive
impairment that met Appropriate Use Criteria33,34 for amyloid PET imaging.
The diagnostic uncertainty stemmed from the patient’s pronounced memory
retrieval deficit. The amyloid PET scan was beneficial in assisting the
physician’s therapeutic decisions and counseling the patient and family.

More recently, several large genome- 20 risk/protective genetic variants.47 Rel-

wide association studies have uncov- ative to APOE4, these variants explain
ered and successfully replicated another only a small fraction of the genetic

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 Alzheimer Disease

KEY POINT
h The search for other
gene variants that may
Case 3-2
A 59-year-old woman with 12 years of education presented to the memory
affect risk of Alzheimer
disorder clinic because of memory difficulties for the past 1 to 2 years. Her
disease is ongoing.
husband reported that for the past few months they had the same conversation
multiple times a day. She misplaced items more often. Her recall of distant
memories and visuospatial function were preserved. She was also becoming
more distractible. She managed their household without a problem and
safely operated a motor vehicle. On a few occurrences, she reportedly paid
some bills twice while being on time with the rest. She was still able to
manage her appointments and medications with occasional reminders.
She had become quieter in social situations and more reluctant to go out.
She was no longer interested in volunteering at their church.
On bedside cognitive testing the patient scored 22 out of 30 on the
Mini-Mental State Examination (MMSE). She showed relatively preserved
encoding, impaired delayed recall, and endorsed multiple false-positive
items on recognition testing. Her language and visuospatial skills were
preserved. She made a few errors on frontal executive tasks. On formal
neuropsychological testing, additional deficits in category fluency and
nonverbal memory were noted.
The patient’s MRI revealed mild global atrophy with medial temporal lobe
predominance and hippocampal atrophy. An amyloid PET scan was performed
and showed diffusely increased tracer uptake throughout the cortical cerebral
gray matter with loss of the normal gray-white matter contrast consistent with
the presence of moderate to severe amyloid pathology. A diagnosis of mild
neurocognitive disorder (ie, mild cognitive impairment) due to early-onset AD
was made. The patient was started on donepezil.
Comment. This patient presented with early-onset prodromal AD. The
patient met the Diagnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5)13 criteria for mild neurocognitive disorder (ie, mild cognitive
impairment) and met the Appropriate Use Criteria for amyloid PET imaging
by virtue of early disease onset. The amyloid PET scan was considered
beneficial in assisting the physician’s therapeutic decisions and counseling
of the patient.

heritability of sporadic AD where each do not.48 Genetic makeup is not the

risk variant conveys a relative risk of only risk; shared environmental and
1.1 to 1.3.47 The vast majority of these lifestyle factors likely also play a role.
risk variants take part in processes im- Several rare autosomal dominant
plicated in the pathogenesis of AD such variants of AD have been described.
as amyloid metabolism, inflammation, The first symptoms usually affect in-
oxidative stress, and energy metabo- dividuals in their 30s and 40s. These
lism. The search for other gene variants families show multiple affected individ-
that may affect risk of AD is ongoing. uals across generations. These autoso-
Family history of sporadic AD is a mal dominant AD variants have been
well-established risk factor. Individuals traced to genetic mutations in the amy-
who have a first-degree relative diag- loid precursor protein (APP), presenilin
nosed with AD are more likely to 1 (PSEN1), and presenilin 2 (PSEN2)
develop the disease than those who genes. Mutations in all three genes

428 www.ContinuumJournal.com April 2016

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 KEY POINTS
increase the levels of "-amyloid. Early- to receive diagnostic and prognostic h Amyloid deposition
onset autosomal dominant AD accounts counseling as well as appropriate is thought to begin
for less than 2% of all AD cases. medications in an optimized regimen. 20 years prior to
Patients’ coexisting behavioral and development of
ALZHEIMER DISEASE non-neurologic conditions need to be clinical symptoms.
PATHOLOGY optimally managed. Vital importance h Vital importance should
AD is thought to result from over- should be placed on coordinating care be placed on
production and impaired clearance of among physicians, nurse practitioners, coordinating care
"-amyloid. Downstream events are tau among physicians,
and social workers, and instituting
hyperphosphorylation and neuronal nurse practitioners, and
appropriate oversight and safety pre- social workers, and
toxicity. The primary pathologic features cautions when patients have functional instituting appropriate
of AD are brain atrophy from regional impairment and poor judgment. It is oversight and safety
neuronal and synaptic loss, extracellu- important to encourage patients to par- precautions when
lar "-amyloid deposition in the form patients have functional
ticipate in social activities, adult day care
of neuritic plaques, and intraneuronal impairment and
centers and exercise programs, as well
tau protein deposition in the form of poor judgment.
as to encourage both patients and care-
intraneuronal neurofibrillary tangles. h Treatment with
givers to take part in support groups.
"-Amyloid also deposits in the cerebral acetylcholinesterase
blood vessels. Cerebral amyloid angio- Acetylcholinesterase Inhibitors inhibitors should be
pathy ranges in severity from small considered in patients
Two classes of medications have been with mild to moderate
amounts of amyloid to major deposits approved for AD: the acetylcholines- Alzheimer disease per
that distort the artery architecture and terase inhibitors (AChEIs) and the the American Academy
cause cortical microinfarcts, microaneu- N-methyl- D -aspartate (NMDA) recep- of Neurology practice
rysms, and cerebral microhemorrhages tor antagonist memantine. Treatment guidelines for dementia.
or macrohemorrhages (multiple micro- with AChEIs should be considered in
hemorhages in the occipital lobes of a patients with mild to moderate AD per
patient with AD are shown in Figure 3-3). the AAN practice guidelines for demen-
Amyloid deposition is thought to tia.51 Three agents are currently ap-
begin 20 years prior to development proved and marketed in the United
of clinical symptoms.2 Longitudinal States: donepezil, rivastigmine, and
studies of cognitively normal individ- galantamine. All three have been shown
uals who are amyloid-positive are to be effective in double-blind placebo-
presently ongoing and are focusing on controlled trials, showing some benefit
ascertainment of the risk for future de- on cognitive measures including mem-
velopment of dementia among these ory and concentration as well as global
individuals. Neurofibrillary tangles are and functional outcome measures;
not exclusive to AD and can be found however, their therapeutic cognitive
in other conditions, such as dementia and functional effects seem to be mod-
pugilistica and chronic traumatic enceph- est in size and purely symptomatic.
alopathy, prion disease, and in normal Gastrointestinal side effects, more
aging. Neurofibrillary tangle burden and commonly seen during the dose esca-
neuronal loss show a robust association lation phase of treatment, occur with
with global cognitive impairment.49,50 all three agents. Bradycardia and heart
block may occur, especially in patients
TREATMENT with underlying cardiac conduction
The clinical management of patients deficits or in those individuals taking
with AD dementia should accomplish medications that cause PR interval
several important tasks. Patients need prolongation such as beta-blockers. If

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 Alzheimer Disease

KEY POINTS
h Memantine is US Food one agent causes intolerable side ef- support or refute use of memantine in
and Drug Administration fects, another AChEI should be tried. moderate to severe AD.59
approved for the
moderate to Glutamate Receptor Medications for Behavioral
severe stages of Modulators Symptoms
Alzheimer disease. Memantine is a low to moderate affin- The first line of treatment for behav-
h The first line of ity NMDA receptor antagonist that is ioral symptoms of AD are nonpharma-
treatment for behavioral used as an add-on to ongoing AChEI cologic techniques. A quiet, familiar
and neuropsychiatric therapy. A recent meta-analysis of nine environment with labels on doors and
symptoms of Alzheimer trials with a combined sample size of sufficient lighting in all rooms is im-
disease are
2433 revealed that memantine had a portant to reduce disorientation. Ag-
nonpharmacologic
modalities. beneficial effect on cognition, behavior, gressive behavior should always be
activities of daily living, and global addressed with positive and clear
function.52 Memantine is approved by language to reassure and distract
the US Food and Drug Administration the patient.
(FDA) for the moderate to severe AD Depressive symptoms are treated
stages (Mini-Mental State Examination with selective serotonin reuptake in-
[MMSE] score of 5 to 15) in the United hibitors (SSRIs) due to their low pro-
States. The main side effects of con- pensity to cause anticholinergic effects.
fusion and dizziness occur only rarely. SSRIs may also ease anxiety, irritability,
The timing of initiation of cholines- or other nonspecific symptoms that
terase inhibitors and memantine ther- may accompany depression. The SSRI
apy is an area of some controversy.53
citalopram may be useful for agitation.
Cholinesterase inhibitors and meman-
Agitation or disruptive behavior
tine are frequently prescribed off-label
may require a neuroleptic for optimal
for mild cognitive impairment in the
therapeutic response. The newer
United States.54 Recent meta-analyses
‘‘atypical’’ antipsychotic medications
have not demonstrated a benefit of
cholinesterase inhibitors in mild cogni- (quetiapine, risperidone, olanzapine)
tive impairment, although a benefit for are often used in low doses with
subgroups of patients remain unde- careful titration. Typical and atypical
termined.55,56 A separate meta-analysis antipsychotic agents, however, carry a
suggests there is not a benefit of black box warning label due to an
memantine in patients with mild AD.57 association with increased cardiovas-
While the 2001 AAN practice parame- cular morbidity and mortality (higher
ter for treatment of dementia is cur- for the typical compared to atypical
rently under revision, 2011 guidelines antipsychotics) and cerebrovascular
from the National Institute for Health adverse events in the elderly with
and Clinical Excellence now recommend dementia-related psychosis.60Y62 In
memantine as an option for managing addition, these medications have ad-
moderate AD for people who cannot ditional adverse effects: anticholiner-
take AChEIs and as an option for man- gic adverse events and orthostatic
aging severe AD.58 In contrast, Canadian and metabolic disturbances. Tradi-
Consensus guidelines on dementia from tional neuroleptics are more likely to
2013 state that, while combination ther- produce extrapyramidal symptoms,
apy of a cholinesterase inhibitor and which may worsen cognitive function.
memantine is rational and appears to All antipsychotics, typical as well as
be safe, there is insufficient evidence to atypical, when used in older adults with
430 www.ContinuumJournal.com April 2016

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

dementia, are associated with risk for Aging (NIA R01 AG040770, NIA K02
death. This risk is quite comparable AG048240, and NIA P30 AG010133).
among atypical and typical antipsy-
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 Review Article

Lewy Body Dementias:

Address correspondence to
Dr Stephen N. Gomperts, 114
16th St, Massachusetts General

Dementia With Lewy

Hospital, Charlestown, MA
02129, [email protected].
Relationship Disclosure:

Bodies and Parkinson

Dr Gomperts receives grant
support from the National
Institutes of Health as principal
investigator of study 1-R21-NS-

Disease Dementia 090243Y01 and receives

research support as principle
investigator from the National
Parkinson Foundation.
Stephen N. Gomperts, MD, PhD Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Gomperts reports
ABSTRACT no disclosure.
Purpose of Review: This article provides an overview of the clinical features, neuro- * 2016 American Academy
pathologic findings, diagnostic criteria, and management of dementia with Lewy of Neurology.
bodies (DLB) and Parkinson disease dementia (PDD), together known as the Lewy
body dementias.
Recent Findings: DLB and PDD are common, clinically similar syndromes that share
characteristic neuropathologic changes, including deposition of !-synuclein in Lewy
bodies and neurites and loss of tegmental dopamine cell populations and basal fore-
brain cholinergic populations, often with a variable degree of coexisting Alzheimer
pathology. The clinical constellations of DLB and PDD include progressive cognitive
impairment associated with parkinsonism, visual hallucinations, and fluctuations of
attention and wakefulness. Current clinical diagnostic criteria emphasize these fea-
tures and also weigh evidence for dopamine cell loss measured with single-photon
emission computed tomography (SPECT) imaging and for rapid eye movement (REM)
sleep behavior disorder, a risk factor for the synucleinopathies. The timing of de-
mentia relative to parkinsonism is the major clinical distinction between DLB and PDD,
with dementia arising in the setting of well-established idiopathic Parkinson disease
(after at least 1 year of motor symptoms) denoting PDD, while earlier cognitive impair-
ment relative to parkinsonism denotes DLB. The distinction between these syndromes
continues to be an active research question. Treatment for these illnesses remains
symptomatic and relies on both pharmacologic and nonpharmacologic strategies.
Summary: DLB and PDD are important and common dementia syndromes that overlap
in their clinical features, neuropathology, and management. They are believed to exist
on a spectrum of Lewy body disease, and some controversy persists in their dif-
ferentiation. Given the need to optimize cognition, extrapyramidal function, and
psychiatric health, management can be complex and should be systematic.

Continuum (Minneap Minn) 2016;22(2):435–463.

INTRODUCTION later !-synuclein immunostains made it

In 1912, Frederick Lewy first described easier to see them3 and demonstrated
the cytoplasmic inclusions now known that Lewy bodies were a common
as Lewy bodies in the substantia nigra in neuropathologic finding in dementia,
Parkinson disease (PD).1 Cortical Lewy second only to Alzheimer disease (AD).
bodies were first reported in associa- Lewy bodyYrelated pathology is ob-
tion with dementia in 1961,2 but they served in dementia with Lewy bodies
were felt to be a relatively rare finding (DLB), idiopathic PD, and multiple
until the 1980s, when first ubiquitin and system atrophy (MSA), and DLB and

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 Lewy Body Dementias

KEY POINTS
h Deposition of !-synuclein the dementia that arises in PD (ie, the hypothesis that PDD and DLB may
is the hallmark Parkinson disease dementia [PDD]) be different phenotypic expressions of
neuropathologic finding together comprise the Lewy body de- the same underlying process.11,12 This
of the synucleinopathies, mentias. The clinical features of DLB hypothesis implies that future disease-
which include and PDD are similar and include hal- modifying therapies will be effective in
dementia with Lewy lucinations, cognitive fluctuations, and both diseases.
bodies, Parkinson dementia in the setting of the extrapy-
disease, and multiple ramidal motor impairments known as CLINICAL FEATURES AND
system atrophy. The parkinsonism. The cognitive domains DIAGNOSTIC EVALUATION OF
Lewy body dementias that are impacted in DLB and PDD DEMENTIA WITH LEWY BODIES
include dementia overlap substantially, with prominent DLB is associated with a stereotyped
with Lewy bodies executive dysfunction and visual-
and Parkinson
set of clinical features.
spatial abnormalities and variable im-
disease dementia. pairment in memory capacities.4 In Cognitive Symptoms
h The Lewy body DLB, dementia often heralds the onset
of illness in advance of parkinsonian The typical patient with DLB presents
dementias are the
second most common motor signs, but by consensus may with early dementia, often in associa-
neurodegenerative follow their development up to 1 year tion with visual hallucinations. Extrapy-
dementia, after from their onset.5 In contrast, a di- ramidal motor symptoms and signs
Alzheimer disease. agnosis of PDD is made when cog- characteristic of PD often develop simul-
h In dementia with Lewy nitive impairments develop in the taneously or soon thereafter. Progres-
bodies, !-synuclein setting of well-established PD.6 sive cognitive decline begins early,
pathology is observed Despite the different temporal se- typically after age 55. It is useful to
beyond the brainstem in quences of motor and cognitive def- identify the first cognitive domains
limbic and neocortical icits, PDD and DLB show remarkably impaired, as these can point toward
regions. In contrast, in convergent neuropathologic changes DLB. Although short-term memory may
Parkinson disease, at autopsy. These changes include be involved, cognitive domains other
!-synuclein pathology is widespread limbic and cortical Lewy than memory are frequently affected as
first observed in the bodies7 and Lewy neurites composed well, including attention, executive
brainstem, in association of aggregates of !-synuclein that in- function, and visual-spatial skill. Patients
with extrapyramidal may therefore report early difficulty
volve the brainstem as well as limbic
impairment, and
and neocortical regions (referred to as multitasking at work or home and may
appears to spread with
Lewy body disease), loss of midbrain start to lose the thread of conversations.
progression of disease
to involve limbic and dopamine cells,8 and loss of choliner- In addition, patients may occasionally
neocortical regions. gic neurons in ventral forebrain nuclei.9 get lost while driving or grow increas-
Neuritic plaques that contain amyloid ingly dependent on global positioning
h Amyloid deposition
and neurofibrillary tangles are found in system (GPS) devices. Short-term mem-
is common and
variably present in the majority of cases of DLB and are ory loss can be significant as well.
dementia with Lewy common in PD.10 Current neuropatho- While reminiscent of the impairment
bodies and Parkinson logic criteria of Lewy body disease of hippocampal-dependent memory
disease dementia. weigh !-synuclein pathology against encoding seen in AD, in many patients
h Early dementia, AD neurofibrillary tangle pathology to with DLB, the impairment of short-
visual hallucinations, estimate the probability that Lewy term memory reflects instead a prob-
fluctuations of attention body disease caused the clinical syn- lem of retrieval of stored information,
and arousal, and the drome in life.5 It is notable that Lewy which can be improved with cues.
motor manifestations body disease at autopsy does not Errors of memory encoding and re-
of parkinsonism successfully predict whether patients trieval can be differentiated on de-
characterize dementia had DLB or PDD syndromes in life. The tailed cognitive testing (see the
with Lewy bodies. overlap of clinical, neuropsychological, following section on diagnostic criteria
and neuropathologic features has led to for DLB). Over time, patients’ cognitive

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impairments progress and spread to Fluctuations of Attention
involve other cognitive domains. When and Arousal
they are sufficiently severe to impair Attention and alertness may fluctuate,
social or occupational function (impact- leading to episodes of staring and per-
ing instrumental or basic activities of turbed flow of ideas, or to frequent day-
daily living), they reach criteria for a time drowsiness and naps during the
diagnosis of dementia.5 day. These episodes can be hard to
quantify and need to be disentangled
Neuropsychiatric Symptoms from toxic metabolic processes such
Recurrent, complex visual hallucina- as medication side effects or infec-
tions are common in patients with DLB, tions. A recent fluctuations scale
and their early presence in a de- vetted for this purpose is the De-
mentia syndrome is diagnostically mentia Cognitive Fluctuation Scale,13
useful. These hallucinations are usu- which aggregates prior scales. The
ally well formed and animate, and it fluctuations screen requires a posi-
is common for these hallucinations tive response to at least three of the
to include adults or small children, following: (1) Does the patient’s in-
deceased family members, and small ability to organize thoughts in a co-
animals. Early in the course of the ill- herent way vary significantly over the
ness, hallucinations are usually uni- course of the day? (2) Does the pa-
modal, without sound, smell, or tient spend more than 1 hour sleep-
touch. They are frequently well- ing during the waking day? (3) Is
tolerated and emotionally neutral, the patient drowsy and lethargic for
but occasionally can be dysphoric or more than 1 hour during the day,
fear provoking. These hallucinations despite getting the usual amount of
are distinct from visual illusions, in sleep the night before? (4) Is the pa-
which an object is visually misin- tient difficult to arouse on a usual
terpreted (eg, a corner lamp that is day? This approach had a sensitivity
misinterpreted as a person). Such ill- of 80% and a specificity of 76% in
usions are common early in the illness differentiating clinical syndromes of
as well, particularly at night in dimly DLB and PDD from AD and vascular
lit environments, but are nonspecific. dementia, but has yet to be neuro-
Delusions can also arise in patients pathologically validated.
with DLB, typically later in the course,
and usually have a paranoid quality. Motor Features of Parkinsonism
Delusions of infidelity, house intruders, Parkinsonian motor signs often de-
and theft are common, the latter often velop concurrently with or subsequent
occurring as patients misplace items to these problems and are also diag-
around the home. As cognition con- nostically very useful. These motor
tinues to deteriorate, patients may signs are often symmetric, and brady-
believe that their spouse or other care- kinesia and gait impairment are more
giver has been replaced by an impos- common than rest tremor. However,
ter, a phenomenon known as Capgras the variance of the motor presentation
syndrome. One hypothesis for this is high. Some patients may present
phenomenon is the loss of valence (ie, with a classic asymmetric pill-rolling
emotional) associations for a memory, tremor of PD while others may have
such that a familiar face, for exam- no motor concerns yet will display clear
ple, loses its ability to retrieve emo- extrapyramidal dysfunction on exami-
tional associations. nation. In contrast to patients with PD,

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 Lewy Body Dementias

KEY POINTS
h Due to neuroleptic who have a sustained beneficial re- and MSA). In addition, many patients
sensitivity in dementia sponse to PD medications such as with DLB will report a chronic, high
with Lewy bodies, D2 carbidopa/levodopa, patients with DLB sensitivity to medications in general. It
receptor antagonists often have a limited response to such is unclear how or whether this relates
such as typical and medications. These patients nonethe- to the underlying disease process.
most atypical neuroleptics less show reduced dopamine trans-
are dangerous porter (DAT) activity on single-photon Rapid Eye Movement Sleep
and contraindicated. emission computed tomography Behavior Disorder
h Rapid eye movement (SPECT) or positron emission tomogra- REM sleep behavior disorder refers to
sleep behavior disorder, phy (PET) imaging, when performed. a syndrome in which the normal pa-
impairment of olfaction, Generalized myoclonus can also occur ralysis of REM sleep is impaired. As a
chronic constipation, in some patients with DLB. result, patients’ bed partners may re-
and neuroleptic port that they act out their dreams with
sensitivity are common Neuroleptic Sensitivity behaviors such as kicking, punching,
in dementia with Lewy
In part as a result of dopamine cell and yelling. The observation that most
bodies and Parkinson
loss, patients with DLB are particu- REM sleep behavior disorder behaviors
disease. These features
may precede the
larly sensitive to neuroleptics. Such are violent suggests that the impair-
development of typical agents can trigger or exacerbate par- ment of paralysis may be relative, with a
clinical symptoms in kinsonism, as they can in PD, and reduction in threshold that is overcome
these illnesses. this may be irreversible. In addition, by only the most emotionally salient
h Clinical diagnostic neuroleptics have been associated dreams, perhaps on the basis of cate-
criteria for dementia with with increased mortality, and patients cholamine or amygdala drive.
Lewy bodies have better with DLB are at increased risk for
neuroleptic malignant syndrome. Autonomic Impairment
specificity than sensitivity.
Neuroleptics can also affect cognition Autonomic impairment is common in
and impair attention and alertness. DLB but is not as profound as in MSA.
This issue of neuroleptic sensitivity is Constipation is common in both and
clinically important, as many patients can be problematic if not treated
will at some time be evaluated in an aggressively. Some patients also expe-
emergency department for psychosis rience orthostatic hypotension and its
or confusion, where haloperidol and complications, particularly syncope
other neuroleptics are dispensed lib- and falls. This is more common later
erally. As such, it is worthwhile to in the course of DLB and can be ex-
teach patients and their caregivers acerbated by medications. Denerva-
that patients with DLB are essentially tion of cardiac sympathetic ganglia is
‘‘allergic’’ to haloperidol and other widespread and can be appreciated
neuroleptics with significant D2 re- using metaiodobenzylguanidine
ceptor antagonism. (MIBG) cardiac scans.15 In addition,
some patients experience neurogenic
Other Associated Symptoms urinary frequency or incontinence.
As in PD (see the following section
on preclinical synucleinopathies), DIAGNOSTIC CRITERIA FOR
rapid eye movement (REM) sleep DEMENTIA WITH LEWY BODIES
behavior disorder, loss of olfaction, The consensus criteria for a clinical di-
and constipation are common and agnosis of DLB reflect the clinical fea-
may antedate the illness by several tures described previously in this article
years. 14 Epidemiologic data suggest (Table 4-1). Progressive cognitive
that these problems are risk factors for decline to dementia is required, often
all of the synucleinopathies (PD, DLB, involving attention, executive function,

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 TABLE 4-1 Diagnostic Criteriaa for the Clinical Diagnosis of Dementia
With Lewy Bodies

b Central Feature (Essential for diagnosis of possible or probable dementia

with Lewy bodies [DLB])
Dementia with progressive cognitive decline of sufficient magnitude to interfere
with social or occupational function. Memory impairment may not necessarily
occur early but usually develops with progression. Deficits on tests of attention,
executive function, and visual-spatial ability may be prominent.
b Core Features (Two core features are sufficient for a diagnosis of
probable DLB, one for possible DLB)
Fluctuating cognition, pronounced variation in attention and alertness
Recurrent visual hallucinations, typically well formed and detailed
Spontaneous motor manifestations of parkinsonism
b Suggestive Features (If one or more of these is present, along with one or
more core features, a diagnosis of probable DLB can be made. In the
absence of any core features, one or more suggestive features are
sufficient for possible DLB. Probable DLB should not be diagnosed on the
basis of suggestive features alone.)
Rapid eye movement (REM) sleep behavior disorder
Severe neuroleptic sensitivity
Single-photon emission computed tomography (SPECT) or positron emission
tomography (PET) imaging evidence of low dopamine transporter
concentration in the basal ganglia
b Supportive Features
Reduced metaiodobenzylguanidine (MIBG) myocardial scintigraphy
SPECT perfusion with reduced occipital activity
Relatively preserved medial temporal lobe structures on CT/MRI
Repeated falls and syncope
Transient, unexplained loss of consciousness
Autonomic dysfunction
Other types of hallucinations
Systematized delusions
Depression
Prominent slow-wave activity on EEG, with temporal lobe transient sharp waves
b A Diagnosis of DLB Is Less Likely
In the presence of cerebral infarcts evident as focal neurologic signs on
examination or on brain imaging
In the presence of other physical illness or brain disorder that can account
in part or in full for the clinical presentation
If parkinsonism only manifests at a stage of severe dementia
Continued on page 440

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 Lewy Body Dementias

KEY POINT
h Early anterograde TABLE 4-1 Diagnostic Criteriaa for the Clinical Diagnosis of Dementia
amnesia is the sine qua With Lewy Bodies Continued from page 439
non of Alzheimer
disease. Hallucinations b Temporal Sequence of Symptoms
and parkinsonism can
DLB is diagnosed when dementia precedes or is concurrent with
arise late in the course of
parkinsonism. Parkinson disease dementia should be used to describe
Alzheimer disease.
dementia that occurs in the context of well-established Parkinson disease.
Early additional cognitive For research studies that distinguish between DLB and Parkinson disease
features and the early dementia, a 1-year rule is recommended for a diagnosis of DLB, such that
appearance of dementia should begin no later than 1 year after onset of parkinsonism.
hallucinations,
CT = computed tomography; EEG = electroencephalogram; MRI = magnetic resonance imaging.
parkinsonism, and a
Modified with permission from McKeith IG, et al; Consortium on DLB, Neurology.5
fluctuations of attention www.neurology.org/content/65/12/1863.full.pdf+html. B 2005 American Academy of Neurology.
or arousal point to
dementia with
Lewy bodies.
and visual-spatial skills. The core fea- earliest feature in AD, where it re-
tures of these criteria include the flects an error of encoding, due to
following: (1) recurrent visual halluci- hippocampal-dependent impair-
nations that are well formed and de- ment. In contrast, the pattern of
tailed; (2) fluctuations in attention and memory loss is more variable in DLB,
alertness; and (3) parkinsonian motor instead reflecting an error of retrieval
signs. Supportive features, also com- in some patients. On cognitive test-
mon in PD, include the presence of ing, controlling for severity of de-
REM sleep behavior disorder, severe mentia, patients with DLB are often
neuroleptic sensitivity, or low DAT more impaired than those with AD in
uptake in the basal ganglia on SPECT tests of attention, executive function,
or PET. A diagnosis of clinically and visual-spatial skills.5 However, late
probable DLB requires at least two out in the course of DLB and AD, the
of three of the core features to be pres- profiles of cognitive impairment may
ent or one core feature and one sup- converge. Although hallucinations and
portive feature. A diagnosis of clinically parkinsonism can occur late in the
possible DLB requires only one of the course of AD, neither is common and
three core features to be present. pervasive in AD, and their early pres-
Although the specificity of these cri- ence should point toward DLB. Fluc-
teria for a diagnosis of DLB is high (esti- tuations of awareness or attention are
mated to range from 79% to 100%), the unusual in early AD except when due
sensitivity can be low (12% to 88%), im- to a toxic-metabolic process, but day-
proving with the addition of the sup- time sleepiness often increases with
portive features.16 These data suggest increasing dementia severity.
that we are missing patients with DLB It is useful to keep in mind that
in our clinics. Thus, further refinement of parkinsonism and cognitive impair-
these criteria is needed. ment can also arise in the parkinsonian
As touched upon previously in tauopathy syndromes, progressive su-
this article, the clinical features of pranuclear palsy (PSP), and corti-
DLB can overlap with those of AD. cobasal syndrome (CBS). The specific
For example, short-term memory loss constellation of cognitive and motor
can occur in both dementias. How- impairments differentiates these clin-
ever, impairment of short-term mem- ical presentations from DLB and PDD
ory is usually the dominant and (Case 4-1). These conditions are

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 Case 4-1
A 63-year-old man presented for a neurologic evaluation for progressive
cognitive and motor symptoms. His symptoms began 2 years ago when he
started to get lost while driving. He then developed a shuffling gait,
kyphosis, and a postural tremor, and noted increasing difficulty with
buttons. He was involved in a minor motor vehicle accident 1 year later.
Short-term memory loss was first noted at this time and was insidiously
progressive. He developed nonthreatening visual hallucinations of small
children, particularly in the evenings. His performance as a computer
technician declined, prompting retirement. His wife took over his
medications and the finances at that time. He became frequently
somnolent and difficult to arouse during the day, regularly sleeping for at
least 2 hours. He grew apathetic and less engaged in conversations. He
gave up most of his household chores due to their cognitive rather than
physical demands, but he still enjoyed driving around town on overlearned
routes. His wife reported that he had been episodically acting out violent
dreams over the last few years but otherwise slept well. On examination, he
had a Montreal Cognitive Assessment (MoCA) score of 21, with 5 out of
5 errors of 5-minute recall, improving to 3 out of 5 errors with cues, and
1 error of concentration. Spatial testing showed markedly distorted figure
copy and clock. Bradyphrenia was prominent. Praxis and language were
normal. Vertical gaze was preserved. He had a masked facies, and tone was
increased in the neck and arms. Fast repetitive movements were slow in the
arms, where a symmetric postural tremor was noted. Gait was slow, with
symmetric, reduced arm swing, narrowed stride, and en bloc turns. He was
slightly unstable on the pull test. The patient’s blood testing was normal.
MRI showed minimal global atrophy, and fluorodeoxyglucose positron
emission tomography (FDG-PET) revealed temporal, parietal, and occipital
hypometabolism. Formal neuropsychological testing confirmed the cognitive
profile observed on examination. On the basis of the clinical history,
examination, and test results, he was diagnosed with probable dementia
with Lewy bodies (DLB). Donepezil was started and was associated with
significantly improved cognitive function, along with resolution of his
hallucinations. Carbidopa/levodopa 25 mg/100 mg 3 times a day was
subsequently initiated and associated with modest improvement of
bradykinesia and gait. Physical therapy, occupational therapy, and a home
safety evaluation were helpful. His possible rapid eye movement (REM)
sleep behavior disorder was deemed mild and left untreated. Visual
hallucinations returned after about 6 months as cognition began to again
deteriorate but were nonthreatening and well tolerated.
Comment. This case illustrates an uncomplicated case of DLB. The
constellation of early parkinsonism and hallucinations in the setting of
cognitive impairment sufficiently severe to interfere with activities of daily
living supports the clinical diagnosis of probable DLB. Occipital
hypometabolism is often present in DLB and is discussed in the following
section on clinical studies. Both cognitive and motor impairments can
impact driving safety in patients with DLB. There are no Lewy body
dementiaYspecific guidelines for driving. Driving issues in patients with
dementia are discussed in the Patient Management Problem by
Elizabeth C. Finger, MD, FRCPC, in this issue of Continuum.

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 Lewy Body Dementias

KEY POINT
h Parkinson disease briefly discussed in the following mortality, antedating death by ap-
hastens cognitive sections. For a more comprehensive proximately 4 years on average. 28
decline and is a risk discussion of PSP and CBS, refer to The risk of developing cognitive
factor for dementia. the article ‘‘Frontotemporal Demen- impairment and dementia in PD has
tias’’ by Elizabeth C. Finger, MD, been associated with older age, greater
FRCPC,17 in this issue of Continuum. severity of extrapyramidal motor im-
pairment, and longer duration of ill-
CLINICAL FEATURES AND ness.20,24,25 Additional risk factors
DIAGNOSTIC EVALUATION OF have been identified as well, in-
PARKINSON DISEASE DEMENTIA cluding male gender, atypical motor
Cognitive and neuropsychiatric im- syndromes (notably the postural
pairments in PDD are common and instability gait disorder (PIGD) vari-
are similar in quality to those of DLB. ant, axial symmetrical parkinsonism,
and akinetic dominant parkinsonism),
Mild Cognitive Impairment and and the early development of halluci-
Dementia in Parkinson Disease nations (Table 4-3).24,27
Contrary to Dr James Parkinson’s The cognitive profile in PD de-
introduction to ‘‘An Essay on the mentia overlaps significantly with
Shaking Palsy,’’18 the intellect is not that observed in DLB. 4 Patients typ-
‘‘uninjured’’ in PD. Although patients ically demonstrate executive dysfunc-
with PD first come to medical atten- tion and visual-spatial impairment.
tion because of characteristic motor Caregivers will note new errors with
signs, including rest tremor, rigidity, the patient’s (usually complex) medi-
bradykinesia, and gait abnormality, cation regimen and will often need to
specific cognitive impairments in ex- intervene. Errors with the finances can
ecutive function, visual-spatial skill, be significant. Attention is often im-
and even memory function in pa- paired and may fluctuate. In fact, late
tients with PD are common and have in the course of PD in some patients,
been known for more than 40 years.19 inattention may cycle as a peak-dose
PD hastens deterioration of these cog- phenomenon, phase-locked to dopa-
nitive abilities over time, with the in- mine replacement dosing. Although
cidence and prevalence of cognitive naming is often impaired to a vari-
impairments increasing with duration able degree, frank language impair-
and severity of illness.20,21 In this sense, ments are not present. As in DLB,
PD can be considered a risk factor for free recall is often impaired but
dementia. Formal criteria have been tends to improve with cues, sug-
developed for mild cognitive impair- gesting an error of recall rather than
ment (MCI) in PD (Table 4-2).22,23 encoding. Lastly, bradyphrenia (slowed
These criteria attempt to account for thinking) may be significant.
the contribution of motor impairment Visual hallucinations are common
to functional decline and are now in PDD. Like those of DLB, these are
being validated. often animate and unimodal and only
Dementia in PD is common, with occasionally dysphoric or fear provok-
prevalence rates as high as 78%24 and ing. Delusions are less common but
incidence rates ranging from 3% to can arise as well. Both hallucinations
10% per year, approximately three- and delusions can be precipitated or
fold higher than in the normal pop- exacerbated by dopamine replace-
ulation. 25Y27 Dementia in PD is ment medications, and dopamine
associated with high morbidity and agonists are particularly notorious.
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TABLE 4-2 Movement Disorder Society Task Force Guidelines for Diagnostic Criteria of Mild
Cognitive Impairment in Parkinson Diseasea

I. Inclusion Criteria
Diagnosis of Parkinson disease (PD) as based on the UK PD Brain Bank Criteria22
Gradual decline in cognitive ability in the context of established PD, reported by either the patient or
informant or observed by the clinician
Cognitive deficits on either formal neuropsychological testing or a scale of global cognitive abilities
(detailed in section III)
Cognitive deficits are not sufficient to interfere significantly with functional independence, although subtle
difficulties on complex functional tasks may be present
II. Exclusion Criteria
Diagnosis of PD dementia based on Movement Disorders Society Task Force proposed criteria6
Other primary explanations for cognitive impairment (eg, encephalopathy, stroke, major depression,
metabolic abnormalities, adverse effects of medication, or head trauma)
Other PD-associated comorbid conditions (eg, motor impairment or severe anxiety, depression, excessive
daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing
III. Specific Guidelines for PDYMild Cognitive Impairment (MCI) Level I and Level II Categories
A. Level I (abbreviated assessment)
Impairment on a scale of global cognitive abilities validated for use in PD
OR
Impairment on at least two tests when a limited battery of neuropsychological tests is performed
(limited in that the battery either includes less than two tests within each of the five cognitive
domains [attention and working memory, executive, language, memory, and visual-spatial], or does
not assess all five cognitive domains)
B. Level II (comprehensive assessment)
Neuropsychological testing that includes two tests within each of the five cognitive domains
Impairment on at least two neuropsychological tests, represented by either two impaired tests in one
cognitive domain or one impaired test in two different cognitive domains
Impairment on neuropsychological tests may be demonstrated by
Performance approximately 1 to 2 standard deviations below appropriate norms, or
Significant decline demonstrated on serial cognitive testing, or
Significant decline from estimated premorbid levels
IV. Subtype Classification for PD-MCI (Optional, requires two tests for each of the five cognitive domains
assessed and is strongly suggested for research purposes)b
PD-MCI single-domain: abnormalities on two tests within a single cognitive domain (specify the domain),
with other domains unimpaired or
PD-MCI multiple-domain: abnormalities on at least one test in two or more cognitive domains (specify
the domains)
a
Reprinted with permission from Litvan I, et al, Mov Disord.23 onlinelibrary.wiley.com/doi/10.1002/mds.24893/abstract. B 2012
Movement Disorder Society.
b
Subtype classifications are applicable only to patients with PD-MCI who have at least two tests within each of the five cognitive
domains administered.

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 Lewy Body Dementias

KEY POINTS
h Parkinson disease such as hallucinations are common.
medications can impair TABLE 4-3 Risk Factors As described previously in the article,
for Cognitive the clinical and neuropsychological
cognition. This is Impairment in
particularly true of Parkinson Disease features of DLB and PDD are similar.
trihexyphenidyl and the Indeed, it is the relative timing of
dopamine agonists but
b Atypical parkinsonian dementia and parkinsonism that de-
can be seen in all agents motor signs fines the clinical distinction between
at sufficient dose. DLB and PDD. Controversy exists
b Early hallucinations
h The relative timing over how or whether to distinguish
of dementia and b Greater motor impairment these syndromes. 30
parkinsonism defines the b Longer duration of illness
clinical distinction CLINICAL STUDIES
between dementia b Male gender
Patients with suspected DLB or PDD
with Lewy bodies b Older age should receive a standard evaluation
and Parkinson
for cognitive impairment, including
disease dementia.
blood testing to exclude reversible
Reducing these agents or shifting from contributions to cognitive impair-
one class of agent to another (eg, ment such as a thyroid disorder or
from dopamine agonist to carbidopa/ vitamin B 12 deficiency; a brain MRI
levodopa) can often dramatically im- scan; and detailed cognitive testing.
prove these problems. The MRI scan is nondiagnostic in
The differential diagnosis for cogni- DLB and PDD, although some de-
tive impairment in PD includes toxic gree of global, symmetric atrophy
metabolic processes in general and PD may be appreciated. 31 The finding
medications specifically. Excessive of marked, disproportionate hippo-
dopamine replacement can worsen campal atrophy would point toward
executive dysfunction and attention AD, while focal cortical atrophy may
and precipitate or exacerbate halluci- point toward CBS (see the following
nations or delusions. Although this is section on differential diagnosis).
true of all agents, dopamine agonists Detailed cognitive testing (if well
are notorious offenders, and aman- performed) can provide a valuable
tadine can be problematic in some assessment of the patient’s function
patients. Carbidopa/levodopa is best across multiple cognitive domains.
tolerated in this regard, but at suffici- This is often diagnostically useful
ently high dose, carbidopa/levodopa and also provides a baseline for fu-
can also exacerbate cognitive impair- ture comparisons. In patients with
ments and precipitate psychosis. Of profound fluctuations of attention
note, the central anticholinergic agent or arousal, an EEG can exclude
trihexyphenidyl, used to treat PD seizure activity. In DLB, the EEG
tremor, can be particularly deleterious often shows diffuse slowing in the
to cognition.
theta or delta range.
In a subset of patients with DLB,
DIAGNOSTIC CRITERIA FOR fluorodeoxyglucose positron emission
PARKINSON DISEASE DEMENTIA tomography (FDG-PET) or cerebral
Consensus criteria for PDD were blood flow SPECT can also be infor-
developed in 2007 (Table 4-4).6,29 mative. These often show a char-
These criteria require cognitive im- acteristic pattern of symmetric
pairments across multiple domains but hypometabolism involving not just
emphasize that noncognitive features the parietal and temporal regions, as
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 a
TABLE 4-4 Consensus Criteria for a Clinical Diagnosis of Parkinson Disease Dementia

I. Clinical Features
A. Core features (Both 1 and 2 must be present)
1. Diagnosis of idiopathic Parkinson disease according to Queen Square Brain Bank criteria22
Bradykinesia and at least one of the following: muscular rigidity, 4Y6 Hz rest tremor, or postural
instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction
No exclusion criteria (such as history of repeated strokes with stepwise progression of parkinsonian
features, supranuclear gaze palsy, cerebellar signs, or early severe dementia)
At least three supportive criteria of the following: unilateral onset, rest tremor present,
progressive disorder, persistent asymmetry, excellent response to L-dopa, severe L-dopaYinduced
chorea, L-dopa response for at least 5 years, clinical course at least 10 years, hyposmia, or
visual hallucinations
2. A dementia syndrome with insidious onset and slow progression, developing within the context of
established Parkinson disease and diagnosed by history, clinical, and mental status examination,
defined as
Impairment in more than one cognitive domain
Representing a decline from premorbid level
Deficits severe enough to impair daily life (eg, social, occupational, or personal care), independent of
the impairment ascribable to motor or autonomic symptoms
B. Associated clinical features
1. Cognitive features
Attention: Impairment may fluctuate during the day and from day to day
Executive functions: Impairment often associated with impaired mental speed (bradyphrenia)
Visual-spatial functions: Impairment in tasks requiring visual-spatial orientation, perception, or construction
Memory: Impairment in free recall of recent events; memory usually improves with cueing, and
recognition is usually better than free recall
Note that core language functions are largely preserved; however, word-finding difficulties and
impaired comprehension of complex sentences may be present
2. Behavioral features
Apathy: Decreased spontaneity and loss of motivation, interest, and effortful behavior
Changes in personality and mood including depressive features and anxiety
Hallucinations: Mostly visual; usually complex, formed visions of people, animals, or objects
Delusions
Excessive daytime sleepiness
C. Features that make the diagnosis of Parkinson disease dementia (PDD) uncertain
Coexistence of any other abnormality that may by itself cause cognitive impairment, but is judged not
to be the cause of dementia (eg, the presence of relevant vascular disease on imaging)
Time interval between the development of motor and cognitive symptoms is not known
Continued on page 446

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 Lewy Body Dementias

a
TABLE 4-4 Consensus Criteria for a Clinical Diagnosis of Parkinson Disease Dementia
Continued from page 445

D. Features that make the diagnosis of PDD unreliable

Cognitive and behavioral symptoms appearing solely in the context of other conditions such as acute
confusion due to systemic diseases or abnormalities or due to drug intoxication
Major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
(DSM-5)29
Features compatible with probable vascular dementia criteria according to the National Institute of
Neurological Disorders and StrokeYAssociation Internationale pour la Recherche et l’Enseignement en
Neurosciences (NINDS-AIREN) (dementia in the context of cerebrovascular disease as indicated by focal
signs in neurologic examination such as hemiparesis, sensory deficits, and evidence of relevant
cerebrovascular disease by brain imaging AND a relationship between the two as indicated by the
presence of one or more of the following: onset of dementia within 3 months after a recognized stroke,
abrupt deterioration in cognitive functions, and fluctuating, stepwise progression of cognitive deficits)
II. Diagnostic Criteria for the Diagnosis of Probable and Possible PDD
A. Probable PDD
1. Core features: Both 1 and 2 must be present
2. Associated clinical features:
Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains
(impaired attention which may fluctuate, impaired executive functions, impairment in visual-spatial
functions, and impaired free recall memory which usually improves with cueing)
The presence of at least one behavioral symptom (apathy, depressed or anxious mood, hallucinations,
delusions, excessive daytime sleepiness) supports the diagnosis of probable PDD; lack of behavioral
symptoms, however, does not exclude the diagnosis
3. None of the group C clinical features present
4. None of the group D clinical features present
B. Possible PDD
1. Core features: Both must be present
2. Associated clinical features:
Atypical profile of cognitive impairment in one or more domains, such as prominent or receptive-type
(fluent) aphasia, or pure storage-failure type amnesia (memory does not improve with cueing or in
recognition tasks) with preserved attention
Behavioral symptoms may or may not be present
OR
3. One or more of the group C clinical features present
4. None of the group D clinical features present
a
Modified with permission from Emre M, et al. Mov Disord.6 onlinelibrary.wiley.com/doi/10.1002/mds.21507/abstract.
B 2007 Movement Disorder Society.

seen in AD, but also the occipital more sensitive than SPECT, with a
lobes. 31 However, in some patients, sensitivity of 83% to 92% and a specific-
only the AD pattern of hypometabolism ity of 67% to 93%.32 Clinical context is
may be present. FDG-PET appears to be important in interpreting the FDG-PET

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 KEY POINT
scan, as occipital hypometabolism has of DLB or PDD. Late in the course of h Dementia with Lewy
also been described in cognitively nor- MSA, cerebellar atrophy and the hot bodies and Parkinson
mal PD,33 in PDD,33,34 and in posterior cross bun pons sign may be appreci- disease dementia can
cortical atrophy.35 ated on MRI. be distinguished from
On SPECT or PET imaging, reduced While it can be straightforward to multiple system atrophy,
DAT levels are also observed in DLB differentiate Richardson syndrome, progressive supranuclear
and PDD.31 Because this has high the most common clinical variant of palsy, and corticobasal
sensitivity (78% to 88%) and specificity PSP, from PD and DLB in advanced syndrome on the basis of
(90% to 100%) to differentiate DLB disease, differentiation can be chal- their clinical features.
from AD, reduction in DAT levels is one lenging early in the disease. Execu- However, no firm
tive dysfunction and extrapyramidal biomarkers have
of the suggestive diagnostic features of
been developed
DLB. However, it is important to note motor symptoms/signs characteristic
that can predict a
that DAT imaging is also abnormal in of PD (parkinsonism) are common in
pathologic diagnosis.
CBD and PSP. both PSP and DLB (as well as in PDD).
CSF assessment is increasingly used While many patients with DLB have
in the workup of dementia patients, as symmetric or axial predominant par-
the pattern of CSF amyloid-" (A") and kinsonism, axial predominant features
tau has high sensitivity and specific- are the rule in Richardson syndrome,
ity for AD.36 Because of the frequent in association with a lordotic posture
coexistence of Alzheimer pathology rather than the kyphotic posture com-
in DLB, however, the AD CSF pattern mon to DLB and PD. Other clinically
does not exclude DLB. Limited data useful features of Richardson syn-
exist for CSF evaluation in DLB, ex- drome include a specific impairment
cept as a research tool, where mole- of vertical gaze, including downgaze,
cules such as !-synuclein are under which is preserved in DLB and PD; a
study and have been found to be re- frequent facial expression of fear or
duced in DLB (see the following sec- surprise uncommon in DLB or PD;
tion on trends for more information). and a propensity for falls backward
early in the course of the illness.
DIFFERENTIAL DIAGNOSIS OF While falls are not uncommon in
THE LEWY BODY DEMENTIAS DLB and PD, falls backward are un-
Few clinically useful biomarkers differ- usual. Late in the course of PSP, mid-
entiate DLB and PD from MSA and the brain atrophy may be appreciated on
parkinsonian tauopathies PSP and CBD, midsagittal T1 sequence MRI, reveal-
and careful history and examination ing the brainstem hummingbird sign.
remain the method of choice. Although CBS refers to a classically asymmetric
unusual, cognitive impairment and de- neurodegenerative syndrome of parkin-
mentia have recently been described in sonism or dystonia, accompanied by
MSA37,38 and can no longer be used as asymmetric cortical signs, such as
strong evidence against the diagnosis. apraxia or cortical sensation loss. Dif-
The early and profound development ferentiation from DLB and PD is made
of dysautonomia, in association with on the basis of the marked asymmetry
parkinsonism and/or cerebellar ataxia and presence of both cortical and extra-
characterizes MSA39 and can help in pyramidal features in CBS. Multiple
its differentiation from DLB and PDD. neuropathologies can underlie the syn-
When present, ataxia is a strong dis- drome, with corticobasal degeneration
tinguishing feature of MSA. Conversely, (CBD) accounting for approximately
the presence of visual hallucinations 50% of cases. CBS is often associated
and fluctuations would argue in favor with hypometabolism on FDG-PET

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 Lewy Body Dementias

around the central sulcus and the fluctuations of attention and arousal.
ipsilateral striatum. Late in the course, The presence of these problems
focal cortical atrophy may be appreci- should direct the clinician toward
ated in the primary motor and primary DLB and PDD. REM sleep behavior
sensory cortices. For more information disorder has been described in both
on PSP and CBS, refer to article ‘‘Fron- PSP and CBD but is more common in
totemporal Dementias’’ by Elizabeth the synucleinopathies (including
C. Finger, MD, FRCPC,17 in this issue MSA). In contrast to PD, motor im-
of Continuum. pairments in MSA, PSP, and CBD are
In addition, hallucinations are un- rarely responsive to dopamine re-
common in MSA, PSP, and CBS, as are placement (Case 4-2).

Case 4-2
A 65-year-old man developed shuffling of his feet and a left arm rest tremor, associated with impaired
fine manual coordination. On examination 6 months after symptom onset, masked facies, hypophonia,
and left predominant rest tremor, rigidity, and bradykinesia were noted. The patient’s gait was
parkinsonian. He was started on ropinirole and had a marked improvement of function. He was
diagnosed with idiopathic Parkinson disease (PD), and rasagiline was added. As his disease progressed,
ropinirole was gradually increased. Physical, occupational, and speech therapy provided additional
benefit. For mild depression and anxiety, he was treated with escitalopram. He subsequently developed
rapid eye movement (REM) sleep behavior disorder, which was managed with lorazepam. Six years into
his illness, he developed the hallucination of a stranger in the living room and began having trouble
maintaining his complex medication regimen. On examination at that time, he was markedly
inattentive and encephalopathic and moderately dyskinetic. Ropinirole was replaced with carbidopa/
levodopa, melatonin was subsequently substituted for lorazepam, and his wife took over his medication
regimen. In this context, hallucinations, confusion, and dyskinesias markedly improved. He resumed his
golf game and bridge, but he underperformed at both compared to baseline. Six months later, his
hallucinations returned. Although attention was improved, he still demonstrated mild executive
dysfunction and visual-spatial impairment. A metabolic panel including thyroid-stimulating hormone
(TSH) and vitamin B12 level was normal. Brain MRI showed mild generalized atrophy without evidence
for medial temporal lobe atrophy. Rivastigmine was started and associated with robust improvement of
cognition and reduced frequency of hallucinations. Over the next 3 years, the patient’s cognition
gradually deteriorated. He gave up his hobbies and grew increasingly reliant on his wife to coordinate
their plans. He required help to get dressed due to the cognitive demands of the task. He was
diagnosed with PD dementia. Memantine was added but was not found to be helpful and was
ultimately discontinued.
One night, he developed escalating agitation and concern about intruders in the house. He was
brought to an outside emergency department, where he was found to be paranoid and anxious.
Mental status testing was notable for disorientation to date, reduced short-term memory, and visual-
spatial impairment. Workup was negative for a toxic metabolic process. ECG confirmed a normal QTc.
Haloperidol was considered by the emergency department staff but the neurology consultant
intervened. After discussion with family about the risks and benefits of starting an atypical
antipsychotic agent, quetiapine was started and slowly uptitrated, and his paranoia improved. He was
discharged home with resolution of the delusions and with neurology follow-up.
Comment. This case illustrates the challenges of managing patients with advanced PD and the
common manifestations of cognitive impairment and psychosis in this setting. The need to avoid D2
receptor antagonists applies to both dementia with Lewy bodies and PD. Given their risks, use of
typical and atypical antipsychotics should be minimized.

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 KEY POINTS
GENETICS OF THE LEWY ever, few of these agents have been h It is generally advisable
BODY DEMENTIAS evaluated for their efficacy in clinical to make single changes
A number of genetic mutations have trials, and such studies remain an in treatment systematically
been associated with DLB and PDD, important need. and serially, starting at
which are interesting clinically but A useful first step is to streamline low dose and tackling
also hold promise to elucidate funda- the medication list to remove possible the most severe problem
mental mechanisms of disease. Some offending agents and drug interactions first. This simple strategy
genetic errors appear to be dose depen- (Table 4-6). In general, there is value accounts for the frequent
in making single changes systematical- sensitivity to medications
dent. For example, mutation or dupli-
ly and serially, starting at low dose, in dementia with Lewy
cation of !-synuclein causes autosomal
bodies and allows for
dominant PD, but triplication is often tackling the most severe problem first.
straightforward
associated with both parkinsonism and This simple strategy accounts for the
interpretation of the effects
dementia.40 Several other genes also frequent sensitivity to medications of manipulations.
confer risk for DLB and PDD. The most observed in DLB and allows for
straightforward interpretation of the h The marked loss of
prominent of these is GBA, the gene acetylcholine neurons in
encoding glucocerebrosidase. 41,42 effects of manipulations. In the pro-
dementia with Lewy
While double mutations of GBA cause cess of treating multiple problems, bodies and Parkinson
Gaucher disease (which is autosomal patients are at risk for complications disease dementia likely
recessive), single GBA mutations are as- of polypharmacy, and agents should underlies the efficacy
sociated with DLB as well as with a be selected cautiously. of acetylcholinesterase
variant of PD that carries an increased inhibitors in these
risk of cognitive impairment. Not all Cognitive Impairment illnesses.
PD-related genes confer such risk, how- The marked loss of acetylcholine
ever. For example, the LRRK2 muta- neurons in DLB and PDD is the basis
tion causes autosomal dominant PD for the use of acetylcholinesterase
without cognitive impairment.43 In inhibitors in these illnesses. In
addition, a small number of genes placebo-controlled clinical trials,
have been identified that carry risk donepezil and rivastigmine have
for DLB but not PDD, including the been demonstrated to be effective
apolipoprotein E (APOE) (4 allele.44 in treating cognitive impairment in
Mutations in the MAPT gene, which DLB and PDD, respectively.47 In some
have been associated with the patients, the benefit can be marked
tauopathies such as FTD with parkin- and unambiguous and may be associ-
sonism, and in the COMT gene, have ated with improvement of hallucina-
also been variably observed in PDD.45 tions or delusions as well.
In patients with a strong family his- There is little evidence to suggest
tory, genetic counseling should be that acetylcholinesterase inhibitors
provided and genetic studies should differ in their efficacy. However, they
be considered. do vary in their probability of com-
mon adverse reactions. Most of these
are dose related, and nausea is par-
SYMPTOMATIC TREATMENT ticularly common. Because such side
IN DEMENTIA WITH LEWY effects most often occur as a peak-
BODIES AND PARKINSON dose phenomenon, they may resolve
DISEASE DEMENTIA with transition to a transdermal for-
This section discusses several thera- mulation (rivastigmine transdermal sys-
peutic strategies for the problems that tem, for example), where the peak dose
arise in DLB and PDD, and Table 4-546 is reduced. Another important side
provides a comprehensive list. How- effect to consider in the appropriate
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 Lewy Body Dementias

TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa

Target
Symptoms Treatment Strategy Dose Comments
Cognitive Acetylcholinesterase Gastrointestinal side effects
impairment inhibitors and, rarely, bradycardia
may limit dosing of
acetylcholinesterase inhibitors
Donepezil 5 mg/d for 4 weeks, then 10 mg/d
Oral rivastigmine 1.5 mg 2 times a day, increase in
1.5 mg steps every 2Y4 weeks,
maximum 6 mg 2 times a day
Transdermal 4.6 mg per 24 hours for 4 weeks, Transdermal formulation of
rivastigmine then increase to 9.5 mg per rivastigmine is useful to
24 hours manage gastrointestinal
side effects
Galantamine 4 mg 2 times a day, increase to 8 mg
2 times a day at 4 weeks, increase to
12 mg 2 times a day at 8 weeks
Galantamine ER 8 mg/d, increase to 16 mg/d at
4 weeks, increase to 24 mg/d
at 8 weeks
N-Methyl-D-aspartate
(NMDA) receptor
antagonist
Memantine 5 mg/d for 1 week, then 5 mg This agent is currently
2 times a day for 1 week, then being replaced with the
10 mg every morning, 5 mg extended release formulation
every evening for 1 week, then immediately below
10 mg 2 times a day

Memantine ER 7 mg/d for 1 week, then 14 mg/d Can switch from memantine
for 1 week, then 21 mg/d for 10 mg 2 times a day to
1 week, then 28 mg/d memantine extended release
28 mg/d without titration
Psychomotor Acetylcholinesterase The same dosages of
slowing inhibitors acetylcholinesterase inhibitors
can be used for psychomotor
slowing as for cognitive impairment
(see earlier entry in table)
Carbidopa/levodopa 25 mg/100 mg 2 times a day Variable efficacy
(upon waking and at dinner) to
ensure tolerability, then increase
to 3 times a day (upon waking,
at lunch, and at dinner)
Continued on page 451

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TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 450

Target
Symptoms Treatment Strategy Dose Comments
Apathy Acetylcholinesterase The same dosages of
inhibitors acetylcholinesterase inhibitors
can be used for apathy as for
cognitive impairment (see earlier
entry in table)
SSRIs/SNRIs Depends on specific drug At this time, experience
(see doses for management is anecdotal
of depression below)
Activating agents such as
sertraline and bupropion may
be useful
Avoid tricyclic
antidepressants given their
anticholinergic activity

Coffee 1Y2 cups before 2:00 PM

Psychosis Acetylcholinesterase The same dosages of

(hallucinations, inhibitors acetylcholinesterase inhibitors
delusions) can be used for psychosis as for
cognitive impairment (see earlier
entry in table)
Quetiapine 12.5 mg 1 hour before the Check QTc with initiation and with
expected hallucination/delusion, dose escalations
as needed, or as a standing dose
Sedating
if required; titrate gradually in
12.5Y25 mg increments every Can cause orthostatic hypotension
2 days as needed; maximum Parkinsonism may worsen at
200 mg/d or as limited by high dose
QTc prolongation
Use minimum dose and
duration required
Use of antipsychotics in older
adults with dementia is associated
with increased risk of death
Clozapine 12.5 mg every night at bedtime, As per quetiapine; complete blood
increase in 12.5 mg steps, cell count is needed weekly to catch
maximum 50 mg 3 times a day agranulocytosis (which occurs with
an incidence of 1% of patients)
Use minimum dose and
duration required
Use of antipsychotics in older
adults with dementia is associated
with increased risk of death

Continued on page 452

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 Lewy Body Dementias

TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 451

Target
Symptoms Treatment Strategy Dose Comments
Motor features Carbidopa/levodopa 25 mg/100 mg 2 times per day If nausea or hypotension arises,
of parkinsonism (upon waking and at dinner) take with carbohydrates
(including to ensure tolerability, then
If necessary, can add carbidopa
bradykinesia, increase to 3 times a day
25 mg to each dose of
rigidity, gait (upon waking, at lunch, and
carbidopa/levodopa
changes, tremor) at dinner)
A high-protein meal will reduce
absorption; the timing of doses
can be adjusted if this proves
to be clinically relevant
Physical therapy Titrated to effect Physical therapy directed
and exercise at motor symptoms and
general exercise are both
highly beneficial
Occupational Titrated to effect Utensil and appliance
therapy, including modifications can be helpful
a home safety Home safety evaluations
evaluation can be useful to identify and
remove fall hazards, such as
loose throw rugs, to add aides
such as grab bars and shower
stools, and, in the setting
of dementia, to evaluate
for need to remove
hazards such as gas stoves
Speech therapy Varies with specific program Lee Silverman voice therapy
can benefit hypophonia
when subjects are able
to participate
Depression Escitalopram Start 10 mg/d, can increase Low risk for worsening tremor
to 20 mg/d
Venlafaxine XR Start 37.5 mg/d, can increase Low risk for worsening tremor
to 225 mg/d
Citalopram Start 10 mg/d, increase after Low risk for worsening tremor
2Y4 weeks to maximum 20 mg/d
Fluoxetine 10 mg/d for 4 weeks; can
increase in steps to maximum
40 mg/d
Sertraline 25 mg/d for 4 weeks, can
increase in steps to maximum
200 mg/d
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TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 452

Target
Symptoms Treatment Strategy Dose Comments
Anxiety Escitalopram Start 5Y10 mg/d, can increase Low risk for worsening tremor
to 20 mg/d
Venlafaxine XR Start 37.5 mg/d, can increase Low risk for worsening tremor
to 225 mg/d
Citalopram Start 10 mg/d, increase after Low risk for worsening tremor
2Y4 weeks to maximum 20 mg/d
Sertraline 25 mg/d for 4 weeks; can increase
in steps to maximum 200 mg/d
Buspirone 5 mg 2 times a day for 4 weeks,
then increase as needed
in steps of 5 mg/d; usual
maintenance dose is 15Y30 mg/d
administered in 2Y3 divided doses
in geriatric patients

Insomnia Melatonin 1Y3 mg 1 hour before bedtime, Before starting a medication,

can increase in 3 mg steps to optimize sleep hygiene
6 mg every night at bedtime
Note that melatonin should be
taken on an empty stomach,
as food will delay absorption
Trazodone 25 mg every night at bedtime, Can cause priapism
increase in 25 mg steps,
Can cause QT prolongation,
maximum of 100 mg/d
especially in elderly patients
Mirtazapine 7.5Y15 mg every night at Appetite stimulant
bedtime, increase in 15 mg steps
as needed, maximum 45 mg
every night at bedtime
Quetiapine 12.5 mg at bedtime, as needed, Best to avoid, but if using, use
or as a standing dose if required. the minimum dose required
Titrate gradually in 12.5Y25 mg
See additional comments on
increments every 2 days as
quetiapine earlier in this table
needed; maximum 200 mg/d or
as limited by QTc prolongation

Continued on page 454

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 Lewy Body Dementias

TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 453

Target
Symptoms Treatment Strategy Dose Comments
Daytime Coffee 1Y2 cups once daily in the Can cause anxiety and
somnolence morning, repeat as needed worsen tremor
before 2:00 PM
Methylphenidate 2Y5 mg/d, can increase by Discontinue if no benefit
2.5Y5 mg/d every 5 days, dose
2 times a day (morning and noon),
maximum 20 mg/d
Amphetamine 5 mg/d, can increase in Discontinue if no benefit
5 mg steps every week, dose
2 times a day (morning and
noon), maximum 25 mg
2 times a day
Modafinil 100 mg/d every morning, Discontinue if no benefit
increase in 100 mg steps every
week, maximum 400 mg/d
Agitation Quetiapine 12.5 mg 1 hour before anticipated Try behavioral strategies
agitation, or as needed for first; use minimum dose and
agitation, as required; titrate duration required
gradually in 12.5Y25 mg
increments every 2 days as needed;
maximum 200 mg/d or as limited
by QTc prolongation or other
adverse reaction
Clozapine 12.5 mg 1 hour before expected Try behavioral strategies
agitation, or provide as a first; use minimum dose and
standing dose, if needed, every duration required
night at bedtime, increase in
12.5 mg steps, maximum 50 mg
3 times a day
Rapid eye Melatonin 1Y3 mg every night, 1 hour
movement before bedtime; can increase in
(REM) sleep 3 mg steps to 12 mg every night
behavior
disorder Clonazepam 0.25 mg every night at bedtime, Can cause sedation and
increase in 0.25 mg steps every encephalopathy, so it is best
week, maximum 1 mg every to minimize this agent in the
night at bedtime setting of cognitive impairment
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TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 454

Target
Symptoms Treatment Strategy Dose Comments
Dysautonomia Behavioral strategies
(eg, promote hydration,
get up slowly, cross legs)
Dietary salt This is particularly effective
liberalization for patients already on a
salt-restricted diet.
Thigh-high antiembolism
compression stockings
or abdominal binder
if severe
Fludrocortisone 0.1 mg/d, can increase after Supine hypertension,
5Y7 days to maximum 0.2 mg/d congestive heart failure
Midodrine 5 mg 3 times daily, can increase to Supine hypertension
10 mg 3 times a day, administered
in a 4-hour dosing interval
(morning, midday, late afternoon),
maximum dose of 30 mg/d
Pyridostigmine 30 mg 2 to 3 times a day, titrate Cholinergic side effects
to 60 mg 3 times a day
Urinary Quaternary amine Less central anticholinergic
incontinence bladder antispasmodics action than tertiary amine
agents, as they are less likely
to cross the blood-brain barrier
Trospium 20 mg every night at bedtime,
may increase to 2 times a day
if patient is able to tolerate
dose-dependent anticholinergic
adverse effects
Darifenacin 7.5 mg/d

Continued on page 456

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 Lewy Body Dementias

TABLE 4-5 Symptomatic Treatments in Dementia With Lewy Bodies and Parkinson
Disease Dementiaa Continued from page 455

Target
Symptoms Treatment Strategy Dose Comments
Constipation Nonpharmacologic
modalities
Assess anticholinergic
burden
Increase physical
activity
Improve hydration Titrate to effect
Diet modification
(prunes/prune juice)
Pharmacologic
modalities
Docusate 100 mg 2 times a day, can increase
as needed to 3 times a day
Osmotic laxatives Titrate to effect Use sparingly but as needed
Polyethylene glycol 3350 1 capful a day
Lactulose 15Y30 mL/d
Stimulant laxatives Titrate to effect
Senna 1 tablet at night, can increase to
2 tablets as needed
Bisacodyl 5Y15 mg/d

ER = extended release; SNRI= serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; XR = extended release.
a
Modified with permission from Galasko DR, Continuum (Minneap Minn).46 journals.lww.com/continuum/Fulltext/2007/04000/
DEMENTIA_WITH_LEWY_BODIES.5.aspx. B 2007 American Academy of Neurology.

KEY POINT patient is bradycardia. Parkinsonism is DLB and PDD.47 Larger studies have
h In Parkinson disease not usually affected, although a minor- not yet been performed to confirm
dementia, it is often ity may experience worsened tremor. these results. Many patients note little
useful to streamline the
A large multicenter clinical trial in 2010 subjective benefit from this agent, but
medication regimen in
suggested greater efficacy, and higher a small subpopulation of patients may
the service of cognition.
adverse reaction rate, for high-dose report significant improvement.
donepezil (23 mg/d) compared to Many patients with PDD develop
standard dose (10 mg/d) in moderate their cognitive impairments in the
to severe AD.48 This study has opened setting of a complex medication reg-
the door to higher dosing in DLB and imen tailored for patients with PD
PDD, and high-dose studies of acetyl- with moderate to severe motor dis-
cholinesterase inhibitors in DLB and ease. When necessary, the cautious
PDD are needed. withdrawal of trihexyphenidyl or
In small studies, memantine has also dopamine agonists, transition to
been found to be modestly effective in carbidopa/levodopa, and, if needed,

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TABLE 4-6 Agents to Avoid in Patients With Dementia With Lewy Bodies and Parkinson
Disease Dementia

Agent Concerns
Dopamine (D2 receptor) antagonists Can precipitate drug-induced parkinsonism,
neuroleptic malignant syndrome, somnolence,
Typical antipsychotics, such as haloperidol
and orthostatic hypotension; have been associated
Atypical antipsychotic agents, such as risperidone with increased mortality in elderly patients
and olanzapine with dementia
Anticholinergics Can cause encephalopathy and memory loss
Trihexyphenidyl, benztropine, peripheral
anticholinergics with blood-brain barrier penetration
(tertiary amines such as oxybutynin); note that
quaternary amines (such as trospium and darifenacin)
are less likely to cross the blood-brain barrier and tend
to be well tolerated
Tricyclic antidepressants
Dopamine agonists Can cause psychosis, behavioral changes,
and encephalopathy
Benzodiazepines (although they can be helpful for Can cause encephalopathy and sedation
rapid eye movement [REM] sleep behavior disorder
and acute agitation)
Diphenhydramine and most sedating sleep aids Can cause encephalopathy and sedation
(eg, zolpidem)

general dose reduction of dopamine delusions. They can be very effective

replacement, may improve cognition for this purpose, and they lack the
in these patients. In part due to the cardiac risk of the neuroleptics. The
complexity of the regimen, medication basis for their benefit is unclear but
errors are a common contributor to suggests that lack of acetylcholine re-
cognitive impairment or psychosis in ceptor activation, possibly in the ven-
this setting. Supervision of medications tral visual stream, contributes to these
can be helpful in both DLB and PDD. psychotic features.
When atypical antipsychotic agents
Psychosis are needed, quetiapine and clozapine
Medication review is also critical in have been found to be least likely to
managing psychosis. For example, in exacerbate parkinsonism49 or to cause
PDD, the cautious withdrawal of do- neuroleptic malignant syndrome. The-
pamine replacement agents, or tran- se agents should be started at a low
sition to carbidopa/levodopa, may dose and slowly titrated to the mini-
improve psychosis. mum dose required. Given the in-
Hallucinations that are not aver- creased risk for death in patients
sive do not require medical treat- with dementia treated with antipsy-
ment. Acetylcholinesterase inhibitors chotic agents, primarily due to car-
are the first line of defense for non- diac arrest, congestive heart failure,
emergency visual hallucinations and and pneumonia,50 and the frequent

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 Lewy Body Dementias

KEY POINTS
h When psychosis in presence of dysautonomia in DLB, the der. Benzodiazepines are particularly
dementia with Lewy QTc should be monitored with a effective, but these carry the risk of
bodies or Parkinson baseline ECG and with follow-up ECGs exacerbating confusion. Melatonin can
disease dementia for significant dose escalation, and the be effective as well and is usually well
requires medical dose and duration of treatment should tolerated. Some patients with REM
treatment, be minimized. Furthermore, the risks sleep behavior disorder have concom-
acetylcholinesterase and benefits should be discussed itant obstructive sleep apnea, and the
inhibitors, quetiapine, frankly with the patient and caregiver. use of positive airway pressure may
and clozapine can be Clozapine is often less sedating than resolve both obstructive sleep apnea
useful. However, the quetiapine. However, due to the low and REM sleep behavior disorder.
latter two agents
but significant risk for agranulocytosis,
require caution, given TRENDS
clozapine use requires weekly com-
their risk of significant
and severe
plete blood cell count monitoring. Recent advances in our understanding of
adverse reactions. DLB and PD are likely to impact future
Parkinsonism diagnosis and management of these
h Physical therapy,
In DLB, a trial of carbidopa/levodopa diseases. These advances include the
occupational therapy,
(25 mg/100 mg 2 or 3 times a day) can concept of preclinical features, the search
and home safety
improve motor features in some for diagnostic features of MCI predictive
evaluations are valuable
patients without worsening cognition of future DLB, and efforts to determine
treatments for motor
impairments in
or psychosis. However, it tends to be the causes of dementia in these illnesses.
dementia with Lewy much less effective in DLB than in
bodies and Parkinson idiopathic PD. Should cognition or Preclinical Synucleinopathies
disease dementia. hallucinations worsen, this agent can Several preclinical features antedate
h Medical and be reduced or discontinued, if necessary. cognitive, motor, and neuropsychiatric
nonmedical strategies Patients with DLB and PDD benefit impairments in DLB, PD, and MSA,
exist to manage rapid from physical therapy, which can pro- including constipation, REM sleep be-
eye movement sleep vide gait assistance and focus on partic- havior disorder, and olfactory loss.
behavior disorder. ular motor impairments such as focal These features support the premise
hand bradykinesia. Occupational ther- that the synucleinopathies can be iden-
apy can be helpful as well, providing tified at a preclinical stage, but they do
tools to help with feeding and other not clearly differentiate between them.
basic functions. A home safety evalua- These impairments are attributed to
tion is useful to guide caregivers, for ascending !-synuclein pathology, cor-
example, in the removal of throw rugs responding respectively with Lewy
and the addition of safety bars. bodies identified in the enteric plexus,
in brainstem sleep centers, and in the
Rapid Eye Movement Sleep olfactory bulb, as suggested by cross-
Behavior Disorder sectional neuropathologic studies.14,51
REM sleep behavior disorder does not Efforts are now underway to improve
require medical treatment if the patient screening to identify at-risk patients.
is not harming himself or his caregiver. Future neuroprotective strategies will
If treatment is required, a number of likely take advantage of these and
nonpharmacologic steps may be use- related preclinical features.
ful. These include removing sharp
objects from the sleep environment, Mild Cognitive Impairment
adding soft bedding to the floor next Preceding Dementia With Lewy
to the patient, and using separate Bodies
beds. Several medications can be ef- Patients with the clinical features of
fective in REM sleep behavior disor- DLB but who remain independent for
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 KEY POINT
their instrumental and basic activities DLB, LB-MCI is a useful construct for h Given its prevalence,
of daily living meet criteria for Lewy therapeutic clinical trials and for bio- dementia with Lewy
body spectrum MCI.14 The sensitivity marker studies. bodies is likely to be a
and specificity for a diagnosis of Lewy common cause of mild
bodyYMCI (LB-MCI) are likely to be Mechanisms for Dementia cognitive impairment.
lower than for DLB, in part due to and Disease-Modifying
milder manifestations of the core Treatment Trials
criteria. Ancillary testing has yet to be Multiple pathologic processes have
validated in LB-MCI. For example, the been linked to cognitive impairment
prevalence of occipital hypometab- and psychosis in DLB and PDD, includ-
olism appears to be reduced in LB- ing !-synuclein deposition with second-
MCI compared with DLB. In addition, ary synapse impairment,7,52,53 amyloid
the sensitivity of the DAT scan may burden, 10,54 and dopamine 55 and
be reduced when extrapyramidal acetycholine9 cell loss (Table 4-7).52Y60
symptoms are mild. Like preclinical The difference in the timing of

TABLE 4-7 Putative Brain Substrates for Major Clinical Features

of Dementia With Lewy Bodies and Parkinson
Disease Dementia

b Cognitive Impairment
!-SynucleinYassociated synapse dysfunction52,53
Impaired midbrain dopamine neuron projections to limbic and cognitive
brain regions, such as the caudate and anterior cingulate55,56
Loss of acetylcholine neurons (diagonal band of Broca and nucleus
basalis of Meynert)9,57
Comorbid Alzheimer pathology, including amyloid deposition and a
variable degree of tau aggregation in neurites and neurofibrillary
tangles; note that amyloid deposition is often greater in dementia with
Lewy bodies than in Parkinson disease dementia10,54
b Hallucinations
Lewy pathology in the ventral visual stream16
Cortical thinning of visual association cortex58
Loss of acetylcholine neurons
b Motor Features of Parkinsonism
Loss of dopamine cells innervating the motor striatum
b Rapid Eye Movement (REM) Sleep Behavior Disorder
Impairment of brainstem sleep centers59
b Fluctuations
Unclear neuropathologic basis
b Autonomic Dysfunction
Lewy body pathology in central autonomic circuits or in autonomic and
enteric ganglia60

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 Lewy Body Dementias

cognitive and motor impairments in selected to avoid worsening other

DLB and PDD likely reflects a differ- domains of impairment. Disease-
ence in the temporal sequence of modifying therapies remain a major
these pathologies. One possibility is unmet need.
that in DLB, cortical lesions, mostly "-
amyloid, arise early, driving cognitive USEFUL WEBSITES
impairment. Then, !-synuclein pathol- Lewy Body Dementia Association. The
ogy ascends from brainstem to cortex. Lewy Body Dementia Association is a
In contrast, in PDD, cortical lesions nonprofit organization that works to
arise late, and ascending !-synuclein support individuals diagnosed with
pathology drives the clinical syndrome. Lewy body dementia and raise aware-
Amyloid PET imaging in DLB and PDD ness about the disease through scien-
supports this model, showing high tific research.
amyloid burden in most cases of DLB, www.LBDA.org
with more modest accumulation in
National Parkinson Foundation. The
PDD.54 Antibodies targeting "-amyloid
National Parkinson Foundation sup-
have entered clinical trials in AD and
ports the care of individuals with
MCI.61 Although the outcomes are
Parkinson disease through its commit-
uncertain, the strategy is applicable to
ment to expert research and education
DLB and possibly to PDD, where
about the disease.
amyloid accumulation appears to con-
tribute to certain clinical features, www.parkinson.org
including the timing and rate of cogni- American Parkinson Disease Associa-
tive decline.54 A similar immune tion. The American Parkinson Disease
targeting approach is under develop- Association funds research and pro-
ment for !-synuclein. If successful, this motes patient care and education, as
strategy would be applicable to both well as working to promote public
DLB and PD, irrespective of cognitive awareness about the condition.
impairment. www.apdaparkinson.org
CONCLUSION Michael J. Fox Foundation for
Parkinson’s Research. The Michael J.
DLB and PDD are clinically and
Fox Foundation for Parkinson’s Re-
neuropathologically similar illnesses
search works toward the goal of curing
distinguished on the basis of the re-
Parkinson disease through funding
lative timing of dementia and parkin-
research and developing improved
sonism. The core features of these
therapies for individuals living with
illnesses include dementia, parkinson-
the disease.
ism, hallucinations, and fluctuations of
attention or arousal. The deposition of www.michaeljfox.org
!-synuclein is central to both of these
illnesses. Additional neuropathologic ACKNOWLEDGMENTS
changes such as dopamine and acetyl- The author thanks John Growdon,
choline cell loss are likely secondary. MD, for helpful comments on the
Superimposed AD-associated neuro- manuscript.
pathologic changes are common in
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 Review Article

Frontotemporal
Address correspondence to
Dr Elizabeth Finger, LHSC
Parkwood Institute,

Dementias
550 Wellington Road, London,
ON N6C 0A7, Canada,
[email protected].
Relationship Disclosure:
Dr Finger has received Elizabeth C. Finger, MD, FRCPC
personal compensation as a
speaker for Western
University and receives grant
support from the Canadian ABSTRACT
Institutes of Health Research
for this work as well as grant Purpose of Review: This article reviews the common behavioral and cognitive
funding from the Alzheimer features of frontotemporal dementia (FTD) and related disorders as well as the
Society of Canada, the distinguishing clinical, genetic, and pathologic features of the most common subtypes.
Ministry of Research and
Innovation, Ontario Brain Recent Findings: Advances in clinical phenotyping, genetics, and biomarkers have
Institute, and the Weston enabled improved predictions of the specific underlying molecular pathology associated
Foundation. Dr Finger has with different presentations of FTD. Evaluation of large international cohorts has led to
provided expert legal
testimony for the Ontario recent refinements in diagnostic criteria for several of the FTD subtypes.
Court of Justice. Summary: The FTDs are a group of neurodegenerative disorders featuring progressive
Unlabeled Use of deterioration of behavior or language and associated pathology in the frontal or
Products/Investigational
Use Disclosure:
temporal lobes. Based on anatomic, genetic, and neuropathologic categorizations, the
Dr Finger discusses the six clinical subtypes of FTD or related disorders are: (1) behavioral variant of FTD, (2)
unlabeled/investigational use semantic variant primary progressive aphasia, (3) nonfluent agrammatic variant primary
of disease-modifying therapies
in development, dopaminergic
progressive aphasia, (4) corticobasal syndrome, (5) progressive supranuclear palsy,
medications, neuroleptic and (6) FTD associated with motor neuron disease. Recognition and accurate
medications, oxytocin, and diagnoses of FTD subtypes will aid the neurologist in the management of patients
selective serotonin reuptake
inhibitors for the treatment of
with FTD.
frontotemporal dementias.
* 2016 American Academy Continuum (Minneap Minn) 2016;22(2):464–489.
of Neurology.

INTRODUCTION corticobasal syndrome (CBS) and pro-

Frontotemporal dementia (FTD) clas- gressive supranuclear palsy (PSP),
sically affects adults in their fifties to which can present with frontal lobe
sixties, although cases have been re- dysfunction. The clinical subtypes of
ported in patients from 30 to more FTD and related disorders are defined
than 90 years of age. FTD is a progres- by the hallmark patterns of symptoms
sive neurodegenerative disorder; thus, and signs observed. Variations in clin-
the patient’s history typically reveals ical presentation across the FTD sub-
a gradual onset and progression of types are attributed to differences in
changes in behavior or language defi- the brain regions affected by FTD pa-
cits for several years prior to presen- thology. The term frontotemporal lobar
tation to a neurologist. The term FTD degeneration (FTLD) is reserved for pa-
is typically used to refer to one of sev- tients with clinical presentations of FTD
eral clinical subtypes including behav- and identification of an FTD-causing
ioral variant of FTD (bvFTD), semantic mutation or histopathologic evidence
variant primary progressive aphasia of FTD (on biopsy or postmortem).
(PPA), nonfluent agrammatic variant
PPA, and FTD associated with motor EPIDEMIOLOGY OF
neuron disease (FTD-MND). FTD- FRONTOTEMPORAL DEMENTIA
related disorders include two tau- FTD is generally considered to be
associated neurodegenerative diseases, the second most common cause of

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 KEY POINTS
early-onset neurodegenerative demen- in public), and impulsivity (eg, inap- h Frontotemporal
tia (before age 65), second only to propriate spending). Apathy is a com- dementia classically
Alzheimer disease (AD).1 The estimated mon early feature and may present as a affects adults in their
prevalence of FTD is highest in the 45 loss of interest in usual social and non- fifties to sixties,
to 64 year age group and ranges from social activities. Patients may be noted although cases have
15 to 22 per 100,000 persons ages 45 to spend hours sitting on the couch been reported from
to 64, with 10% of FTD occurring in pa- staring at the television or wall. Some 30 to more than
tients less than 45 years of age and ap- patients will develop simple or com- 90 years of age.
proximately 30% occurring in patients plex repetitive behaviors such as h The prevalence of
older than 65.1 There is consensus that touching items in a room, counting fig- frontotemporal
the prevalence is likely underestimated ures on patterned wallpaper, or picking dementia is likely
due to lack of recognition and diagno- up scraps of paper in public places. Hy- underestimated due to
sis of the FTD syndromes by non- perorality typically involves increased lack of recognition and
neurologists.1,2 Of the FTD subtypes, consumption, particularly of sweets, and diagnosis of the
bvFTD is the most common clinical in the extreme, can include consump- frontotemporal
presentation, accounting for more tion of spoiled foods and inedible
dementia syndromes by
than 50% of patients with autopsy- non-neurologists.
objects. Some patients will begin to use
confirmed FTLD.3 FTD affects both tobacco or alcohol for the first time or h Behavioral variant of
genders in roughly equal distribution. increase their use of such substances. frontotemporal
dementia is defined by
Although not included in the core cri-
BEHAVIORAL VARIANT OF teria, patients with FTD, particularly
the gradual onset and
FRONTOTEMPORAL DEMENTIA progression of changes
those with C9ORF72 expanded repeat in behavior, including
bvFTD is defined by the gradual on- mutations, may also exhibit psychotic disinhibition, loss of
set and progression of changes in be- features early in the disease course, in- empathy, apathy, and
havior, including disinhibition, loss of cluding visual or auditory hallucina- may include hyperorality
empathy, apathy, and may include hy-
tions and bizarre or somatic delusions.5 and perseverative or
perorality and perseverative or com- compulsive behaviors.
pulsive behaviors (Table 5-1).4 Patients Neurologic Examination
presenting with symptoms consistent h Patients with
with bvFTD but with normal brain Evidence of the above behavioral frontotemporal dementia
imaging (ie, CT, MRI, positron emission changes may be observed during the may exhibit psychotic
tomography [PET]/single-photon emis- course of the neurologic examination. features early in the
sion computed tomography [SPECT]) Patients with bvFTD may show evi- disease course, including
are classified as possible bvFTD, while dence of poor grooming and hygiene visual or auditory

patients meeting symptom criteria on presentation and loss of manners, hallucinations and

who show focal atrophy, hypometa- such as belching during the examina- bizarre or somatic

bolism, or hypoperfusion in the fron- tion. Either a flat affect may be ob- delusions.

tal or temporal lobes are classified as served, or conversely, a silly, childlike

having probable bvFTD. affect may be seen and manifested by
a patient hugging the examiner or
giggling after being instructed to stick
Symptoms
out his or her tongue or during the
Disinhibition may manifest in a variety testing of the reflexes. Patients with
of ways, including increased disclosure bvFTD may appear obviously restless,
of personal information to strangers or standing up and even attempting to
acquaintances (eg, medical information, leave the room midexamination. Pa-
finances), increased sexual interest or tients with a flat affect may appear
comments, loss of manners (such as apathetic and lack spontaneous
belching in public), new use of derog- speech, giving only brief one- to two-
atory or racist language in reference to word responses to questions despite
others (eg, calling someone fat or bald preserved language abilities. Although

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 Frontotemporal Dementias

TABLE 5-1 International Consensus Criteria for Behavioral Variant

of Frontotemporal Dementiaa

I. Neurodegenerative Disease
The following symptom must be present to meet criteria for behavioral
variant of frontotemporal dementia (bvFTD).
A. Shows progressive deterioration of behavior and/or cognition by
observation or history (as provided by a knowledgeable informant)
II. Possible bvFTD
Three of the following behavioral/cognitive symptoms (AYF) must be present
to meet criteria. Ascertainment requires that symptoms be persistent or
recurrent, rather than single or rare events.
A. Earlyb behavioral disinhibition (one of the following symptoms
[A.1YA.3] must be present)
A.1. Socially inappropriate behavior
A.2. Loss of manners or decorum
A.3. Impulsive, rash, or careless actions
B. Earlyb apathy or inertia (one of the following symptoms [B.1YB.2]
must be present)
B.1. Apathy
B.2. Inertia
C. Earlyb loss of sympathy or empathy (one of the following symptoms
[C.1YC.2] must be present)
C.1. Diminished response to other people’s needs and feelings
C.2. Diminished social interest, interrelatedness, or personal warmth
D. Earlyb perseverative, stereotyped, or compulsive/ritualistic behavior
(one of the following symptoms [D.1YD.3] must be present)
D.1. Simple repetitive movements
D.2. Complex, compulsive, or ritualistic behaviors
D.3. Stereotypy of speech
E. Hyperorality and dietary changes (one of the following symptoms
[E.1YE.3] must be present)
E.1. Altered food preferences
E.2. Binge eating, increased consumption of alcohol or cigarettes
E.3. Oral exploration or consumption of inedible objects
F. Neuropsychological profile: executive/generation deficits with relative
sparing of memory and visuospatial functions (all of the following
symptoms [F.1YF.3] must be present)
F.1. Deficits in executive tasks
F.2. Relative sparing of episodic memory
F.3. Relative sparing of visuospatial skills
III. Probable bvFTD
All of the following symptoms (AYC) must be present to meet criteria.
A. Meets criteria for possible bvFTD
B. Exhibits significant functional decline (by caregiver report or as
evidenced by Clinical Dementia Rating Scale or Functional Activities
Questionnaire scores)

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 KEY POINTS
International Consensus Criteria for Behavioral Variant h Standard neurocognitive
TABLE 5-1
of Frontotemporal Dementiaa Continued from page 466 testing in behavioral
variant of frontotemporal
C. Imaging results consistent with bvFTD (one of the following [C.1YC.2] dementia classically
must be present) demonstrates deficits in
executive function tasks,
C.1. Frontal and/or anterior temporal atrophy on MRI or CT
with relative sparing
C.2. Frontal and/or anterior temporal hypoperfusion or
in memory and
hypometabolism on positron emission tomography (PET) or
visuospatial domains.
single-photon emission computed tomography (SPECT)
IV. bvFTD With Definite Frontotemporal Lobar Degeneration Pathology h Consideration
Criterion A and either criterion B or C must be present to meet criteria. of qualitative aspects
A. Meets criteria for possible or probable bvFTD of performance
during neurocognitive
B. Histopathologic evidence of frontotemporal lobar degeneration on
testing, such as
biopsy or at postmortem
impulsive behaviors and
C. Presence of a known pathogenic mutation
error types, may be
V. Exclusionary Criteria for bvFTD more helpful than raw
Criteria A and B must be answered negatively for any bvFTD diagnosis. Criterion scores in detecting
C can be positive for possible bvFTD but must be negative for probable bvFTD. behavioral variant of
A. Pattern of deficits is better accounted for by other nondegenerative frontotemporal dementia.
nervous system or medical disease
B. Behavioral disturbance is better accounted for by a psychiatric diagnosis
C. Biomarkers strongly indicative of Alzheimer disease or other
neurodegenerative process
CT = computed tomography; MRI = magnetic resonance imaging.
a
Reprinted with permission from Rascovsky K, et al, Brain.4 brain.oxfordjournals.org/content/
134/9/2456.short. B The Author (2011). Published by Oxford University Press on behalf of the
Guarantors of Brain.
b
As a general guideline, early refers to symptom presentation within the first 3 years.

such abnormal behaviors typically in- may still perform well on executive
crease over the course of the disease, at tasks, particularly those patients with
early stages patient’s conduct may be right temporal predominant atrophy.
generally appropriate for the limited It is now appreciated that some pa-
time of the examination. Positive snout tients with bvFTD have significant
or grasp reflex may be present, al- episodic memory deficits.7 While spe-
though these frontal release signs are cific standardized tests of social cog-
not sensitive or specific for FTD.6 nition are in validation stages for
Cranial nerve, motor, sensory, and bvFTD, patients with bvFTD generally
the remainder of reflex examinations show poor performance on tasks of
are typically normal. facial expression recognition, particu-
larly for negative emotions, as well as on
Neuropsychological Testing theory of mind tasks, such as visual
in Behavioral Variant of cartoons in which they must under-
Frontotemporal Dementia stand the mental state of others. Con-
Standard neurocognitive testing in pa- sideration of qualitative aspects of
tients with bvFTD classically demon- performance during neurocognitive
strates deficits in executive function testing including behaviors and error
tasks, with relative sparing in memory types may be more helpful than raw
and visuospatial domains. However, scores in detecting bvFTD. Specifically,
many patients with early-stage disease during testing, patients with bvFTD

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 Frontotemporal Dementias

may appear restless, apathetic, persev- some atrophy also observed in the
erative, confabulatory, and impulsive, anterior temporal lobes, parietal lobes,
failing to wait for the examiner to finish occipital lobes, and cerebellum and
task instructions and including exple- thalamus; in MAPT mutations, atrophy
tives in phonemic fluency tests.8 is greatest in the anteromedial tempo-
ral lobes; patients with bvFTD and
Neuroimaging Characteristics GRN mutations show temporal, insular,
Atrophy or hypometabolism of the and parietal lobe atrophy.10,11 On
right frontal or right temporal lobe is fluorodeoxyglucose positron emission
the hallmark neuroimaging finding in tomography (FDG-PET) imaging,
patients with bvFTD (Case 5-1). Bilat- hypometabolism in the right temporal
eral frontal lobe involvement may also or right or bilateral frontal lobes is sug-
be seen, although when atrophy is gestive of FTD (Figure 5-212). Patterns
of frontal or anterior temporal hypo-
observed in the dominant hemisphere,
perfusion with preserved parietal signal
language symptoms are typically also on SPECT can distinguish FTD from
present (see later discussion of seman- AD with a sensitivity and specificity of
tic variant PPA and nonfluent agram- approximately 80%.13 Similar patterns of
matic variant PPA). Patterns of atrophy hypometabolism on FDG-PET imaging
in other brain regions vary according to show approximately 90% diagnostic
mutation type. Patients with C9ORF72 accuracy when distinguishing FTD
expanded repeats demonstrate atrophy from AD.14 PET amyloid imaging
predominantly in the frontal lobes, with shows a similarly high accuracy of

Case 5-1
A 54-year-old man presented to the psychiatric emergency department for bizarre behavior, claiming he
had won the lottery. The family reported that 6 years prior to presentation he became less organized
managing his finances. The family discovered 3 years ago that bills, including the mortgage, were going
unpaid, and he had accumulated significant credit card debt. His affect became flat, and his family
reported that it was ‘‘hard to get a reaction out of him.’’ He began to cook in an impulsive way, turning
the burners on maximum for everything. The patient had lost his job for inappropriate borrowing of
money from clients 1 year prior to presentation. He began buying multiple lottery tickets each week, and
despite financial difficulties, he purchased a luxury motorcycle. He began wearing the same clothing
multiple days in a row and required encouragement to shower. He lost interest in his hobbies and
spent increasing amounts of time ‘‘staring’’ at the television. Family history was negative for any
neurodegenerative diseases, although his father died in his forties of a myocardial infarction, and his
mother died in her early sixties of cancer. On examination, the patient was mildly unkempt, with a flat
affect, and appeared apathetic. His speech was fluent with preserved naming, repetition, and
comprehension. Cranial nerves were intact, including normal saccades. There was no evidence of
bradykinesia. Sensory and motor examinations were normal. He had mild difficulty performing the
Luria hand sequence (a three-step hand movement sequence of fist-side-flat) on the left compared to the
right. Snout and grasp reflexes were absent (normal). On cognitive testing, he scored 26 out of 30 on the
Mini-Mental State Examination (MMSE) and 14 out of 30 on the Montreal Cognitive Assessment (MoCA),
losing points for attention, concentration, working memory items, and Trail Making B test sample. Semantic
and phonemic fluency were both moderately impaired. MRI imaging demonstrated bifrontal and temporal
atrophy (Figure 5-1). Subsequent genetic testing for C9ORF72, GRN, and MAPT did not reveal any
pathogenic mutations. A diagnosis of probable behavioral variant of frontotemporal dementia (FTD)
was made. He was advised to stop driving and was reported to the Department of Transportation. Family
were referred to a social worker and an FTD caregiver support group. Citalopram 20 mg/d was started
with modest improvement of the obsessive behaviors.
Continued on page 469

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 Continued from page 468

FIGURE 5-1 T2-weighted axial MRI shows bifrontal and temporal atrophy in the patient in Case 5-1
with sporadic behavioral variant of frontotemporal dementia.

Comment. There is commonly a long delay between the onset of symptoms and time of presentation,
given the subtle nature of the personality and behavior changes that are the hallmark of early FTD.
Patients often accumulate significant debt prior to diagnosis. It is important for caregivers to put a power
of attorney in place for care and finances to limit patients’ access to spending money. In patients with
frontal lobe deficits, inattention and impulsivity pose significant risks during driving and typically are
indications for driving cessation. While there are no treatments specifically approved for use in patients
with FTD, off-label use of selective serotonin reuptake inhibitors (SSRIs) may help with agitation,
obsessive-compulsive behaviors, and hyperphagia.9

distinguishing FTD from AD, with pa- with a history obtained from a caregiver
tients with FTD typically showing low KEY POINTS
that meets symptom-based criteria for
levels of amyloid binding on PET (amy- h Consideration of the
possible FTD but who lack focal atro-
patient’s baseline
loid negative), while patients with AD phy on neuroimaging and who do not personality, life events,
show elevated amyloid binding (amy- progress to demonstrate objective be- and relationship factors
loid positive).12 Several PET tau ligands havioral or cognitive deficits.16 Patients that may influence
are currently under investigation in FTD with bvFTD phenocopy syndrome who behavior, and the
but are not validated to date. fail to progress have increased rates of caregiver’s perspective
mood disorders, substance abuse, on behaviors, is
Diagnostic Challenges in obsessive-compulsive personality traits, necessary for accurate
Behavioral Variant of Asperger syndrome traits, or recent diagnosis of behavioral
Frontotemporal Dementia intense life events that likely contribute variant frontotemporal
Making and confirming a diagnosis of to the observed behaviors.17 Thus, dementia.
bvFTD can be challenging as the per- careful consideration of the patient’s h The hallmark symptom
sonality or behavioral changes are baseline personality, life events, and of semantic variant
insidious, and diagnosis in the early relationship factors that may influence primary progressive
stages is highly reliant on caregiver behavior, and the caregiver’s perspec- aphasia is the loss of
word meaning.
reports of behavioral changes. Further- tive on behaviors, is necessary.18
more, the degree of frontal atrophy
can overlap with that observed in SEMANTIC VARIANT PRIMARY
normal controls.15 The term bvFTD PROGRESSIVE APHASIA
phenocopy syndrome has been used The hallmark symptom of semantic
to characterize patients who present variant PPA, previously called semantic

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 Frontotemporal Dementias

FIGURE 5-2 Example of amyloid (Pittsburgh compound B [PiB]) and fluorodeoxyglucose

positron emission tomography (FDG-PET) scans demonstrating typical patterns
of diffuse amyloid deposition and temporal and parietal hypometabolism in
Alzheimer disease (A) in contrast to the absence of amyloid deposition and presence of frontal
hypometabolism in a patient with frontotemporal dementiaYmotor neuron disease, confirmed
on autopsy to have frontotemporal lobar degeneration (FTLD) with TDP-43 inclusions (B).
AD = Alzheimer disease; DVR = distribution volume ratio; neg = negative; pos = positive; SUVR =
standardized uptake value ratio.
12
Modified with permission from Rabinovici GD, et al, Neurology. www.neurology.org/content/77/23/2034.full.
B 2011 American Academy of Neurology.

dementia, is the loss of word mean- what words mean (ie, ‘‘What is spa-
ing.19 Due to atrophy in the dominant ghetti?’’). While fluency and grammar
anterior temporal pole (Case 5-2), are generally maintained, speech be-
patients with semantic variant PPA comes increasingly empty, with vague
demonstrate anomia and single-word words or jargon phrases replacing spe-
comprehension deficits and may ask cific nouns and verbs (Table 5-220).

Case 5-2
A 69-year-old right-handed retired secretary was referred for a neurologic consultation for difficulties with
‘‘memory’’ and behavior. She had a long history of anxiety and depression that had been managed by
medications until 2 years prior to presentation, when she was dismissed from her volunteer job for ‘‘lacking
control.’’ Her family noted trouble with word comprehension, as the patient would ask, ‘‘What is a
screwdriver?’’ and ‘‘What is a buffet?’’ Circumlocutions were noted in her descriptions, such as describing a
pizza as a ‘‘round thing.’’ This was followed by lack of recognition of objects. For example, when her
husband handed her an ice cream cone, she grabbed at the ice cream on top rather than from the cone.
Recently, she had not recognized her niece and nephew or herself in photographs. The patient stopped
initiating household chores, such as doing the dishes or laundry, and appeared confused when attempting
such tasks. According to her husband, she was ‘‘always walking, pacing, or standing.’’ She became very
self-centered and seemed to lack appreciation of others’ needs. She became fixated on daily routines
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 Continued from page 470
even if inconvenient to others. Her personal hygiene declined. Family history was notable for multiple
family members on her mother’s side with anxiety and depression. There was no known history of
neurodegenerative dementia or amyotrophic lateral sclerosis in any family members.
On examination, while her speech rate was generally high, she used frequent fillers, such as ‘‘thing’’ or
‘‘da da da.’’ Her responses to direct questions were tangential. The remainder of her neurologic examination
was normal, including the absence of frontal release signs. On further cognitive testing, she scored 8 out of
30 on the Mini-Mental State Examination (MMSE), typically not understanding the question being asked.
Her clock drawing skills were reasonably preserved. Semantic fluency was severely impaired with only two
animals named in 1 minute. In contrast, phonemic fluency was only mildly impaired with a total of 20 F-A-S
Test words named over the 3 minutes (patient was given 1 minute to list words beginning with the letter F,
followed by 1 minute to list words beginning with A, and then 1 minute to list words beginning with
the letter S). Naming on the Western Aphasia Battery was impaired, with only 11 out of 20 items correct
and some evidence of visual object agnosia, including nonrecognition of a pipe. Deficits in semantic
association were also demonstrated on the Pyramid and Palm Trees Test. Trail Making B test was normal at
the 50th percentile.
Review of a recently performed brain MRI demonstrated severe anterior left temporal lobe atrophy
and moderate atrophy of the right temporal pole (Figure 5-3). A diagnosis of semantic variant primary
progressive aphasia was made.

FIGURE 5-3 Imaging of the patient in Case 5-2. A, Axial fluid-attenuated inversion recovery (FLAIR) MRI
demonstrating left temporal pole atrophy suggestive of semantic variant primary progressive
aphasia. B, With disease progression, severe atrophy is observed in the left temporal pole
as well as significant atrophy in the right temporal pole on axial FLAIR MRI.

Comment. This patient demonstrates a classic presentation of semantic variant primary

progressive aphasia. Often, the family members may identify the chief complaint as memory deficits,
but with careful assessment, it is clear that loss of word meaning and comprehension deficits underlie
the observed changes. Behavioral features are usually present early on and progress with increasing
atrophy of the right temporal lobe.

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 Frontotemporal Dementias

KEY POINT
h Atrophy of the dominant TABLE 5-2 Diagnostic Criteria for Semantic Variant Primary
anterior temporal Progressive Aphasiaa
pole is the characteristic
finding in semantic Both of the following core features must be present
variant primary 1. Impaired object naming
progressive aphasia. 2. Impaired single-word comprehension
Three of the following ancillary features must be present
1. Impaired object knowledge, particularly for low-frequency
or low-familiarity items
2. Surface dyslexia or dysgraphia
3. Spared repetition
4. Spared grammaticality and motor aspects of speech
a
Modified with permission from Gorno-Tempini ML, et al, Neurology.20 www.neurology.
org/content/76/11/1006.full. B 2011 American Academy of Neurology.

Patients with semantic variant PPA tic associations, such as the palms and
may lose the normal give and take of pyramids task, show deficits for words,
conversation, talking incessantly and and over time, often for picture stim-
requiring interruption to conduct the uli. (In the palms and pyramids task,
examination. Patients with semantic patients are shown a stimulus [a picture
variant PPA also demonstrate abnormal or word] and must choose the related
behaviors, largely overlapping with picture or word from two choices; eg,
those described above for patients with a vest is shown with choices of a bow-
bvFTD, likely due to involvement of the tie [correct] and necklace [incorrect]).
right anterior temporal lobe and con- Patients with semantic variant PPA
nections to the orbitofrontal cortex.21,22 may show an interesting pattern of
Patients with right-sided temporal atro- episodic memory deficits opposite to
phy may present with behavioral fea- that observed in AD, with better recall
tures and relatively preserved language, of recent events and people and
but over time will also develop semantic relative loss of more remote autobio-
deficits. As the disease progresses and graphic memories.23
begins to involve the posterior tempo-
Neurologic Examination
ral regions and visual temporal associa-
tion areas, patients may also develop Loquacious but empty, tangential, or
visual agnosia and prosopagnosia. repetitive speech is evident during
the course of the interview and ex-
Neuropsychological Testing in amination. Patients may repeat short
Semantic Variant Primary catch phrases or jokes. The remainder
Progressive Aphasia of the neurologic examination, includ-
Patients with semantic variant PPA dem- ing frontal reflexes, is typically normal.
onstrate deficits in single-word compre-
Neuroimaging
hension when asked to define single
words (eg, ‘‘What is an accordion?’’). Atrophy of the dominant anterior
Speech production during picture de- temporal pole is the hallmark finding
scriptions (ie, cookie jar theft picture) in semantic variant PPA (Figure 5-3).24
shows a normal or near-normal word While involvement is typically asym-
production rate but frequent use of metric at onset, over time the contra-
filler words (Case 5-2). Tests of seman- lateral temporal lobe is also affected.
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 KEY POINTS
NONFLUENT AGRAMMATIC Neurologic Examination h Hallmark features of
VARIANT PRIMARY Nonfluent speech with word-finding dif- nonfluent agrammatic
PROGRESSIVE APHASIA ficulties, circumlocutions, stuttering, variant primary
Nonfluent agrammatic variant PPA, also and grammatical errors with relative progressive aphasia
known as progressive nonfluent aphasia, preservation of comprehension is typi- include nonfluent
features progressively nonfluent, cally observed, although deficits may be speech with
agrammatic speech that is hesitant or mild at first. Subtle right-side motor word-finding difficulties,
halting (Table 5-320). Grammatical er- deficits (slower fine motor movements, circumlocutions,
rors are observed in spontaneous stuttering, and
pronator drift) may be observed in some
speech and frequently include omission grammatical errors with
patients with more widespread pathol-
of small, closed class words (eg, and, relative preservation
ogy in the left (or dominant) frontal lobe. of comprehension.
or, a, the), dropping of verb endings,
and errors in subject/verb agreement Neuroimaging h Approximately 20% of
(Case 5-3). Patients with nonfluent patients with progressive
Nonfluent agrammatic variant PPA is
agrammatic PPA frequently also dem- supranuclear palsy first
associated with atrophy of the domi- present with
onstrate apraxia of speech, defined as nant inferior frontal lobe (Figure 5-4).
impaired motor speech planning, man- frontotemporal dementia
ifest by articulation deficits.25 Although symptoms including
PROGRESSIVE SUPRANUCLEAR behavioral changes
comprehension is generally preserved PALSY or progressive
in early stages of disease, deficits com-
Although originally classified as a language deficits.
prehending grammatically complex
sentences such as those featuring ob- Parkinson-plus syndrome, PSP is now
jective relative clauses are common (ie, also included as an FTD-related disor-
‘‘The lion was killed by the tiger. Which der based on the presence of frontal
animal is alive?’’). Patients presenting lobe involvement and tau pathology.
with nonfluent agrammatic variant PPA Prior to the onset of hallmark features
may also demonstrate or develop be- including early postural instability and
havioral changes of bvFTD or features vertical gaze impairments, approxi-
of CBS or PSP. Longitudinal, autopsy- mately 20% of patients with PSP first
confirmed studies of patients present- present with FTD symptoms, includ-
ing with nonfluent agrammatic variant ing behavioral changes or progressive
PPA demonstrate several final clinical language deficits (Table 5-4). The
and pathologic diagnoses, most com- most common behavioral symptoms
monly bvFTD, PSP, or CBS.26 in patients with PSP include apathy,

TABLE 5-3 Diagnostic Criteria for Nonfluent Agrammatic Variant

Primary Progressive Aphasiaa

One of the following core features must be present

1. Agrammatism in language production
2. Effortful, halting speech with inconsistent speech sound errors and
distortions (apraxia of speech)
Two of the following three ancillary features must be present
1. Impaired comprehension of syntactically complex (noncanonical) sentences
2. Spared single-word comprehension
3. Spared object knowledge
a
Modified with permission from Gorno-Tempini ML, et al, Neurology.20 www.neurology.org/
content/76/11/1006.full. B 2011 American Academy of Neurology.

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 Frontotemporal Dementias

Case 5-3
A 66-year-old woman presented for a neurologic consultation because of difficulty speaking. She
reported 2 to 3 years of gradually increasing deficits in ‘‘getting the words out.’’ She stated, ‘‘I know
what I want to say, but the words get stuck at the tip of my tongue.’’ Her spouse noticed that at
times she would get part of the sound of the word correct, and part wrong, such as calling a ‘‘fork’’ a
‘‘fort.’’ She had also developed a mild stutter. Her husband noticed she was often able to describe
the meaning of the word, even when she could not say the word itself.
On examination, she demonstrated halting, hesitant speech although she could generally answer
questions appropriately. She correctly named a chair and key, but could not name the glove, instead
gesturing to her hand. She could not name cactus, but said ‘‘it is a thing that growsIdesertIouch.’’
During repetition she omitted small words and made paraphasic errors. She followed all verbal and
written commands. When asked to write a sentence, she wrote, ‘‘Today very sunny outside.’’ When
asked to describe the picnic scene from the Western Aphasia Battery, she demonstrated word-finding
deficits, paraphasic errors, and hesitations (item she was pointing to in parentheses): ‘‘The carpet,
and man, and womanIon their black (blanket). Man’s foodIfood there (sandals). The manIbagIbark
(book). The man glass (glasses). Bag (basket). Boy has a kiteIa gagsI(dog). GirlIsongIsandImake
(rake), sarvs (shovels), cakeIcast (castle). Man on dark (dock) and fish. Sailboat and two babli
(people)Ithere. A house there. A carI garange (garage) there and flangs (flag). Tree.’’ The remainder
of her neurologic examination was unremarkable. Neuroimaging demonstrated atrophy in the left
inferior frontal lobe (Figure 5-4).

FIGURE 5-4 Imaging of the patient in Case 5-3 who presented with nonfluent agrammatic variant
primary progressive aphasia. Axial fluid-attenuated inversion recovery (FLAIR) MRI
demonstrating left posterior frontal and frontoinsular atrophy (circled in red).

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 Continued from page 474
One year later, the patient presented with further deficits in articulatory speech consistent with verbal
apraxia. She also demonstrated worsening short-term verbal memory deficits and new difficulty with
dressing (despite normal strength). On examination, mild rigidity and odd involuntary posturing of her
right arm were noted, with ideomotor apraxia and deterioration of handwriting (Figure 5-5).

FIGURE 5-5 Handwriting sample and attempt at clock drawing of the patient in Case 5-3
with corticobasal syndrome including symptoms of the nonfluent agrammatic
variant primary progressive aphasia. The handwriting sample demonstrates
spelling and grammatical errors, as well as difficulty forming and spacing letters. Visual
construction deficits are apparent on the clock drawing.

Comment. This patient initially presented with symptoms meeting criteria for nonfluent agrammatic
variant primary progressive aphasia and indicative of dominant frontal lobe pathology. Over time,
her symptoms progressed to include apraxia and alien limb phenomenon, consistent with evolution to
corticobasal syndrome. In addition to progression to corticobasal syndrome, patients presenting with
nonfluent agrammatic variant primary progressive aphasia may also develop symptoms consistent with
behavioral variant of frontotemporal dementia or progressive supranuclear palsy.

disinhibition, anxiety, dysphoria, ste- with PSP may also present with primary
reotypic or repetitive behaviors, and apraxia of speech, combined apraxia of
up to 30% of patients with PSP will speech and progressive nonfluent
meet criteria for bvFTD.26,27 Patients aphasia, or develop these symptoms

TABLE 5-4 Clinical Presentations of Progressive Supranuclear Palsy

b Richardson syndrome (early falls, cognitive dysfunction, vertical gaze

abnormalities, axial rigidity, postural instability, symmetric bradykinesia,
little or no response to levodopa)
b Progressive supranuclear palsyYparkinsonism (early asymmetric
bradykinesia, some response to levodopa)
b Corticobasal syndrome
b Pure akinesia with freezing of gait
b Primary progressive apraxia of speech
b Progressive nonfluent aphasia
b Behavioral variant of frontotemporal dementia
b Cerebellar ataxia

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 Frontotemporal Dementias

KEY POINTS
h Most commonly, during the disease course.25 In patients commonly, patients with PSP dem-
patients with progressive presenting with primary apraxia of onstrate cognitive slowing and
supranuclear palsy speech, atrophy or hypometabolism is poorer performance on timed tests
demonstrate cognitive found in the superior premotor cortex of executive function and verbal flu-
slowing and poorer and supplementary motor area, and ency.27 Comprehension and memory
performance on timed PSP is the most common underlying are generally preserved.
tests of executive function
pathology.28
and verbal fluency. Neuroimaging
h In patients presenting Neurologic Examination Structural imaging in PSP may reveal
with primary apraxia of In the most common subtype of PSP, midbrain atrophy referred to as the
speech, progressive Richardson syndrome, increased axial hummingbird sign on sagittal images
supranuclear palsy is the rigidity of the neck and trunk, slowed (Figure 5-629), as well as hypometa-
most common vertical saccades, dysarthria, apathy or bolism in frontal, caudate, midbrain,
underlying pathology. depression, and general slowing of and thalamic regions on FDG-PET.30
h Patients with speech and thought are observed.26
corticobasal degeneration Gait is often narrow based in early CORTICOBASAL DEGENERATION
may first present with stages of the disease despite a history Corticobasal degeneration (CBD) is a
behavioral changes, of falls and imbalance. As the disease progressive neurodegenerative disor-
executive function deficits, progresses, patients often develop der affecting the frontal and parietal
or language features ophthalmoplegia particularly of verti-
consistent with early
cortices and basal ganglia associated
cal gaze, akinetic rigid parkinsonism, with abnormal 4-repeat tau isoform
frontal lobe pathology.
dystonia, verbal apraxia, pseudobulbar pathology. The term corticobasal
palsy, and frontal release signs. syndrome (CBS) is used to describe
patients presenting with the clinical
Neuropsychological Testing features associated with CBD but who
Cognitive deficits are found in the lack histologic confirmation, as CBS
majority of patients with PSP. Most presentations may be associated with a
variety of underlying neuropathologies
including AD, FTD, and CBD. CBD is
typically sporadic, although occasion-
ally CBS is the presenting phenotype for
patients with MAPT, GRN, or C9ORF72
mutations. Classic features of CBS in-
clude apraxia and alien limb phenome-
non, frontal deficits, and extrapyramidal
motor symptoms such as myoclonus or
rigidity. Five phenotypic presentations
of CBD have recently been proposed
(Table 5-5).31 As in PSP, patients with
CBD may first present with behavioral
changes, executive function deficits, or
language features consistent with early
FIGURE 5-6 Midbrain atrophy in progressive frontal lobe pathology. Behavioral
supranuclear palsy. Midsagittal MRI in a
patient with progressive supranuclear changes include those described for
palsy demonstrating thinning of the rostral midbrain bvFTD. Language presentations of CBS
resulting in the hummingbird sign.
29
are most commonly agrammatic non-
Modified with permission from Boeve B, Parkinsonism Relat Disord.
www.sciencedirect.com/science/article/pii/S1353802011700608. B 2011
fluent aphasia or apraxia of speech.
Elsevier Ltd. Symptoms referable to the parietal

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TABLE 5-5 Proposed Clinical Phenotypes Associated With the
Pathology of Corticobasal Degenerationa

Syndrome Features
Probable corticobasal syndrome Asymmetric presentation of two of the
following symptoms
Limb rigidity or akinesia
Limb dystonia
Limb myoclonus
Plus two of the following symptoms
Orobuccal or limb apraxia
Cortical sensory deficit
Alien limb phenomena (more than
simple levitation)
Possible corticobasal syndrome May be symmetric: one of the following
symptoms
Limb rigidity or akinesia
Limb dystonia
Limb myoclonus
Plus one of the following symptoms
Orobuccal or limb apraxia
Cortical sensory deficit
Alien limb phenomena (more than
simple levitation)
Frontal behavioral-spatial syndrome Two of the following symptoms
Executive dysfunction
Behavioral or personality changes
Visuospatial deficits
Nonfluent agrammatic variant Effortful, agrammatic speech plus at least
primary progressive aphasia one of the following symptoms
Impaired grammar/sentence
comprehension with relatively
preserved single-word comprehension
Groping, distorted speech production
(apraxia of speech)
Progressive supranuclear palsy Three of the following symptoms
syndrome Axial or symmetric limb rigidity
or akinesia
Postural instability or falls
Urinary incontinence
Behavioral changes
Supranuclear vertical gaze palsy or
decreased velocity of vertical saccades
a
Reprinted with permission from Armstrong MJ et al, Neurology.31 www.neurology.org/content/80/
5/496.full. B 2013 American Academy of Neurology.

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 Frontotemporal Dementias

KEY POINT
h Frontotemporal lobes, including apraxias and visuospa- Neuroimaging
dementia symptoms are tial deficits, may also be a presenting Structural brain imaging in patients
found in approximately feature.32 Motor abnormalities may be with CBS may show asymmetric fron-
30% of patients absent in as many as approximately 50% tal and parietal lobe atrophy,33 al-
diagnosed with of patients at the time of presentation though imaging findings may overlap
amyotrophic with cognitive deficits, although dur- with those seen in other FTDs and
lateral sclerosis. ing the course of the disease the AD. Thus, diagnosis at present is
majority of patients will show motor based on clinical criteria, with neuro-
features. Approximately 30% of patients imaging performed to rule out other
with CBS will develop alien limb syn- structural causes of symptoms.
drome, in which one arm may levitate
FRONTOTEMPORAL
or assume involuntary postures or
DEMENTIAYMOTOR
movements, and 25% will have cortical
NEURON DISEASE
sensory deficits.31
Frontotemporal dementia symptoms
Neurologic Examination are found in approximately 30% of
Patients presenting with frontal or patients diagnosed with amyotrophic
aphasic subtypes of CBS may present lateral sclerosis (ALS). Patients with
with inappropriate behavioral fea- FTD-ALS may present with behavioral
changes consistent with bvFTD or a
tures described above for bvFTD, or
milder dysexecutive profile including
language deficits consistent with
verbal fluency deficits.34 Hallucina-
nonfluent agrammatic variant PPA, or
tions and delusions are more common
apraxia of speech. Asymmetric limb in patients with FTD-ALS, in particular
rigidity and bradykinesia are the most in patients with C9ORF72 expanded
common motor findings, present in repeat mutations (see the following
approximately 50% of patients at the section on genetic risk factors), the
time of presentation. 31 Ideomotor most common genetic cause of famil-
apraxia is a frequent finding and may ial FTD-ALS.35,36
also be asymmetric. Other motor features
can include tremor, postural instability PROGNOSIS
and falls, axial rigidity, dystonia includ- The average survival for patients diag-
ing blepharospasm, alien limb, and nosed with FTD is approximately 7 to
myoclonus. Cortical sensory deficits 10 years. Estimates differ somewhat
may include sensory extinction, according to FTD subtype, with survival
agraphesthesia, and astereognosia. in FTD-MND averaging just 2 to 3 years,
approximately 6 to 8 years in PSP, ap-
Neuropsychological Testing proximately 9 to 10 years in bvFTD and
Performance patterns on cognitive test- nonfluent agrammatic variant PPA, and
ing may vary according to the sub- the longest median survival in patients
type. Many patients with CBS will with semantic variant PPA of approxi-
demonstrate deficits on tasks of execu- mately 12 years.2 Common proximate
tive function, writing, visuospatial, and causes of death in patients with FTD
construction tasks (Figure 5-5). Pa- related to the disease include pneumo-
tients presenting with dominant frontal nia or complications of falls.
lobe involvement may show word-
finding deficits, agrammatism, and RISK FACTORS
spelling errors similar to patients with Although approximately 50% to 60%
nonfluent agrammatic PPA.32 of FTD is considered to be sporadic in

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 KEY POINTS
etiology, genetic mutations account for cases of genetically confirmed FTD h Approximately 40%
the majority of risk factors identified (Table 5-635,36,41Y53).41 Several other of frontotemporal
for developing FTD. genetic mutations are known to be dementia cases are
rare causes of familial FTD, including associated with an
Environmental mutations in the CHMP2B gene autosomal dominant
To date there have been few studies encoding charged multivesicular body pattern of inheritance,
of environmental risk factors for FTD. protein 2B and mutations in the gene with remaining cases
Retrospective case-control studies have for valosin-containing protein (VCP), considered sporadic.
found an increased incidence of head which is associated with the clinical h A genetic mutation
injury in patients with a clinical diagno- triad of FTD, inclusion body myopathy, may be found in
and Paget disease. Of interest, variants
sis of FTD (odds ratios of 3 to 4).37,38 approximately 6% of
in the gene for transmembrane protein patients with no family
While repetitive concussions have been
106B (TMEM106B) have been identi- history of frontotemporal
linked to progressive neuropsychiatric
fied to confer protection and delay dementia; thus, referral
symptoms, cognitive deficits, and path-
onset of FTD in patients with GRN to a genetic counselor for
ologic tau deposition in the frontal and
and C9ORF72 mutations.54 A genetic consideration of genetic
temporal lobes in chronic traumatic
mutation may be found in approxi- testing may be considered
encephalopathy,39 the relationship of mately 6% of patients with no family for all patients presenting
isolated concussion or mild head injury history of FTD; thus, referral to a with frontotemporal
in relation to chronic traumatic en- genetic counselor for consideration of dementia.
cephalopathy and other forms of FTD genetic testing may be considered for h Abnormal accumulations
is not yet understood. all patients presenting with FTD.55 of tau or TDP-43 account
for the majority of
Genetic NEUROPATHOLOGY pathologically confirmed
Approximately 40% of FTD is associated Abnormal accumulations of tau or cases of frontotemporal
with an autosomal dominant pattern of TDP-43 account for the majority of
dementia, with FUS
inheritance, with remaining cases con- pathologically confirmed cases of FTD,
inclusions most common
sidered sporadic.40 A careful family his- with FUS inclusions most common in
in the remaining 10%.
tory considering not only diagnosis, but
the remaining 10% (Figure 5-756).55
also possible FTD symptoms in other
Abnormal aggregations of tau can be
family members is essential, as FTD was
found in patients with sporadic bvFTD,
rarely diagnosed before the 1990s, and
CBS, nonfluent agrammatic variant PPA,
family members may have been mis-
and PSP as well as MAPT-associated
diagnosed with AD, vascular dementia, or
familial FTD (Figure 5-857). Tau inclu-
late-onset psychiatric disorders. bvFTD
sions are rare in patients with seman-
and nonfluent agrammatic variant PPA
tic variant PPA. Abnormal TDP-43
are the most common phenotypes in
genetic FTD, although CBS presenta-
tions can also occur. Semantic variant Box 1 Glossary of Gene and Protein Abbreviations
PPA is almost always sporadic. PSP is not
associated with the FTD mutations C9ORF72: Chromosome 9 open reading frame 72
described below, although is linked to CHMP2B: Charged multivesicular body protein 2B
the H1 haplotype in the MAPT gene FUS: Fused in Sarcoma RNA binding protein
(see Box 1 Glossary of Gene and Pro- GRN: Progranulin
tein Abbreviations). Mutations in ap- MAPT: Microtubule-associated protein tau
proximately eight genes have been
TDP-43: Transactive response DNA binding protein 43 kDa
linked to FTD, accounting for approx-
TMEM106B: Transmembrane protein 106B
imately 50% of familial FTD, with
VCP: Valosin containing protein
mutations in GRN, C9ORF72, and
MAPT accounting for the majority of

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 Frontotemporal Dementias

TABLE 5-6 Frontotemporal Dementia Gene Mutationsa

Genes Chromosome Protein Main Clinical Phenotypes

GRN 17q21.32 Progranulin bvFTD 9 PPA, semantic
variant PPA, CBS

C9ORF72 9p21.2 Unknown bvFTD, ALS, FTLD-ALS

MAPT 17q21.32 Microtubule-associated tau protein bvFTD 9 PSP, CBS

VCP 9p13.3 Valosin-containing protein Multisystem proteinopathy/IBMPFD

TARDBP 1p36.21 TDP-43 ALS 9 FTLD-ALS, FTD

FUS/TLS 16p11.2 Fused in sarcoma protein ALS 9 bvFTD, FTLD-ALS
SQSTM1 5q35 Sequestome 1/p62 Paget disease of bone,
ALS, bvFTD
CSF1R 5q32 Colony-stimulating factor 1 receptor bvFTD, CBS, strokelike
TREM2 6p21.1 Triggering receptor expressed on PLOSL, bvFTD,
myeloid cells
CHMP2B 3p11.2 Chromatin-modifying protein 2B bvFTD, FTLD-ALS
UBQLN2 Xp11.21 Ubiquilin 2 ALS 9 FTLD-ALS
hnRNPA2B1 7p15 Heterogeneous nuclear Multisystem proteinopathy/IBMPFD
ribonucleoprotein A2/B1
ALS = amyotrophic lateral sclerosis; bvFTD = behavioral variant of frontotemporal dementia; CBS = corticobasal syndrome;
FTD = frontotemporal dementia; FTLD = frontotemporal lobar degeneration; HDLS = hereditary diffuse leukoencephalopathy with
spheroids; IBMPFD = inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia;
PLOSL = polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy; PPA = primary progressive aphasia;
PSP = progressive supranuclear palsy.
a
Reprinted with permission from Le Ber I, Rev Neurol (Paris).41 www.em-consulte.com/article/840375/alertePM. B 2013 Elsevier Masson SAS.

KEY POINT inclusions account for the majority of region and frontoinsular junction may
h CSF biomarkers may the remaining tau-negative patients. be the first site of disease pathology,
help to distinguish
TDP-43 pathology is found in patients as early loss of these neurons is found
between frontotemporal
with semantic variant PPA, FTD-MND, in patients with FTD compared to AD
dementia and Alzheimer
disease, but at present and bvFTD, as well as in genetic and controls.58
there are no validated variants including C9ORF72, GRN, and
biomarkers that VCP mutations. TDP-43 pathology is CEREBROSPINAL FLUID AND
can reliably distinguish characterized by four patterns that SERUM BIOMARKERS
patients with show associations with FTD clinical At present, CSF biomarkers may help
frontotemporal phenotypes (Figure 5-957). FUS pa- to distinguish between FTD and AD,
dementia from controls thology is associated with an ear- but there are no validated biomarkers
or other non-Alzheimer lier age of onset of FTD, prominent that can reliably distinguish patients
disease dementias. neuropsychiatric features, and a more with FTD from controls or other non-
rapid course.55 It has been hypothe- AD dementias. The presence of an AD
sized that von Economo neurons, pattern of biomarkers is considered
large bipolar neurons in layer V of an exclusion criterion for probable
the cortex, in the anterior cingulate FTD.4 CSF biomarkers demonstrating

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Mode of Mutation Frequencies
Inheritance in Familial FTLD Pathology References
Autosomal dominant 5 to 22% FTLD with TAR DNA Cruts et al, 200642
binding protein-43 (TDP-43)
proteinopathy (type A)
Autosomal dominant FTLD: 7 to 29% FTLD with TDP-43 Renton et al, 201135;
FTLD-ALS: up to 66% proteinopathy (types A DeJesus-Hernandez et al,
and B) 201136
Autosomal dominant 5 to 15% FTLD with tauopathy Hutton et al, 199843
Autosomal dominant 3% FTLD with TDP-43 Watts et al, 200444
proteinopathy (type D)
Autosomal dominant 2% Undetermined Benajiba et al, 200945
Autosomal dominant 1% Undetermined Broustal et al, 201046
Autosomal dominant 2% FTLD with TDP-43 Fecto et al, 201147;
proteinopathy Rubino et al, 201248
Autosomal dominant Undetermined HDLS Rademakers et al, 201149
Autosomal recessive G1% Undetermined Guerreiro et al, 201350

Autosomal dominant G 1% FTLD with no inclusions Skibinski et al, 200551

X-linked dominant G1% Undetermined Gellera et al, 201352
Autosomal dominant Undetermined Undetermined Kim et al, 201353

reduced amyloid-"4 2 (A"4 2 ) and function of age, gender, and other

increased tau/phosphorylated-tau genetic factors.60
can distinguish AD from FTD (sensi-
tivity of approximately 80%, speci- DIAGNOSTIC WORKUP OF
ficity of approximately 80%), in which PATIENTS WITH SUSPECTED
tau levels are normal or low and A"42 FRONTOTEMPORAL DEMENTIA
levels are higher than in AD.59 To aid Assessment of patients with possible
in FTD diagnosis and track disease FTD requires a thorough history with
progression, several candidate CSF the patient and caregiver or informant.
biomarkers are currently under in- As most patients with bvFTD and
vestigation, including neurofilament semantic variant PPA will have limited
light chains, TDP-43, and progranulin. insight into their symptoms, it is es-
Low serum progranulin levels can sential to obtain a history of behav-
predict GRN mutation status in car- ioral, cognitive, or functional decline
riers and patients; however, serum from a reliable informant who has
and CSF progranulin levels are only known the patient for some time in
modestly correlated and may vary as a order to assess the extent to which

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 Frontotemporal Dementias

FIGURE 5-7 Neuropathologic classification of frontotemporal lobar degeneration.

aFTLD-U = atypical frontotemporal lobar degeneration; AGD = argyrophilic
grain disease; ALS = amyotrophic lateral sclerosis; BIBD = basophilic inclusion
body disease; CBD = corticobasal degeneration; CTE = chronic traumatic encephalopathy;
DLDH = dementia lacking distinctive histology; FTLD = frontotemporal lobar degeneration;
FTD-3 = frontotemporal dementia associated with chromosome 3; FTLD-FUS = frontotemporal
lobar degeneration with fused in sarcoma proteinopathy; FTLD-ni = frontotemporal lobar
degeneration with no inclusions; FTLD-tau = frontotemporal lobar degeneration with tauopathy;
FTLD-TDP = frontotemporal lobar degeneration with TDP-43 proteinopathy; FTLD-UPS =
frontotemporal lobar degeneration with involvement of the ubiquitin proteasome system; MSTD =
multiple system tauopathy with dementia; NIFID = neuronal intermediate filament inclusion
dementia; PiD = Pick disease; PSP = progressive supranuclear palsy; TPSD = tangle predominant
senile dementia; Ub = ubiquitin; WMT-GGI = white matter tauopathy with globular glial
inclusions; 3R = 3 microtubule-binding repeats; 4R = 4 microtubule-binding repeats;
?-opathy = subtype without a hallmark protein aggregate identified to date; + = inclusions
present; - = inclusions absent.
a
Unclassifiable and MAPT related: 3R, 4R, or both.
56
Reprinted with permission from Bigio EH, Arch Pathol Lab Med. www.archivesofpathology.org/doi/abs/10.5858/
arpa.2012-0075-RA. B 2013 College of American Pathologists.

behavior represents a change from parkinsonism, cortical sensory tests,

baseline personality traits and habits. apraxia testing, and frontal release
Ascertainment of behavioral changes signs. Brain imaging, preferably MRI, is
can be facilitated by standardized ques- essential to rule out structural and
tionnaires such as the Frontal Behav- vascular abnormalities and to assess
ioral Inventory61 or the Frontotemporal for patterns of focal atrophy. When
Dementia Rating Scale (available at structural imaging is inconclusive,
www.ftdrg.org/ace-r-download/ FDG-PET or SPECT imaging may help
frontotemporal-dementia-rating-scale- to identify the presence of hypo-
frs-download/ ).62,63 A full neurologic metabolism or hypoperfusion and
examination should be performed, whether the pattern observed is most
including assessment of vertical sac- consistent with FTD. Where available,
cades, axial tone, the presence of Pittsburgh compound B (PiB)-PET

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 Pathologic features in frontotemporal lobar degeneration with tauopathy. A, Pick bodies in the temporal cortex of a patient
FIGURE 5-8 with Pick disease; B, tufted astrocyte in a patient with progressive supranuclear palsy; C, a globose tangle in a case with
progressive supranuclear palsy; D, astrocytic plaque as a hallmark lesion of corticobasal degeneration; E, neuronal and glial
tau pathology in the frontal cortex of a patient with MAPT gene mutation. Panels A, C, and D are tau immunohistochemistry; Panels B
and E are Gallyas-Braak silver stain. Scale bars: 50 mm.
57
Reprinted with permission from Neumann M, et al, Expert Rev Mol Med. journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5988276&
fileId=S1462399409001136. B 2009 Cambridge University Press.

FIGURE 5-9 Types of TDP-43 pathology in frontotemporal lobar degeneration. A, Type A is characterized by compact neuronal
cytoplasmic inclusions and short neurites and is most commonly associated with behavioral variant of frontotemporal
dementia, progressive nonfluent aphasia, and GRN mutations. B, Type B is characterized by compact and granular
cytoplasmic inclusions and is associated with frontotemporal dementiaYmotor neuron disease, behavioral variant of frontotemporal
dementia, and C9ORF72 expanded repeats. C, Type C is characterized by long neurites and is found in semantic variant primary progressive
aphasia. D, Type D is characterized by numerous neuronal intranuclear inclusions and is found in patients with VCP mutations.
57
Reprinted with permission from Neumann M, et al, Expert Rev Mol Med. journals.cambridge.org/action/displayAbstract?fromPage=online&aid=5988276&
fileId=S1462399409001136. B 2009 Cambridge University Press.

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 Frontotemporal Dementias

imaging or CSF A"1-42 and tau analysis which is common, particularly in pa-
may aid in distinguishing FTD from tients with nonfluent agrammatic vari-
frontal or language presentations of ant PPA and PSP. Physical therapy
AD. For patients interested in genetic evaluations of gait when falls or balance
testing, or those with a family history problems are reported and occupa-
suggestive of FTD or ALS, referral to a tional therapy assessments of home
genetic counselor for consideration safety are also indicated. Caregivers
of genetic testing is indicated. Knowl- should be referred to local FTD or
edge of genetic status can confirm a dementia support groups for support
diagnosis of familial FTD and may aid and education of behavioral manage-
referral of patients and carriers to ment strategies. The changes in behav-
current and future clinical trials ior chart offers helpful strategies for
targeting specific FTD mutations. problematic behaviors (www.theaftd.org/
wp-content/uploads/2011/09/Packet-
PATIENT MANAGEMENT Changes-in-behavior-chart.pdf ).66
There are currently no therapies specif-
ically approved for FTD. Thus, educa- Pharmacologic Treatment
tion and supportive management of Current treatment approaches are lim-
safety and behavioral issues for the ited to symptomatic treatments that
patient and caregiver are essential in employ off-label uses of medications
supporting patients with FTD.64,65 modulating neurotransmitter systems,
usually to modify difficult behaviors.9,67
Supportive Management and Most commonly, selective serotonin
Follow-up Assessments reuptake inhibitors (SSRIs), such as ci-
A power of attorney for personal care talopram, or trazodone are used to im-
and finances should be put into place prove behavioral symptoms including
for patients with FTD, as impaired disinhibition, agitation/irritability, or
judgment and impulsivity can result in compulsive behaviors (Table 5-79,68Y75).
significant financial difficulties. There Psychosis and aggression may require
are few studies of driving safety in neuroleptic medications, although
patients with FTD. Those available gold standard randomized clinical trials
suggest that the risk of accidents is of these agents are not available in
increased even in patients with mild patients with FTD. If needed, initia-
disease and is related to inattention, tion at a low dose and frequent re-
assessment of efficacy and need for
impulsivity, and poor emotion regu-
continued use are required given
lation. Careful and frequent reassess-
black box warnings for this class of
ment of patient’s behavioral symptoms
medications due to increased mor-
and cognitive testing performance tality. Although parkinsonism in pa-
when considering driving privileges is tients with FTD is usually not
necessary, potentially supported by on- dopamine responsive, as a fraction
road driving assessments. Caregivers of patients may benefit, a trial of
and families should also be counseled carbidopa/levodopa titrating up to
regarding gun safety or other poten- 25 mg/250 mg 3 times daily for parkin-
tially hazardous activities or pastimes. sonism is generally indicated. Cholin-
Speech and swallowing assessments are esterase inhibitors may frequently
indicated to optimize communication increase agitation in patients with
strategies and screen for dysphagia, bvFTD and, thus, are not indicated.

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TABLE 5-7 Treatment Approaches for Behavioral Symptoms in Frontotemporal Dementiaa

bvFTD Current Evidence for Possible Future

Symptom Treatment Options Current Treatments Treatment Options
Apathy None NA Dopaminergic medications
Behavioral SSRIs: fluoxetine, Open-label studies
disinhibition sertraline, paroxetine, supporting
fluvoxamine, citalopram use of SSRIs68Y70
Trazodone Double-blind,
placebo-controlled
study supporting the
use of trazodone71
Atypical antipsychotics: Case reports supporting
risperidone, aripiprazole, use of antipsychotics70,72,73
olanzapine, quetiapine
Loss of empathy None NA Oxytocin
Perseverative SSRIs: fluoxetine, Open-label studies
behavior sertraline, paroxetine, supporting
fluvoxamine, citalopram use of SSRIs68,74,75
Trazodone Double-blind,
placebo-controlled study
supporting the use
of trazodone71

Hyperorality SSRIs: fluoxetine, Open-label studies

sertraline, paroxetine, supporting use of SSRIs68,70,75
fluvoxamine, citalopram
Trazodone Double-blind,
placebo-controlled
study supporting the
use of trazodone71
Executive None NA Dopaminergic medications
dysfunction
Neuroprotective None NA Medications that prevent
tau hyperphosphorylation
and accumulation
Medications that increase
progranulin levels
Medications that reduce
C9ORF72 expanded repeat
dipeptide production
bvFTD = behavioral variant of frontotemporal dementia; NA = not available; SSRIs = selective serotonin reuptake inhibitors.
a
Modified with permission from Manoochehri M, Huey ED, Curr Neurol Neurosci Rep.9 link.springer.com/article/10.1007/s11910-012-
0302-7. B 2012 Springer Science + Business Media, LLC.

For patients with CBS or nonfluent trial of a cholinesterase inhibitor is

agrammatic variant PPA who have warranted. A double-blind, placebo-
memory deficits, approximately 30% controlled randomized trial of
to 40% may have underlying AD pa- memantine for cognitive and behav-
thology, and therefore a 2- to 3-month ioral symptoms of FTD showed no

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 Frontotemporal Dementias

benefit. 76 Clinical trials of novel 7. Pennington C, Hodges JR, Hornberger M.

Neural correlates of episodic memory in
agents targeting specific genes, related behavioral variant frontotemporal dementia.
proteins and pathways for tau, prog- J Alzheimers Dis 2011;24(2):261Y268.
ranulin, and C9ORF72 are anticipated doi:10.3233/JAD-2011-101668.
in the near future. 8. Rankin KP, Santos-Modesitt W, Kramer JH, et al.
Spontaneous social behaviors discriminate
behavioral dementias from psychiatric
CONCLUSION disorders and other dementias. J Clin
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neuroanatomical changes in genetic
Although not yet widely available for frontotemporal dementia in the Genetic
clinical use, molecular-specific diag- Frontotemporal dementia Initiative
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 Review Article

Vascular Cognitive
Address correspondence to
Dr Eric Smith, University of
Calgary, Room C1261, Foothills

Impairment
Medical Centre, 1403 29 St NW,
Calgary, AB, Canada,
[email protected].
Relationship Disclosure:
Dr Smith serves as a board Eric Smith, MD, MPH
member of the Quality
Oversight Committee of the
American Heart Association
and as an assistant editor for ABSTRACT
Stroke. Dr Smith receives grant
support from the Alzheimer Purpose of Review: This article provides a diagnostic framework for vascular cog-
Society of Canada, the nitive impairment, discusses prevalence and relationships to other neurodegenerative
Canadian Institutes of Health pathologies, and provides advice on diagnostic workup and management.
Research, the Canadian
Partnership Against Cancer, Recent Findings: Vascular cognitive impairment is the second most common cause
and the Heart and Stroke of cognitive impairment and frequently coexists with other neurodegenerative neu-
Foundation of Canada and ropathologies. Three new diagnostic criteria have been published recently; common
receives research support
from McMaster University. diagnostic elements include the need to classify cognitive impairment as mild cog-
Unlabeled Use of nitive impairment or dementia and to link the cognitive impairment to evidence of
Product/Investigational clinically significant cerebrovascular disease. Vascular cognitive impairment may be
Use Disclosure:
Dr Smith discusses the
further subclassified into poststroke vascular cognitive impairment and nonstroke
unlabeled/investigational vascular cognitive impairment, most commonly caused by cerebral small vessel
use of cholinesterase disease, which may only be recognized on neuroimaging.
inhibitors for the treatment
of vascular dementia.
Summary: Vascular cognitive impairment is a potentially treatable common cause
* 2016 American Academy of cognitive impairment, progression of which may be slowed or halted by secondary
of Neurology. prevention of vascular disease.

Continuum (Minneap Minn) 2016;22(2):490–509.

INTRODUCTION CLASSIFICATION OF VASCULAR

Vascular cognitive impairment is the COGNITIVE IMPAIRMENT
second most common cause of demen- Classification criteria for vascular cogni-
tia and may be the most preventable tive impairment have been published
and treatable cause. Vascular cognitive by the International Classification
impairment is commonly encountered of Diseases, Tenth Revision (ICD-10),1
in two forms. In poststroke vascular cog- National Institute of Neurological
nitive impairment, the cognitive im- Disorders and Stroke-Association
pairment is the immediate and direct Internationale pour la Recherche et
consequence of a symptomatic stroke. l’Enseignement en Neurosciences
In nonstroke-related vascular cognitive (NINDS-AIREN),2 State of California
impairment, the cognitive impairment Alzheimer’s Disease Diagnostic and
is the consequence of clinically hard- Treatment Centers (ADDTC),3 American
to-detect cerebrovascular disease, which Heart Association/American Stroke As-
may be evident only on neuroimaging sociation (AHA/ASA),4 the International
with CT or MRI. Additionally, vascular Society of Vascular Behavioural and Cog-
cognitive impairment is a frequent nitive Disorders (Vas-Cog),5 and in the
contributor to mixed dementia, accom- Diagnostic and Statistical Manual
panied by other neuropathologies such of Mental Disorders, Fourth Edition
Supplemental digital content: as Alzheimer pathology. This article (DSM-IV)6 and Fifth Edition (DSM-5).7
Direct URL citations appear in summarizes the classification, diagno- Common elements of recent criteria
the printed text and are provided
in the HTML, PDF, and app
sis, and management of vascular cog- are given in Table 6-1. All of these clas-
versions of this article. nitive impairment. sification schemes require that some

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TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment

AHA/ASA4 Vas-Cog Society5 DSM-57

Cognitive criteria Discriminates between vascular Discriminates between Discriminates between
mild cognitive impairment mild and major vascular mild and major vascular
and vascular dementia cognitive disorder (dementia) neurocognitive disorder
Criteria for There is imaging evidence of Either: The criteria are met
probable vascular cerebrovascular disease The onset of cognitive deficits for major or mild
cognitive and either: follows one or more strokes neurocognitive disorder.
impairment or there are physical signs The clinical features are
There is a clear temporal
relationship between a vascular consistent with stroke. consistent with a vascular
event (eg, clinical stroke) and etiology, as suggested by
OR
onset of cognitive deficits. either of the following:
If history of stroke or transient
OR Onset of the cognitive
ischemic attack is absent, then there
deficits is temporally
There is a clear relationship is evidence of cognitive decline in
related to one or more
in the severity and pattern of speed of information processing,
cerebrovascular events.
cognitive impairment and complex attention or frontal
the presence of diffuse, executive functions, accompanied OR
subcortical cerebrovascular by one or more of: gait
disturbances, urinary symptoms, Evidence for decline is
disease pathology. prominent in complex
or personality and mood changes.
There should be no history of attention (including
gradually progressive There should be neuroimaging processing speed) and
cognitive deficits before or evidence of either large vessel frontal-executive function.
after stroke that suggest the infarct, strategically placed single There is evidence of
presence of a nonvascular infarct(s) or intracerebral the presence of
cognitive disorder (eg, hemorrhages(s), multiple (more cerebrovascular disease
Alzheimer disease). than two) lacunar infarcts outside from history, physical
the brainstem, or extensive and examination, and/or
confluent white matter lesions. neuroimaging considered
There should not be evidence sufficient to account for
of other nonvascular cognitive, the neurocognitive deficits.
medical, psychiatric, or neurologic The symptoms are not
disorders sufficient to explain the better explained by
cognitive impairment (including another brain disease
Alzheimer disease). or systemic disorder.
Probable vascular
neurocognitive disorder
is diagnosed if one of
the following is present;
otherwise possible
vascular neurocognitive
disorder should
be diagnosed:
Clinical criteria are
supported by
neuroimaging evidence
of significant parenchymal
injury attributed to
cerebrovascular disease
(neuroimaging supported).
Continued on page 492

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 Vascular Cognitive Impairment

TABLE 6-1 Recent Classification Criteria for Vascular Cognitive Impairment Continued from page 491

AHA/ASA4 Vas-Cog Society5 DSM-57

OR
The neurocognitive
syndrome is temporally
related to one or
more documented
cerebrovascular events.
OR
Both clinical and genetic
(eg, cerebral autosomal
dominant arteriopathy
with subcortical
infarcts and
leukoencephalopathy)
evidence of
cerebrovascular
disease is present.
Criteria for Meets criteria except that Meets criteria except that Clinical criteria are met
possible vascular there is no clear relationship neuroimaging is not available. but neuroimaging is
cognitive between the vascular not available and the
impairment disease and the cognitive temporal relationship
impairment, there is of the neurocognitive
insufficient information syndrome with one or
(eg, neuroimaging studies more cerebrovascular
are not available), severe events is not
aphasia precludes accurate established.
cognitive assessment, or
there is evidence of
other neurodegenerative
conditions (eg, Alzheimer
disease) in addition to
cerebrovascular disease.
Classification Possible vascular mild cognitive Vascular mild/major cognitive Not specifically
when other impairment or dementia disorder with concomitant addressed.
potential causes should be diagnosed when Alzheimer disease may be
are present (ie, there is evidence of other diagnosed when the patient
mixed disease) neurodegenerative conditions. additionally meets criteria for
probable or possible AD.

AHA/ASA = American Heart Association/American Stroke Association; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition; Vas-Cog = International Society of Vascular Behavioural and Cognitive Disorders.

degree of cognitive impairment should tion to the cognitive impairment. The

be present along with evidenceV term vascular cognitive impairment is
from some combination of history, intended to encompass all forms of cog-
physical examination, cognitive pro- nitive impairment, not only dementia,
file, and diagnostic testing, including and to include all cases where vascu-
neuroimagingVof a vascular contribu- lar disease contributes to impairment,

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 KEY POINTS
including in cases where it is not the atheroembolism, cardiac embolism, h Diagnostic criteria for
sole contributor. More recent classifica- hypoperfusion, and hemorrhage) such vascular cognitive
tion systemsVthe AHA/ASA, Vas-Cog, that patient prognosis and manage- impairment are based
and DSM-5Vdistinguish between vas- ment must be highly individualized. on the presence of
cular mild cognitive impairment (MCI) With appropriate case-specific man- cognitive impairment
(or minor vascular neurocognitive agement of the vascular risk factors and vascular disease
disorder in the DSM-5) and vascular relevant to the patient’s vascular pa- as well as a clinical
dementia (or major vascular neurocog- thology, it may be possible to arrest judgment that the
nitive disorder in the DSM-5). progression of vascular cognitive im- vascular disease is
AHA/ASA and Vas-Cog criteria fur- pairment by preventing further cere- causing the impairment.
ther classify vascular cognitive impair- brovascular injury. h The term vascular
ment as probable or possible based cognitive impairment
on the completeness of the diagnos- encompasses all severity
DIAGNOSIS AND DIAGNOSTIC of cognitive impairment
tic workup and the presence or absence TESTING caused by vascular
of evidence for competing causes of
The diagnosis of a patient with possi- disease, including mild
dementia, such as Alzheimer disease
ble vascular cognitive impairment may cognitive impairment
(AD). In practice, probable vascular and dementia.
be considered to consist of three stages.
cognitive impairment may be the mi-
First, a determination should be made h Vascular cognitive
nority of cases because comorbid pa-
of whether evidence of cognitive im- impairment may be
thologies such as AD are commonly
pairment exists, including classification subclassified as
identified, or at least cannot be ruled poststroke vascular
out with certainty. as MCI or dementia. Second, a workup
for the presence of vascular disease cognitive impairment,
AHA/ASA, Vas-Cog, and DSM-5 cri- which refers to the
teria acknowledge that vascular cog- should be completed, including its
direct immediate
nitive impairment may come in the location, severity and underlying
consequence of
form of poststroke vascular cognitive causes, and risk factors. Third, consid- clinical stroke, or as
impairment or nonstroke forms of vas- eration should be given as to whether nonstroke vascular
cular cognitive impairment, such as the vascular disease is sufficient to cognitive impairment,
that caused by subcortical ischemic partly or wholly explain the cogni- which is most commonly
disease. This distinction is important tive impairment. caused by cerebral small
vessel disease.
as it makes clear that the absence of a
clinical history of stroke does not ex- Assessing Cognitive h Vascular cognitive
clude vascular cognitive impairment. Impairment in Vascular impairment has many
Indeed, neuroimaging and neuropa- Cognitive Impairment vascular causes. The
The assessment for cognitive impair- cause of the vascular
thology studies have established that
disease should be
clinically silent, or ‘‘covert,’’ cerebro- ment should follow the same prin-
identified so that
vascular disease becomes extremely ciples for assessment of MCI and
further progression
common with aging, is associated with dementia as provided in the article or recurrence can
cognitive impairment and the presence ‘‘The Mental Status Examination in be prevented.
of dementia, and is sufficient to cause Patients With Suspected Dementia’’ by
clinically relevant cognitive impairment. Murray Grossman, MD, FAAN, and
Furthermore, Vas-Cog criteria sub- David J. Irwin, MD,8 and in the article
classify vascular cognitive impairment ‘‘Mild Cognitive Impairment’’ by
according to cerebrovascular pathology Ronald C. Petersen, PhD, MD,9 in this
(Table 6-2). It is important to recog- issue of Continuum. The sensitivity
nize that the vascular pathologies un- for detecting vascular cognitive im-
derlying vascular cognitive impairment pairment is enhanced by the use of
are extremely diverse (including arterio- screening or assessment tools that
sclerosis, cerebral amyloid angiopathy, interrogate executive function and

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 Vascular Cognitive Impairment

KEY POINT
h The clinical assessment a
TABLE 6-2 Vascular Pathology of Vascular Cognitive Impairment
for vascular cognitive
impairment can be b Parenchymal Lesions of Vascular Etiology
conceived as a
Large vessel atherothromboembolic disease
three-stage process
that includes the Multiple infarcts
following steps: Single strategically placed infarct
(1) assess for cognitive
Small vessel disease
impairment; (2) assess
the presence, severity, Multiple lacunar infarcts
and cause of vascular Ischemic white matter damage
disease; and (3) assess
whether the vascular Dilated perivascular spaces
disease is sufficient to Microinfarcts
cause the impairment,
Microhemorrhages
in whole or in part.
Hemorrhage
Intracerebral hemorrhage
Multiple microbleeds
Subarachnoid hemorrhage
Hypoperfusion
Hippocampal sclerosis
Laminar cortical necrosis
b Types of Vascular Pathologies
Atherosclerosis
Cardiac, atherosclerotic, and systemic emboli
Arteriolosclerosis
Lipohyalinosis
Cerebral amyloid angiopathy
Vasculitis
Venous collagenosis
Arteriovenous fistulae
Hereditary angiopathies (eg, cerebral autosomal dominant arteriopathy
with subcortical infarcts and leukoencephalopathy [CADASIL])
Berry aneurysms
Miscellaneous vasculopathies (eg, moyamoya disease)
Cerebral venous thrombosis
a
Modified with permission from Sachdev P, et al, Alzheimer Dis Assoc Disord.5 journals.lww.com/
alzheimerjournal/Abstract/2014/07000/Diagnostic_Criteria_for_Vascular_Cognitive.2.aspx. B 2014
Lippincott Williams & Wilkins.

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 KEY POINTS
processing speed, which are frequently when a history of stroke is absent. h Cerebrovascular disease
affected in patients with vascular cog- Neuroimaging can identify evidence should be diagnosed by
nitive impairment. For example, the of silent strokes and other manifesta- history, examination,
Montreal Cognitive Assessment (MoCA) tions of cerebral small vessel disease and diagnostic testing,
tool appears to be a more sensitive that are hard to detect clinically. Clini- including neuroimaging.
tool for vascular cognitive impairment cal history, signs, and symptoms may h Neuroimaging provides
than the Mini-Mental State Examination be suggestive of nonstroke vascular useful evidence of
(MMSE), attributed to the relatively cognitive impairment but are not the presence, location,
greater degree of executive function highly sensitive or specific and should and severity of
assessment on the MoCA (www. not be relied on to diagnose vascular cerebrovascular disease.
mocatest.org).10,11 When clinical un- cognitive impairment in the absence
certainty persists despite the use of a of neuroimaging confirmation. These
validated bedside cognitive screening signs and symptoms include frontal
tool, neuropsychological testing is gait disorder, urinary incontinence,
often helpful. The cognitive profile a stepwise progression of cognitive
of vascular cognitive impairment is impairment with intervening static pe-
further described later in this article. riods, prominent executive dysfunc-
tion and slowed processing speed on
Assessing the Presence of neuropsychological testing, and minor
Cerebrovascular Disease in asymmetric neurologic signs such as
Patients With Vascular increased tone, reflex asymmetry, Ba-
Cognitive Impairment binski responses, or frontal release signs.5
The presence of vascular risk factors
The determination of the presence of
such as diabetes mellitus and hyperten-
cerebrovascular disease may be based
sion should increase suspicion for vas-
on a combination of history, examina-
cular cognitive impairment but should
tion, and diagnostic testing such as
not be taken as proof of its presence.
neuroimaging. The clearest evidence Neuroimaging is recommended by
of cerebrovascular disease is when a the AHA/ASA as helpful for the diag-
clinical history of stroke exists. How- nosis of vascular cognitive impair-
ever, the physician should be sure ment.4 Neuroimaging is useful not
that the diagnosis of stroke is well only for identifying the presence of
supported by clinical history, medical cerebrovascular disease, but also the
records, physical examination showing location and severity of the cerebro-
neurologic signs consistent with past vascular lesions, which help determine
stroke (such as aphasia, dysarthria, the clinical significance of the lesions,
hemianopia, or other focal neurologic including whether they are sufficient
signs) and, if needed or available to account for the cognitive impair-
from previous stroke workup, neuro- ment. MRI is superior to CT for iden-
imaging evidence of cerebral infarc- tifying small infarcts and hemorrhages
tion or hemorrhage consistent with the and demonstrates more manifesta-
signs and symptoms. Patient-reported tions of cerebral small vessel disease;
history of stroke is generally reli- therefore, MRI should be preferred
able; however, nonspecific neurologic over CT.12 In patients with a history
symptoms can sometimes be falsely of stroke, neuroimaging should gen-
reported as stroke, introducing diag- erally identify the previous infarct or
nostic confusion. hemorrhage unless it is small. In
Identifying the presence of cere- patients with cerebral small vessel
brovascular disease is more difficult disease, MRI may identify a range of
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 Vascular Cognitive Impairment

KEY POINT
h Because cerebrovascular manifestations, including small in- ment for vascular cognitive impair-
disease is common farcts, lacunae of presumed vascular ment. Although general principles
and can be incidental, origin, white matter hyperintensi- relating the location and severity of
clinical judgment is ties, and others (Figure 6-1). A recent cerebrovascular disease to the risk for
needed in individual consensus statement offers rec- cognitive impairment have been
patients to determine ommendations for terms, defini- established, there are no objectively
whether cerebrovascular tions, and reporting of cerebral derived models or risk scores to pre-
lesions are sufficient small vessel disease as a contributor dict the presence of cognitive impair-
to cause cognitive to neurodegeneration.12 ment in individual patients based on
impairment in the
affected individual. Assessing the Relationship their clinical characteristics and bur-
Between Cerebrovascular Disease den of cerebrovascular disease. There-
and Cognitive Impairment fore, clinical judgment is required
Determining whether the identified to determine whether identified cere-
cerebrovascular disease is sufficient to brovascular disease is clinically rele-
account for, in whole or in part, cog- vant, or merely an incidental finding.
nitive impairment may be the most This judgment is difficult because
clinically difficult part of the assess- cerebrovascular disease is a common

FIGURE 6-1 MRI manifestations of cerebral small vessel disease.

DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; GRE = gradient
recalled echo; SWI = susceptibility-weighted imaging.
12
Reprinted with permission from Wardlaw JM, et al, Lancet Neurol. www.thelancet.com/journals/laneur/article/
PIIS1474-4422(13)70124-8/abstract. B 2013 Elsevier Ltd.

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

 KEY POINT
accompaniment of aging that is fre- as the Informant Questionnaire on Cog- h In poststroke vascular
quently seen in nonimpaired individ- nitive Decline in the Elderly (IQCODE)17 cognitive impairment,
uals, as well as in impaired individuals (Supplemental Digital Content 6-1, the link between
(where it tends to be more severe http://links.lww.com/CONT/A172) can be stroke and subsequent
and diffuse). For example, silent used to assess for prestroke cognitive vascular cognitive
brain infarcts, extensive white matter decline, or a careful clinical history of impairment should
performance on instrumental activi- be readily apparent.
hyperintensities, and microbleeds,
are frequently detected on MRI of ties of living (such as driving, shop-
older individuals without dementia ping, and handling finances) can be
(Table 6-3).14Y16 used to screen for prestroke cog-
The clearest circumstance where nitive disabilities.
cerebrovascular disease can be defin- The number, volume, and location
itively related to cognitive impairment of infarcts or hemorrhages is related
is in poststroke vascular cognitive im- to the risk for poststroke cognitive im-
pairment, where there is a clinical pairment. Single, strategic locations
history of stroke, preceded by the ab- have been identified that are associated
sence of cognitive symptoms but im- with poststroke cognitive impairment
mediately followed by cognitive when affected by stroke. 18 These
impairment (Case 6-1). In this case, locations include left hemisphere
the diagnosis of vascular cognitive im- perisylvian language areas, the thala-
pairment is essentially certain. How- mus, midbrain, medial temporal lobe,
ever, a pitfall to avoid is to overlook a and medial frontal lobe. Single strokes
history of prestroke cognitive decline, in these regions can cause cognitive
which, if present, could indicate impairment by affecting brain networks
either a competing neurodegenera- sustaining language, attention, or
tive cause of dementia or a mixed memory. Cognitive impairment may
dementia. Formal questionnaires such also result from the combined effect

TABLE 6-3 Prevalence of Cerebral Small Vessel Disease on Magnetic Resonance Imaging in
the General Population Without Dementiaa

Beginning Microbleedsc
Infarcts Confluent or Confluent Susceptibility-Weighted
White Matter T2*-Weighted Imaging (SWI)/
Age Hyperintensities Gradient Recalled High-Sensitivity
Decade Q1 infarct Q2 infarcts on MRIb Echo (GRE) Sequence
50Y59 5Y8% 1Y2% 1% 3% 12%
60Y69 7Y12% 2Y3% 1Y4% 5Y10% 15Y17%
70Y79 12Y23% 3Y6% 6Y14% 8Y16% 30Y31%
80+ 25Y38% 6Y9% 19% 18% 40%

MRI = magnetic resonance imaging.

a
Data are aggregated from multiple population-based studies.
b
As measured using the Fazekas scale.13
c
As can be seen from the table, susceptibility-weighted imaging (SWI) and other newer, high-sensitivity MRI sequences detect about
twice as many microbleeds as older T2*-weighted gradient recalled echo (GRE) sequences.

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 Vascular Cognitive Impairment

Case 6-1
A 71-year-old woman presented acutely with
confusion, vomiting, left hemianopia, left
hemiparesis, and skew deviation. Head CT was
unremarkable but CT angiography showed that
the basilar artery was occluded due to thrombus
formation on an atherosclerotic plaque. The
patient was treated with IV tissue plasminogen
activator and endovascular thrombectomy. The
patient’s motor and oculomotor findings resolved
after treatment. However, the patient remained
cognitively impaired, with deficits in verbal
learning and recall. Diffusion-weighted MRI showed
acute infarction (bright signal) in the right occipital
and bilateral medial temporal lobes (Figure 6-2).
During follow-up 3 months later, the patient
described symptoms of persistent forgetfulness
that interfered with shopping, finances, and driving.
Poststroke vascular dementia was diagnosed.
Comment. Strategic infarctions in the bilateral
medial temporal lobes caused vascular dementia in
this case. Poststroke dementia has also been FIGURE 6-2 Axial diffusion-weighted MRI of the
patient in Case 6-1 shows acute
associated with infarcts in locations such as the left infarction (bright signal) in the right
perisylvian cortex, medial frontal lobe, or thalamus, occipital and bilateral medial temporal lobes.
or with the presence of multiple cortical infarcts.

KEY POINTS of multiple strokes affecting sufficient based on a pattern of diffuse, severe
h Location, as well as size brain regions, such as the prefrontal cerebrovascular disease.4,5 In most
and severity, must be lobes, involved in cognitive process- cases, nonstroke vascular cognitive
taken into account
ing. This syndrome has been termed impairment is caused by subcortical
when considering the
multi-infarct dementia. By contrast, ischemic cerebral small vessel dis-
cognitive consequences
of infarcts and other
the clinician should generally be scep- ease, also called Binswanger disease
cerebrovascular lesions. tical of relating cognitive impairment (Case 6-2). However, our understand-
to single, small to moderately sized ing of the relationship between the
h The diagnosis of
infarcts in brain regions outside the location, extent, and severity of the ce-
nonstroke vascular
cognitive impairment
aforementioned strategic areas for rebral small vessel disease and the
should be supported cognitive processing. No single vol- resulting clinical syndromes is still in-
by the presence of ume threshold reliably discriminates complete; therefore, only general prin-
diffuse, severe patients with poststroke vascular cog- ciples can be discussed. Silent brain
cerebrovascular disease. nitive impairment versus those with- infarcts and white matter hyperin-
out because the cognitive effects of tensities on MRI predict risk for de-
infarcts and hemorrhages depends on mentia in population-based studies, and
the locations of the lesions as well as silent brain infarcts are associated with
their size. presence of dementia in autopsy-based
Consensus criteria recommend that studies,19Y21 while the relationship of
the diagnosis of nonstroke vascular cerebral microbleeds to cognition is
cognitive impairment should be less clear. Small infarcts in the thalamus

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 Case 6-2
A 65-year-old man presented with cognitive slowing, forgetfulness, and decreased gait speed that he
had experienced for approximately 1 year. He was no longer able to manage his own finances or do
his own shopping. He had a history of poorly controlled hypertension. The patient’s Montreal Cognitive
Assessment (MoCA) score was 14 out of 30. Neurologic
examination showed mild hyperreflexia, a few beats
of clonus at each ankle, and a slow, unsteady gait
with a shortened stride length but nearly normal
base width. Brain MRI showed severe white matter
hyperintensities with multiple lacunae of presumed
vascular origin (Figure 6-3). A diagnosis of probable
vascular dementia caused by hypertensive small
vessel disease was given. Despite initiation of aspirin,
improved blood pressure control, and a trial of
cholinesterase inhibition, progressive cognitive
decline ensued.
Comment. This case is consistent with vascular
dementia due to diffuse subcortical cerebrovascular
pathology, also called Binswanger disease. Despite
the absence of symptomatic stroke, the silent brain
infarcts and white matter hyperintensities appear
to be sufficient to cause cognitive decline. The
relatively young age at onset suggests that Alzheimer
pathology is probably absent. However, the presence
of comorbid Alzheimer pathology cannot be FIGURE 6-3 Axial fluid-attenuated inversion
recovery (FLAIR) MRI of the patient in
completely excluded as amyloid imaging studies in Case 6-2 shows severe white matter
patients with subcortical ischemic dementia show hyperintensities (double arrow) with multiple lacunae
that mixed dementia, with a contribution from of presumed vascular origin (single arrow).
Alzheimer pathology, is relatively common.

may be more likely to affect cognition clinical judgment, have not been stud-
than small infarcts in other locations. ied for their validity in clinical practice.
Higher numbers of infarcts and Promising new MRI techniques not
higher volumes of white matter yet ready for clinical use may, in the
hyperintensities are associated with future, allow better discrimination of
higher risk of cognitive impairment; clinically relevant from less clinically
however, exact thresholds are not relevant cerebrovascular lesions by
well defined and likely vary based on interrogating their impact on brain net-
the location of the lesions. To support a work function. Subcortical infarction
diagnosis of vascular cognitive impair- and ischemic white matter demyelin-
ment, the AHA/ASA recommends that ation are presumed to cause cognitive
‘‘diffuse, subcortical cerebrovascular impairment by disconnecting brain net-
disease pathology’’ should be present,4 works subserving cognition. Recent MRI
while the Vas-Cog Society recommends techniques have demonstrated that
that at least three supratentorial white matter hyperintensities of pre-
brain infarcts or ‘‘extensive and con- sumed vascular origin are associated
fluent’’ white matter hyperintensities with reduced structural brain con-
should be present.5 However, these nectivity measured using diffusion-
recommendations, while useful aids to tensor imaging,22 and that subcortical

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 Vascular Cognitive Impairment

KEY POINTS
h Microinfarcts are a infarction is associated with remote impairment should not be made based
substrate for vascular cortical atrophy in connected areas.23 on neuropsychological profile alone,
cognitive impairment, While neuroimaging remains the but should be supported by other
but are only visible at most useful diagnostic test to link evidence from clinical history, neuro-
autopsy because they are the presence and severity of cerebro- logic examination, and neuroimaging
too small to see on MRI. vascular disease with the presence of that is consistent with vascular cognitive
h Although patients vascular cognitive impairment, the impairment. Nonetheless, neuropsy-
with vascular cognitive clinician must keep in mind that neu- chological testing may be very help-
impairment often roimaging does not have perfect ful when uncertainty exists regarding
exhibit impairments in sensitivity for all clinically relevant the clinical significance of cerebrovas-
executive function and cerebrovascular lesions. Specifically, cular disease by identifying whether
processing speed, other neuroimaging is unable to detect mi- the neuropsychological profile is
cognitive domains may croinfarcts, which are infarcts as small more or less consistent with the iden-
also be affected. as 0.2 mm in diameter that are visible tified cerebrovascular lesions in that
h Motor signs that may at autopsy in approximately one- individual patient. Some vascular cog-
accompany vascular quarter of all deceased elderly but nitive impairment diagnostic criteria
cognitive impairment in up to half of all deceased elderly pa- require specific supportive clinical fea-
include frontal gait tients with dementia.24 These infarcts
disorder, lower body
tures, such as executive dysfunction,
fall below the limit of spatial resolution to be present to diagnose nonstroke
parkinsonism, apathy,
of clinical MRI. About half the time they vascular cognitive impairment,5,7 while
depression, urinary
incontinence, spasticity,
occur in the absence of gross infarcts, others do not.1,4
hyperreflexia, and such that neuroimaging may falsely sug- The clinician’s case for clinically
frontal release signs. gest the absence of infarction. relevant cerebrovascular disease can
When the patient’s neuropsycho- be further strengthened if other mo-
logical profile matches the location tor manifestations of cerebral infarc-
and severity of cerebrovascular dis- tion or hemorrhage are identified
ease, the case for clinically relevant ce- based on history and clinical exam-
rebrovascular disease is strengthened. ination. Noncognitive manifestations
Most commonly, vascular cognitive im- of cerebrovascular disease include
pairment is associated with relatively frontal gait disorder, lower-body par-
greater impairments in executive func- kinsonism, apathy, depression, urinary
tion and processing speed than in incontinence, spasticity, hyperreflexia,
episodic memory for a given level of and frontal release signs.5 Addition-
overall disability.4 By contrast, early AD ally, behavioral disturbances such as
is most often associated with episodic
apathy, depression, and emotional in-
memory impairment.25 However, it is
continence are frequent as well.5 The
important to recognize that some de-
presence of these signs, in the absence
gree of memory impairment is very
of competing nonvascular causes, sug-
common in vascular cognitive impair-
gests symptomatic cerebrovascular dis-
ment as well.4 Furthermore, the clini-
ease with the implication that the
cian should be aware that there can be
cerebrovascular disease could also be
great variety in the spatial distribution
affecting cognition.
and severity of cerebrovascular disease,
which determines the neuropsycholog-
ical profile. Therefore, there is no one Nonatherosclerotic and
uniform pattern of neuropsycho- Nonarteriolosclerotic Causes of
logical impairment in all patients with Vascular Cognitive Impairment
vascular cognitive impairment. For this The next sections review two impor-
reason, a diagnosis of vascular cognitive tant causes of vascular cognitive

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impairment unrelated to the conven- the basis for clinical diagnosis during
tional vascular factors that cause ath- life (Table 6-4).27
erosclerosis and arteriolosclerosis: The diagnosis of cerebral amyloid
cerebral amyloid angiopathy and angiopathy is greatly aided by the use
monogenic inherited cerebrovascu- of MRI with hemorrhage-sensitive
lar diseases. sequences such as susceptibility-
Cerebral amyloid angiopathy. Ce- weighted imaging (SWI), which allows
rebral amyloid angiopathy is caused demonstration of microbleeds caused
by vascular "-amyloid deposition in by cerebral amyloid angiopathy. Posi-
the cerebral cortex and leptomeninges, tron emission tomography (PET) am-
leading to fragility of the vessel wall yloid tracers bind to vascular amyloid
with rupture and bleeding in some as well as senile plaques, and, there-
patients. 26 Cerebral amyloid angi- fore, cannot be used to distinguish be-
opathy is the second most common tween vascular and parenchymal
cause of intracerebral hemorrhage amyloid deposits.
in elderly patients, after hypertensive Cerebral amyloid angiopathy and
vasculopathy. Because vascular amyloid AD exist on a spectrum. Most pa-
tends to spare the arteries supplying tients with AD have some amount of
the internal part of the brain, cerebral vascular amyloid, although compared
amyloid angiopathyYrelated hemor- to patients with cerebral amyloid
rhages predominately occur in the super- angiopathyYrelated hemorrhage, the
ficial, lobar portions of the cortex and deposits are more likely to be around
underlying white matter, or in the capillaries than within the walls of
adjacent subarachnoid space, with arterioles. Patients with AD rarely have
sparing of the basal ganglia and the hemorrhagic strokes, although the
brainstem. This lobar pattern of hem- frequency of microbleeds is higher
orrhages and superficial siderosis forms than in non-AD controls. Conversely,

TABLE 6-4 Modified Boston Criteria for Cerebral Amyloid

Angiopathy–Related Hemorrhagea

Probable Cerebral Amyloid Angiopathy

1. Age Q55
2. Either multiple hemorrhages restricted to lobar, cortical, or
cortico-subcortical regions (cerebellar hemorrhage allowed) OR single
lobar, cortical, or cortico-subcortical hemorrhage and focal or
disseminated superficial siderosis
3. Absence of other cause of hemorrhage or superficial siderosis
Possible Cerebral Amyloid Angiopathy
1. Age Q55
2. Either single lobar, cortical, or cortico-subcortical hemorrhage OR focal
or disseminated superficial siderosis
3. Absence of other cause of hemorrhage or superficial siderosis
a
Modified with permission from Linn J, et al, Neurology.27 www.neurology.org/content/74/17/
1346.short. B 2010 American Academy of Neurology.

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 Vascular Cognitive Impairment

KEY POINTS
h Cerebral amyloid most patients with cerebral amyloid cause vascular cognitive impairment
angiopathy is an angiopathy do not have AD dementia. include cerebral autosomal recessive
important cause of Community-based autopsy studies arteriopathy with subcortical infarcts
vascular cognitive show that cerebral amyloid angiopathy and leukoencephalopathy (CARASIL)
impairment, with effects is associated with cognitive impair- (a CADASIL-like disease caused by
that are independent ment and risk for dementia, even mutations in HTRA1) and mutations
of the degree of after accounting for the association in the COL4A1 gene.31
accompanying Alzheimer between cerebral amyloid angiopathy
disease pathology. and AD (Case 6-3).28 Controlling for PREVALENCE, NEUROPATHOLOGY,
h Cerebral autosomal the degree of coexisting Alzheimer AND RELATIONSHIP TO OTHER
dominant arteriopathy pathology, cerebral amyloid angiopathy NEURODEGENERATIVE DISEASES
with subcortical was associated with worse episodic Both clinical and autopsy data show
infarcts and
memory and perceptual speed.29 These that vascular cognitive impairment is
leukoencephalopathy is
the most common
cognitive impairments could be caused the second most common cause of
inherited monogenic by cerebral amyloid angiopathyY later life dementia, after AD. Specialty-
cause of vascular related microinfarction, ischemic clinicYbased studies show that vascular
cognitive impairment. white matter demyelination, impaired cognitive impairment is the diagnosis
h Vascular cognitive vascular reactivity, or the cumulative in about 10% of patients, while mixed
impairment is the effects of hemorrhages.30 There are dementia with a vascular component,
second most common no disease-modifying treatments for often in combination with AD, is the
cause of cognitive cerebral amyloid angiopathy. diagnosis in a similar or even greater
impairment and Monogenic inherited causes of proportion of cases.32 Epidemiologic
frequently coexists with vascular cognitive impairment. The studies are generally consistent with
other neurodegenerative presence of confluent white matter the clinic-based studies in showing
pathologies as hyperintensities or multiple lacunae that vascular dementia is the second
mixed dementia.
in excess of that expected by age most common cause of dementia.33
and not explained by conventional However, exact numbers on incidence
vascular risk factors should prompt and prevalence are difficult to estab-
consideration of an inherited cause lish because the different vascular de-
of vascular cognitive impairment, par- mentia criteria appear to vary in their
ticularly when a family history is sensitivity and specificity, inhibiting
present.31 The inherited cause of cross-cohort comparisons.
va scul ar cognitiv e impairment, Autopsy-based neuropathology
which is the most commonly en- studies of prevalence have a number
countered and best studied, may of advantages over clinic-based stud-
be cerebral autosomal dominant ies. The autopsy allows quantitative
arteriopathy with subcortical infarcts or semiquantitative measurement of
and leukoencephalopathy (CADASIL). cerebrovascular lesions difficult to
CADASIL is an autosomal dominant identify on in vivo imaging, such as
disease caused by mutations in the microinfarction, and allows quantita-
NOTCH3 gene. Affected patients de- tive assessment of comorbid patholo-
velop migraine, lacunar stroke, and gies such as neurofibrillary tangles,
then vascular cognitive impairment amyloid plaques, and Lewy bodies.
due to the cumulative effects of mul- Ideally, neuropathology studies would
tiple lacunar infarcts and extensive be nested within community repre-
white matter hyperintensities. There sentative samples and have a high
are no disease-modifying treatments. degree of participation in the au-
Other inherited diseases that can topsy arm to avoid the referral and

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 Case 6-3
A 73-year-old man was seen for forgetfulness and apathy that had been present for approximately
2 years. Activities of daily living were essentially preserved, with the exception of occasional minor
errors such as purchasing incorrect items at the grocery store. The patient’s Montreal Cognitive
Assessment (MoCA) score was 24 out of 30. Scores on the Trail Making B test and a test of verbal
recall were one standard deviation below the mean compared to normative values. Brain MRI
showed six microbleeds on the gradient recalled echo (GRE) sequence, all in lobar locations
(Figure 6-4A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery
(FLAIR) sequence (Figure 6-4B). Fluorodeoxyglucose positron emission tomography (FDG-PET)
scan showed patchy hypometabolism, including in brain regions with microbleeds. However,
metabolism in the posterior cingulate gyrus, a region typically affected by Alzheimer disease,
was preserved, suggesting that Alzheimer disease was probably not the cause of the cognitive
impairment. A diagnosis of probable vascular mild cognitive impairment was given, with cerebral
amyloid angiopathy as the most likely vascular cause. Over the next 2 years, the patient progressed
to mild dementia, with an essentially unchanged FDG-PET scan. Two years after the initial
presentation, the patient had a right parietal intracerebral hemorrhage (Figure 6-4C), typical of
cerebral amyloid angiopathy.

FIGURE 6-4 Axial MRI of the patient in Case 6-3 shows six microbleeds on the gradient recalled echo (GRE) sequence, all
in lobar locations (A), and severe white matter hyperintensities on the fluid-attenuated inversion recovery
(FLAIR) sequence (B). Two years after initial presentation, the patient had a right parietal intracerebral
hemorrhage (C), typical of cerebral amyloid angiopathy.

Comment. Probable cerebral amyloid angiopathy was diagnosed in this case on the basis of
the Boston criteria (Table 6-4), which indicate that cerebral amyloid angiopathy is highly probable
in patients with a lobar intracerebral hemorrhage and MRI evidence of one or more microbleeds
restricted to lobar locations. Patients with multiple lobar-only microbleeds, without hemorrhagic
stroke, are also likely to have cerebral amyloid angiopathy, although the Boston criteria have not
been validated in this setting. Neuropathology studies show that more severe cerebral amyloid
angiopathy is a predictor of cognitive impairment, controlling for the degree of accompanying
Alzheimer pathology.

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 Vascular Cognitive Impairment

KEY POINTS
h Vascular cognitive selection bias that may affect clinic- actions between these most common
impairment accounts based studies. pathologies of dementia. This interest
for up to one-third of Cerebrovascular lesions commonly has been heightened by recent obser-
dementia risk. measured at autopsy include infarcts, vations that sporadic AD is associated
h Patient and caregiver hemorrhages, arteriolosclerosis, and with a failure of soluble amyloid-" (A")
support to maintain atherosclerosis. Microinfarcts, which clearance37 and that soluble A" can
quality of life and may be the most clinically relevant exit the brain through vascular and
prolong community vascular neuropathologic lesion, can perivascular clearance pathways.38 How-
living are important be identified on histology but are ever, autopsy studies generally show
aspects of vascular usually not visible grossly or on in that the burden of cerebrovascular and
cognitive impairment vivo MRI.24 Conversely, it is impor- Alzheimer pathology are independent
management. tant to recognize that some lesions of one another and that effects on
readily visible on MRI, such as mi- the odds of dementia are additive, not
crobleeds, may be hard to find at multiplicative.39 Thus, interactions be-
autopsy and that MRI white matter tween cerebrovascular and Alzheimer
hyperintensities, which have such a pathology seem to be in their com-
dramatic appearance on MRI, are bined effects on brain cellular and net-
difficult to visualize at autopsy with- work function, and not because one
out special stains and, therefore, can disease directly causes the other; how-
be overlooked. ever, note that this observation does
Vascular pathology is extremely not exclude a role for variance in (non-
common at time of death, both in diseased) vascular clearance of A" in
persons with and without dementia, the pathogenesis of AD.
being present in roughly 80% of
brains overall.34 By comprehensively
MANAGEMENT OF VASCULAR
measuring both vascular as well as
COGNITIVE IMPAIRMENT
comorbid neurodegenerative pathol-
ogies it is possible to estimate, in an Management of vascular cognitive im-
unbiased and objective manner, the pairment may be categorized as pa-
relationship between vascular pathol- tient and caregiver support, cognitive
ogies and risk for dementia in rehabilitation for poststroke vascular
community-based studies, while simul- cognitive impairment, consideration of
taneously controlling for other pathol- cognitive enhancing medications, and
ogies. Using this approach, autopsy treatment and secondary prevention
studies consistently show that vascu- of the causative cerebrovascular pro-
lar pathology, mostly consisting of man- cess. Recommendations for the man-
ifestations of cerebral small vessel a g e m e n t of vascular c ogni tive
disease such as small infarcts, indepen- impairment have been published by
dently predicts the risk of dementia the AHA/ASA.4
even when accounting for Alzheimer Personal and caregiver support
and Lewy body pathology. These data should follow general principles of
suggest that vascular pathology ac- management for patients with MCI
counts for roughly one-quarter to or dementia and should include
one-third of dementia risk.35,36 assessments of driving safety, safety
The frequent co-occurrence of in the home, financial and medical ad-
Alzheimer and vascular pathology with vanced planning, management of
deleterious effects on cognition has neuropsychiatric complications, and
raised scientific interest in whether palliative care, as appropriate for the
there are deeper, fundamental inter- individual patient.40

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 KEY POINTS
For patients with poststroke vascular Table 6-2. Many vascular diseases can h Acetylcholinesterase
cognitive impairment, cognitive re- be prevented or their progression inhibitors have a
habilitation may speed or improve re- can be slowed by existing therapies modest beneficial
covery. Many patients with poststroke proven effective by randomized con- effect in vascular
vascular cognitive impairment will ex- trolled trials. With adequate control cognitive impairment.
perience improvements in cognition, or of vascular risk factors, it may be h The most important
even resolution of cognitive deficits, possible to reduce the rate of progres- component of vascular
during the stroke recovery process. sion of vascular cognitive impair- cognitive impairment
Cognitive rehabilitation may include ment or even arrest any progression, management is
training for compensatory strategies or as long as comorbid neurodegener- identifying and
cognitive skills training.41 ative pathologies are not also present treating the underlying
Randomized controlled trials of cho- and symptomatic. For patients with cerebrovascular
processes that lead to
linesterase inhibitors show that they poststroke vascular cognitive impair-
brain injury.
have a modest benefit in patients with ment, stroke recurrence is a strong
vascular dementia, including in mixed risk factor for cognitive worsening or h Patients with vascular
vascular and AD dementia.4 The AHA/ cognitive impairment
onset of new dementia.
with stroke should be
ASA and Canadian Best Practice Rec- For patients with ischemic stroke,
treated according to
ommendations for Stroke Care recom- diagnosis of the causes and manage- secondary prevention
mend consideration of cholinesterase ment of risk factors should be done guidelines for stroke.
inhibitor therapy with intermediate- according to ischemic stroke second-
level evidence.4,41 The 2012 Canadian ary prevention guidelines from the
Consensus Conference on the Di- AHA/ASA.43 For patients with intrace-
agnosis and Treatment of Dementia rebral hemorrhage, diagnosis and man-
recommends that cholinesterase in- agement of risk factors should be done
hibitor therapy should be considered according to intracerebral hemorrhage
in patients with AD with concomi-
guidelines.44 Hypertension is the stron-
tant cerebrovascular disease, with
gest risk factor for stroke overall and
intermediate-level evidence, but that
for each main stroke type individually,
there is insufficient evidence to rec-
and therefore warrants careful atten-
ommend cholinesterase inhibitor
therapy for patients with pure vascu- tion to achieve adequate blood pres-
lar dementia. 4 2 Donepezil and sure control.
galantamine are the best-studied cho- The management of patients with
linesterase inhibitors.4 The benefits of nonstroke vascular cognitive impair-
memantine are not well established.4 ment, which is predominantly caused
This author frequently uses acetylcho- by cerebral small vessel disease, is less
linesterase inhibitors in patients with certain and lacks evidence from ran-
progressive probable or possible vas- domized trials. The most common
cular dementia, particularly when a cause of cerebral small vessel disease
contribution from comorbid AD can- is arteriolosclerosis due to aging and
not be excluded. vascular risk factors such as hyperten-
Perhaps the most important part of sion and diabetes mellitus. However,
management of vascular cognitive im- cerebral amyloid angiopathy is an im-
pairment is the identification of the portant alternative cause in a minority
causative cerebrovascular processes of patients.45 This author suggests
and initiation of secondary prevention that patients with arteriosclerotic cere-
strategies to prevent their progression bral small vessel disease should have
or recurrence. A list of causes of vas- measurement of blood pressure, an
cular cognitive impairment is shown in ECG to assess for atrial fibrillation,
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 Vascular Cognitive Impairment

KEY POINT
h Careful control of measurement of serum lipid profile, arm, but only in patients with severe
vascular risk factors and measurement of either fasting hyperintensities at baseline.49 A limita-
may be an important blood glucose or glycosylated hemo- tion of all of these trials is that the
component of globin A1c to assess for diabetes mel- sample sizes were not large enough to
dementia prevention. litus. More intensive investigations link slowing of white matter hyperin-
for proximal sources of embolism, tensity progression with reduction in
such as echocardiography, prolonged clinical end points such as cognitive
cardiac rhythm monitoring for atrial decline or stroke.
fibrillation, and noninvasive carotid im-
aging for carotid-territory infarcts, PREVENTION OF VASCULAR
should be considered in patients with COGNITIVE IMPAIRMENT
infarcts that could be of embolic ori- Improved population control of vas-
gin, such as cortical infarcts, but may cular risk factors is one of the most
not be necessary in patients with only promising approaches to dementia
small subcortical infarcts likely caused prevention. Stroke and cardiovascular
by intrinsic small vessel disease. mortality has been declining for sev-
There are no proven therapies for eral decades, probably partly related
prevention of cognitive decline in pa- to better control of vascular risk fac-
tients with cerebral small vessel dis- tors as well as better acute manage-
ease.45 Secondary prevention should ment. There is emerging evidence
focus on addressing the vascular risk that the age-standardized incidence
factors identified in the diagnostic of dementia is declining, but the
workup. It is reasonable to start aspirin degree to which this declining inci-
in patients with silent brain infarcts, dence can be attributed to better
and this treatment may also be con- vascular risk factor control is un-
sidered in patients with extensive, con- known.50 The Finnish Geriatric Inter-
fluent white matter hyperintensities. vention Study to Prevent Cognitive
When considering indications for Impairment and Disability (FINGER)
statin therapy, it is not proven whether study randomly assigned participants
cerebral small vessel disease should be to a vascular risk factor control reg-
considered an atherosclerotic disease imen as part of a multidomain ap-
equivalent; therefore, the use of statins proach to dementia prevention and
may be considered on a case-by-case found that the multidomain interven-
basis in individual patients, particularly tion, which also included diet, exer-
when there is hypercholesterolemia. cise, and cognitive training, prevented
White matter hyperintensity progres- decline in cognitive test scores.51
sion has been evaluated as a secondary
end point in several randomized con- CONCLUSION
trolled trials. Progression is probably Vascular cognitive impairment is the sec-
slowed by good blood pressure con- ond most common cause of dementia
trol46 but was not slowed by intensive and is a frequent contributor to mixed
glucose management (to glycosylated dementia. All patients with cognitive
hemoglobin A1c level of less than impairment should be assessed for
6.0%),47 with mixed results for two contributing vascular causes. The di-
trials of statin therapy.48 A single trial of agnostic approach should be based on
homocysteine-lowering vitamin therapy identifying cognitive impairment,
showed less MRI white matter hyper- identifying vascular disease, including
intensity progression in the treatment clinically hard-to-recognize cerebral
506 www.ContinuumJournal.com April 2016

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small vessel disease on neuroimaging, 9. Petersen RC. Mild cognitive impairment.
Continuum (Minneap Minn) 2016;
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10. Nasreddine ZS, Phillips NA, Bedirian V, et al.
Vascular cognitive impairment should The Montreal Cognitive Assessment, MoCA:
be classified into poststroke and non- a brief screening tool for mild cognitive
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 Review Article

Rapidly Progressive
Address correspondence to
Dr Michael D. Geschwind,
University of California,

Dementia
San Francisco, Memory and
Aging Center, Box 1207,
San Francisco, CA 94143-1207,
[email protected].
Relationship Disclosure: Michael D. Geschwind, MD, PhD
Dr Geschwind serves on the
board of directors for San
Francisco Bay Area Physicians
for Social Responsibility and ABSTRACT
serves as a consultant for
Advance Medical, Best Purpose of Review: This article presents a practical and informative approach to
Doctors Inc, the Franciscan the evaluation of a patient with a rapidly progressive dementia (RPD).
Physician Network, the Recent Findings: Prion diseases are the prototypical causes of RPD, but reversible
Gerson Lehrman Group Inc,
Lewis Brisbois Bisgaard & causes of RPD might mimic prion disease and should always be considered in a
Smith LLP, MEDACorp, and differential diagnosis. Aside from prion diseases, the most common causes of RPD are
Quest Diagnostics. Dr atypical presentations of other neurodegenerative disorders, curable disorders includ-
Geschwind receives personal
compensation as a speaker for ing autoimmune encephalopathies, as well as some infections, and neoplasms. Nu-
grand rounds lectures and merous recent case reports suggest dural arterial venous fistulas sometimes cause RPDs.
receives research/grant Summary: RPDs, in which patients typically develop dementia over weeks to months,
support from Cure PSP, the
Michael J. Homer Family require an alternative differential than the slowly progressive dementias that occur over
Fund, the National Institute a few years. Because of their rapid decline, patients with RPDs necessitate urgent
on Aging, Quest Diagnostics, evaluation and often require an extensive workup, typically with multiple tests being
and the Tau Consortium.
Unlabeled Use of
sent or performed concurrently. Jakob-Creutzfeldt disease, perhaps the prototypical
Products/Investigational RPD, is often the first diagnosis many neurologists consider when treating a patient
Use Disclosure: with rapid cognitive decline. Many conditions other than prion disease, however,
Dr Geschwind reports
no disclosure.
including numerous reversible or curable conditions, can present as an RPD. This chapter
* 2016 American Academy discusses some of the major etiologies for RPDs and offers an algorithm for diagnosis.
of Neurology.
Continuum (Minneap Minn) 2016;22(2):510–537.

INTRODUCTION domain with functional impairment) in

Neurologists generally are familiar with less than 1 to 2 years, although most
the differential diagnoses of slowly pro- occur over weeks to months. This
gressive neurodegenerative dementias, article presents some of the major
many of which are discussed individ- adult-onset causes of RPDs and pro-
ually in this issue of Continuum. The poses some diagnostic algorithms.
general approach to a patient with de-
mentia is discussed in the article ‘‘The FINDINGS FROM
Mental Status Examination in Patients JAKOB-CREUTZFELDT DISEASE
With Suspected Dementia’’ by Murray AND RAPIDLY PROGRESSIVE
Grossman, MD, FAAN, and David J. Irwin, DEMENTIA REFERRAL CENTERS
MD,1 in this issue of Continuum, but Perhaps the prototypical RPDs are prion
the diagnosis of rapidly progressive de- diseases, such as Jakob-Creutzfeldt dis-
mentias (RPDs) entails a different diag- ease, which was covered in detail in the
nostic approach. Although there is no article ‘‘Prion Diseases’’ by Michael D.
clear definition for the time frame of Geschwind, MD, PhD,2 in the December
an RPD, the author typically uses the 2015 Continuum issue and thus is not
term to refer to conditions that progress discussed in detail in this article. (As
from onset of first symptom to demen- discussed in the December 2015 arti-
tia (decline in more than one cognitive cle, Jakob-Creutzfeldt disease was
510 www.ContinuumJournal.com April 2016

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commonly referred to for many decades suspected prion disease cases have
as Jakob or Jakob-Creutzfeldt disease been referred to the RPD program and
until Clarence J. Gibbs, a prominent dementia clinic at the University of
researcher in the field, started using California, San Francisco (UCSF). The
the term Creutzfeldt-Jakob.3 However, distribution of diagnoses for these
only two of five of Jakob’s cases and referrals through June 1, 2015, is shown
not even Creutzfeldt’s case had what in Figure 7-1A.5,6 Of all RPD cases re-
we would now consider prion disease. ferred to the UCSF center (Figure 7-1A),
Thus, in the author’s opinion, the about one-fourth came in person for
disease should be called Jakob or an inpatient or outpatient evaluation
Jakob-Creutzfeldt disease,4 which is (Figure 7-1B); for those patients not
what this article uses to discuss the evaluated in person, a detailed records
disease.) Many patients referred to review was conducted and communi-
various national prion referral centers cated with the families, patients, or
with suspected Jakob-Creutzfeldt disease their physicians. As a center with ex-
turn out not to have prion disease. Over pertise in prion diseases, there is a re-
the past 14 years, more than 2500 ferral bias toward these diagnoses.

FIGURE 7-1 Major diagnostic categories of patients with rapidly progressive dementia (RPD)
referred to, versus evaluated at, the University of California, San Francisco (UCSF)
rapidly progressive dementia program over 13 years. A, Diagnostic distribution
of patients with RPD referred to UCSF over about a 13-year period, most of whom had
extensive medical record review, but only about one-fourth of whom were evaluated in
person at UCSF. Almost one-third of cases referred to (as well as evaluated at) UCSF were
diagnosed with sporadic Jakob-Creutzfeldt disease. In more than one-fourth of referred cases,
although a sporadic Jakob-Creutzfeldt disease diagnosis (potential sporadic Jakob-Creutzfeldt
disease) was suspected, not enough information existed to make a probable Jakob-Creutzfeldt
disease diagnosis.5,6 Acquired Jakob-Creutzfeldt disease includes iatrogenic and infectious
forms of prion disease. The genetic prion diseases category included patients who had
confirmed mutations (autosomal dominant) in the prion protein gene, PRNP, or were from
families with genetic prion disease. Whereas many of the genetic prion diseases presented
similarly to sporadic Jakob-Creutzfeldt disease, as an RPD, a significant minority had clinical
presentations more similar to other more slowly progressive diseases, such as Alzheimer disease
or atypical parkinsonian or ataxic syndromes.2 One-fourth of cases were diagnosed with a
nonprion etiology for their RPD. B, Diagnostic distribution of patients with RPD evaluated in
person at UCSF. A larger percentage of nonprion RPDs and genetic prion diseases is evident;
the latter is a bias partly because of the UCSF research program in genetic prion diseases and
antibody-mediated encephalopathies.
JCD = Jakob-Creutzfeldt disease.

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 Rapidly Progressive Dementia

KEY POINT
h In most larger rapidly At the UCSF center, the nonYJakob- by Deborah L. Renaud, MD,10 in this issue
progressive dementia Creutzfeldt disease/nonYprion disease of Continuum. Despite CSF pleocytosis
series, the most group comprises 25% of all referrals being extremely rare in prion disease,
common causes of (both records review or in-person eval- several patients with meningoencepha-
rapidly progressive uation) and 44% of those evaluated in litis were referred as suspected Jakob-
dementia are nonprion person. Figure 7-1B shows the diag- Creutzfeldt disease; in only a few patients
neurodegenerative
nostic distribution for the subset of with encephalitis was the agent identi-
diseases, prion diseases,
referred patients who were evaluated fied (human immunodeficiency virus
and autoimmune/
antibody-mediated in person at our center over about the [HIV], Lyme disease, and enterovirus).5
encephalopathies. past 13 years. Many cases referred for In the German center publication, 34%
potential sporadic Jakob-Creutzfeldt of patients initially suspected of having
disease were found to have nonprion Jakob-Creutzfeldt disease by referring
diagnoses when evaluated in person at physicians were ultimately found by
our center.5 pathology or clinical follow-up to have
Table 7-1 shows the types of diag- other diagnoses. Importantly, many pa-
noses of nonprion RPDs referred to tients had not only treatable, but po-
UCSF, the German Jakob-Creutzfeldt tentially reversible conditions.
disease surveillance unit, and the US In the United States, to help monitor
National Prion Disease Pathology Sur- for potential new forms of human prion
veillance Center (NPDPSC), based on disease, the Centers for Disease Control
publications from these three major and Prevention funds the NPDPSC to
prion referral centers.7,8 The UCSF perform brain autopsies on all referred
cohort was during an approximately suspected prion cases. In an important
8-year period and includes some pre- study, they reviewed 1106 autopsies
viously published cases.5 In many cases, performed over about a 10-year period
for those in whom prion disease was
Jakob-Creutzfeldt disease was sus-
not identified (N = 352). Among the
pected by the referring physicians.
304 in whom they confirmed another,
Overall, the most common nonprion
nonprion pathologic diagnosis, 73% had
RPD diagnostic categories were non-
what they deemed as ‘‘untreatable’’ con-
prion neurodegenerative diseases. Neu-
ditions, but 23% had ‘‘treatable’’ (po-
rologic autoimmune conditions were
tentially curable) dementias.8 Of the
very common even in some of these
71 ‘‘treatable’’ cases they identified,
cohorts, which are a few years old, 37% were immune mediated, 35% were
predating the discovery of some of the neoplasms, 20% were infections, and
more recently discovered antibodies 8% were metabolic disorders.8 Although
associated with autoimmune encepha- one advantage of this study from the
lopathies. It is likely that antibody- NPDPSC is that all cases were autopsy
mediated encephalopathies today are proven, this is also a shortcoming as
an even larger percentage of nonprion they do not include patients with RPD
RPDs than shown in Table 7-1. Several who did not die or did not come to
patients from the UCSF center had autopsy. This study also would not
leukoencephalopathies of unclear eti- include RPD cases diagnosed premor-
ology. For reviews of these disorders, tem or those who might have recovered
refer to the article ‘‘Autoimmune En- (from treatment or other reasons).
cephalopathies and Dementias’’ by Two retrospective studies examined
Andrew McKeon, MD,9 and to the article the causes of RPD in patients admit-
‘‘Adult-Onset Leukoencephalopathies’’ ted to two European tertiary medical

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TABLE 7-1 Diagnostic Breakdown of Non–Jakob-Creutzfeldt Disease Rapidly Progressive
Dementia Referrals to Three Jakob-Creutzfeldt Disease Referral Centersa

University of California, National Prion Disease Pathology

San Francisco (UCSF), German Cohort7 Surveillance Center (NPDPSC)
Cohort N = 104 (21)b % N = 124 (37)b % Cohort8 N = 304 (304)b %
c
Autoimmune/antibody-mediated 13 Alzheimer disease 27 Alzheimer disease 51
Unclassified dementia 13 Unclassified dementia 16 Vascular disease 12
Psychiatric 12 Cerebrovascular (vascular 9 Immune mediated 9
dementia, cerebrovascular
accident)
Dementia with Lewy bodies 8 Encephalitis, unknown 8 Neoplasia 8
Encephalitis, not otherwise specified 8 Parkinson disease 5 Infections 5
Neoplasm 8 Psychiatric 5 Unspecified degenerative disease 3
Frontotemporal dementia with or 7 Motor neuron disease 2 Frontal lobe degeneration 3
without motor neuron disease
Corticobasal syndrome or 6 Multiple sclerosis 2 Metabolic 2
corticobasal degeneration
Alzheimer diseased 5 Paraneoplastic 2 Hippocampal sclerosis 2
Central nervous system vasculitis 3 Toxicity 2 Dementia with Lewy bodies 1
Encephalopathy, not otherwise 3 Alcohol induced 2 Tauopathy, not otherwise specified 1
specified
Leukoencephalopathy 3 Brain tumor 2 Hereditary diffuse leukoencephalopathy 1
with spheroids
Progressive supranuclear palsy 3 Chronic epilepsy 2 Progressive supranuclear palsy 1
e
Vascular dementia 2 Corticostriatonigral 2 Other 2
degeneration
Othere 8 Familial spastic paraplegia 2 Total 100
Total 100 Hashimoto encephalopathy 2

Hereditary ataxia 2
Huntington disease 2
Metabolic disorder 2
Primary central nervous 2
system lymphoma
Othere 4
Total 100

a
If only a single case of any given condition presented to a cohort, it was placed under ‘‘other.’’
b
Numbers in parentheses indicate the number of pathology-proven cases.
c
Includes antiYvoltage-gated potassium channel complex, glutamic acid decarboxylase (GAD65), Yu, Hu, CV2, adenylate kinase5, "-amino-3-
hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptor, glial, neuropil, and other antibodies as well as Hashimoto encephalopathy.
d
Includes two cases of mixed Alzheimer disease with Lewy bodies.
e
Other UCSF cohort cases include hydrocephalus, mesial temporal sclerosis, vertigo, germinoma, methylmalonic acidemia, multiple sclerosis,
methotrexate toxicity, and pathology-proven sarcoid. Other German cohort cases include leukoencephalopathy, amyloid angiopathy, fatal
familial insomnia, hypoxia, and Niemann-Pick lipoid histiocytosis. Other NPDPSC cohort cases include corticobasal degeneration, adult
polyglucosan body disease, Huntington disease, Marchiafava-Bignami disease, and superficial siderosis.

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 Rapidly Progressive Dementia

centers (Table 7-2).11,12 In the first, at Lewy bodies [DLB], Parkinson disease
a tertiary referral center in Greece, dementia, progressive supranuclear
RPD was defined as progression to palsy, and corticobasal syndrome). Sec-
dementia from first symptom onset in ondary dementias included four patients
less than 1 year. The authors of this with normal pressure hydrocephalus,
study also excluded cases with acute two with neurosyphilis, and one each
cognitive impairment in the context of with scleroderma, sarcoidosis, system-
a confusional state due to acute infec- atic lupus erythematosus, central ner-
tious, metabolic, or toxic causes (eg, vous system (CNS) primary vasculitis,
acute viral encephalitis, acute hy- limbic encephalitis, HIV encephalitis,
ponatremia, hypoglycemia, and recent CNS tumor, Q fever, vitamin B12 defi-
use of anticholinergic drugs). Over a ciency, multiple sclerosis, drug-
3-year period, they identified 68 sub- induced dementia, and dementia in
jects with RPD meeting their criteria. the context of chronic psychosis. The
The largest single category were non- mean age at onset T standard devia-
prion neurodegenerative diseases tion (SD) was 65.5 T 10.0 (median
(47.1%), followed by secondary de- 66.7; range 35.3 to 82.8) years of age.
mentias (26%). Some of the larger For nonYJakob-Creutzfeldt disease
single diagnoses were Alzheimer dis- causes, the mean time to dementia
ease (AD) (17.6%), followed by front- was about 8 (range 1 to 11) months,
otemporal dementia (FTD) (16.2%), but for Jakob-Creutzfeldt disease it
and equally represented (among was 3 (range 1 to 5) months.11
13.2% of the cohort) vascular demen- The second retrospective study
tia, Jakob-Creutzfeldt disease, and vari- reviewed all admissions for RPD
ous other neurodegenerative diseases from 1994 to 2009 at a major hospital
(multiple system atrophy, dementia with in Barcelona, Spain (Table 7-2).12 The

TABLE 7-2 Causes of Rapidly Progressive Dementia in Two European

Tertiary Care Hospitals

Athens Cohort11 Diagnoses Barcelona Cohort12 Diagnoses

(N = 68) % (N = 49) %
Alzheimer disease 17.6 Jakob-Creutzfeldt disease 30.6
Other secondary dementias 17.6 Other secondary dementias 18.4
Frontotemporal dementia 16.2 Alzheimer disease 14.3
Jakob-Creutzfeldt disease 13.2 Frontotemporal dementia 12.2
Vascular dementia 13.2 Dementia with Lewy bodies 10.2
Dementia with Lewy bodies 5.9 Vascular dementia 8.2
Normal pressure hydrocephalus 5.9 Unknown 6.1
Multiple system atrophy 2.9 Total 100
Neurosyphilis 2.9
Other neurodegenerative 4.4
dementias
Total 100

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study authors applied similar diagnos- tory is a critical first step to the evalua-
tic criteria to the study from Athens, tion of an RPD. It is important to rule
Greece.11 Among 49 subjects identified, out delirium in any initial evaluation.
similar to the Athens study, the largest The first symptoms of a dementia can
group was nonprion neurodegenerative help with diagnosis. This is particularly
diseases (36.8%), but Jakob-Creutzfeldt true of the neurodegenerative demen-
disease was the second most common tias, which often start in specific neu-
(30.6%), followed by secondary de- roanatomic regions.13,14 Autoimmune
mentias (18.4%). Regarding the distri- encephalopathies early on often affect
bution of each of the nonprion the limbic system and, thus, typically
neurodegenerative diseases in the present with memory loss or behavioral
cohort, 14% were AD, 12% were FTD, changes. Viral encephalopathies or
and 10% were DLB. The percent due acute demyelinating encephalomyelitis
to vascular disease was 8.25%, not too may be preceded by a flulike illness.
dissimilar from the Athens cohort.11 The evaluation of an RPD typically
The mean age of onset was 72.4 T occurs in stages in which several tests
11.6 (range 41 to 86) years of age, and are performed in parallel. For an initial
the time from onset to evaluation was RPD evaluation, recommended blood,
4.6 T 3.8 (range 1 to 12) months. urine, CSF, imaging, and other tests are
Among the 19 cases followed to death, shown in Table 7-3.15 Not all of these
mean survival time was 8.6 T 9.5 months tests will need to be done, depending
overall, but the prion cases had signif- on the clinical scenario and the results
icantly shorter survival than the non- of tests that have already returned.
prion cases, of 3.3 T 2.4 (range 1 to 8) Ruling out a simple metabolic per-
versus 14 T 11.1 (range 5 to 34) turbation or infection is particularly im-
months (P=0.04).12 portant, especially in more susceptible
persons, such as elderly patients or
DIAGNOSTIC APPROACH those with a preexisting mild dementia
TO RAPIDLY PROGRESSIVE or cognitive impairment, as these pa-
DEMENTIAS tients sometimes experience a rapid
The diagnostic approach for evaluat- decline in these circumstances. Simple
ing standard dementia has been pres- blood tests and urine analysis, to rule
ented in the article ‘‘The Mental Status out common toxic-metabolic causes,
Examination in Patients With Suspected should be done. If seizures (including
Dementia’’ by Murray Grossman, MD, nonconvulsive status epilepticus) are
FAAN, and David J. Irwin, MD,1 in this possible, an EEG should be performed.
issue of Continuum. For evaluating pa- Brain imaging usually is done prior to
tients with RPDs, many of the same CSF analysis as it might direct what CSF
principles apply, but because of the tests are sent, as well as rule out a space-
rapidity of decline, and as many causes occupying lesion. Certain treatable or
of RPD are treatable, it is essential to reversible conditions, such as autoim-
have a systematic, comprehensive ap- mune diseases, HIV, or other infections,
proach to the diagnostic plan. depending on the geographic location,
should always be considered. HIV can
Initial Evaluation of a Rapidly occur in anyone; there should be a low
Progressive Dementia threshold for testing for treatable con-
RPDs are rather rare and can be dif- ditions, even if the likelihood is low.
ficult to diagnose. Establishing the Although American Academy of Neurol-
time course through a thorough his- ogy (AAN) guidelines currently do not
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 Rapidly Progressive Dementia

TABLE 7-3 Recommended Initial Screening Tests for Evaluation of a Rapidly

Progressive Dementia

Secondary Tier (Depending on Initial Screen

Category Initial Screen and Clinical Scenario)
Blood tests Complete blood cell count with differential Cancer screen (eg, serum protein electrophoresis,
serum immunoelectrophoresis, cancer antigen 125)
Basic metabolic panel (including calcium,
magnesium, phosphorus) Blood smear
Liver function tests Coagulation profile
Rapid plasma reagin (RPR) Hypercoagulability testing
Rheumatologic screen (erythrocyte Homocysteine
sedimentation rate, antinuclear antibody,
Methylmalonic acid
and C-reactive protein)
Thyroid function tests (thyroid-stimulating Additional rheumatologic tests (eg, cytoplasmic
hormone [TSH], free thyroxine) antineutrophil cytoplasmic antibody, perinuclear
antineutrophil cytoplasmic antibody,
Vitamin B12 double-stranded DNA, Smith
Human immunodeficiency virus antigen-ribonucleoprotein, SCL-70, SSA/SSB,
rheumatoid factor, C3, C4, CH50)
Medication levels as clinically indicated (eg,
lithium, phenytoin) Antithyroglobulin and antithyroperoxidase
antibodies
Lyme antibodies
Paraneoplastic/autoimmune antibodies
Additional endocrinologic tests (eg, cortisol)
Lymphoma markers15
Urine Urine analysis (with or without culture) Urine culture
Urine toxicology screen (if indicated) Heavy metal screen (24 hours)
CSF Cell count and differential Whipple PCR
Protein Metagenomic deep sequencing (CSF, biopsy tissue)
Glucose Phosphorylated tau, amyloid-"42
IgG index CSF "2-microglobulin and Epstein-Barr virus
PCR (lymphoma)
Oligoclonal bands
Venereal Disease Research Laboratory (VDRL)
14-3-3 protein western blot
Total tau enzyme-linked immunosorbent
assay (ELISA)
Neuron specific enolase ELISA
Real-time quaking induced conversion
(RT-QuIC) test

Cryptococcal antigena
Continued on page 517

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TABLE 7-3 Recommended Initial Screening Tests for Evaluation of a Rapidly Progressive
Dementia Continued from page 516

Secondary Tier (Depending on Initial

Category Initial Screen Screen and Clinical Scenario)
Viral polymerase chain reactions (PCRs),
antibodies, and culturesb
Bacterial, fungal, acid-fast bacilli stains,
and culturesc
Cytologyd
Flow cytometryd
Imaging Brain MRI (including T1, T2, CT head
fluid-attenuated inversion recovery CT chest, abdomen, and pelvis with and
[FLAIR], diffusion-weighted imaging, without contrast
apparent diffusion coefficient map,
hemosiderin sequence) with and Magnetic resonance angiography/magnetic
without contrast resonance venography
Computed tomography angiography/brain
Chest x-ray (if clinically indicated)
angiogram
Magnetic resonance spectroscopy (for lesions
or masses)
Mammogram
Body fluorodeoxyglucose positron emission
tomography (FDG-PET)/CT scan
Testicular or pelvic ultrasound
Carotid ultrasound

Echocardiogram

Other tests EEG Electromyogram/nerve conduction study

Ophthalmologic examination or vitreous
sampling (eg, for lymphoma)
Brain biopsy with or without meningeal biopsy
(especially if above tests are nondiagnostic)

CSF = cerebrospinal fluid; CT = computed tomography; DNA = deoxyribonucleic acid; EEG = electroencephalogram; IgG = immunoglobulin G;
MRI = magnetic resonance imaging; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B.
a
Initial screening for cryptococcal antigen depends on the clinical scenario and the geographic location.
b
Initial screening for viral PCRs, antibodies, and cultures depends on the clinical scenario, MRI findings, geographic location, and patient’s
travel history.
c
Initial screening for bacterial, fungal, acid-fast bacilli stains, and cultures depends on the clinical scenario and imaging findings.
d
Initial screening for cytology and flow cytometry depends on the clinical scenario, MRI findings, if cancer is suspected, or if CSF pleocytosis is
present.

recommend rapid plasma reagin (RPR) tia. CSF pleocytosis or elevated CSF
as a screening test for dementia, at IgG index or oligoclonal bands might
the UCSF center the author prefers to indicate an autoimmune or inflam-
send this test, as it is a relatively in- matory process, such as paraneo-
expensive test for a treatable demen- plastic or other neuroimmunologic

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 Rapidly Progressive Dementia

KEY POINTS
h Sending the CSF conditions. Although oligoclonal bands workup including fluorodeoxyglu-
biomarkers 14-3-3, total or elevated IgG index can occur in cose positron emission tomography
tau, and neuron-specific Jakob-Creutzfeldt disease,2 their pres- (FDG-PET)/CT and various ultrasounds
enolase is always ence probably should prompt an auto- might be indicated.
recommended, not immune and paraneoplastic evaluation. Additional, or second-tier, tests that
necessarily as diagnostic In the author’s UCSF Jakob-Creutzfeldt may be considered, depending on the
tests for prion disease, diseaseYRPD cohort, several patients results of the initial screen or the clin-
because they are not, with RPD were identified who had ical scenario, are shown in Table 7-3.
but rather as markers of either an elevated IgG index or oli- These include additional blood work,
rapid neuronal injury. If goclonal bands and the presence of urine testing, CSF analysis, brain and
these biomarkers are
novel antineuronal antibodies in their body imaging, and other tests. With
elevated, they help
serum and/or CSF. Although some pa- the exception of lymphomas, RPDs that
confirm the history of a
rapidly progressive
tients had cancer, in many, no cancers present with space-occupying brain
neurologic condition. were identified despite thorough eval- masses are easily identified by CT or
uation.5,16,17 At the author’s center, MRI scan, and the details of most of
h The use of a mnemonic
sending the CSF biomarkers 14-3-3, total these disorders are omitted from
device, such as VITAMINS
(vascular, infectious,
tau (t-tau), and neuron-specific enolase this chapter.
toxic-metabolic, is always recommended, not necessarily
autoimmune, malignancy, as diagnostic tests for prion disease, CONSIDERATION OF RAPIDLY
iatrogenic, because they are not,2 but rather as PROGRESSIVE DEMENTIAS BY
neurodegenerative, and markers of rapid neuronal injury. If ETIOLOGIC CATEGORY
systemic), when these biomarkers are elevated, they Several RPDs come under more than
evaluating a patient with help confirm the history of a rapidly one etiologic category; paraneoplastic
rapidly progressive progressive neurologic condition. If antibody-mediated encephalopathies,
dementia can help the prion disease is in the differential, the for example, are both autoimmune
clinician consider many CSF real-time quaking induced con- and neoplastic. In addition, not all
diverse etiologies for
version (RT-QuIC) test that detects conditions mentioned present as de-
such conditions.
prion seeding activity should be mentia, but may have other rapidly
performed.2 If AD is a consideration, progressive neurologic signs, such as
consider sending CSF for phosphory- ataxia or chorea. One useful mnemonic
lated tau (p-tau) and amyloid-"42 device for the differential evaluation of
(A"42). As A"42 sticks very strongly to RPDs is the acronym VITAMINS, which
regular plastic (lowering the measured stands for vascular, infectious, toxic-
value of the enzyme-linked immuno- metabolic, autoimmune, malignancy,
sorbent assay [ELISA]), only polypro- iatrogenic, neurodegenerative, and sys-
pylene tubes should be used for temic (as well as seizures and sarcoid)
collection; the CSF for that test should etiologies (Table 7-4). The following
not touch regular plastic tubes or the sections discuss several nonprion RPDs
manometer found in lumbar punc- by their diagnostic category or etiol-
ture trays. For a patient with an ogy, in the order of the mnemonic
undiagnosed RPD after the ini- VITAMINS. A diagnostic algorithm for
tial workup, a body CT scan with and RPDs is shown in Figure 7-2.
without contrast should be per-
formed for malignancy, sarcoid, or Vascular
other etiology. If a body CT is not ini- As noted in Table 7-2 and Table 7-4,
tially feasible, start with a chest x-ray. numerous vascular conditions can
If paraneoplastic antibodies are posi- cause RPDs, including strokes or mul-
tive, depending on the specific anti- tiple infarcts, cerebral amyloid angio-
body identified, an aggressive cancer pathy, dural arteriovenous fistulas
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TABLE 7-4 Partial Differential Diagnosis for Rapidly Progressive
Dementias by Etiologic Category

b Vascular/Ischemic

Multi-infarct
Thalamic or callosum infarcts
Cerebral amyloid angiopathy
Dural arteriovenous fistulas
Central nervous system (CNS) vasculitis
Venous thrombosis
Cerebroretinal microangiopathy with calcifications and cysts
Posterior reversible encephalopathy syndrome (PRES)
Subacute diencephalic angioencephalopathy
b Infectious
Viral encephalitis, including herpes simplex virus
Human immunodeficiency virus dementia
Progressive multifocal leukoencephalopathy
Fungal infections (eg, CNS aspergillosis, coccidioidomycosis)
Amoebic infection (eg, Balamuthia mandrillaris)
Spirochete infection
Lyme disease (rarely encephalopathy)
Whipple disease (rarely rapid)
Subacute sclerosing panencephalitis (young adults)
Urinary tract infection, pneumonia in elderly patient or patient with
mild dementia
b Toxic-Metabolic
Electrolyte disturbances (sodium, calcium, magnesium, phosphorus)
Endocrine abnormalities (thyroid, parathyroid, adrenal)
Extrapontine myelinolysis
Vitamin B12 (cyanocobalamin) deficiency
Vitamin B1 (thiamine) deficiency (Wernicke encephalopathy)
Niacin deficiency (not usually rapid)
Folate deficiency (dementia rare)
Uremic encephalopathy
Portosystemic shunt encephalopathy
Poikilothermia
Continued on page 520

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 Rapidly Progressive Dementia

TABLE 7-4 Partial Differential Diagnosis for Rapidly Progressive

Dementias by Etiologic Category Continued from page 519

Hepatic encephalopathy
Acquired hepatocerebral degeneration
Hypoxia/hypercarbia
Hyperglycemia/hypoglycemia
Porphyria
Metal toxicity (bismuth, lithium, mercury, magnesium [Parkinsonism])
Mitochondrial disease (eg, mitochondrial myopathy, encephalopathy, lactic
acidosis, and strokelike episodes syndrome [MELAS])
b Autoimmune
Antibody-mediated dementia/encephalopathy
CNS lupus
Acute disseminated encephalomyelitis (ADEM)
Hashimoto encephalopathy (steroid-responsive encephalopathy associated
with autoimmune thyroiditis [SREAT])
Other CNS vasculitides
b Metastases/Neoplasm Related
Paraneoplastic diseasesVlimbic encephalopathy
Metastases to CNS
Primary CNS lymphoma
Intravascular lymphoma
Lymphomatoid granulomatosis
Lymphomatosis cerebri
Gliomatosis cerebri
Metastatic encephalopathy
Carcinomatous meningitis
b Iatrogenic
Medication toxicity (eg, lithium, methotrexate, chemotherapy)
Illicit drug use
b Neurodegenerative
Prion disease
Alzheimer disease
Dementia with Lewy Bodies
Frontotemporal dementia
Corticobasal degeneration
Continued on page 521

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TABLE 7-4 Partial Differential Diagnosis for Rapidly Progressive
Dementias by Etiologic Category Continued from page 520

Progressive supranuclear palsy

Neurofilament inclusion body disease
Progressive subcortical gliosis
b Systemic/Seizures/Structural
Sarcoidosis
Epilepsy
Nonconvulsive status epilepticus
Subdural hematoma
Mitochondrial disease (eg, MELAS)

FIGURE 7-2 Algorithm for evaluating rapidly progressive dementia. Refer to the text and
Table 7-3 for details about the workup for each diagnostic category.
CSF = cerebrospinal fluid; IV = intravenous; RPD = rapidly progressive dementia.

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 Rapidly Progressive Dementia

(DAVFs), and hypertensive enceph- dementia.23,24 Diffusion-weighted im-

alopathy.18Y22 CNS vasculitis and intra- aging (DWI) and gradient echo
vascular lymphoma might also be (hemosiderin-sensitive sequence) MRI
considered under vascular etiologies, as well as vascular imaging such as
although they also might be consid- magnetic resonance angiography (MRA),
ered under autoimmune and malig- magnetic resonance venography (MRV),
nancy, respectively. Any vascular CT angiography, and conventional angi-
disruption of the thalamus, especially ography can help diagnose vascular
if bilateral involvement, such as through causes of RPD. At least 20 cases of
venous thrombosis, can result in an DAVFs causing dementia, most present-
RPD. Even small focal strokes, particu- ing as RPDs, have been reported in the
larly in the thalamus, can cause acute literature. Most patients presented
with headache, progressive confusion,
and memory loss, which progressed
rapidly over the course of 2 weeks to
12 months. Some patients developed
seizures, gait instability, or some focal
neurologic deficit such as aphasia,
facial palsy, or hemiparesis. In some
cases, a bruit was heard over the skull.
In all 20 cases, diagnosis was made
by angiogram, and treatments such as
surgery alone (one patient), emboliza-
tion and surgery (two patients), or
embolization alone (17 patients) im-
proved cognitive function profoundly
in all cases except one, who only
showed minimal improvement and
died of brain herniation after embo-
lization. Mean age is 60 (range 55 to 77)
years. Duration from onset to RPD
ranges from about 2 months to just over
12 months.19Y22,25Y28 Common MRI
findings are diffuse high-signal inten-
FIGURE 7-3 Imaging of a dural arteriovenous fistula (DAVF). sities in the cerebral or cerebellar white
A 70-year-old woman developed amnesia,
aphasia, incoherent speech, and progressive matter along with enlarged vessels over
gait disturbance over 2 weeks, progressing over the next the hemispheric surface on T2-weighted
3 weeks to develop myoclonus with a startle reflex, flaccid
tetraparesis with brisk deep tendon reflexes, extensor plantar
images (Figure 7-3). Basal ganglia
responses, pronounced primitive reflexes, and akinetic mutism. hyperintensity has been, albeit rarely,
Initial diagnosis was Jakob-Creutzfeldt disease until brain
imaging revealed a DAVF. A, Axial T2-weighted MRI shows
reported.19 Considering the reversibil-
multiple dilated vessels in the temporal regions, predominantly ity of clinical symptoms, it is critical to
in the right temporal region with venous ectasia and consider DAVF in a patient presenting
hyperintensity of the white matter including the centrum
semiovale. B, Digital subtraction angiogram (right common with RPD and MRI showing diffuse
carotid injection [left panel]) and left external carotid injection white matter lesions.
[right panel]), lateral views, shows multiple DAVFs of the
superior sagittal sinus, torcula, and the lateral sinuses. Venous sinus thrombosis often man-
ifests with headaches, papilledema, vi-
Reprinted with permission from Mendonça N, et al, Neurologist.21
journals.lww.com/theneurologist/pages/articleviewer.aspx?year= sual loss, seizures, focal neurologic
2012&issue=05000&article=00005&type=Abstract. deficits, altered mental status, or coma
B 2012 Lippincott Williams & Wilkins, Inc.
depending on the location of the
522 www.ContinuumJournal.com April 2016

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thrombus. Brain MRI shows cerebral
edema and venous infarction, and CT
venogram (CTV) or MRV can detect the
thrombus. If the deep veins are
thrombosed, there might be unilateral
or symmetric basal ganglia involve-
ment.29 Cerebral amyloid angiopathy
involving small and medium-sized ar-
teries in the brain may result in RPD.30
Hemosiderin sequences often show
multiple large or small hemorrhages,
often in areas in which there are T2-
weighted white matter hyperintensi-
ties (Figure 7-431),32 particularly when
there is cerebral amyloid angiopathyY
related inflammation, which might be
somewhat responsive to steroids.
Cerebroretinal microangiopathy with
calcifications and cysts is a very rare
condition that can manifest as RPD,
more commonly in children. In one
FIGURE 7-4 MRI findings of cerebral amyloid
adult case, a 62-year-old man pres- angiopathyYrelated inflammation. An elderly
ented with a 2-month history of rapidly man presented with relatively acute onset
left hemiparesis, left homonymous hemianopia, dysarthria,
progressive cognitive decline, ataxia, spatial and temporal disorientation, sensory aphasia, and
spasticity, and seizures. CT showed mul- psychomotor slowness. Cerebral amyloid angiopathyYrelated
tiple calcifications in the cerebral hemi- inflammation was suspected and the finding of APOE
genotype (4/(4 supported the diagnosis. AntiYamyloid-" (A")
spheres, brainstem, and cerebellum and autoantibody concentration in CSF was elevated at
enhancement in the brain calcification 55.9 ng/mL. Physical therapy and corticosteroid therapy with
dexamethasone 24 mg/d were started and the patient showed
areas on MRI. He died 3 years after onset clinical improvement. Initial axial fluid-attenuated inversion
without a definite diagnosis. Autopsy recovery (FLAIR) MRI shows bilateral hyperintense lesions (A)
and gradient recalled echo (GRE) image shows cortical and
showed an adult-onset case of cere- subcortical microhemorrhages (B). After 1 month of steroid
broretinal microangiopathy with cal- therapy, FLAIR MRI (C) and GRE (D) sequence show reduction
of both cerebral edema and microhemorrhages.
cifications and cysts.33 Another rare
vascular cause of RPD is subacute Modified with permission from Crosta F, et al, Case Rep Neurol Med.31
www.hindawi.com/journals/crinm/2015/483020/. B 2015 Francesca
diencephalic angioencephalopathy, Crosta et al.
which is considered a severe form of
posterior reversible encephalopathy cipital and temporal lobes and pons
syndrome (PRES). Approximately seven as well as the thalamus (Figure 7-5).34
cases of subacute diencephalic an-
gioencephalopathy have been reported Infectious
to date and are characterized by acute Most infectious causes of encephalop-
cognitive changes with rapid pro- athy have certain suggestive features,
gression to death, bilateral thalamic such as fever, pleocytosis, meningeal
involvement, and profound vascul- signs (if a meningoencephalitis), and
opathy with noninflammatory paren- have acute onset (eg, over days). CSF
chymal necrosis. MRI typically shows and imaging, however, may be normal.
nonenhancing confluent subcortical When viral encephalitis is suspected,
fluid-attenuated inversion recovery depending on the clinical scenario,
(FLAIR)/T2 hyperintensities in the oc- treatable conditions, such as herpes

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 Rapidly Progressive Dementia

FIGURE 7-5 Brain MRI of a 68-year-old man with recent hyperintensive encephalopathy
leading to subacute diencephalic angioencephalopathy. His first symptoms
were hypernasal dysarthria and palatal weakness that resolved over 3 months
after treatment of hypertension. Thirteen months after initial onset, he developed headaches,
confusion, and speech and language problems due to hyperintensive encephalopathy, which
again resolved with treatment. About 15 months after initial onset, he began a downward,
but fluctuating course (with treatments), over 8 weeks, of a rapidly progressive neurologic
decline leading to his death. Brain autopsy revealed findings consistent with subacute
diencephalic angioencephalopathy. Nonenhancing, confluent subcortical axial
fluid-attenuated inversion recovery (FLAIR) hyperintensities in the occipital lobes (A) and left
temporal lobe (B) at the time of initial onset. Confluent nonenhancing abnormal coronal
T2-weighted signal symmetrically in the pons, as well as confluent periventricular FLAIR
signal, at 13 months after onset (C). One month later, imaging demonstrated bilaterally
symmetric T1 and T2/FLAIR hyperintense abnormal signal in the thalami (D, coronal FLAIR;
E, axial FLAIR). Thalamic abnormalities enhanced minimally following gadolinium
administration on axial T1-weighted images (F, unenhanced; G, enhanced). Small
T1-weighted (H) and T2-weighted hyperintense cortical foci were also seen.
Reprinted with permission from Graffeo CS, et al, J Clin Neurosci.34 www.jocn-journal.com/article/S0967-
5868(15)00354-9/abstract. B 2015 Elsevier Ltd.

simplex virus, should be ruled out. With as aspergillosis in the CNS, may also
herpes simplex virus, serial CSF PCR cause RPD, although most commonly
may be needed. It is important to rule in immunocompromised patients.
out HIV35,36 and, when clinically indi- Although Whipple disease classi-
cated, acquired immune deficiency syn- cally presents with gastrointestinal
drome (AIDS)-related CNS conditions symptoms, lymphadenopathy, fever,
such as toxoplasmosis, primary CNS and arthralgia, neurologic involve-
lymphoma, and progressive multifocal ment occurs in 5% to 45% of cases
leukoencephalopathy. Depending on (depending on the study) and can be
the geographic location, Lyme disease the presenting symptom. Symptoms
or other local infectious agents, such as of CNS Whipple disease often include
Balamuthia mandrillaris in California, cognitive and psychiatric dysfunction,
most of which are treatable, should be hemiparesis, seizures, and ataxia, and
considered.37 Fungal infections, such may present as an RPD. Although

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Whipple disease is rare, it is curable leptospirosis and B. mandrillaris. At
with antibiotics; when indicated, physi- this time, this testing is primarily being
cians should test for the bacterium done only through research, but soon
Tropheryma whippelii by PCR from should be clinically available.41 Several
the blood, CSF, jejunal biopsy, or brain other infections to consider are shown
biopsy. Diagnosis may also be made by in Table 7-4 and in the December
duodenal biopsy revealing periodic 2015 issue of Continuum.2
acidYSchiff positive macrophages in the
lamina propria containing nonYacid-fast Toxic-Metabolic
Gram-positive bacilli.38 If the etiology Identification of toxic causes of en-
of a probable infectious encepha- cephalopathy requires a thorough
lopathy or encephalitis is not iden- medication and exposure history, in-
tified, both acute and convalescent cluding assessing work and home en-
serum and CSF should be saved to vironments. Elevated lithium levels,
help with later identification of the often iatrogenic, can cause encepha-
infectious agent. In the United States, lopathy. Inorganic lead poisoning in
the Centers for Disease Control and Pre- adults typically leads to peripheral
vention, including several state health neuropathy, whereas in children, cog-
department encephalitis programs they nitive impairment and encephalopa-
fund, has divisions to help diagnose thy can occur. Organic lead, a gasoline
various encephalitides. These sites can additive, is much more toxic than
help analyze acute and convalescent inorganic lead, and even minimal ex-
serum and CSF, which should be kept posure may cause psychiatric and
for analysis in all undiagnosed but behavioral symptoms, including agita-
suspected infectious cases. Histori- tion, disturbed sleep patterns, and
cally, for most cases of encephalitis, hallucinations. Inorganic and organic
the etiology unfortunately is never mercury, similar to lead toxicity, can
found. Among more than 300 refer- lead to very toxic states, such as the
rals to the California Encephalitis Pro- Mad Hatter syndrome, caused by inor-
ject over a 2.5-year period, 62% of cases ganic mercury exposure in industrial
remained unexplained, 39 although settings and marked by tremor and
some cases recently have been found psychological disturbance. Organic
to be due to antiYN-methyl-D-aspartate mercury exposure, possibly due to
(NMDA) receptor antibodies.40 Al- grain contamination or industrial ex-
though many suspected infectious de- posure, usually causes a triad of con-
mentias or encephalopathies have centric visual field loss, paresthesia,
previously been unidentified, the ad- and cerebellar ataxia, without tremor.
vent of metagenomic deep sequenc- Although commonly tested for in heavy
ing in clinical practice will likely metal screens, acute arsenic toxicity
change this. Metagenomic deep se- does not cause RPD but, rather, causes
quencing involves the study of genetic early gastrointestinal and circulatory
material recovered from a sample, problems, followed weeks later by a
such as bodily fluids or tissue, and is length-dependent sensorimotor poly-
a powerful diagnostic tool with the neuropathy and desquamation of palms
potential for rapid and unbiased path- and soles.42 A 24-hour urine (not a spot
ogen identification. It recently has urine) and possibly a hair or nail
been used to detect nonhuman DNA analysis should be performed for heavy
and RNA in human CSF, leading to metal testing. Bismuth toxicity, such
the identification of uncommon but as from excess use to treat gastroin-
treatable infections, including neuro- testinal illnesses (bismuth subsalicylate

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 Rapidly Progressive Dementia

KEY POINTS
h Any patient in whom [BSS] or Pepto-Bismol in the United diarrheal illnesses, and thyrotoxicosis.
Wernicke encephalopathy States or colloidal bismuth [CBS] or In industrialized nations, pellagra is
is a consideration should De-Nol in Europe), can cause RPD, most often seen in alcoholics and in
be urgently treated even mimicking Jakob-Creutzfeldt dis- patients taking isoniazid. Clinical diag-
with empiric ease. Symptoms include cognitive dys- nosis is usually made on suspicion,
thiamine replacement. function, tremor, ataxia, dysarthria, and ruling out other etiologies, and then
h In sporadic myoclonus. A careful history and bis- treating patients empirically (niacin
Jakob-Creutzfeldt muth level testing can confirm the 40 mg/d to 250 mg/d), usually re-
disease, there is usually diagnosis. Symptoms are often revers- sulting in improvement of neuro-
relative sparing of the ible if caught early.43 logic symptoms.46,47
perirolandic cortex on There are far too many metabolic Thiamine (vitamin B1) deficiency
fluid-attenuated disorders that can cause RPD to be can cause Wernicke encephalopathy,
inversion recovery and discussed in this article, from hyper- which classically presents as an acute/
diffusion-weighted calcemia 44 to poikilothermia 45 A subacute dementia with ophthalmo-
imaging MRI, particularly few important reversible categories, paresis (with vertical or horizontal nys-
in comparison to however, are vitamin deficiencies and tagmus), ataxia, and memory loss.
adjacent cortex. endocrinologic dysfunction. Niacin Often, however, not all features are
(vitamin B3) deficiency, or pellagra present. Pathologically, there may be
(‘‘rough skin’’), is often described as hemorrhagic necrosis of the mam-
‘‘the three Ds’’: dermatitis, diarrhea, millary bodies or dorsomedial nucleus
and dementia. Neurologic deficits of the thalamus that may be detected
can include peripheral neuropathy, on MRI. Restricted diffusion may be
myelopathy, and subacute cognitive present on DWI and apparent diffusion
deficits. Other nutritional deficiencies coefficient (ADC) maps,48 and some
often occur in conjunction with pel- imaging features can overlap with
lagra. Niacin deficiency occurs most those seen in Jakob-Creutzfeldt disease
commonly in nutritionally deprived (Case 7-1 and Figure 7-6). Any patient
patients (eg, alcoholics, malnourished, in whom Wernicke encephalopathy is
impoverished), and in association with a consideration should be urgently
systemic disorders, including diabetes treated with empiric thiamine replace-
mellitus, neoplasms, chronic infections, ment. All patients with a dementia
cirrhosis, chronic gastrointestinal or should be screened for vitamin B12

Case 7-1
A 61-year-old woman was evaluated at an outside hospital several times over the course of 8 months
for insidious onset of psychiatric symptoms (depressed mood and severe anxiety with panic attacks)
followed by gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting) and anorexia of unclear
etiology. She had a history of obesity and had lost more than 40% of her initial body weight over
this time period, became progressively confused, and was unable to live independently. Results from
broad urinary and serologic investigations were nondiagnostic, and her EEG reportedly showed diffuse
slowing. Notably, her CSF analysis showed elevated total tau and 14-3-3 proteins, and brain MRI
showed fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI)
hyperintensities in the deep nuclei and cortical ribboning along the rolandic cortex, interpreted as
consistent with Jakob-Creutzfeldt disease. Given her rapidly progressive dementia and CSF and MRI
findings, she was diagnosed with sporadic Jakob-Creutzfeldt disease, and further workup was not
pursued. Upon review of her medical records, we assessed that her clinical syndrome and brain MRI
findings (involvement of periaqueductal gray matter, midbrain tectum, medial thalamus, and perirolandic
cortex) (Figure 7-6) were more consistent with thiamine deficiency and not with Jakob-Creutzfeldt
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 Continued from page 526

FIGURE 7-6 MRI of the patient in Case 7-1. Wernicke encephalopathy (compared to a sporadic
Jakob-Creutzfeldt disease case). Fluid-attenuated inversion recovery (FLAIR) (AYD),
diffusion-weighted imaging (DWI) (EYH), and apparent diffusion coefficient (ADC) map (IYL)
sequences showing FLAIR and DWI hyperintense signal changes involving the periaqueductal gray and
midbrain tectum, medial thalami, and perirolandic cortex in the patient with Wernicke encephalopathy. There
is relative sparing of the mammillary bodies across all sequences (B,F,J). The ADC sequences (IYL) primarily show
subtle hypointensity in the perirolandic cortex (L), corresponding to hyperintensities on FLAIR (D) and DWI (H). This
pattern preferentially involving the perirolandic cortex is the opposite of what we typically see in sporadic
Jakob-Creutzfeldt disease (MYP; DWI sequences), in which there is generally sparing of the perirolandic region,
particularly the primary motor cortex.

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 Rapidly Progressive Dementia

Continued from page 527

disease. Unfortunately, the patient died prior to treatment for Wernicke encephalopathy could be
initiated. Brain autopsy, performed through the US National Prion Disease Pathology Surveillance
Center, confirmed thiamine deficiency without evidence of prion disease. The patient’s final
neuropathologic diagnosis was Wernicke encephalopathy.
Comment. There is considerable clinical and radiographic overlap between Wernicke encephalopathy
and Jakob-Creutzfeldt disease; FLAIR and DWI hyperintensities are observed commonly in the mammillary
bodies, midbrain tectum, and medial thalami in Wernicke encephalopathy, which somewhat overlap with
the imaging findings of Jakob-Creutzfeldt disease. Focal cortical involvement of the motor cortex, as shown
in this case, however, was reported in Wernicke encephalopathy49 but this area is usually spared in
Jakob-Creutzfeldt disease.6 Although Wernicke encephalopathy is largely known to occur in alcoholic
patients with the classic triad of cognitive impairment, incoordination, and oculomotor abnormalities, now
it more commonly occurs in nonalcoholic patients, resulting from malnutrition or malabsorption, which
appears to have been the case with this patient. Occurrence of all three signs is also rare. Wernicke
encephalopathy always should be considered in patients with rapidly progressive dementia and significant
weight loss or malnutrition.

deficiency, as the clinical deficits are basic electrolytes (including serum

potentially reversible. calcium, magnesium, and phospho-
As thyroid dysfunction is well rus levels), in any dementia screen
known to cause cognitive impairment, (Table 7-3). Some other metabolic
all patients with RPD should have a conditions that might mimic sporadic
basic thyroid function screen. De- Jakob-Creutzfeldt disease are adult-
pending on the clinical scenario, other onset seizure disorders, due to severe
endocrine dysfunction should also be hypoglycemia and hyperglycemia
considered. It is important to include (Case 7-250 and Figure 7-7) or other

Case 7-2
A 66-year-old right-handed woman with a history of poorly controlled insulin-dependent diabetes
mellitus, hypothyroidism, and primary biliary cirrhosis was found unconscious. She had not been
compliant with her insulin treatment, and her blood glucose level was 99 mg/dL, which was taken by a
paramedic, although it was not clear if this was after she was given glucose. For the first 3 days of
admission her blood sugar was in the range of 96 mg/dL to 366 mg/dL, which decreased to 25 mg/dL
and 42 mg/dL on the fourth and fifth days of admission. She regained her consciousness after a day or
two without focal neurologic deficits, but was confused (eg, using her telephone as a television
remote control). Blood tests were unremarkable. CSF analysis showed normal white blood cell count,
red blood cell count, protein, and glucose, but positive 14-3-3 protein, elevated neuron-specific enolase of
78 ng/mL (more than 35 ng/mL consistent with Jakob-Creutzfeldt disease according to Mayo Medical
Laboratories),51 very elevated total tau of 17,585 pg/mL (greater than 1200 ng/mL consistent with
Jakob-Creutzfeldt disease according to Athena Diagnostics, Inc),52 and very elevated phosphorylated tau
of 88.4 pg/mL (more than 61 pg/mL considered elevated according to Athena Diagnostics, Inc), and
normal amyloid-"42 of 828.8 pg/mL (according to Athena Diagnostics Inc). Brain MRI fluid-attenuated
inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC)
map 2 days after the onset demonstrated cortical ribboning and left caudate hyperintensity with restricted
diffusion (Figure 7-7A, 7-7B, and 7-7C). Her cognitive functions gradually improved, but she had
intermittent confusion and disorientation. A second MRI 3 weeks after the onset showed less diffusion
restriction in the left caudate but possible new reduced diffusion in the right caudate head and anterior
putamen (Figure 7-7D, 7-7E, and 7-7F). She was referred to our center for a Jakob-Creutzfeldt disease
treatment trial. Notably, 1 month after the onset, at our center, she had continued to improve
significantly in cognitive and behavioral domains, although had mild cognitive impairment. A third
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 Continued from page 528

FIGURE 7-7 MRI of the patient in Case 7-2. A 66-year-old woman with hypoglycemic
encephalopathy. Fluid-attenuated inversion recovery (FLAIR) (A, D, G),
diffusion-weighted images (DWI) (B, E, H), and apparent diffusion coefficient
(ADC) map (C, F, I) sequences 2 days (AYC), 3 weeks (DYF), and 1 month (GYI) after onset.
Initial MRI (AYC) showed left frontal (white arrows), left insular (red arrows), bilateral medial
occipital (blue arrows), and left caudate (white arrowhead) FLAIR/DWI hyperintensity with
restricted diffusion, which is subtle but definitely appreciable. Repeat MRI about 3 weeks later
(DYF) showed possible reduced FLAIR/DWI hyperintensity in the left caudate head and medial
occipital regions, and possible increased right caudate FLAIR hyperintensity and restricted
diffusion (DYF; white arrowheads). A third MRI 1 week later, 1 month after onset (GYI),
revealed more intense FLAIR/DWI insular (G, H; red arrows) and frontal cortical hyperintensities
(G, H; white arrows) and possible restricted diffusion and FLAIR hyperintensity still present in
the caudate heads (G, H; arrowheads). The resolution of occipital cortical ribboning in such a
short time argued against a diagnosis of sporadic Jakob-Creutzfeldt disease.
50
Reprinted with permission from Rosenbloom MH, et al, Neurol Clin Pract. cp.neurology.org/content/5/2/108.full.
B 2015 American Academy of Neurology.

Continued on page 530

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 Rapidly Progressive Dementia

Continued from page 529

MRI showed more intense DWI cortical ribboning and greater right caudate head involvement
(Figure 7-7G, 7-7H, and 7-7I).
Given her profound clinical improvement, she was diagnosed with hypoglycemia-related encephalopathy
with MRI abnormalities that might be secondary to seizure or hypoglycemia. She was discharged home,
but several weeks later had another episode of hypoglycemia leading to coma and death. Brain autopsy
revealed hypoxic/hypoglycemic nerve loss in multiple brain regions (cortices, CA1/CA4 hippocampus, deep
nuclei, cerebellar Purkinje cells, and dentate nucleus) without evidence of prion disease.
Comment. Sustained hypoglycemia can cause various symptoms such as confusion, seizures, weakness,
and coma, and MRI FLAIR/DWI hyperintensities with restricted diffusion in the cortices, basal ganglia,
and hippocampus.50 Seizures are also known to result in reduced diffusion in the cortex and deep nuclei,
which is reversible.50 Although the patient’s CSF biomarkers and overall MRI findings were suggestive
of prion disease, significant clinical improvement with less diffusion restriction in the left caudate within
a few weeks was not consistent with Jakob-Creutzfeldt disease. A thorough clinical history, as well as
an extensive metabolic workup, and serial MRIs can help differentiate a reversible metabolic
encephalopathy from prion disease. A detailed description of this case is published.50
Modified with permission from Rosenbloom MH, et al, Neurol Clin Pract. 50 cp.neurology.org/content/5/2/108.full. B 2015 American Academy
of Neurology.

causes, and extrapontine myelinolysis Autoimmune

due to inappropriate correction of hy- As seen in our and other RPD cohorts
ponatremia (Case 7-3 and Figure 7-8).50 (Table 7-1 and Table 7-2), several
These conditions can also have DWI autoimmune conditions present as
and ADC MRI findings that overlap with RPDs. These conditions, particularly
those seen in Jakob-Creutzfeldt disease, antibody-mediated causes of CNS dys-
including basal ganglia hyperintensity function, including RPD, are discussed
and cortical ribboning. in detail in the article ‘‘Autoimmune

Case 7-3
A 50-year-old right-handed man with a history of alcoholism (current), hypertension, hypercholes-
terolemia, and hepatitis C developed nausea, vomiting, and diarrhea for 3 days. He reduced his
alcohol consumption and increased his water intake for hydration. One week later, he had two
episodes of generalized tonic-clonic seizures and was treated for encephalopathy and hyponatremia at a
local intensive care unit. His brain CT was unremarkable but he had behavioral symptoms (emotional
blunting, violent outbursts, delusions, and hallucinations), impaired episodic memory, speech disturbance
(slurred, halting), executive problems, gait imbalance, and myoclonus of the hands and trunk. His first
brain MRI at approximately 2 months after the onset of symptoms showed restricted diffusion with
hyperintensities on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging
(DWI) in the bilateral striata with corresponding hypointensity on apparent diffusion coefficient (ADC)
map, and T1 hyperintensities in bilateral globus pallidi (Figure 7-8A, 7-8B, 7-8C, and 7-8D). Because of his
clinical symptoms and MRI findings, he was diagnosed with sporadic Jakob-Creutzfeldt disease and
referred to our center. At our center, 3 months after the onset, we noted that although he had deficits
(mild cognitive and motor deficits), he had improved profoundly. A repeat brain MRI showed
resolution of the diffusion and T2 striatal abnormalities (Figure 7-8E, 7-8F, 7-8G, and 7-8H).
Extensive laboratory workup for rapidly progressive dementia was negative, but a careful review of
his outside medical records determined that at his initial hospitalization his first sodium level was
106 mEq/L, which decreased to 102 mEq/L within 3.5 hours and then was corrected to 130 mEq/L in
less than 36 hours. Given the MRI findings and the history of rapidly corrected hyponatremia, he
was diagnosed with extrapontine myelinolysis.
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 Continued from page 530

FIGURE 7-8 MRI of the patient in Case 7-3. A 50-year-old man with extrapontine myelinolysis. Initial MRI
2 months after onset (AYD) showed symmetric bilateral striatal fluid-attenuated inversion recovery
(FLAIR) (A)/diffusion-weighted imaging (DWI) (B) hyperintensities (A, B; white arrows) with
corresponding hypointensities on the apparent diffusion coefficient (ADC) map suggesting restricted diffusion
(C; black arrows). Bilateral globus pallidus hyperintensities were present on T1-weighted images (D; green
arrows). MRI 1 month later, 3 months after onset (EYH), showed resolution of the prior FLAIR (E), DWI (F), and
ADC (G) map abnormalities but no change in the globus pallidus T1 hyperintensities (H; green arrows).
Reprinted with permission from Rosenbloom MH, et al, Neurol Clin Pract.50 cp.neurology.org/content/5/2/108.full. B 2015 American
Academy of Neurology.

Comment. Extrapontine myelinolysis results from rapid metabolic shifts, such as rapid correction of
hyponatremia, and mostly affects the basal ganglia, internal capsule, white matter, and cerebral
cortices, sparing the pons.44 Three radiologic features suggested against Jakob-Creutzfeldt disease in
this case: (1) such quick resolution of the restricted diffusion without volume loss; (2) the striatal
involvement was uniformly bright, whereas in Jakob-Creutzfeldt disease there is usually an anterior to
posterior decreasing gradient; and (3) isolated striatal involvement without any cortical ribboning is
uncommon in Jakob-Creutzfeldt disease (approximately 2% of cases).1 Symptoms such as dysarthria,
bradykinesia, dystonia, and akinetic mutism mimic sporadic Jakob-Creutzfeldt disease, but clinical and
radiologic improvement are different from those seen in sporadic Jakob-Creutzfeldt disease. A
detailed description of this case is published.50
Modified with permission from Rosenbloom MH, et al, Neurol Clin Pract. 50 cp.neurology.org/content/5/2/108.full. B 2015 American Academy
of Neurology.

Encephalopathies and Dementias’’ by on what this should include, but one

Andrew McKeon, MD,9 in this issue of possible initial and a secondary screen
Continuum, so they will be discussed are shown in Table 7-3. Unfortunately,
here only briefly. For most RPDs, we most cases of CNS vasculitis have
generally recommend a basic autoim- normal serologic findings.36 MRI may
mune screen. There is no consensus show contrast enhancement, infarcts,

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

 Rapidly Progressive Dementia

and involvement of gray or white perturbation. Determination of non-

matter.5,43 When MRI and the clinical RPD dementia diagnoses is typically
picture suggest vasculitis, it is impor- made by obtaining history from family
tant to note that other conditions, such members who did not see the patient
as intravascular lymphoma, can have regularly (eg, a child who comes to
the appearance of vasculitis on brain visit for the holidays), friends, or col-
angiogram, and may temporarily leagues, who had noticed cognitive
respond to steroids. When per- changes well before those who saw the
forming a brain biopsy for potential patient on a daily basis.5 As noted in
vasculitis, it is important to take an Table 7-1, Table 7-2, and Table 7-4,
appropriately sized piece of tissue some nonprion neurodegenerative de-
(typically 1 cm 3 ), including meninges, mentias, however, do rarely progress
ideally from an area that is abnor- rapidly, with dementia occurring within
mal on MRI. 36 If a paraneoplastic or 1 year from first symptom onset or from
antibody-mediated dementia syndrome onset of first symptom to death in 1 to
is suspected in a patient who has none 3 years. 54,55 These include corti-
of the known or commercially avail- cobasal degeneration, FTD, FTD with
able antibodies, the clinician may motor neuron disease, and rare cases
wish to send blood or CSF to a of AD and DLB.5,7,43 These neurode-
research laboratory that specializes in generative conditions are discussed
identifying novel antibodies.53 elsewhere in this volume.
A patient with FTD with the C9ORF72
Neurodegenerative/Neoplastic mutation recently was reported to man-
As shown in Table 7-1 and Table 7-2, ifest with an RPD.56 The initial symp-
nonprion neurodegenerative diseases toms were profound behavioral and
are often the most common forms of personality changes (blunt affect, beg-
RPD. Although many nonprion neuro- ging for money, collecting cigarette
degenerative diseases can truly pres- butts, and social withdrawal) followed
ent as RPD, at the author’s center, by delusions, disorganized and aggres-
such patients are often found to have sive behavior, progressive cognitive de-
had a slow course over several years cline and motor neuron disease,
that has been unnoticed or undiag- leading to death within 1 year.
nosed until a rapid decline occurs.
Neoplastic
Many patients referred to our center
with an RPD diagnosis did not have an Neoplastic causes of RPD can be quite
RPD, but rather a slowly progressive difficult to diagnose, particularly when
neurodegenerative dementia. In the they do not present as isolated mass
author’s experience, often, those clos- lesions on MRI. Primary CNS lymphoma
est to the patient, particularly when and intravascular lymphoma often pres-
with the patient daily, miss the first ent as an RPD and even may resemble
signs of illness, and do not bring the Jakob-Creutzfeldt disease clinically.
patient to a doctor until the symptoms MRI can be helpful in these diagnoses.
became obvious or there is a sudden Primary CNS lymphoma presents as a
steep decline. These declines are solitary or multiple mass lesions in
sometimes part of the natural disease contact with the subarachnoid space
course and, other times, are due to an and is uniformly contrast-enhancing
infection (eg, urinary tract infection, i n i m m u n o c o m p e t e n t patients.
pneumonia) or another metabolic Multifocal lesions and peripheral

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enhancement, however, are character- gray and white matter MRI abnor-
istic MRI findings in immunosuppressed malities or clinical features consis-
patients. 15 In lymphoma, certain tent with mitochondrial disease.
markers such as serum lactate dehydro- Systems frequently affected are the
genase, "2-microglobulin, and CA-125 peripheral nervous system (myopa-
may be elevated, although some of thy, polyneuropathy, lactic acidosis),
these markers have somewhat low brain (leukoencephalopathy, calcifica-
sensitivity and specificity. CSF "2 - tions, strokes, seizures, upper motor
microglobulin appears to be some- neuron findings, ataxia, extrapyrami-
dal symptoms, unexplained fatigue),
what correlated with CNS lymphoma
endocrine (short stature, pubertal ab-
rather than with systemic lymphoma
normalities), cardiac (conduction de-
in small numbers of patients. CSF lactate fects, cardiomyopathy, unexplained
dehydrogenase 5 (LD5) (anaerobic lac- heart failure), visual (early cataracts,
tate dehydrogenase [LDH] isoenzyme) retinopathy, optic atrophy), auditory
proportions greater than or equal to (deafness, vertigo), gastrointestinal (dys-
2.8% of total LDH had a high sensitivity phagia, nausea/vomiting, diarrhea, liver
(about 93%) and a low specificity for abnormalities, pancreatic insufficiency),
CNS lymphoma.15 In intravascular lym- kidney (renal failure, cysts), and bone
phoma, brain angiogram shows a pat- marrow (sideroblastic anemia).57 Mito-
tern indistinguishable from vasculitis, chondrial dementia may rarely present
and, thus, pathology or CSF cytology acutely.58 A strong lactate signal on
may be the necessary and preferred magnetic resonance spectroscopy and
diagnostic methods. When considering genetic analysis of mitochondrial mu-
CNS lymphoma, repeated large- tations are useful for differentiating
volume CSF analyses for cytology and mitochondriopathy from Jakob-
flow cytometry should be done, al- Creutzfeldt disease.59 An unusual pat-
tern of neurologic disease in the family
though they are often negative. 36
may also be a clue to mitochondrial
Avoid giving steroids if a biopsy is
disease. An MRI of a patient with mito-
being considered, as this will result in
chondrial myopathy, encephalopathy,
necrosis of the lymphoma cells, render- lactic acidosis, and strokelike episodes
ing pathologic diagnosis difficult to syndrome (MELAS) presenting as an
impossible (Figure 7-2). When a neo- RPD with some imaging features
plastic condition is in the differential, a overlapping with Jakob-Creutzfeldt
thorough general medical examination, disease is shown in Figure 7-9.59
a chest/abdomen/pelvis CT (with and
without contrast), possibly with a full CONCLUSION
body PET scan, should be considered, The evaluation of a patient with an RPD
depending on the clinical context.15 can be challenging and time consuming.
Therefore, it is important to have a
Systemic/Structural structured approach to the diagnostic
There are too many systemic condi- evaluation. A few important factors per-
tions that can present as RPDs to dis- haps have led to the improved ability
cuss in detail here, but several to to differentiate and diagnose RPDs
consider are listed in Table 7-4.5,43 In over the past few years. Diagnosis of
a patient with an unexplained mul- many forms of human prion diseases
tisystem disorder, consider mitochon- and distinction from other RPDs has
drial disease, particularly if there are become easier and more accurate

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 Rapidly Progressive Dementia

FIGURE 7-9 MRI and spectroscopy in a case of mitochondrial myopathy,

encephalopathy, lactic acidosis, and strokelike episodes syndrome
(MELAS). A 59-year-old woman developed confusion, progressive
aphasia, mutism, and fluctuations of alertness over 2 weeks.
Diffusion-weighted imaging (DWI) MRI revealed abnormalities overlapping with
Jakob-Creutzfeldt disease (A), although the fluid-attenuated inversion recovery
(FLAIR) MRI (B) with white and gray matter hyperintensity was not consistent with
Jakob-Creutzfeldt disease. CSF showed normal cell counts, negative polymerase
chain reaction (PCR) for herpes simplex virus, elevated lactate (4.6 mmol/L), and
increased levels of 14-3-3 and tau protein (1300 pg/L), both concerning for
Jakob-Creutzfeldt disease. There were no periodic sharp-wave complexes on EEG
recordings. Magnetic resonance spectroscopy revealed a lactate signal indicative of
mitochondriopathy and genetic analysis confirmed the MELAS A3243G mutation.
The DWI (A) displays bitemporal neocortical hyperintense signals. The FLAIR (B) 2 days
after the initial MRI scan reveals newly emerging symmetric lesions in the pulvinar
thalami. Magnetic resonance spectroscopy (C) displays a strong lactate signal.
Cho = choline; Cr = creatine; Cr2 = phosphocreatine; Ins dd1 = myoinositol;
LAC = lactate; NAA = N-acetylaspartate; ppm = parts per million.
Reprinted with permission from Weiss D, et al, Neurology.59 www.neurology.org/content/77/9/
914.full. B 2011 American Academy of Neurology.

534 www.ContinuumJournal.com April 2016

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because of the more common use of 5. Geschwind MD, Shu H, Haman A, et al.
Rapidly progressive dementia. Ann Neurol
diffusion MRI (DWI and ADC maps) 2008;64(1):97Y108. doi:10.1002/ana.21430.
for diagnosis of Jakob-Creutzfeldt dis-
6. Vitali P, Maccagnano E, Caverzasi E, et al.
ease as well as improved methods for Diffusion-weighted MRI hyperintensity patterns
detection of prions (not just biomark- differentiate CJD from other rapid dementias.
ers) in the CSF using protein misfolding Neurology 2011;76(20):1711Y1719.
doi:10.1212/WNL.0b013e31821a4439.
cyclic amplification assay and RT-QuIC.2
The identification of novel antibody- 7. Poser S, Mollenhauer B, Kraubeta A, et al.
How to improve the clinical diagnosis of
mediated dementias, particularly those Creutzfeldt-Jakob disease. Brain 1999;122
with cell surface antigens, has expanded (pt 12):2345Y2351. doi:10.1093/brain/
dramatically over the past decade. 122.12.2345.
These conditions have led to a new 8. Chitravas N, Jung RS, Kofskey DM, et al.
field within neurology that is particu- Treatable neurological disorders misdiagnosed
as Creutzfeldt-Jakob disease. Ann Neurol
larly exciting because of the reversibility 2011;70(3):437Y444. doi:10.1002/ana.22454.
of many of these conditions. 9. McKeon A. Autoimmune
encephalopathies and dementias.
ACKNOWLEDGMENTS Continuum (Minneap Minn) 2016;22(2
Dementia):538Y558.
The author would like to thank the
10. Renaud DL. Adult-onset leukoencephalopathies.
National Institutes of Health/National
Continuum (Minneap Minn) 2016;
Institute on Aging (R01 AG031189; K23 22(2 Dementia):559Y578.
AG0219889; P01 AG021601); National 11. Papageorgiou SG, Kontaxis T, Bonakis A,
Institutes of Health/National Center et al. Rapidly progressive dementia: causes
for Research Resources, University of found in a Greek tertiary referral center in
Athens. Alzheimer Dis Assoc Disord 2009;
California, San Francisco, Clinical and 23(4):337Y346. doi:10.1097/WAD.
Translational Science Institute (UL1 0b013e31819e099b.
RR024131); the Michael J. Homer 12. Sala I, Marquié M, Sánchez-Saudinós MB,
Family Fund; and Quest Diagnostics et al. Rapidly progressive dementia:
experience in a tertiary care medical
for support of his research in rapidly center. Alzheimer Dis Assoc Disord
progressive dementia and related dis- 2012;26(3):267Y271. doi:10.1097/
orders. He also thanks Mee-Ohk Kim, WAD.0b013e3182368ed4.
MD, PhD, for help in preparation of 13. Lindau M, Almkvist O, Kushi J, et al. First
this manuscript. symptomsVfrontotemporal dementia versus
Alzheimer’s disease. Dement Geriatr Cogn
Disord 2000;11(5):286Y293. doi:10.1159/
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 Review Article

Autoimmune
Address correspondence to
Dr Andrew McKeon,
Neuroimmunology Laboratory,

Encephalopathies and
Mayo Clinic, 200 1st St SW,
Rochester, MN 55905,
[email protected].

Dementias
Relationship Disclosure:
Dr McKeon receives research
funding from MedImmune.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Andrew McKeon, MD
Dr McKeon discusses the
unlabeled/investigational
treatments for autoimmune ABSTRACT
encephalopathies and
dementias, none of which Purpose of Review: This article describes the methods of diagnosis and manage-
have been approved by ment of autoimmune encephalopathies and dementias. The expedited distinction of
the US Food and Drug
Administration for
autoimmune encephalopathies and dementias from neurodegenerative disorders is
these indications. important because treatment is most effective at the early stage of illness.
* 2016 American Academy Recent Findings: The spectrum of antibody biomarkers of treatable autoimmune
of Neurology. encephalopathies continues to broaden and now includes antibodies targeting glu-
tamate receptors (N-methyl-D-aspartate [NMDA] and !-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid [AMPA]), +-aminobutyric acid A and B (GABA-A and GABA-B)
receptors, glycine receptors, potassium channel complexes (Kv1, which includes
leucine-rich, glioma inactivated 1 [LgI1], contactin-associated proteinlike 2 [CASPR2],
and unknown specificity, and Kv4.2, which includes dipeptidyl-peptidase 6 [DPPX]),
and glutamic acid decarboxylase 65 (GAD65). Early treatment of certain autoimmune
encephalopathies with rituximab or cyclophosphamide improves outcome when cor-
ticosteroids, IV immunoglobulin (IVIg), and plasma exchange have proven ineffective.
Summary: Despite the progress made in diagnostics, in many instances, patients with
immunotherapy-responsive encephalopathies and dementias are seronegative for
encephalitis-specific antibodies. Other clues to an autoimmune cause include a
subacute symptom onset, rapid progression, personal history of autoimmunity or
cancer, an inflammatory CSF, non-neural antibodies detected in serum, and a response
to immunotherapy.

Continuum (Minneap Minn) 2016;22(2):538Y558.

INTRODUCTION CSF (eg, leucine-rich, glioma inactivated

An autoimmune cause for cognitive 1 [LgI1] antibody, a subtype of voltage-
impairment is frequently considered gated potassium channel [VGKC] com-
by neurologists because of the potential plex antibodies) (Case 8-1). In other
for reversibility with immunotherapy. instances, patients may present with
Classic limbic encephalitis is usually ac- rapid cognitive decline only, without de-
companied by an altered sensorium, lirium or seizures, and a rapidly progres-
rapid cognitive decline, altered mood
sive neurodegenerative dementia, such
and personality, and seizures. Because
as Jakob-Creutzfeldt disease, as well as
of the classic presentation and typical
mesial temporal T2 findings, limbic an autoimmune cause, may enter the
encephalitis is usually recognized by differential diagnosis. One or more of
neurologists. Once infection has been the following may serve as diagnostic
excluded from consideration, a well- clues for an autoimmune cause in that
characterized and diagnostic neural context: a rapidly progressive or fluctu-
antibody may be detected in serum or ating course, a clinical history of

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 Case 8-1
A 57-year-old man presented with left arm tingling that he experienced every
10 minutes. Oral corticosteroids were prescribed by his primary physician for
what was thought to be a cervical radiculopathy, and his symptoms resolved.
One month later, he developed a subacute onset of episodic dysphasia and
rapidly progressive memory difficulties. He underwent neurologic evaluation.
Neuropsychometric testing demonstrated an amnestic profile. Brain MRI
showed mesial temporal T2 signal abnormality more prominent on the left
than the right. His EEG demonstrated left temporal sharp waves and temporal
intermittent rhythmic delta activity. Voltage-gated potassium channel
complex (VGKC) antibodies were detected at a value of 1.00 nmol/L and
were determined to specifically target leucine-rich, glioma inactivated 1 (LgI1).
Initial treatment consisted of levetiracetam 1000 mg 2 times a day, and IV
methylprednisolone 1000 mg/d for 5 days followed by weekly infusions.
Although initial improvements occurred, the patient began to relapse with
weekly treatments. His memory was worse, he had also developed a new
mood disorder, and the abnormality in the right hippocampus on MRI
appeared more prominent. Plasma exchange was started (five treatments,
every other day, for 10 days) followed by prednisone 60 mg/d for 3 months,
followed by tapering the daily dose each subsequent month by 10 mg, until
the dose of 10 mg/d was reached, which was then tapered by 1 mg each
subsequent month until the prednisone was discontinued.
He developed a cushingoid physical appearance, which resolved on
discontinuation of prednisone. Prophylaxis with calcium, vitamin D, and
trimethoprim/sulfamethoxazole was used until prednisone was discontinued.
Despite this, he developed osteoporosis, and bisphosphonate therapy was
started. Because of his initial relapsing course, azathioprine was started with the
intention of the patient receiving 2.5 mg/kg/d for 5 years of treatment.
However, his thiopurine methyltransferase value was mildly low (16.6 units/mL,
where greater than 17.0 units/mL is normal), indicating that he might not
metabolize azathioprine well and be prone to drug toxicity. The patient had
steady improvements in cognitive function, regaining normal function over
the course of 1 year. His mood disorder did not improve with immunotherapy,
nor with tapering and discontinuing levetiracetam. Citalopram was started,
and his mood improved. The patient developed elevated liver transaminase
enzyme levels, which were attributed to azathioprine (thiopurine
metabolites were elevated in serum). Mycophenolate mofetil was used in
the place of azathioprine for remission maintenance for 3 years.
Comment. This case demonstrates a number of important points,
including the possibility for complete remission with sustained, multimodal
immunotherapy; the complications that can arise with corticosteroid therapy;
the importance of prophylaxis for the bone demineralizing and opportunistic
infectious effects of steroids; the high probability of developing side
effects from azathioprine if the thiopurine methyltransferase is low; and
the complementary role for symptom-based treatments (antiepileptics
and antidepressants).

coexisting autoimmunity, the presence may persist at the end of testing and a
of inflammatory markers in the CSF, trial of immunotherapy may prove
and detection of autoantibodies in diagnostic, one way or the other.
serum or CSF. Sometimes, uncertainty Autoimmune cognitive disorders are

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 Autoimmune Encephalopathies

KEY POINTS
h The clinical phenotypically and immunologically DIAGNOSTIC CLUES
manifestations of diverse. Ordinarily, the terms enceph- The following diagnostic clues are
neurologic autoimmunity alopathy or encephalitis imply the worth considering when an autoim-
are diverse (including presence of an altered sensorium or mune etiology is suspected for a patient
encephalopathy) and are consciousness, while the term demen- presenting with a new-onset cognitive
often multifocal. tia does not. For brevity, this article disorder (Table 8-13).
h In the absence of will refer to these disorders as autoim-
mune encephalopathies. Clinical Manifestations
detection of an
encephalitis-specific The clinical manifestations of neuro-
antibody (eg, leucine-rich, EPIDEMIOLOGY logic autoimmunity are diverse and
glioma inactivated 1 or Precise frequency data for autoimmune often multifocal. While certain disor-
N-methyl-D-aspartate encephalopathies, dementias, and epi- ders have been syndromically associ-
receptor antibody), a lepsies are not available. These disor- ated with certain autoantibody markers
history of autoimmune (eg, limbic encephalitis and LgI1 auto-
ders are clearly underrecognized. A
disease or seropositivity antibodies),4 a spectrum often emerges
review of over 1000 brain autopsy cases
for other autoantibodies over time through individual case re-
(organ-specific or referred to the US National Prion Dis-
ports or by systematic serologic evalu-
nonYorgan-specific ease Pathology Surveillance Center as ation of large numbers of patients not
autoantibodies) are risk Jakob-Creutzfeldt disease demonstrated selected by neurologic syndrome.5 For
factors for an autoimmune an undiagnosed, treatable cause for example, VGKC complex antibodies
encephalopathy. dementia in 7% of cases, most preva- were initially considered to be specific
lent of which were autoimmune disor- for autoimmune limbic encephalitis
ders.1 Among Mayo Clinic patients or disorders of peripheral nervous
diagnosed with and treated for an au- hyperexcitability, but, over time, other
toimmune encephalopathy or demen- presentations have been reported, in-
tia, 35% had been diagnosed with a cluding a rapidly progressive course
neurodegenerative disorder.2 mimicking Jakob-Creutzfeldt disease.6

a
TABLE 8-1 Key Features of Autoimmune Encephalopathy or Dementia

b Subacute onset
b Fluctuating course
b Tremor
b Headache
b Personal or family history (first-degree relative) of autoimmunity
b History of recent or past neoplasia
b Evidence of central nervous system inflammation on CSF (elevated protein,
pleocytosis, oligoclonal bands, elevated CSF index)
b Evidence of central nervous system inflammation on MRI (mesial temporal
or other regional T2 hyperintensity)
b Hypometabolism on functional imaging
b Detection of neural autoantibody
CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.
a
Data from McKeon A, et al, Continuum (Minneap, Minn).3 journals.lww.com/continuum/
Fulltext/2010/04000/IMMUNOTHERAPY_RESPONSIVE_DEMENTIAS_AND.8.aspx.

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 KEY POINTS
Morvan syndrome is a rare multifocal cell-surface antigens (eg, LgI1) may be h Detection of a neural-
manifestation of VGKC complex auto- pathogenic, while antibodies directed specific autoantibody
immunity that includes features of at an intracellular antigen (eg, antineu- serves as a marker of
limbic encephalitis, sleep disturbance, ronal nuclear antibody type 1 [ANNA-1], neurologic autoimmunity.
and peripheral nerve hyperexcitability.4 also known as anti-Hu) are more likely
h A profile of neural-
markers of a T-cellYmediated disease.7 specific autoantibodies
Risk Factors
may aid the identification
In the absence of detection of an Identifying a Paraneoplastic of a paraneoplastic
encephalitis-specific antibody (eg, Disorder encephalopathic disorder.
LgI1 or N-methyl-D-aspartate [NMDA] A profile of neural-specific autoanti- h Neurologic improvement
receptor antibody), a history of auto- bodies may aid in the identification of after immunotherapy
immune disease or seropositivity for a paraneoplastic disorder.7 may be diagnostically
other autoantibodies (organ-specific Antibodies with neural specificity informative of
or nonYorgan-specific autoantibodies) have varying degrees of paraneoplastic autoimmune
are risk factors for an autoimmune significance (Table 8-2 and Table 8-3). encephalopathy.
encephalopathy. h In many instances, the
Multiple autoimmune disorders may Improvement After diagnosis of autoimmune
occur in the same patient, and individ- Immunotherapy encephalopathy is based
uals with an autoimmune disease are Neurologic improvement after immu- on clinical improvements
at higher risk of developing a second notherapy may be diagnostically infor- obtained with
autoimmune disorder. For example, mative. In many instances, the diagnosis immunotherapy.
just as systemic lupus erythematous may of autoimmune encephalopathy is based Therefore, baseline
develop in a patient with type 1 diabetes on clinical improvements obtained with objective clinical,
mellitus, autoimmune thyroiditis (a immunotherapy. Therefore, baseline electrophysiologic,
very common form of autoimmunity) objective clinical, electrophysiologic, radiologic, and
and an autoimmune encephalopathy radiologic, and neuropsychological neuropsychological
(a relatively uncommon form of auto- testing provides reference points for testing provides
immunity) also may occur in the same reference points for
evaluating clinical improvement with
patient. Thus, the presence of autoim- evaluating clinical
immunotherapies.
improvement with
mune thyroiditis reflects a risk for de-
immunotherapies.
veloping other autoimmune diseases, Personal or Family History of
including an autoimmune encephalop- Autoimmunity h Patients with an
athy. However, the detection of thy- autoimmune neurologic
Patients with an autoimmune neuro-
roid, systemic lupus erythematous, or disorder may have a
logic disorder may have a background
Sjögren syndrome antibodies in a pa- background of having
of having a relatively common sys- a relatively common
tient with an autoimmune encepha- temic autoimmune disease or may have systemic autoimmune
lopathy does not imply neurologic several first-degree relatives affected disease or may have
pathogenicity of the antibodies de- (Case 8-2). several first-degree
tected. Also, some connective tissue These autoimmune disorders may relatives affected by
disease antibodies are commonly de- be organ specific (including thyroid dis- common systemic
tected in the general healthy popula- ease, diabetes mellitus, pernicious ane- autoimmune diseases.
tion and should be interpreted with mia, Sjögren syndrome, rheumatoid
caution in the context of a cogni- arthritis, alopecia, vitiligo, and Addison
tive disorder. disease) or nonYorgan specific (sys-
temic lupus erythematous, systemic
Identifying Neural-Specific sclerosis, and mixed connective tissue
Autoantibodies disease). A personal history of cancer
Detection of a neural-specific autoan- or smoking may also serve as clues
tibody serves as a marker of neurologic to a paraneoplastic cause. A review of
autoimmunity. Antibodies directed at systems for symptoms consistent with

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 Autoimmune Encephalopathies

TABLE 8-2 Neuronal Nuclear, Cytoplasmic, and Nucleolar Antibodies

Antibody Cognitive Disorders Other Neurologic Manifestations Cancer Association

ANNA-1 (Hu) Limbic or Peripheral neuropathy (most Small cell carcinoma;a
extralimbic commonly sensory), cerebellar thymoma; neuroblastoma
encephalitis syndrome, cranial neuropathy (children)
ANNA-2 (Ri) Dementia, limbic Brainstem encephalitis, cerebellar Breast adenocarcinoma,
encephalitis, disorder, myelopathy, peripheral small cell carcinomaa
encephalopathy neuropathy
ANNA-3 Limbic encephalitis Peripheral neuropathy (sensory/ Small cell carcinoma,a
sensorimotor), cerebellar ataxia, adenocarcinoma (lung
brainstem encephalitis, or esophagus)
myelopathy
PCA-2 Limbic encephalitis Brainstem encephalitis, cerebellar Small cell carcinomaa
disorder, Lambert-Eaton
myasthenic syndrome, peripheral
and autonomic neuropathies
Amphiphysin Cognitive dysfunction, Neuropathy, myelopathy, stiff Small cell carcinoma,a
IgG encephalopathy, person syndrome, Lambert-Eaton breast adenocarcinoma
limbic encephalitis myasthenic syndrome
CRMP-5 IgG Subacute dementia, Seizures, chorea, ataxia, psychiatric Small cell carcinoma,a
personality change symptoms, cranial neuropathy thymoma
(optic neuropathy, abnormal
olfaction/taste), myelopathy,
radiculopathy, neuropathy,
Lambert-Eaton myasthenic syndrome
Ma1, Ma2 Memory impairment, Brainstem encephalitis, cerebellar Testicular germ cell
antibodies dementia, limbic syndrome, hypothalamic disorder, tumors (Ma2); lung cancer,
encephalitis psychiatric symptoms gastrointestinal cancer,
non-Hodgkin lymphoma,
breast cancer (Ma1, Ma2)
GAD65 IgG Limbic encephalitis Seizures, cerebellar ataxia, Thymoma, renal cell,
brainstem encephalitis, stiff person adenocarcinoma (breast or
syndrome, extrapyramidal colon) are rarely reported
signs, myelopathy
AGNA (SOX1) Limbic encephalitis Lambert-Eaton myasthenic Small cell carcinomaa
syndrome, cerebellar dysfunction
AGNA = antiglial/neuronal nuclear antibody; ANNA-1 = antineuronal nuclear antibody type 1; ANNA-2 = antineuronal nuclear antibody
type 2; ANNA-3 = antineuronal nuclear antibody type 3; CRMP-5 = collapsin response mediator protein-5; GAD65 = glutamic acid
decarboxylase 65; IgG = immunoglobulin G; PCA-2 = Purkinje cell cytoplasmic antibody type 2; SOX1 = sex-determining region Y box 1.
a
Small cell carcinoma can be pulmonary or extrapulmonary.

KEY POINT an underlying malignancy, including subacute onset (ie, evolving over days
h Autoimmune weight loss, night sweats, and altered to weeks).
encephalopathic bowel habit, should be undertaken.
symptoms are almost Limbic Encephalitis
always of subacute CLINICAL AND SEROLOGIC Limbic encephalitis classically presents
onset (ie, evolving over SPECTRUM with altered mood, memory, and per-
days to weeks).
Symptoms of autoimmune encephalop- sonality as well as delirium and focal sei-
athy and dementia are almost always of zures of mesial temporal origin, with or

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TABLE 8-3 Antibodies Targeting Neural Ion Channels and Receptors

Other Neurologic
Antibody Cognitive Disorders Manifestations Cancer Association
VGKC complex Limbic encephalitis, amnesia, Seizures, psychiatric symptoms, Small cell lung cancer,
antibody (antigenic executive dysfunction, insomnia, extrapyramidal thymoma, prostate
targets may be LgI1 dementia (including disorder, myoclonus, adenocarcinoma,
or CASPR2) frontotemporal hypothalamic disorder, breast adenocarcinoma
dementiaYlike syndrome autonomic disorders, peripheral
and Jakob-CreutzfeldtY hyperexcitability
like disease)
NMDA receptor Memory impairment, Characteristic multistage Ovarian teratoma
antibody depression, psychosis, syndrome of prodrome,
agitation, behavioral psychiatric symptoms, seizures,
change abnormal movements (including
orofacial dyskinesia), followed
by decreased responsiveness,
hypoventilation, and autonomic
instability
GABA-A and GABA-B Limbic encephalitis, Seizures (limbic encephalitis), Small cell lung
receptor antibodies sometimes seizure visual hallucinations, aphasia, carcinoma,
predominant, other orolingual movements, neuroendocrine
encephalitides cerebellar ataxia neoplasia
AMPA receptor Memory loss, disorientation, Seizures (limbic encephalitis), Breast cancer, lung
antibody psychiatric symptoms, nystagmus, hypersomnia, cancer, thymus cancer
behavioral change, agitation progressive unresponsiveness,
(limbic encephalitis) dysdiadochokinesia, hallucinations
DPPX antibody Cognitive impairment Seizures, myoclonus, sleep B-cell neoplasms
disorders, eye movement
disorders, ataxia,
gastrointestinal dysmotility
Ganglionic Cognitive impairment, Dysautonomia, peripheral Adenocarcinoma,
acetylcholine receptor executive dysfunction, neuropathy renal cell carcinoma,
antibody frontotemporal syndrome, lymphoid cancers
encephalopathy
mGluR5 antibody Limbic encephalitis None Hodgkin lymphoma
Glycine receptor Progressive encephalomyelitis Stiff person syndrome B-cell neoplasms,
with rigidity and myoclonus thymoma
(PERM)
IgLON5 Cognitive decline Chorea, ataxia, dysarthria, None reported
dysphagia, sleep apnea,
dream enactment
AMPA = !-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CASPR2 = contactin-associated proteinlike 2; DPPX = dipeptidyl-peptidase
6; GABA-A = +-aminobutyric acid A; GABA-B = +-aminobutyric acid B; IgLON5 = IgLON family member 5; LgI1 = leucine-rich, glioma
inactivated 1; mGlurR5 = metabotropic glutamate receptor 5; NMDA = N-methyl-D-aspartate; VGKC = voltage-gated potassium channel.

without secondary generalization. Brain bilateral temporal slowing or epilepti-

MRI usually reveals T2 signal abnor- form discharges. The main differential
mality in one or both hippocampal diagnosis is herpes encephalitis. Auto-
regions. EEG may reveal unilateral or immune encephalitis may also have an

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 Autoimmune Encephalopathies

KEY POINTS
h Limbic encephalitis
classically presents with
Case 8-2
A 65-year-old man presented with an abrupt onset and fluctuating course
altered mood, memory,
of memory loss that began 3 months prior to neurologic evaluation. His
and personality as well
symptoms were characterized by inability to recall recent events and
as delirium and focal
conversations. The patient’s personal history was remarkable for pernicious
seizures of mesial
anemia. The patient’s sister had Hashimoto thyroid disease. The Kokmen
temporal origin, with or
Short Test of Mental Status revealed a score of 36 out of 38 (losing 2 of 4 for
without secondary
recall). His MRI brain scan demonstrated nonspecific white matter change,
generalization.
and his EEG showed moderate generalized slowing. Neuropsychological
h Autoimmune evaluation revealed learning and memory impairments consistent with the
dementia phenotypes amnestic variant of mild cognitive impairment. Serum and CSF testing for
may resemble neural and non-neural autoantibodies was negative. Because of the abrupt
Jakob-Creutzfeldt onset of symptoms, and the presence of both personal and family histories of
disease, which, classically, autoimmunity, a course of IV methylprednisolone was undertaken (1000 mg/d
is a rapidly progressive for 3 consecutive days, followed by 1000 mg/wk for 5 weeks). The patient
neurodegenerative reported dramatic improvement of cognition, and learning and memory
disorder accompanied by were significantly improved on neuropsychometric reevaluation.
ataxia and myoclonus. Comment. This case demonstrates an autoimmune cognitive disorder limited
h Central nervous system to mild cognitive impairment. Personal and family histories of autoimmunity
infection and other were key diagnostic clues, despite the absence of neural autoantibodies in the
inflammatory central serum and CSF. Neuropsychological evaluations performed before and after
nervous system disorders immunotherapy allowed objective assessment of the response to treatment.
are major differential
diagnostic considerations
extratemporal localization, affecting ease, which, classically, is a rapidly
when evaluating patients
one or more of frontal, parietal, and progressive neurodegenerative disor-
with rapidly progressive
cognitive decline and an occipital regions.8 der accompanied by ataxia and myoc-
inflammatory spinal fluid. Neural autoantibody and cancer as- lonus.6 Rapidly progressive forms of
sociations are protean, and thus a Alzheimer disease and dementia with
comprehensive serologic and CSF anti- Lewy bodies also are difficult to dis-
body evaluation is required (Table 8-2 tinguish clinically from an auto-
and Table 8-3).8 Information regarding immune dementia. Tremulousness and
cancer type and likely treatment re- headache at presentation, marked fluc-
sponsiveness can be obtained from a tuations in the clinical course, and
serologic or CSF diagnosis. For exam- spontaneous remission suggest an au-
ple, a patient with ANNA-1 detected toimmune cause.2
would likely have small cell carcinoma
(90% of patients) usually of lung,9 but N-Methyl-D-aspartate Receptor
improvements with immunotherapy Encephalitis
would be unlikely to occur. In some instances, autoimmune neu-
In contrast, a patient with VGKC com- rologic disorders can be named with
plex antibody would be unlikely to have reference to an autoantibody with high
cancer detected (less than 20% of pa- specificity for encephalitis, detected in
tients), but would likely have very large serum, CSF, or both. Examples include
improvements in cognitive function (or anti-NMDA receptor encephalitis and
even full recovery) if treated early (and LgI1 encephalitis.10,11 Patients with
comprehensively) with immunotherapy.5 NMDA receptor antibody (targeting the
Autoimmune Dementia GluN1 [NR1] subunit) have a stereo-
Autoimmune dementia phenotypes typed neurologic disorder that often
may resemble Jakob-Creutzfeldt dis- evolves in stages, as described by Dalmau

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 KEY POINTS
and colleagues.11 Initial symptoms may Other Autoimmune h N-Methyl-D-aspartate
include headache, fever, nausea, and Encephalopathies receptor encephalitis
prominent psychiatric symptoms. The Sometimes encephalopathy is but one often has a stereotyped
majority of patients initially come to manifestation of an immunologically course evolving from a
the attention of psychiatrists. Depres- well-characterized disorder, examples psychiatric-predominant
sion, anxiety, insomnia, fear, delusions, of which include dipeptidyl-peptidase phenotype to
6 (DPPX) encephalitis, a multifocal cen- encephalopathy, seizures,
mania, and paranoia frequently occur.
tral nervous system (CNS) and auto- and hyperkinetic
Other behavioral changes include so-
movement disorders.
cial withdrawal and stereotyped behav- nomic disorder in which patients may
ior. Amnesia and an unusual language experience seizures, sleep disorders, h Presenting symptoms of
myelopathy, and gastrointestinal dis- brainstem encephalitis
disorder ensue. In children, behav-
ioral change is a common presenting orders (Case 8-3).14,15 Patients with include eye movement
DPPX or glycine receptor autoimmunity disorders, other cranial
symptom (such as temper tantrums and neuropathies, nausea,
may have a multifocal phenotype known
hyperactivity), which is followed by vertigo, postural
as progressive encephalomyelitis with
neurologic disorders including seizures instability, and
rigidity and myoclonus (PERM).16
and dyskinesia, which may also be the parkinsonism.
In other instances, the more generic
presenting symptoms in children. After term of autoimmune encephalopathy
these initial symptoms, decreased re- without reference to a specific neural
sponsiveness ensues in both adults and antibody is appropriate. This is because
children. Movement disorders are di- the neural antibody detected has less
verse and include oro-lingual-facial dys- specificity for encephalitis (eg, !-3
kinesia, generalized limb and truncal ganglionic acetylcholine receptor), or
dyskinesia, oculogyric crisis, dystonia, no neural antibody has been detected
and rigidity. Central autonomic mani- despite comprehensive evaluation, but
festations, including hyperthermia, other clues for an autoimmune diag-
tachycardia, and hypertension, may be nosis have emerged. These clues could
severe and necessitate intensive care include one or more of a history of co-
unit management. Hypoventilation may existing autoimmune diseases (eg,
occur, necessitating prolonged ventila- thyroid disease), the detection of non-
tory support (often months). neural autoantibodies (such as thyroid
autoantibodies) in serum, or an inflam-
Brainstem Encephalitis matory spinal fluid, an encephalitic-
Presenting symptoms of brainstem appearing head MRI, and a response
encephalitis include eye movement to immunotherapy.2
disorders, other cranial neuropathies, Both Hashimoto encephalopathy
nausea, vertigo, postural instability, and steroid-responsive encephalopathy
and parkinsonism.12 These are com- associated with autoimmune thyroiditis
mon presentations for patients with (SREAT) refer to a triad of encepha-
Ma2 antibodies (anti-Ta, which usually lopathy, thyroid autoimmunity, and
occurs in young men with testicular clinical improvements with immuno-
carcinoma) or both Ma1 and Ma2 anti- therapy.17 Because both thyroid auto-
bodies (anti-Ma, which occurs in both antibodies and cognitive symptoms are
men and women with a variety of common in the general population, this
cancer types).12 Jaw dystonia is an un- example serves to underline the im-
usual manifestation of brainstem en- portance of objectifying cognitive im-
cephalitis reported in antineuronal provements with immunotherapy.
nuclear antibody type 2 (ANNA-2) sero- Corticosteroids have nonspecific acti-
positive patients.13 vating effects (eg, improved mood,
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 Autoimmune Encephalopathies

KEY POINTS
h Caution is advised
regarding making a
Case 8-3
A 27-year-old man presented with cognitive impairment, incoordination,
diagnosis of Hashimoto
and vision disturbance that began 1 year prior to neurologic evaluation.
encephalopathy
His neurologic symptoms were preceded by a 3-year history of weight loss
(also known as
and irritability. Examination revealed an amnestic syndrome, multifocal
steroid-responsive
myoclonus, diffuse hyperreflexia, ataxia, and nystagmus. Gastrointestinal
encephalopathy
motility studies documented gastroparesis and bowel hypomotility, and
associated with
autonomic reflex testing demonstrated cardiovagal and vasomotor
autoimmune thyroiditis)
dysfunction. A sleep study demonstrated obstructive sleep apnea and
in patients with
ambiguous sleep (where rapid eye movement [REM] sleep and non-REM
cognitive symptoms
sleep are difficult to distinguish during polysomnography). Video EEG
(without objective
demonstrated continuous tremulousness without epileptiform correlate,
abnormalities) and
which was confirmed by surface EMG to be myoclonus. Dipeptidyl-peptidase
thyroid autoimmunity,
6 (DPPX) antibody was detected in the serum and CSF. His symptoms
which is common in
improved after treatment with IV methylprednisolone. Oral prednisone and
the general population.
a steroid-sparing immunosuppressant (mycophenolate mofetil) were added.
h Other inflammatory His weight, cognition, and balance improved but did not normalize. Five
disorders that can cause months after the initial neurologic presentation and after discontinuing
a dementia phenotype, corticosteroid therapy, visual hallucinations developed and were accompanied
but are of unknown by profound diaphoresis and hypothermia. Cardiac arrest ensued; after
cause, include central successful resuscitation, fluctuating blood pressure and body temperature
nervous system vasculitis, necessitated extended intensive care. Diaphoresis, blood pressure, and
sarcoidosis, and temperature normalized following IV methylprednisolone treatment.
multiple sclerosis. Dysautonomic signs improved greatly following plasma exchange, rituximab,
and slowly tapered prednisone therapy. The patient had remitted from his
encephalitic illness 2 years after initial presentation, with rituximab doses
administered every 6 months used as maintenance therapy. However, he had
mild residual ataxia and cognitive impairment, but was still much troubled
by his sleep disorder.
Comment. This case is illustrative of multifocality (central nervous
system and autonomic disorders) occurring in a patient with autoimmune
encephalopathy, the need for aggressive, sustained immunotherapy in
some patients, and the possibility of residual neurologic problems despite
maximal treatment.

wakefulness, and energy) as well as headache and psychiatric disturbance)

an immunosuppressive capacity. In and one or more of branch retinal artery
the author’s experience, true SREAT occlusions and sudden hearing loss,
is a rare entity, while patients with Susac syndrome should be considered.18
nonspecifically elevated thyroid anti-
bodies and subjective cognitive symp- DIFFERENTIAL DIAGNOSIS
toms occurring in the context of Other causes of cognitive decline
untreated sleep disorders, depression, should be considered and excluded as
and narcotic pain medication use are necessary. In particular, one needs to
commonly encountered. exclude other potentially treatable
In some disorders, characteristic causes of dementia (Table 8-4). Other
noncognitive symptoms may assist in inflammatory disorders that can cause
making an autoimmune diagnosis. For a dementia phenotype, but are of
instance, in patients with rapid cogni- unknown cause, include CNS vasculitis,
tive decline (often accompanied by sarcoidosis, and multiple sclerosis.

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 a
TABLE 8-4 Differential Diagnostic Considerations for Patients With Cognitive Impairment

Potentially Treatable Causes

of Cognitive Impairment Examples
Autoimmune encephalopathies Immunotherapy-responsive disorders of presumed autoimmune
and dementias etiology; some patients have an associated neural-specific antibody
(see Table 8-2 and Table 8-3)
Other inflammatory central Multiple sclerosis, acute disseminated encephalomyelitis,
nervous system (CNS) disorders neurosarcoidosis
Vasculopathies CNS vasculitis, posterior reversible encephalopathy syndrome (PRES),
subdural hematoma
Neoplastic Primary CNS lymphoma (including intravascular and meningeal presentations)
Seizure disorders Nonconvulsive status epilepticus
Iatrogenic Benzodiazepines, antidepressants, antipsychotics, antiepileptics,
anticholinergics, analgesics
Toxic Alcohol, opiates, cocaine, amphetamines, organic solvents
Nutritional deficiency Vitamin B12, thiamine, folic acid
Psychiatric illness Anxiety, depression, psychosis
CNS infection Herpes simplex virus, human herpesvirus 6, human immunodeficiency virus,
fungal (eg, cryptococcus), mycobacterial, Whipple disease, neurosyphilis
Metabolic Respiratory, renal, or liver failure; obstructive sleep apnea syndrome;
mitochondrial disorders (eg, mitochondrial myopathy, encephalopathy,
lactic acidosis, and strokelike episodes syndrome [MELAS])
Endocrine Disturbances in pituitary, thyroid, parathyroid, endocrine, pancreatic, or
adrenal function
a
Reprinted with permission from McKeon A, et al, Continuum (Minneap Minn).3 journals.lww.com/continuum/Fulltext/2010/04000/
IMMUNOTHERAPY_RESPONSIVE_DEMENTIAS_AND.8.aspx. B 2010 American Academy of Neurology.

CLINICAL EXAMINATION AND posttreatment cognitive profile may KEY POINTS

COGNITIVE TESTING be compared. Where possible, a more h Where possible, a
more detailed
Bedside tests include the Mini-Mental detailed neuropsychological profile
neuropsychological
State Examination (MMSE), the Kokmen should be obtained to document mild profile should be
Short Test of Mental Status, and the abnormalities not detectable by bed- obtained to document
Montreal Cognitive Assessment (MoCA). side testing and to exclude potential mild abnormalities not
Autoimmune neurologic disorders are confounders (such as mood disorders detectable by bedside
often multifocal; thus, it is important to and the side effects of psychoactive testing and to exclude
note neurologic symptoms and signs medications). potential confounders
(such as mood
accompanying cognitive impairment IMAGING disorders and the side
or seizures. These signs may include
Imaging of the brain can provide both effects of psychoactive
ataxia, brainstem abnormalities, parkin- medications).
structural and functional clues to an
sonism, myoclonus, tremor, myelopathy,
autoimmune cause for encephalopathy. h Imaging of the brain
or a peripheral nervous system disor- can provide both
der. These evaluations enable documen- Magnetic Resonance Imaging structural and functional
tation of the specific cognitive deficits Mesial temporal hyperintensities, ei- clues to an autoimmune
and serve as a baseline to which the ther unilateral or bilateral with or cause for encephalopathy.

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 Autoimmune Encephalopathies

without enhancement after gadolinium white matter lesions involving the cor-
administration, are classic autoim- pus callosum, somewhat mimicking
mune limbic encephalitis findings multiple sclerosis, but with prominent,
(Figure 8-1). Normal imaging is com- extensive leptomeningeal enhancement.
mon, particularly in the early illness Rapidly resolving large hemispheric
stages, and is the norm in patients T2 abnormalities should raise concern
with anti-NMDA receptor encephali- for a mitochondrial disorder, such as
tis.11 Extratemporal abnormalities are mitochondrial myopathy, enceph-
sometimes observed. If lesions are not alopathy, lactic acidosis, and stroke-
in a typical distribution or have avid en- like episodes syndrome (MELAS).
hancement, other inflammatory (eg, Nonenhancing posterior predominant
neurosarcoidosis) or oncologic (eg, white matter lesions should raise
lymphoma) diagnoses should be con- concern for progressive multifocal
sidered. Patients with Susac syndrome leukoencephalopathy. Cortical ribbon
usually have multiple hemispheric hyperintensities can be observed in

FIGURE 8-1 MRI findings in autoimmune encephalopathy, including unusual extratemporal disorders. MRI images include
T2 fluid-attenuated inversion recovery (FLAIR) coronal (A, B, D, E), axial (C), and turbo spin echo axial (F).
A, Classic limbic encephalitis (arrows). B, image also shows limbic encephalitis, but bilateral T2 signal change
is more subtle (arrows). C, Normal MRI in patient with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. D, F, Images
from two patients demonstrate unilateral frontal abnormalities (arrows). Panel D shows a patient with antineuronal nuclear
antibody type 1 (ANNA-1) (anti-Hu antibody), which is more commonly associated with limbic encephalitis. Panel F shows a
patient with a syndrome mimicking corticobasal degeneration, but occurred on a paraneoplastic basis in patient with breast
cancer. E, Image shows bilateral frontoparietal T2 hyperintensities (arrows) in a patient with seronegative autoimmune encephalitis.

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 KEY POINTS
some patients (and thus may be mis- form discharges) also commonly h EEG is also helpful for
leading for Jakob-Creutzfeldt disease).6 occurring. Regional abnormalities documenting functional
most commonly emanate from the abnormalities in patients
Functional Imaging temporal lobes, although extratempo- with autoimmune
Global hypometabolism is the most ral abnormalities have also been re- encephalitis.
common feature encountered in pa- ported.20 Again, improvements in these h Objectifying the
tients with autoimmune encephalopa- abnormalities can be reassuring regard- cognitive abnormalities
thies. However, focal hypometabolism ing the efficacy of treatment. through clinical
can also be encountered (Figure 8-2).2 examination, cognitive
In instances where the patient has sei- ROUTINE CEREBROSPINAL FLUID testing, imaging,
zures, hypermetabolism can occur.19 PARAMETERS and EEG is critical
Further clues to an autoimmune eti- to the diagnosis
ELECTROPHYSIOLOGY ology for a cognitive disorder may be of autoimmune
EEG is helpful for documenting func- encephalopathy and
found on CSF evaluation. Elevated
provides a baseline
tional abnormalities in patients with protein concentration (greater than
for treatment.
autoimmune encephalitis. Moderate 100 mg/dL), elevated numbers of white
to severe generalized slowing is usual, blood cells, abnormal numbers of CSF-
with superimposed regional abnor- exclusive oligoclonal bands, and ele-
malities (eg, focal slowing or epilepti- vated IgG index and synthesis rate all

FIGURE 8-2 Fluorodeoxyglucose positron emission tomography (FDG-PET) pretreatment (A)

and postimmunotherapy (B), in a patient with autoimmune encephalopathy.
Sagittal (A, B, top) and coronal (A, B, bottom) views of brain metabolism are
demonstrated. Metabolism ranges from normal (blue) to increasingly abnormal (through green,
yellow, and red). Images demonstrate functional improvement after treatment (arrows).
2
Modified with permission from Flanagan EP, et al. Mayo Clin Proc. www.mayoclinicproceedings.org/article/
S0025-6196(11)60229-2/fulltext. B 2010 Mayo Foundation for Medical Education and Research.

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 Autoimmune Encephalopathies

support an autoimmune cause. These antibodies alone is not diagnostic of

CSF findings, however, are encoun- an autoimmune encephalopathy but
tered in many idiopathic inflammatory generally supports the suspicion of
CNS disorders, including multiple autoimmunity. Also, a patient with cog-
sclerosis. Oligoclonal bands are occa- nitive symptoms who is seropositive for
sionally detected in nonautoimmune antinuclear and double-stranded DNA
contexts such as pathologically proven antibodies might have CNS lupus,22
primary neurodegenerative disorders for which there is no specific antibody
or Jakob-Creutzfeldt disease.21 biomarker available.
The detection of a neural-specific
ANTIBODY TESTING antibody in serum or CSF may be di-
Antibody profiles include neural rectly diagnostic of an autoimmune
(Table 8-2, Table 8-3, and Figure 8-3) neurologic disorder. Antibody tests
and non-neural IgG markers. Seroposi- performed on serum alone might
tivity for non-neural autoantibodies suffice for paraneoplastic antibody
does not confirm a diagnosis of an auto- testing, although overall combined
immune CNS disorder, but does sup- serum and CSF testing increases the
port consideration of an autoimmune diagnostic yield for classic paraneoplas-
pathogenesis, particularly in those who tic antibodies (such as collapsin response
have negative testing for encephalitis- mediator protein-5 [CRMP-5] IgG)
specific antibodies. Seropositivity may somewhat.23 However, in the case of
also trigger a trial of treatment. For NMDA receptor antibodies, CSF is al-
example, detection of thyroid auto- ways more informative than serum.24

FIGURE 8-3 Typical patterns of patient neural IgG antibody staining. Indirect immunofluorescence testing employs
composite of mouse brain tissues on which patient serum or CSF is applied. Panels A, B, and C show
cerebellum, and panels D, E, and F show hippocampus. Dipeptidyl-peptidase 6 (DPPX) antibody (A and D),
+-aminobutyric acid B (GABA-B) receptor antibody (B and E), and N-methyl-D-aspartate (NMDA) receptor antibody (C and F)
are shown.

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 In contrast, VGKC complex anti- profile may predict the cancer type in
bodies are more readily detectable in some circumstances. An algorithmic
serum than in CSF.25 Although these approach to testing for autoantibody
antibodies target antibodies physically profiles is usually a more sensitive
related to Kv1.1, Kv1.2, and Kv1.6 diagnostic strategy than physician-
potassium channels, they may not tar- selected single antibody testing. Some-
get the potassium channels themselves, times a single antibody will be positive,
and some target proteins physically but in others positivity for multiple auto-
coupled to potassium channels (LgI1 antibodies will be detected. For ex-
and contactin-associated proteinlike 2 ample, seropositivity for amphiphysin
[CASPR2]). However, in more than 50% antibody predicts either small cell car-
of VGKC complex antibodyYpositive cinoma or breast adenocarcinoma, but
cases, the LgI1 and CASPR2 antibodies the presence or absence of coexisting
are not detected.5 Although caution is antibodies narrows that differential
advised in interpreting such results, it diagnosis. Among 63 patients at the
is sometimes inaccurately stated that Mayo Clinic with amphiphysin anti-
VGKC complex IgGs that are LgI1 or body and cancer history, 33 had small
CASPR2 negative are always nonspecific. cell lung carcinoma; of those patients,
Examples of other antibodies that 27 had coexisting neural-specific au-
target neural plasma membrane an- toantibodies that also predicted small
tigens that have been described in cell carcinoma. In contrast, 30 patients
autoimmune encephalitis include gluta- with amphiphysin-IgG seropositivity
matergic !-amino-3-hydroxy-5-methyl- in whom breast adenocarcinoma was
4-isoxazolepropionic acid (AMPA) found were otherwise seronegative.30
receptor,26 +-aminobutyric acid A Seronegativity does not exclude a
(GABA-A) receptor,27 +-aminobutyric paraneoplastic cause. Suspicion for a
acid B (GABA-B) receptors,28 and paraneoplastic cause may also be raised
IgLON family member 5 (IgLON5) by risk factors obtained from the clin-
(Table 8-3).29 The latter disorder is ical history, such as a smoking history
possibly at the interface of current or previous cancer history. A thorough
knowledge between autoimmune physical examination and CT of chest,
and neurodegenerative disorders. abdomen, and pelvis are commonly
Described in one study to date, pa- undertaken as primary screening
tients seropositive for IgLON5 anti- tests. Other tests may be required de-
body have obstructive sleep apnea,
pending on age, sex, and other risk
sleep behavior symptoms, move-
factors. Testicular ultrasound or prostate-
ment disorders, a lack of response to
specific antigen testing and digital rec-
immunotherapy, and a brainstem-
and hypothalamus-restricted tauo- tal prostate examination are required
pathy at autopsy. Of the patients to evaluate for testicular and prostate
described in one study, two out of carcinomas, respectively. MRI or ultra-
eight had cognitive impairment.29 sound (including transvaginal imaging)
of the pelvis and gynecologic examina-
ONCOLOGIC SIGNIFICANCE tion are required to evaluate for ovarian
An autoimmune encephalopathy or carcinoma or teratoma. Mammography
dementia may occur as an aberrant and breast examination are required to
by-product of an immune response evaluate for breast adenocarcinoma.
directed against a non-neurologic can- Endoscopic examination of the upper
cer. A paraneoplastic autoantibody and lower gastrointestinal tracts should

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 Autoimmune Encephalopathies

KEY POINTS
h Normal results of MRI, also be considered where appropriate. pathogenic effects of these antibodies
CSF testing, and Positron emission tomography (PET) (impaired neuronal or glial function,
antibody testing do not coregistered with CT (PET/CT) imag- but not destruction, at least early on),
exclude an autoimmune ing increases the diagnostic yield for which may be reversed by immuno-
encephalopathy cancer by 20% for patients in whom therapy (eg, removal by plasma ex-
diagnosis, but normal change) resulting in reversal of
standard evaluations have been unre-
findings in all neurologic dysfunction.34 The timing
vealing for cancer.31
three make the of immunotherapy is important. Case
diagnosis unlikely. TREATMENT series of patients with autoimmune
h In a paraneoplastic CNS disorders have demonstrated that
Randomized, controlled treatment tri-
context, the early immunotherapy confers a better
als for the treatment of autoimmune
autoantibody profile treatment outcome than delayed ther-
CNS disorders are lacking. Treatment
may narrow the search apy.2,35,36 A lack of response to one
data are derived from case reports, case
for cancer. modality (eg, corticosteroids) does not
series, and expert opinion.32 Based on
exclude a response to another agent
the available literature and the author’s (eg, IV immunoglobulin [IVIg]).
experience, a therapeutic approach is The immunotherapy protocol has
outlined.32 The treatment protocol two components: acute therapy and
must be individualized for the patient, chronic therapy. Before starting treat-
dictated by clinical severity, types of ment, baseline neurologic and ancillary
antibodies detected, and the presence evaluations should be performed to
or absence of cancer. Also, responses to establish parameters for objective
short-term treatments usually inform treatment-response monitoring, as de-
the approach to long-term treatment, scribed earlier. Antibody titers have
if needed. limited use as a surrogate of clinical
Immunotherapy outcome in the acute phase of treat-
ment because values usually reduce
Most of the recommendations dis- with treatment even if therapy is not
cussed in the following sections are clinically beneficial. There may be a role
supported by observational studies and for antiepileptic drug therapy in addi-
the experiences of the author and other tion to immunotherapy in those pa-
colleagues at Mayo Clinic for managing tients who have seizures as well as
autoimmune neurologic disorders cognitive dysfunction.
(Table 8-5 and Figure 8-4).
The type of antibody identified may Acute Therapy
predict the neurologic response to im- For acute therapy, a trial of high-dose
munotherapy. Detection of antibodies pulse IV corticosteroid therapy is
targeting intracellular antigens such as usually the first treatment. IVIg may
Purkinje cell cytoplasmic antibody be used in patients who are unlikely to
type 1 (PCA-1) (anti-Yo) portends limi- tolerate corticosteroids or are at risk for
ted responses to immunotherapy and diabetes mellitus (including patients
a poor prognosis. This may be the case positive for glutamic acid decarboxylase
because the immune process is medi- 65 [GAD65] antibodies). Typical treat-
ated by cytotoxic T cells, leading to ment protocols include 1000 mg/d of
irreversible neuronal degeneration.33 IV methylprednisolone or 0.4 g/kg/d
On the other hand, detection of anti- of IVIg for 5 consecutive days. Most
bodies targeting neural surface antigens patients with autoimmune encepha-
(such as NMDA receptors and LgI1) litis require maintenance treatment
usually predicts a more favorable out- thereafter. In those patients with se-
come. This may be explained by the vere encephalitis, daily oral or IV

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 a
TABLE 8-5 Commonly Used Therapies for Autoimmune Encephalopathies

Therapeutic
Treatment Regimen Route Common Side Effects Phase
Methylprednisolone 1000 mg/d for 3 days, followed IV Insomnia, psychiatric symptoms, Acute and
by 1000 mg/wk for 6Y8 weeks hyperglycemia, electrolyte maintenance
imbalances, fluid retention, (tapering
hypertension, peptic ulcer, dose)
Cushing syndrome, cataracts,
infection and osteoporosis,
avascular necrosis, addisonian
crisis on rapid withdrawal of
corticosteroid
IV immunoglobulin 0.4 g/kg/d for 5 days, followed IV Headache, aseptic meningitis, Acute and
(IVIg) by 0.4 g/kg/wk for 6Y8 weeks thromboembolic events, acute maintenance
renal failure and anaphylaxis (tapering
due to IgA deficiency (rare) dose)
Plasma exchange 1 exchange every other day IV (usually Hypotension, electrolyte Acute
for 10Y14 days through imbalance (hypocalcemia-
a central related perioral paresthesia)
line)
Related to IV central line:
infection, hemorrhage,
thrombosis, and pneumothorax
Azathioprine Initially 1.5 mg/kg/d, target Oral Gastrointestinal symptoms Maintenance
2Y3 mg/kg/d (guided by (eg, nausea, vomiting,
5-point mean corpuscular diarrhea), hypersensitivity
volume increase reactions, alopecia, cytopenia,
from baseline) and hepatotoxicity; rare
complications are lymphoma
and infection
Mycophenolate Initially 500 mg twice daily, Oral Gastrointestinal symptoms Maintenance
mofetil target 1000 mg twice daily (eg, diarrhea, nausea,
vomiting), hypertension,
peripheral edema, infections,
myelosuppression, lymphoma,
and other malignancies
Rituximab 375 mg/m2/wk for 4 weeks, or IV Allergic reaction, opportunistic Acute or
1000 mg/wk for 2 weeks infection, reactivation of maintenance
tuberculosis infection or
hepatitis B infection
Cyclophosphamide IV: 500Y1000 mg/m2/mo IV or oral Gastrointestinal symptoms Acute or
for 3Y6 months (eg, nausea, vomiting), maintenance
alopecia, mucositis,
Oral: 1Y2 mg/kg/d
hemorrhagic cystitis
(50Y100 mg/d)
(administer mesna
prophylaxis), infertility,
and myelosuppression
IgA = immunoglobulin A; IV = intravenous.
a
Modified with permission from McKeon A et al, Continuum (Minneap Minn).3 journals.lww.com/continuum/Fulltext/2010/04000/
IMMUNOTHERAPY_RESPONSIVE_DEMENTIAS_AND.8.aspx. B 2010 American Academy of Neurology.

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 Autoimmune Encephalopathies

FIGURE 8-4 A nonYevidence-based treatment algorithm for the treatment of autoimmune

encephalopathy or dementia.
CSF = cerebrospinal fluid; EEG = electroencephalogram; IV = intravenous; IVIg =
intravenous immunoglobulin; MRI = magnetic resonance imaging; PET = positron emission tomography.
Modified with permission from McKeon et al, Continuum (Minneap Minn).3 journals.lww.com/continuum/Fulltext/2010/
04000/IMMUNOTHERAPY_RESPONSIVE_ DEMENTIAS_AND.8.aspx. B 2010 American Academy of Neurology.

steroids are usually needed. For 10 to 14 days. If IVIg is the primary

those with milder disorders, weekly IV treatment used, a weekly infusion of
methylprednisolone infusions may suf- 0.4 g/kg can be used.
fice. In patients with limited early re- After the initial trial of therapy, the
sponses to steroids, plasma exchange patient should be reevaluated to
can be given as every other day ex- objectively determine the response to
changes (five to seven treatments) for immunotherapy. If a rapid series of trials

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 KEY POINT
of immunotherapy are not beneficial notherapy for an even longer period of h In patients in
in an acutely ill hospitalized patient time. The duration for which patients whom a response
with a well-characterized antibody- should be treated has not been deter- to immunotherapy
mediated encephalitis, steroid or mined by clinical trials. In essence, the is documented,
IVIg therapy should be continued, and duration of treatment is determined by maintenance treatment
another immunosuppressant (such as the treating clinician based on enceph- for 6 to 9 months
rituximab or cyclophosphamide) alitis severity and presence or absence (depending on severity)
should be introduced early.37 In addi- of relapses. For patients in whom is usually required.
tion, therapeutic levels of antiepilep- rituximab therapy was employed during
tic drugs and supportive therapy for the acute illness, that may also suffice as
weeks to months are required. Sup- maintenance therapy (every 6 months
portive therapies may be required in or when the B-lymphocyte marker
an intensive care unit setting and CD20 becomes detectable).
include optimized blood pressure Azathioprine or mycophenolate
control, treatment of autonomic insta- mofetil could be used as an oral main-
bility, deep venous thrombosis prophy- tenance immunosuppressive agent in
laxis, monitoring and treatment of those patients in whom it is desirable to
intercurrent infections, and mainte- transition from corticosteroid or cyclo-
nance of fluid and electrolytes. This phosphamide treatment. The initiation
scenario is particularly relevant for of a chronic oral immunosuppressive
patients with anti-NMDA receptor en- agent should overlap with gradual taper
cephalitis, who frequently require of oral corticosteroids and/or IVIg
months of supportive care in addition infusions over that time frame. This
to immunosuppression. approach facilitates the oral immuno-
For patients with severe disorders, suppressants taking effect before the
upon completion of the initial rounds steroids or IVIg treatments are com-
of acute IV treatments, the author favors pleted. Some patients relapse despite
60 mg/d oral prednisone for 3 months this approach and are corticosteroid
followed by taper by 10 mg/mo until a dependent. In these patients, a low oral
dose of 10 mg/d is reached, and then prednisone dose (10 mg/d to 20 mg/d
taper by 1 mg/mo until discontinued. or alternate day) may be needed.
For patients with a history of difficult Careful monitoring for side effects
to treat or relapsing disorders, the of long-term immunotherapy is criti-
author simultaneously starts an oral cal. Surveillance includes monitoring
steroidYsparing agent. of blood counts and tests of liver and
renal function. Before using azathio-
Chronic Therapy prine, thiopurine methyltransferase
The most important principle is the (TPMT) deficiency needs to be excluded
need for aggressive treatment in the by establishing the TPMT genotype
first 6 to 9 months when relapse is most or measuring the TPMT enzyme level
likely to occur. Relapses frequently (both are blood tests). Among patients
occur during rapid immunotherapy with neuromyelitis optica, a rise of
taper or discontinuation, as noted to mean corpuscular volume of at least 5
occur in patients with NMDA receptor, points from baseline is indicative of
AMPA receptor, and VGKC complex efficacy. 38 For those treated with
antibodies. Gradual tapering doses of mycophenolate mofetil, the drug level
steroids or IVIg may suffice for mainte- can be measured to avoid undertreat-
nance of remission, but some patients ment or toxicity. The level of mycophe-
may benefit from maintenance immu- nolic glucuronide (an enzyme that
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 Autoimmune Encephalopathies

KEY POINT
h Prophylaxis against metabolizes mycophenolate) may be are severe despite cancer treatment,
opportunistic infection indicative of risk for drug toxicity (if cyclophosphamide (given as 6 monthly
and osteoporosis and the level is low) or a subtherapeutic IV pulses or daily oral therapy for 6 to
monitoring for drug level (if the level is high). 12 months) may be of utility in those
hypertension and diabetes Patients taking glucocorticoids must patients with limited-stage cancer, com-
mellitus should be also take elemental calcium, at least plete cancer remission, short duration
undertaken in patients 1500 mg/d and vitamin D 1000 IU/d, of neurologic symptoms, and a good
taking corticosteroids. either through diet or supplements, as oncologic performance status.39
deterioration of bone mineral density
may occur soon after starting steroid CONCLUSION
use. Baseline and follow-up bone den- Autoimmune encephalopathies and
sitometry and bisphosphonate treat- dementias are important to recognize
ment should be considered in patients because they are potentially treatable.
requiring more than 3 months of gluco- The comprehensive evaluation consists
corticoid treatment. Pneumocystis of detailed clinical history (including
jiroveci pneumonia prophylaxis should autoimmune), imaging, electrophysio-
consist of 1 trimethoprim/sulfamethox- logic, and immunologic studies. Early
azole double-strength tablet 3 times per treatment with immunotherapy is crit-
week for patients on chronic cortico- ical to optimize outcomes.
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 Review Article

Adult-Onset
Address correspondence to
Dr Deborah L. Renaud,
Mayo Clinic, 200 First St SW,

Leukoencephalopathies
Rochester, MN 55905,
[email protected].
Relationship Disclosure:
Dr Renaud serves on the
Deborah L. Renaud, MD editorial boards of the Journal
of Child Neurology and
Pediatric Neurology.
Unlabeled Use of
ABSTRACT Products/Investigational
Use Disclosure:
Purpose of Review: This article describes the clinical, genetic, and radiographic Dr Renaud reports
features of inherited leukoencephalopathies presenting in adulthood. no disclosure.
Recent Findings: In recent years, the molecular basis for several inherited * 2016 American Academy
leukoencephalopathies, presenting exclusively in adults, has been discovered. Inherited of Neurology.
leukoencephalopathies, previously described in children, have been found to have
milder or later onset forms presenting in adults.
Summary: Although individually rare, inherited leukoencephalopathies are important
to consider in the differential diagnosis of cognitive decline. Patients with inherited
leukoencephalopathies frequently present to multiple sclerosis and dementia clinics.
Clinical and radiographic features can be used to guide investigations in these patients.

Continuum (Minneap Minn) 2016;22(2):559–578.

INTRODUCTION dysmyelination. This may coexist with

Leukoencephalopathies are disorders demyelination or hypomyelination,
that selectively involve the white matter which is a lack of myelin formation.
of the brain. Many leukoencephalo- Children with delayed myelination dem-
pathies are associated with demyelin- onstrate a gradual, but delayed, increase
ation, which is the loss or damage of in myelin over time. Serial MRI scans
previously formed myelin. Acquired at least 6 months apart are required
causes of leukoencephalopathy include to distinguish between hypomyelination
inflammatory conditions such as multi- and delayed myelination in children. In
ple sclerosis (MS), infections, vascular adults, serial MRI scans may help dis-
disorders, neoplasia (such as central tinguish progressive demyelination from
nervous system lymphoma), and toxic dysmyelination, hypomyelination, and
causes. Acute demyelination secondary other forms of stable leukoencepha-
to acquired causes of leukoencephalo- lopathy. The pattern of white matter
pathy is generally asymmetric and non- involvement may be characteristic and
confluent. Leukodystrophy refers to help refine the diagnostic process. The
inherited disorders with progressive presence of calcification or cystic changes
destruction or loss of previously ac- may also be characteristic of particu-
quired myelin. Metachromatic leuko- lar inherited leukoencephalopathies.
dystrophy, Krabbe disease, and X-linked Variations in phenotype-genotype
adrenoleukodystrophy are examples correlation can make prediction of
of leukodystrophies. Chronic demye- the underlying condition challeng-
lination associated with inherited leu- ing. Despite recent advances in mo-
koencephalopathies is more commonly lecular studies, approximately 40%
bilateral, symmetric, and confluent in of patients with hereditary leuko-
distribution. Defects of myelin bio- encephalopathies remain undiag-
synthesis and metabolism result in nosed. A systematic approach to
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 Leukoencephalopathies

KEY POINTS
guide investigations is important in The initial laboratory investigation
h Leukoencephalopathies
are disorders that order to lead to a diagnosis. of an adult with leukoencephalopathy
selectively involve the should include very long chain fatty
white matter of the brain. CLINICAL APPROACH TO acids, lysosomal enzyme studies for
LEUKOENCEPHALOPATHIES metachromatic leukodystrophy, Krabbe
h Acute demyelination
secondary to acquired Clinical1Y3 and MRI-based4,5 approaches disease, and GM1 gangliosidosis, and
causes of to the diagnosis of adult-onset leuko- sulfatides in the urine for metachro-
leukoencephalopathy is encephalopathies have been proposed. matic leukodystrophy. Specific molec-
generally asymmetric A detailed clinical history and careful ular studies may be indicated based
and nonconfluent. physical examination are the first and on clinical and MRI features.
h Chronic demyelination most important steps in the evaluation
associated with inherited of neurologic and non-neurologic DEMENTIA IN MULTIPLE
leukoencephalopathies symptoms. The temporal evolution of SCLEROSIS AND INHERITED
is more commonly symptoms and signs may provide valu- LEUKOENCEPHALOPATHIES
bilateral, symmetric, able clues leading to a diagnosis. A Cognitive impairment affects 40% to
and confluent family history of a similarly affected 70% of patients with MS, can occur at
in distribution. sibling, parent, or family member may any disease stage, and, once present, is
h Cognitive impairment suggest the pattern of inheritance. progressive in nature. Cognitive im-
affects 40% to 70% of Some adult-onset leukoencephalopa- pairment is more common and more
patients with multiple thies result from de novo autosomal severe in secondary progressive MS
sclerosis and is more dominant mutations and, therefore, than in relapsing remitting MS. Infor-
common and more the family history will be negative. mation processing speed, episodic
severe in secondary memory, and executive function are
Macrocephaly, although more com-
progressive multiple
monly seen in children, has been most commonly affected with relative
sclerosis than in
associated with specific leuko- preservation of language abilities. Co-
relapsing remitting
multiple sclerosis. encephalopathies, such as Alexander morbid fatigue and depression may
disease. Dysmorphic features (usually contribute to the effects of cognitive
h Psychiatric manifestations,
evident in childhood) associated with impairment on quality of life and daily
personality change, and
a static leukoencephalopathy may be function. A role for education and cog-
slowly progressive
cognitive decline are seen with specific genetic syndromes nitive reserve has been suggested
frequently seen early in and chromosomal microdeletions or since the degree of cognitive impair-
the clinical presentation microduplications. Distinctive skin ment is variable.6Y8 The underlying
of adult-onset features may include bronzing asso- pathogenesis of cognitive impairment
leukoencephalopathies ciated with adrenal insufficiency in in MS is complex and multifactorial.
and generally precede peroxisomal disorders, and xanthomas White matter lesion volume and loca-
the diagnosis of a in cerebrotendinous xanthomatosis. tion, cortical lesion burden, deep gray
leukoencephalopathy. The involvement of the liver, heart, or matter involvement, and damage to
kidneys may be suggestive of a lyso- normal-appearing white and gray mat-
somal or mitochondrial disorder. Eye ter have been implicated. The radio-
manifestations may be characteristic of logic and pathologic studies have been
specific inherited leukoencephalo- reviewed in detail by DeLuca and
pathies (Table 9-1). The finding of colleagues6 and Rocca and colleagues.8
decreased deep tendon reflexes de- Psychiatric manifestations and per-
spite the presence of spasticity may be sonality change frequently occur early
suggestive of a concomitant peripheral in the clinical presentation of adult-
neuropathy (Table 9-2). MRI findings onset leukoencephalopathies, leading
may be characteristic of a specific to psychiatric referral. Slowly progres-
inherited leukoencephalopathy or may sive cognitive decline occurs in most
be nonspecific. disorders and generally precedes the

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TABLE 9-1 Eye Manifestations Associated With Leukoencephalopathies

b Abnormal Eye Movements

Pelizaeus-Merzbacher disease
Pelizaeus-MerzbacherYlike disease
b Corneal Abnormalities
Fabry disease
b Cataracts
Cerebrotendinous xanthomatosis
Fabry disease
Mitochondrial respiratory chain disorders
Peroxisomal disorders
b Retinal Degeneration/Retinopathy
Cobalamin C disease
Cockayne syndrome
GM1 and GM2 gangliosidosis (cherry red spot)
Krabbe disease (late onset)
Mitochondrial disorders
Mucolipidosis type IV
Peroxisomal disorders
b Retinal Vasculopathy
Labrune syndrome (cerebroretinal microangiopathy with calcifications
and cysts)
COL4A1-associated disorders
TREX1-associated retinal vasculopathy with cerebral leukodystrophy
b Optic Neuropathy
Krabbe (globoid cell) disease
Metachromatic leukodystrophy
Mitochondrial disorders
Pelizaeus-Merzbacher disease

diagnosis of a leukoencephalopathy. ADULT-ONSET INHERITED

The coexistence of pyramidal signs such LEUKOENCEPHALOPATHIES
as spastic paraparesis and hyperreflexia, Adult-onset forms of many leuko-
ataxia, extrapyramidal signs, bulbar encephalopathies originally described
dysfunction, peripheral neuropathy, or in childhood have been found in recent
autonomic dysfunction in a patient with years. Many of these are rare in adults
dementia should raise the possibility and, therefore, detailed discussion of
of an inherited leukoencephalopathy. these conditions is beyond the scope
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 Leukoencephalopathies

TABLE 9-2 Inherited Leukoencephalopathies Associated With

Peripheral Neuropathy

b Autosomal dominant adult-onset leukodystrophy (autonomic neuropathy)

b Cockayne syndrome
b Krabbe disease
b Metachromatic leukodystrophy
b Mitochondrial disorders (especially mitochondrial neurogastrointestinal
encephalopathy syndrome)
b Pelizaeus-Merzbacher disease and Pelizaeus-MerzbacherYlike disease
b Peroxisomal disorders (including peroxisomal biogenesis defects and X-linked
adrenoleukodystrophy)

of this review. The genetic basis and with both early and adult forms are
associated clinical features of these discussed here, as well as those with
conditions, in addition to the condi- primarily adult onset.
tions described in more detail in this
review, are presented in Table 9-3. Lysosomal Storage Disease
Mitochondrial disorders associated Lysosomal storage diseases are in-
with leukoencephalopathy will not be herited metabolic disorders that result
covered here but have been reviewed from the defective degradation or
by Wong.9 The most frequently en- transport of complex macromole-
countered leukoencephalopathies cules due to a deficiency of lysosomal

TABLE 9-3 Inherited Leukoencephalopathies That May Present in Adulthood

Disease Inheritance Gene(s) Protein(s) Associated Features

Alexander disease AD GFAP Glial fibrillary Palatal myoclonus,
acidic protein bulbar signs, autonomic
dysfunction
Childhood ataxia with AR EIF2B1, Eukaryotic translation Ovarian failure
central hypomyelination/ EIF2B2, initiation factor 2B,
vanishing white matter EIF2B3, subunits 1Y5
disease EIF2B4,
EIF2B5
Leukoencephalopathy AR CLCN2 CLC2 chloride channels
with ataxia
Megalencephalic AR MLC1 Macrocephaly
leukoencephalopathy
with subcortical cysts
Megalencephalic AR HEPACAM Glial cell adhesion Macrocephaly
leukoencephalopathy molecule
with subcortical cysts

Continued on page 563

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TABLE 9-3 Leukoencephalopathies That May Present in Adulthood Continued from page 562

Disease Inheritance Gene(s) Protein(s) Associated Features

Lysosomal Disorders
Metachromatic AR ARSA Arylsulfatase A Neuropathy,
leukodystrophy PSAP Saposin B cholecystitis
Multiple sulfatase AR SUMF1 Sulfatase modifying
deficiency factor 1

Krabbe disease AR GALC Galactosylceramidase Neuropathy

PSAP Saposin A
GM1 gangliosidosis AR GLB1 "-Galactosidase
Tay-Sachs disease, AR HEXA Hexosaminidase A
GM2 gangliosidosis
Mucolipidosis type IV AR MCOLN1 Mucolipin 1
Fucosidosis AR FUCA1 !-L-Fucosidase Angiokeratoma
Fabry disease X-linked GLA !-Galactosidase A Neuropathy,
angiokeratoma,
nephropathy
Peroxisomal Disorders
Adrenoleukodystrophy X-linked ABCD1 ATP-binding Neuropathy,
(ALDP) cassette myelopathy, adrenal
transporter insufficiency
Peroxisomal biogenesis AR Multiple Various Hepatopathy, adrenal
defects (Zellweger PEX genes peroxins insufficiency
spectrum disorders)
Mitochondrial Disorders
Respiratory chain defects Any Multiple Multiple Multisystem
nuclear and involvement
mitochondrial
DNA genes
Mitochondrial AR TYMP Thymidine Neuropathy,
neurogastrointestinal phosphorylase gastrointestinal
encephalopathy syndrome pseudo-obstruction
Mitochondrial AR RRM2B P53 inducible-
neurogastrointestinal ribonucleotide
encephalopathy syndrome reductase
with normal thymidine
POLG-related disorders AD, AR POLG DNA polymerase +
Navajo neurohepatopathy AR MPV17 Neuropathy,
hepatopathy
Continued on page 564

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 Leukoencephalopathies

TABLE 9-3 Leukoencephalopathies That May Present in Adulthood Continued from page 563

Associated
Disease Inheritance Gene(s) Protein(s) Features
Leukoencephalopathy AR DARS2 Mitochondrial
with brainstem and aspartyl-tRNA
spinal cord involvement synthetase
and lactate elevation
Autosomal recessive AR MARS2 Mitochondrial
spastic ataxia with methionyl-tRNA
leukoencephalopathy synthetase
Remethylation Cycle Disorders
Methylenetetrahydrofolate AR MTHFR Methylenetetrahydrofolate
reductase deficiency reductase
Cobalamin C disease AR MMACHC Retinopathy
Cerebral folate AR FOLR1 Folate receptor !
deficiency
Organic Acidemias
Glutaric aciduria type 1 AR GCDH Glutaryl-CoA
dehydrogenase
L-2-Hydroxyglutaric AR L2HGDH L-2-Hydroxyglutarate Macrocephaly,
aciduria dehydrogenase risk of brain
tumors
3-Methylglutaconic AR AUH 3-Methylglutaconyl-
aciduria type 1 CoA hydratase
Associated With Calcifications
Nasu-Hakola disease, polycystic AR TREM2 Triggering receptor Osteodysplasia
lipomembranous osteodysplasia expressed on myeloid
with sclerosing cells 2
leukoencephalopathy
DAP12 DNAX-activation
protein 12
Cockayne syndrome AR ERCC6 Excision repair Premature
ERCC8 cross-complementing aging
groups 6 and 8
Associated With Hypomyelination
Pelizaeus-Merzbacher X-linked PLP1 Proteolipid protein 1 Autonomic
disease dysfunction,
nystagmus
Pelizaeus-MerzbacherY AR GJC2 Connexin 46.6
like disease
Continued on page 565

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TABLE 9-3 Leukoencephalopathies That May Present in Adulthood Continued from page 564

Disease Inheritance Gene(s) Protein(s) Associated Features

Associated With Vasculopathy
Cerebral autosomal AD NOTCH3 Notch Migraine
dominant arteriopathy receptor
with subcortical infarcts
and leukoencephalopathy
Cerebral autosomal recessive AR HTRA1 Serine
arteriopathy with subcortical protease
infarcts and leukoencephalopathy HTRA1
Hereditary angiopathy with AD COL4A1 Collagen,
nephropathy, aneurysms, and type IV, !-1
muscle cramps
Retinal vasculopathy with AD TREX1 3’-5’ DNA Retinopathy
cerebral leukodystrophy exonuclease
Associated With Abnormal Lipid Metabolism
Cerebrotendinous AR CYP27A1 Sterol 27- Cataracts, xanthoma,
xanthomatosis hydroxylase neuropathy
Adult-Onset Leukodystrophies
Adult-onset autosomal AD LMNB1 Lamin B1 Autonomic
dominant leukodystrophy duplication dysfunction
Adult polyglucosan AR GBE1 Glycogen Neuropathy, bladder
body disease branching dysfunction
enzyme
Hereditary diffuse AD CSF1R Colony- Seizures
leukoencephalopathy with stimulating
axonal spheroids factor 1
receptor
Chromosome Abnormalities
Fragile XYassociated X-linked FMR1 Fragile X Ataxia, intention
tremor/ataxia syndrome Trinucleotide mental tremor, neuropathy,
repeat retardation 1 parkinsonian features
expansion
Microdeletion syndromes De novo Various

AD = autosomal dominant; AR = autosomal recessive; DNA = deoxyribonucleic acid.

enzymes or associated proteins. Meta- $-galactosidase deficiency, may present

chromatic leukodystrophy and Krabbe with clinical and MRI features indistin-
disease are the most common condi- guishable from these conditions and
tions presenting in adulthood and should be considered in the differential
present with progressive white matter diagnosis. Other lysosomal storage dis-
destruction. These two entities will be eases may present with hypomyelination
described in more detail in the follow- including fucosidosis and Salla disease.
ing sections. GM1 gangliosidosis, due to Secondary white matter changes may

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 Leukoencephalopathies

KEY POINTS
h The evaluation be seen in lysosomal storage diseases White matter volume loss results in
for metachromatic associated primarily with gray matter brain atrophy in late stages of the dis-
leukodystrophy should involvement including late-onset forms ease.11,13Y15 Treatment is primarily
include both the of GM2 gangliosidosis, neuronal ceroid symptomatic. Hematopoietic stem cell
measurement of lipofuscinosis, and disorders of muco- transplantation may stabilize the cen-
sulfatides in the polysaccharide metabolism.10 Fabry tral nervous system demyelination in
urine as well as the disease, due to !-galactosidase defi- some patients with adult-onset meta-
arylsulfatase A ciency, is a lysosomal storage disease chromatic leukodystrophy if performed
enzyme activity in presenting with leukoencephalopathy early in the disease course.16 Unfortu-
white blood cells. primarily on a vascular basis, which may nately, the diagnosis is often delayed
h MRI in Krabbe disease present with symptoms suggestive of due to the predominant early psychi-
may demonstrate vascular dementia. atric symptoms and slow progression
bilateral white matter Metachromatic leukodystrophy. of neurologic symptoms.
involvement or may be Metachromatic leukodystrophy is an Krabbe disease. Krabbe disease
normal even in the
autosomal recessive condition that re- (globoid cell leukodystrophy) is an
presence of significant
sults in the accumulation of 3-O- autosomal recessive condition due to
neurologic signs.
sulfogalactosylceramide (sulfatide) in a deficiency of galactocerebrosidase,
oligodendrocytes, Schwann cells, which results in the accumulation of
and some neurons due to deficiency of galactosylceramide and psychosine in
arylsulfatase A. In rare cases, deficiency the central and peripheral nervous sys-
of the activator protein, saposin B, tem white matter. Approximately 5%
results in a similar clinical phenotype of patients have onset in adolescence
but with normal arylsulfatase A activity or adulthood. A change in gait due to
in vitro in the presence of sulfatides in either spastic paraparesis, peripheral
the urine. A pseudodeficiency allele neuropathy, or both is the most com-
has been described in 0.2% to 0.5% mon presenting feature. Approximately
of Caucasians, resulting in decreased 60% of adult patients develop periph-
arylsulfatase A activity, but no clinical eral neuropathy. Slowly progressive
symptoms and negative sulfatides in vision loss and cognitive decline may
the urine.11 Adult-onset patients present be present in some patients but are
with behavioral and psychiatric changes usually not the presenting symptoms.
accompanied by a slow decline in MRI may demonstrate bilateral white
memory and intellectual abilities. Gait matter involvement or may be normal
disturbance due to progressive spasticity, even in the presence of significant neu-
peripheral neuropathy, or both may be rologic signs.17Y21 Treatment is pri-
a presenting feature. Cholecystitis due marily symptomatic. Individuals with
to sulfatide accumulation in the gall Krabbe disease may receive a diagno-
bladder wall is an important non- sis of hereditary spastic paraparesis,
neurologic complication of metachro- peripheral neuropathy, amyotrophic
matic leukodystrophy.11 MRI findings lateral sclerosis, or MS due to overlap-
consist of confluent, symmetrical T2 ping clinical features.
hyperintensity in the periventricular
white matter with sparing of the sub- X-Linked Adrenoleukodystrophy
cortical U fibers, which are frontal and Adrenomyeloneuropathy
dominant in juvenile and adult-onset X-linked adrenoleukodystrophy is the
patients but eventually involve the most common peroxisomal disorder
white matter diffusely (Case 9-1). affecting approximately 1 in 15,000
Tigroid stripes extending radially males. This X-linked condition results
consist of spared perivascular spaces. from mutations in the ABCD1 gene,
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which codes for an ATP-binding cas- majority of males with the cerebral form
sette (ABC) transporter located in the (ie, childhood cerebral adrenoleuko-
peroxisomal membrane. The biochem- dystrophy) are boys between the ages
ical hallmark is an elevation of very of 3 and 10 years, presenting with at-
long chain fatty acids. Molecular con- tention and learning difficulties follow-
firmation can be performed by se- ing normal development. Neurologic
quencing the ABCD1 gene. symptoms evolve rapidly after onset with
Clinical phenotypes include cerebral the development of spasticity, cortical
forms with progressive leukodystrophy, blindness, seizures, and cognitive de-
adrenomyeloneuropathy in affected cline, leading to complete disability and
males and in female carriers, and Addison death. Adult men who develop the
disease alone. Adrenal insufficiency is cerebral form without preceding
present in approximately 90% of males adrenomyeloneuropathy usually pres-
and less than 2% of females and is ent with dementia and behavioral
independent of the presence of neu- change, followed by a progression
rologic symptoms. Cerebral forms af- similar to that of boys with child-
fect approximately 50% of males. The hood cerebral adrenoleukodystrophy.

Case 9-1
A previously healthy, 50-year-old woman, who was university-educated and worked as a manager of a
department store, presented with a 4- to 5-year history of progressive dementia. She was initially reported
to have become forgetful, disorganized, and inconsistent in the performance of her duties at work.
She was placed on leave and then dismissed. Her family described a progressive cognitive decline with
short-term memory impairment and disorientation, which led to wandering. She subsequently lost her
abilities to write and read and would confabulate when asked questions. Her communication became
limited to single words and two- to three-word combinations. At the time of presentation, she was unable
to perform her activities of daily living. She had been followed by psychiatry but was referred to neurology
for evaluation due to progressive cognitive decline and change in gait. There was no history of seizures,
weakness, paresthesia, visual changes, or hallucinations. Her family history was negative apart from
possible schizophrenia in her father. Her parents were nonconsanguineous, and she had two healthy siblings.
Her neurologic examination was significant for inappropriate uninhibited behavior and significant
speech impairment. She exhibited marked echolalia, perseveration of speech, use of illogical sentences,
and tangentiality. Significant comprehension difficulties were evident. She showed poor judgment
and insight with inappropriate lability and uninhibited behavior. Her Mini-Mental State Examination
(MMSE) score was 11 out of 30. Cranial nerves were normal. Her strength was normal, but she had mildly
increased tone in the lower extremities, and her gait was spastic and clumsy. Deep tendon reflexes
were brisk at the knees bilaterally, and toes were downgoing.
Her initial investigations including routine dementia bloodwork and extensive stroke workup
(including evaluation for dyslipidemia, hyperhomocysteinemia, chronic inflammatory disorders,
hypercoagulable states, and cardiac and cerebrovascular causes) were normal. Her brain MRI
demonstrated diffuse periventricular white matter abnormalities with cerebral atrophy and atrophy of
the corpus callosum (Figure 9-112). An EEG revealed normal background activity with theta activity
bifrontally. Her single-photon emission computed tomography (SPECT) scan, and her conventional
cerebral angiogram to rule out cerebral vasculitis, were normal. CSF analysis revealed normal
cell count, microscopy, venereal disease research laboratory (VDRL) test, protein, and glucose, but
oligoclonal bands were present. Arylsulfatase A activity in white blood cells was markedly reduced, and
sulfatides were present in the urine, confirming the diagnosis of metachromatic leukodystrophy.

Continued on page 568

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 Leukoencephalopathies

Continued from page 567

Comment. Adults with metachromatic leukodystrophy frequently have a delayed diagnosis due to the
initial psychiatric presentation and slow progression of neurologic features. Progressive gait disturbance
and spasticity accompanying psychiatric features or cognitive decline should suggest the possibility of an
inherited leukoencephalopathy such as metachromatic leukodystrophy.

FIGURE 9-1 MRI of the patient in Case 9-1 demonstrates diffuse fluid-attenuated inversion
recovery (FLAIR) and T2 hyperintensities of the periventricular white matter
associated with cerebral atrophy (A) and atrophy of the corpus callosum (B),
characteristic of adult-onset metachromatic leukodystrophy.
12
Reprinted with permission from Tillema JM, Renaud DL, Semin Neurol. www.thieme-connect.com/DOI/DOI?10.1055/s-0032-
1306391. B 2012 Thieme Medical Publishers.

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Approximately 20% to 40% of men
with adrenomyeloneuropathy will
also present with cerebral involve-
ment over the course of their neuro-
logic disease.22Y24
Adrenomyeloneuropathy is a pri-
mary axonopathy affecting adult men,
most commonly in their twenties and
thirties. Symptoms include slowly pro-
gressive spastic paraparesis, sensory
loss, and bowel and bladder dysfunc-
tion, which result from a combination
of myelopathy and peripheral neu-
ropathy. Intellectual abilities are not
affected in men with pure adreno-
myeloneuropathy unless they develop
the cerebral form. Approximately 50%
of female carriers will develop a milder
form of adrenomyeloneuropathy at a
later age.22Y24
FIGURE 9-2 Brain MRI of patient with adult-onset
Approximately 80% of males with cerebral adrenoleukodystrophy
the cerebral form have signal changes demonstrating confluent nonenhancing
T2 fluid-attenuated inversion recovery (FLAIR) white matter
on brain MRI in the parieto-occipital hyperintensity, which predominates in the bilateral
white matter, splenium of the corpus parieto-occipital lobes, as well as the splenium of the
callosum, visual and auditory pathways, corpus callosum.
and, occasionally, the corticospinal
tracts (Figure 9-2). The anterior white
early. Gene therapy trials are also un- KEY POINT
matter (including the frontal white mat- h Men with X-linked
derway. Monitoring of boys and men
ter, genu of the corpus callosum, and adrenoleukodystrophy
with X-linked adrenoleukodystrophy
frontopontine tract) is involved in ap- may develop the
for MRI changes consistent with early
proximately 15% of males. Concomitant cerebral form of the
cerebral disease is important since
involvement of the parieto-occipital disease without
MRI changes may precede neurologic
and frontal white matter is the most preceding neurologic
symptoms by 6 months or more. features of
rapidly progressive MRI pattern. Iso-
lated corticospinal tract or cerebellar adrenomyeloneuropathy.
white matter involvement on brain MRI Alexander Disease
is seen in a small fraction of patients Alexander disease results from an auto-
and is more slowly progressive.25,26 somal dominant toxic gain in function
Contrast enhancement on T1-weighted mutation in the glial fibrillary acidic
MRI images at the leading edge of the protein (GFAP) gene. These mutations
affected white matter is predictive of are usually de novo but may be familial
clinical and MRI disease progression.27 in adult-onset cases. The pathologic
Treatment of adrenal insufficiency hallmark of Alexander disease is the
can be lifesaving. Once neurologic presence of Rosenthal fibers in astro-
symptoms have developed, treatment cytic processes around small blood
is primarily supportive. Hematopoietic vessels and astrocytic cell bodies.
stem cell transplantation may stabilize Molecular testing is diagnostic and,
the progression of the cerebral form therefore, brain biopsy is no longer
in both boys and men if performed required to confirm the diagnosis.

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 Leukoencephalopathies

KEY POINTS
h The adult-onset The adult-onset form of Alexander racts are common. In adults, clinical
form of Alexander disease presents with bulbar signs (dys- findings include xanthomas, particu-
disease presents with phagia, dysarthria, and dysphonia), larly of the Achilles tendon, associated
bulbar signs spastic paraplegia, ataxia, and other with premature atherosclerosis and neu-
(dysphagia, dysarthria, neurologic features, including palatal rologic complications. Early psychiatric
and dysphonia), myoclonus/tremor, autonomic dysfunc- manifestations may occur and may pre-
spastic paraplegia, tion, ocular movement abnormalities, cede neurologic manifestations, which
ataxia, and other and sleep disturbance. Symptoms are can include pyramidal and cerebellar
neurologic features, variable and slowly progressive. Unlike signs, seizures, and palatal myoclonus.
including palatal early-onset forms of Alexander disease, Developmental delay may be present
myoclonus/tremor,
where all previously acquired skills in childhood and lead to progressive
autonomic dysfunction,
are lost, neurocognitive deficits may cognitive decline in adulthood.34
and sleep disturbance.
not be prominent in juvenile or adult- MRI findings include periventricular
h Xanthomas are an onset forms of Alexander disease.28Y32 white matter abnormalities with signal
important clue that may
MRI findings in adult-onset Alexander changes in the dentate nucleus, sub-
lead to the diagnosis
disease are characteristic (Figure 9-3) stantia nigra, and globus pallidus. Dif-
of cerebrotendinous
xanthomatosis. Early
but differ significantly from the early- fuse cerebral and cerebellar atrophy
treatment can prevent onset form. Cerebral periventricular are also found.35
the development white matter changes may be minimal Treatment with chenodeoxycholic
of progressive or absent. Atrophy and signal change acid normalizes bile acid synthesis and
neurologic decline. in the medulla and upper cervical decreases cholestanol levels in blood.
h Leukoencephalopathies cord are typical and account for the Early treatment is needed in order to
associated with small predominant lower brainstem signs. prevent the irreversible neurologic in-
vessel vasculopathy Signal changes are frequently seen in volvement.34 Unfortunately, diagnosis
predispose patients to the dentate nucleus and middle cere- is often delayed until early adulthood
ischemic and bellar peduncles. Patchy enhancement when behavioral, cognitive, and motor
hemorrhagic strokes may be present in affected regions.28Y32 impairment appears. Starting chenode-
and are associated Treatment is currently symptom- oxycholic acid once neurologic symp-
with vascular atic; however, future treatment strate- toms have appeared may temporarily
cognitive impairment. gies may include pharmacologic result in stabilization but does not re-
interventions, which decrease expres- sult in improvement.36 The combina-
sion of GFAP, enhance protective tion of chenodeoxycholic acid and a
stress responses, or minimize detri- statin may result in stabilization of
mental downstream effects of mutant cognitive decline but does not improve
GFAP expression.33 neurologic symptoms.37

Cerebrotendinous Leukoencephalopathies
Xanthomatosis Associated With Small
Cerebrotendinous xanthomatosis is a Vessel Vasculopathy
rare autosomal recessive condition due In recent years, a number of inherited
to mutations in the gene for mitochon- disorders affecting small blood vessels
drial sterol 27-hydroxylase (CYP27A1). have been described that predispose
Deficiency of this enzyme results in patients to ischemic and hemorrhagic
elevation of cholestanol in plasma and strokes and white matter changes
bile with accumulation in the brain, associated with vascular cognitive im-
eyes, tendons, and other tissues. pairment.38,39 The most common dis-
Clinical symptoms may begin in orders will be discussed in detail here.
infancy or early childhood with failure Cerebral autosomal dominant
to thrive and diarrhea. Juvenile cata- arteriopathy with subcortical infarcts
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FIGURE 9-3 MRI features of late-onset Alexander disease. Axial fluid-attenuated inversion
recovery (FLAIR) MRIs showing the pial FLAIR signal change along the midbrain
(A, arrows), pons (B, arrow), and medulla (C, arrow). Sagittal (D) and axial
(E) T2-weighted MRIs showing an area of intramedullary signal change (D, arrow) and
moderate cord atrophy (E, arrow).
29
Reprinted with permission from Graff-Radford J, et al, Neurology. www.neurology.org/content/82/1/49.short.
B 2013 American Academy of Neurology.

and leukoencephalopathy (CADASIL) gene (which encodes for a cell-signaling

is the most common of these condi- receptor) have been identified in pa-
tions and was the first identified. tients with CADASIL. The clinical pre-
Dominant mutations in the NOTCH3 sentation and age of onset are variable,
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 Leukoencephalopathies

although young or middle adulthood is become more diffuse and preferen-

most common. When present, migraine tially affect the external capsule and
headaches are frequently atypical or anterior portion of the temporal lobe,
with aura and may precede ischemic a pattern which should suggest CADASIL
events. Recurrent ischemic events are (Figure 9-5). Lacunar infarcts occur in
the most consistent feature (Case 9-2). similar regions and may also involve
The cognitive decline is slowly pro- the basal ganglia and thalamus. Treat-
gressive with stepwise deterioration, ment is based on the usual preventa-
and mood disturbances may also be tive measures for noncardioembolic
present.40Y42 MRI findings consisting of ischemic stroke and migraine with aura.
periventricular white matter changes Vasoconstrictor medications such as
may precede clinical symptoms. The triptans should be avoided for the
white matter abnormalities eventually acute treatment of migraine. 41

Case 9-2
A 52-year-old man presented with a 6-year history of recurrent ischemic strokes and short-term
memory difficulties. His history was negative for typical risk factors for ischemic events including
hypertension, elevated cholesterol, diabetes mellitus, or smoking. His past history was significant
for migraine with aura beginning in his late twenties. He noted that his mother and maternal
grandfather also had a history of migraines and recurrent ischemic strokes starting in their forties.
Neurologic examination was normal. His brain MRI revealed a diffuse confluent pattern of
periventricular T2 hyperintensity (Figure 9-4). Molecular evaluation detected a dominant
mutation in the NOTCH3 gene, confirming the diagnosis of cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

FIGURE 9-4 MRI of the patient in Case 9-2 with cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) demonstrating a diffuse
confluent pattern of periventricular T2 hyperintensity.
12
Reprinted with permission from Tillema JM, Renaud DL, Semin Neurol. www.thieme-
connect.com/DOI/DOI?10.1055/s-0032-1306391. B 2012 Thieme Medical Publishers.

Comment. Migraine with aura, although not always present, may be an indication of CADASIL.
This case is an example of a slowly progressive cognitive decline with stepwise deterioration.
The white matter findings are initially subtle but become more extensive over time.

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 FIGURE 9-5 Specific MRI features in cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL). A, B, Fluid-attenuated inversion recovery (FLAIR)
MRI scans show multiple hypointense lesions (lacunes related to dilated
perivascular spaces) at the corticosubcortical junction (arrows). These lesions
are the most specific feature seen in CADASIL, are present in about 67% of
patients, and are associated with confluent white matter hyperintensities in
the anterior part of the temporal lobes.
Reprinted from Chabriat H, et al, Lancet Neurol.42 www.thelancet.com/journals/laneur/article/
PIIS1474-4422(09)70127-9/abstract. B 2009 Elsevier Ltd.

Cerebral autosomal recessive arte- dominant with familial and de novo

riopathy with subcortical infarcts and mutations. Hemorrhagic stroke may
leukoencephalopathy (CARASIL) is as- occur in the prenatal or perinatal peri-
sociated with mutations in HTRA1, od, resulting in porencephaly. Hemi-
which encodes a serine protease. Pa- paresis and seizures may result from
tients present in a similar fashion to stroke at any age. Recurrent ischemic
CADASIL, with leukoencephalopathy events lead to cognitive decline. Reti-
and lacunar strokes with progressive nal arteriolar tortuosity, cataracts, glau-
cognitive impairment. Spondylosis and coma, and anterior segment dysgenesis
alopecia are features that may help of the eye may occur. Large vessel
distinguish CARASIL from CADASIL.38 involvement may include aneurysms
Retinal vasculopathy with cerebral in the intracranial segment of the
leukodystrophy is associated with mu- internal carotid artery and other sys-
tations in TREX1. Symptoms usually begin temic vessels.38
in the fourth to fifth decade. Retinop-
athy results in progressive visual impair- Adult-Onset Autosomal
ment. Recurrent ischemic events are Dominant Leukodystrophy
associated with headaches, behavioral Adult-onset autosomal dominant leu-
changes, mood disorder, and progres- kodystrophy results from tandem ge-
sive cognitive decline.38 nomic duplication of LMNB1, which
Collagen type IV, !-1 (COL4A1)Y encodes the nuclear lamina protein
related disorders are highly variable lamin B1.43
conditions with systemic and neurologic Beginning in the fourth to fifth
symptoms. Inheritance is autosomal decade, autonomic dysfunction occurs

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 Leukoencephalopathies

KEY POINTS
h Adult-onset autosomal with bladder and bowel dysfunction The majority of patients described
dominant leukodystrophy and orthostatic hypotension. This is have been of Ashkenazi Jewish des-
is associated with followed by slowly progressive pyra- cent; however, panethnic cases have
autonomic dysfunction, midal and cerebellar features.43,44 A been described. A recent review of 50
presenting as bladder slowly progressive cognitive decline cases described a mean age of onset of
and bowel dysfunction is commonly seen. 51 years with progression to confine-
and orthostatic MRI findings consist of symmet- ment to a wheelchair within 10 years
hypotension, followed rical, often extensive, white matter ab- and a mean age of death of 70 years.
by slowly progressive normalities in the frontal and parietal Symptoms consistent with neurogenic
pyramidal and white matter and cerebellar peduncles bladder occur early in the clinical
cerebellar features.
(Figure 9-645). The periventricular course accompanied by spastic paraple-
h The majority of patients white matter is relatively spared. Thin- gia, vibration sense loss, and axonal
with adult polyglucosan ning of the corpus callosum and atro- sensorimotor polyneuropathy. Mild
body disease due to phy of the entire spinal cord with signal cognitive decline may be present in
mutations in GBE1 have
intensity abnormalities occur.44 The up to 50% of individuals. Orthostatic
been of Ashkenazi
findings in the spinal cord may pre- hypotension may develop later in the
Jewish descent; however,
panethnic cases have
cede the onset of clinical findings.46 course of the disease. Occasionally,
been described. patients present initially with relapsing
Adult Polyglucosan Body Disease remitting neurologic symptoms that
Adult polyglucosan body disease is may be mistaken for MS.47,48
a rare autosomal recessive condition MRI findings consist of T2 and fluid-
due to mutations in GBE1 resulting attenuated inversion recovery (FLAIR)
in glycogen branching enzyme defi- hyperintensity in the periventricular
ciency. This condition is allelic to gly- white matter, particularly in the occip-
cogen storage disease type IV but ital regions, posterior limb of the inter-
presents primarily as a neurodegener- nal capsule, pyramidal tracts, and medial
ative condition with accumulation of lemniscus of the pons and medulla.
amylopectin-like polysaccharide in the Atrophy of the medulla and spinal cord
central and peripheral nervous system. is characteristic.47 The diagnosis can

FIGURE 9-6 Adult-onset autosomal dominant leukodystrophy. AYC, Axial T2 MRI from three patients with LMNB1
gene duplication show white matter hyperintensities with sparing of U fibers and relative sparing of
periventricular areas.
Reprinted with permission from Zanigni S, et al, Brain Res Bull.45 www.sciencedirect.com/science/article/pii/S0361923015300125. B 2015
Elsevier Inc.

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 KEY POINT
be confirmed by measuring glycogen MRI findings consist of bilateral con- h Adult-onset
branching enzyme activity in fibro- fluent white matter abnormalities with leukoencephalopathy
blasts or by genetic testing. Treatment frontal predominance involving the with axonal spheroids
is supportive. periventricular and deep white matter and pigmented glia
as well as the corpus callosum. There is should be considered
Adult-Onset no gadolinium enhancement.50Y54 The in the differential
Leukoencephalopathy diagnosis can be confirmed by molec- diagnosis of
With Axonal Spheroids and ular analysis of the CSF1R gene, and frontotemporal dementia.
Pigmented Glia treatment is supportive.
Hereditary diffuse leukoencephalop-
athy with spheroids (HDLS) and CONCLUSION
pigmented orthochromatic leukodys- Inherited leukoencephalopathies, al-
trophy (POLD) have been consid- though individually rare, are an impor-
ered to be distinct, pathologically tant consideration in the differential
defined clinical entities. Abnormal diagnosis of dementia. Psychiatric fea-
white matter with myelin loss and tures may be seen early in many leuko-
axonal swelling is present in both encephalopathies, resulting in a delay
conditions with predominant neu- in diagnosis. The presence of neu-
raxonal spheroids in the first and rologic features including pyramidal
predominant pigmented glia and neu- signs such as spastic paraparesis and
rons in the latter condition. Recent hyperreflexia, ataxia, extrapyramidal
studies have demonstrated that both signs, bulbar dysfunction, periph-
of these pathologically defined entities eral neuropathy, or autonomic dys-
are the result of autosomal dominant function in a patient with dementia
mutations in the colony stimulating should raise the possibility of an in-
factor 1 receptor (CSF1R) gene. Both herited leukoencephalopathy.
familial and de novo mutations have been
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 Review Article

Diagnosis and Treatment

Address correspondence to
Dr Michael A. Williams,
University of Washington

of Idiopathic Normal
Medical Center, Department of
Neurology, 1959 NE Pacific St,
Box 356470, Seattle, WA 98195,
[email protected].

Pressure Hydrocephalus Relationship Disclosure:

Dr Williams serves on the
technical advisory board for
and holds stock options in
Michael A. Williams, MD, FAAN; Jan Malm, MD, PhD Aqueduct Critical Care, Inc,
and has received personal
compensation and travel
expenses as a lecturer
ABSTRACT for Codman Neuro, Canada.
Purpose of Review: This article provides neurologists with a pragmatic approach Dr Williams has received
to the diagnosis and treatment of idiopathic normal pressure hydrocephalus (iNPH), research support from the
National Space Biomedical
including an overview of: (1) key symptoms and examination and radiologic findings; Research Institute as principle
(2) use of appropriate tests to determine the patient’s likelihood of shunt re- investigator of study
sponsiveness; (3) appropriate referral to tertiary centers with expertise in complex SMST02801, comparing the
continuous noninvasive and
iNPH; and (4) the contribution of neurologists to the care of patients with iNPH fol- invasive intracranial pressure
lowing shunt surgery. management therapies, and as
Recent Findings: The prevalence of iNPH is higher than previously estimated; how- co-investigator of study
CA02801, investigating the
ever, only a fraction of persons with the disorder receive shunt surgery. iNPH should be effects of microgravity on
considered as a diagnosis for patients with unexplained symmetric gait disturbance, a intracranial pressure.
frontal-subcortical pattern of cognitive impairment, and urinary urge incontinence, Dr Williams has received
research support from NeuroDx
whose MRI scans show enlarged ventricles and whose comorbidities are not sufficient Development for research
to explain their symptoms. Physiologically based tests, such as the tap test (large- funded by the National Institutes
volume lumbar puncture) or temporary spinal catheter insertion for external lumbar of Health. Professor Malm
receives royalty payments from
drainage with gait testing before and after CSF removal, or CSF infusion testing for Likvor AB, where he holds
measurement of CSF outflow resistance, can reliably identify patients who are likely to patents related to the CELDA
respond to shunt surgery. Properly selected patients have an 80% to 90% chance of infusion device, which is
approved within the European
responding to shunt surgery, and all symptoms can improve following shunt surgery. Union, but not in the United
Longitudinal care involves investigating the differential diagnosis of any symptoms that States, and receives payments
either fail to respond to shunt surgery or that worsen after initial improvement from for a patent of a new CSF shunt
design created with Medtronic,
shunt surgery. Inc. Professor Malm receives
Summary: Neurologists play an important role in the identification of patients who research support as principal
should be evaluated for possible iNPH. With contemporary diagnostic tests and treat- investigator for studies from
the Swedish Heart-Lung
ment with programmable shunts, the benefit-to-risk ratio of shunt surgery is highly Foundation and the Swedish
favorable. For more complex patients, tertiary centers with expertise in complex iNPH National Space Board.
are available throughout the world. Unlabeled Use of
Products/Investigational
Use Disclosure:
Continuum (Minneap Minn) 2016;22(2):579–599. Dr Williams and Professor
Malm report no disclosures.
* 2016 American Academy
of Neurology.
INTRODUCTION usually configured between the lateral
Idiopathic normal pressure hydro- ventricle and the abdomen (ventric-
cephalus (iNPH) is the most common uloperitoneal [VP] shunt).1 Between
form of hydrocephalus in adults. Pa- 60% and 80% of patients improve
tients develop a syndrome character- following shunt surgery. The average
ized by dilated cerebral ventricles in age of onset is about 70 years, and
combination with impaired gait, cog- men and women are affected in equal
nition, and urinary control (urgency numbers. In a population-based study
and incontinence). The only effective from western Sweden, the prevalence
treatment for iNPH is a CSF shunt, of iNPH was estimated at 0.2% (200

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

 Normal Pressure Hydrocephalus

KEY POINTS
h The only effective out of 100,000 individuals) in the age atrophy, and may have other diagnoses
treatment for idiopathic group of 70 to 79 years, and 5.9% that contribute to the patient’s symp-
normal pressure (5900 out of 100,000 individuals) for toms, but do not explain them entirely.7
hydrocephalus is a age 80 years and older.2 In the same Patients with probable iNPH also have
CSF shunt. geographic area, the incidence of physiologic evidence in support of
h Approximately 700,000 patients with iNPH who were treated the diagnosis.
persons may have with a CSF shunt was about only two
to three operations per 100,000, which Typical Presentations
idiopathic normal
pressure hydrocephalus implies that iNPH may be underdiag- iNPH should be suspected in elderly
in the United States. nosed.3 If the prevalence of iNPH in patients presenting with unexplained,
the United States is the same, then symmetric gait disturbance, which is
h Idiopathic normal pressure
hydrocephalus should be based on US census data,4 approximately the primary symptom of iNPH. Although
suspected for elderly 700,000 persons may have iNPH in the dementia and incontinence are part of
patients presenting with United States. For comparison, the the so-called iNPH triad and are fre-
unexplained, symmetric number of people in the United States quently present, the complete triad is
gait disturbance. with multiple sclerosis is about 400,000, not required to suspect the disorder.
according to the National Multiple Scle- Because the diagnosis of iNPH re-
h History, clinical
quires the exclusion of other diagno-
examination, and rosis Society website.5 It is thus impor-
ses that would completely explain the
ventriculomegaly are the tant for neurologists to know when to
basis for the diagnosis of patient’s symptoms, an extensive and
suspect this disorder and also how to
idiopathic normal detailed history of each of the symp-
verify and confirm the diagnosis.
pressure hydrocephalus. toms is required, which can be difficult
This article will first focus on eval- if the patient has impaired memory.
uation approaches for general neurol- Thus, it is best to have a family member
ogists and then describe methods in accompany the patient. With careful
use at tertiary centers with expertise review, most patients will be found to
in complex iNPH. For a review of the have symptoms starting insidiously and
pathophysiology of iNPH, see Malm progressing slowly over at least 3 to
and Eklund (Figure 10-1).6 6 months prior to presentation in clinic.
Known causes of hydrocephalus,
CLINICAL EVALUATION such as intracranial hemorrhage,
iNPH is a clinical diagnosis that is trauma, or infections of the central ner-
based on medical history, neurologic vous system, should be sought, as pa-
examination, and brain imaging with tients with these risk factors may have
CT or MRI. The international iNPH secondary hydrocephalus. Patients who
guidelines and the Japanese iNPH have undergone an intracranial neuro-
guidelines both describe diagnostic surgical procedure should be suspected
criteria for iNPH.7Y9 The international of having secondary hydrocephalus.
guidelines have three different levels of Some patients are referred for eval-
diagnostic criteria: probable, possible, uation of possible iNPH because a CT
and unlikely. In this review, for sim- or MRI scan reveals ventriculomegaly as
plicity, we have combined the defini- an incidental finding. Sometimes, the
tions of probable and possible, and patient is asymptomatic and has no
describe them together as iNPH. neurologic examination findings to sug-
Briefly, patients with possible or gest iNPH. Such patients do not meet
probable iNPH present with one or the criteria of iNPH and do not require
more of the iNPH symptoms (typically prognostic testing; however, they may
gait) with insidious onset over 3 months be at risk for future development
or more, have an MRI or CT that shows of symptoms and should be seen at
ventriculomegaly and may also show intervals between 1 and 2 years for

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 KEY POINT
h Spasticity, hyperreflexia,
and other upper motor
neuron findings are
atypical in patients with
idiopathic normal
pressure hydrocephalus.

FIGURE 10-1 This schematic drawing illustrates various models of the pathophysiology of
idiopathic normal pressure hydrocephalus (iNPH). Any model must explain how
and why the ventricles enlarge, how neuronal and glial dysfunction occurs to
produce the clinical features, and why symptoms improve with shunt surgery (ie, reversible
neuronal and glial dysfunction). Proposed disturbances in the CSF dynamic system that
contribute to ventricular enlargement and dysfunction of the brain parenchyma include impaired
CSF outflow resistance and increased intracranial pressure pulsatility. The gait and cognitive
disturbances of iNPH are thought to be of periventricular/subcortical/frontal origin. The arterial
supply of this area is mainly via periventricular end arteries, sensitive to a subcritical ischemia
that causes dysfunction, but not infarction in an anatomic distribution, that affects the axons
related to symptoms (eg, those to the leg, as represented in the homunculus). The altered CSF
dynamics and reduced subcortical blood flow and metabolism may give rise to periventricular
hyperintensities seen on MRI in iNPH.
CSF = cerebrospinal fluid; ICP = intracranial pressure.

reevaluation, or patients should be Gait impairment. The gait impair-

advised to seek medical care if they ment in iNPH is best characterized as
develop any symptoms of concern. a higher-level gait disorder, which, in
the absence of primary sensorimotor
Neurologic Examination and deficits, cerebellar dysfunction, or in-
Typical Symptoms voluntary movements, involves diffi-
Except for abnormal findings of bal- culty integrating sensory information
ance, gait, and cognitive functions, the about the position of the body in its
neurologic examination in patients environment, including the effect of
with iNPH is normal. Symptoms of iNPH gravity and properly selecting and
are symmetric; therefore, lateralizing executing motor plans for gait or
findings should increase suspicion of postural reflexes.10,11 The impairment
other disorders. There should be no should be symmetric unless coexisting
signs of hemiparesis or paraparesis (ie, musculoskeletal disorders (eg, knees,
myelopathy). Spasticity, hyperreflexia, hips, spine) cause asymmetry. Findings
and other upper motor neuron find- include difficulty with transitional
ings are atypical. movements (sitting to standing or

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 Normal Pressure Hydrocephalus

KEY POINTS
h The features of gait standing to sitting); gait initiation fail- iNPH. Patients or family should be
impairment in patients ure; shuffling and poor foot clearance; asked about the use of incontinence
with idiopathic normal tripping, falling, or festination; unstable pads or undergarments, as occasionally
pressure hydrocephalus multistep turns; and retropulsion or they do not consider the patient to be
can be difficult to anteropulsion.11,12 The severity of gait incontinent if the urine is contained by
distinguish from those impairment in iNPH is variable, and the the pads or undergarments. Because
of neurodegenerative features can be difficult to distinguish bladder symptoms are very common
disorders with motor from neurodegenerative disorders with among the elderly, other causes are
involvement, such as motor involvement, such as parkinson- frequently present in patients with
parkinsonism or ism or dementia with Lewy bodies. suspected iNPH.
dementia with
Cognitive impairment and demen-
Lewy bodies. Imaging
tia. Symptoms of dementia in iNPH
h Neuroimaging with overlap with those of other demen- Neuroimaging with either CT or MRI is
either CT or MRI is tias, including difficulty managing fi- required for the diagnosis of iNPH;
required for the diagnosis
nances, taking medications properly, however, MRI is preferable. In iNPH,
of idiopathic normal
driving, and keeping track of appoint- the lateral and third ventricles are
pressure hydrocephalus.
ments. Some patients with iNPH pres- enlarged and no obstruction to CSF
h An Evans ratio of more ent with mild cognitive impairment flow should be present. If obstructive
than 0.3 indicates large
rather than dementia. Screening tests hydrocephalus is suspected, which
ventricles, and a ratio
such as the Mini-Mental State Examina- occurs in a small percentage of pa-
of more than 0.33
indicates very large
tion (MMSE) or Montreal Cognitive tients, MRI should be obtained to
ventricles, but is Assessment (MoCA) are advised.13 The evaluate for sites of obstruction.
not specific for cognitive findings of iNPH reflect in- A screening test for ventricular
idiopathic normal volvement of the prefrontal brain struc- enlargement is the Evans ratio or
pressure hydrocephalus. tures, similar to a subcortical dementia, index, which is the ratio of the widest
with executive dysfunction (eg, slow frontal horn span to the widest diam-
processing, difficulty with problem solv- eter of the brain on the same axial
ing) and memory deficits with poor image (Figure 10-219). An Evans ratio
retrieval and relatively intact recogni- of more than 0.3 indicates large ventri-
tion memory.14Y16 Impaired naming, cles, and a ratio of more than 0.33 in-
agnosia, rapid forgetting that does not dicates very large ventricles, but is not
benefit from cueing, hallucinations, specific for iNPH.
and failure to recognize close family Distinguishing dilated ventricles due
or friends should raise concern for to cerebral atrophy from iNPH is diffi-
other causes of dementia. Symptoms cult. Focal atrophy is often indicative of
of depression are common in iNPH, a degenerative dementia, particularly if
and depression screening is helpful.17 it is asymmetric (eg, frontotemporal
Delirium is not typical in iNPH and dementia) or is stereotypical, such as
implies the presence of a concomi- hippocampal atrophy in Alzheimer de-
tant disorder or medication side effect. mentia. In iNPH, the sylvian fissures
Urinary urgency and incontinence. are often widened out of proportion to
Urgency and frequency are the most the cortical sulci, which are flattened
common urinary symptoms and may (‘‘high tight’’ convexity)20 (Figure 10-2),
occur with or without incontinence.18 which is thought to suggest a block of
Patients are usually aware of the urinary CSF flow over the cerebral convexity to
urge and are concerned about their the arachnoid granulations. Japanese
incontinence. Incontinence without researchers have described this as
awareness of urinary urge or that one’s disproportionately enlarged subarach-
clothes are wet is not characteristic of noid space hydrocephalus (DESH).
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 FIGURE 10-2 MRI of a 73-year-old woman with impairment of gait and balance, bladder
control, and cognition for 3 years. A, Axial T2 MRI consistent with the
Japanese ‘‘high and tight’’ criteria for the convexity. The interhemispheric
fissure is effaced. B, Axial T1 MRI shows a widened third ventricle with a span of 1.0 cm.
C, Sagittal T1 MRI shows bowing of the corpus callosum and a pulsation artifact (flow void)
in the sylvian aqueduct D, Axial fluid-attenuated inversion recovery (FLAIR) MRI shows
measurement of the Evans ratio. The diameter of the frontal horns is 4.4 cm, the widest
brain diameter is 13.7 cm, and the Evans ratio is 0.32.
Reprinted with permission from Williams MA, Relkin NR, Neurol Clin Pract.19 cp.neurology.org/content/3/5/
375.full. B 2013 American Academy of Neurology.

The absence of DESH may be sugges- ventricular wall are considered to re-
tive of brain atrophy, but does not flect fluid movement from the ventri-
exclude the possibility of iNPH.9,21 cles into the parenchyma, but white
Almost all patients with iNPH have matter lesions that are more peripheral
periventricular white matter lesions (eg, in the corona radiata) or that are
that are best seen in the fluid-attenuated diffuse and confluent are more likely to
inversion recovery (FLAIR) or T2 se- represent ischemic change. Extensive
quences. Periventricular white matter white matter lesions are not a contrain-
lesions immediately adjacent to the dication to shunt surgery and should

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 Normal Pressure Hydrocephalus

KEY POINTS
h Gait impairment is not be used to rule out the need for sidered for spinal cord disorders be-
typically either the prognostic testing; however, extensive fore evaluating for iNPH.
first or worst ischemic white matter lesions may limit Third, patients who have been ad-
symptom in patients the patient’s response to shunting. mitted to the hospital for delirium or
with idiopathic normal The appearance of a pulsation arti- failure to thrive and are incidentally
pressure hydrocephalus. fact in the cerebral aqueduct, or mea- found to have ventriculomegaly on neuro-
h Attempts to investigate surements of CSF stroke volume or imaging should not be investigated
acutely hospitalized velocity in the aqueduct using phase- for iNPH until the underlying cause of
patients for idiopathic contrast methods22 cannot be used the delirium has been found, treatment
normal pressure alone to recommend shunt surgery, has been initiated, and the patient has
hydrocephalus are but can support the diagnosis of iNPH been discharged from the hospital and
fraught with the risk and the need for further testing. had time to return to a stable baseline.
of misattribution. Attempts to investigate acutely hospi-
h Identification of DIFFERENTIAL DIAGNOSIS talized patients for iNPH are fraught
comorbidities is an The diagnosis of iNPH is rarely an with the risk of misattribution, as an
essential part of the either/or situation, as it is uncommon apparent response to CSF removal could
clinical management of to see ‘‘pure’’ iNPH. Table 10-119 de- be due to recovery from the underlying
idiopathic normal scribes common differential diagnoses illness, or an apparent lack of response
pressure hydrocephalus.
that should be considered. Tests com- to CSF removal could be due to persis-
h The presence of monly ordered to evaluate the differen- tence of the underlying illness.
comorbidities does not tial diagnosis include typical dementia
exclude the possibility blood work (eg, complete blood count, ROLE OF COMORBIDITIES
of idiopathic normal
biochemical profile, vitamin B12, folate, iNPH affects the elderly, many of whom
pressure hydrocephalus;
thyroid-stimulating hormone [TSH], and have other conditions (ie, comor-
however, comorbidities
do influence the
when indicated, rapid plasma reagin bidities that contribute to their symp-
prognosis after [RPR], Lyme titers, and vitamin D), as toms).23 However, if the comorbidities
shunt surgery. well as imaging of the cervical or lumbo- are not sufficient to explain the pa-
sacral spine. Polyneuropathy, which is tient’s symptoms, then iNPH should be
common in the elderly, is an important investigated. The presence of comor-
comorbidity. As a general rule, a dif- bidities does not exclude the possibil-
ferential diagnosis that is sufficient to ity of iNPH; however, comorbidities do
explain the patient’s symptoms and is influence the prognosis after shunt
treatable should be treated before any surgery. The specific symptoms that
further testing or treatment of iNPH will improve and the extent of clinical
is undertaken. improvement that can be expected
Three important and common pre- after treatment of iNPH will depend
sentation variations deserve special at- on the proportional contribution of the
tention for the differential diagnosis. iNPH and the comorbidities to the
First, patients with ventriculomegaly patient’s clinical presentation. For in-
who have only cognitive impairment or stance, a patient with possible Alzheimer
only incontinence should be evaluated disease dementia, along with the iNPH,
for other disorders before considering is likely to have a worse cognitive re-
iNPH. Most published research and sponse to shunting than a patient with
guidelines indicate that nearly all patients pure iNPH. Thus, an important part of
have gait impairment, which is typically the iNPH investigation is to identify
either the first or worst symptom. and treat any treatable comorbidities
Second, patients with gait impair- and discuss their potential influence
ment and urinary symptoms but no on surgical outcome with the patient
cognitive impairment should be con- and family. If there is any doubt as to
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TABLE 10-1 Differential Diagnosis of Idiopathic Normal Pressure
Hydrocephalusa

Gait Dementia Incontinence

Disorders that may have all three symptoms
Idiopathic normal pressure hydrocephalus X X X
(iNPH) with or without comorbidities
Parkinsonism X X X
Dementia with Lewy bodies X X X
Corticobasal degeneration X X X
Progressive supranuclear palsy X X X
Multiple system atrophy X X X
Vascular dementia X X X
Neurosyphilis X X X
Medication side effects X X X
MultifactorialVany combination of X X X
diagnoses with or without iNPH
Disorders that may have two symptoms
MultifactorialVany combination of X X X
diagnoses with or without iNPH
iNPH with or without comorbidities X X
Vitamin B12 deficiency X X
Cervical stenosis and myelopathy X X
Lumbosacral stenosis X X
Peripheral neuropathy X X
Disorders that may have only one symptom
iNPH X
Degenerative arthritis of the hips, knees, ankles X
Spinocerebellar degeneration X
Peripheral vascular disease (claudication) X
Alzheimer dementia X
Frontotemporal dementia X
Depression X
Hypothyroidism X
Sleep apnea X
Prostatic hypertrophy/obstructive uropathy X
Pelvic floor abnormalities X
Interstitial cystitis X
Continued on page 586

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 Normal Pressure Hydrocephalus

KEY POINT
h The international and TABLE 10-1 Differential Diagnosis of Idiopathic Normal Pressure
Japanese guidelines Hydrocephalusa Continued from page 585
support shunt surgery as
effective treatment of Gait Dementia Incontinence
idiopathic normal
Disorders that can aggravate other
pressure hydrocephalus, symptoms
as does the American
Academy of Neurology Visual impairment X X
practice guideline. Hearing impairment X
Obesity X
Cardiovascular disease X
Pulmonary disease X
Chronic lower back pain X
Vestibular disorders X
a
Reprinted with permission from Williams MA, Relkin NR, Neurol Clin Pract.19 cp.neurology.org/
content/3/5/375.full. B 2013 American Academy of Neurology.

whether comorbidities completely ex- scopic third ventriculostomy is not

plain the patient’s symptoms, then effective in treatment of iNPH.25,26 As
testing for iNPH should be performed. of 2016, no medical treatments are
effective in iNPH, and, specifically, no
INDICATIONS FOR SHUNT SURGERY evidence supports the use of acetazol-
The clinical presentation of iNPH by amide,27 although this medication is
itself is usually not sufficient to rec- occasionally prescribed and has been
ommend shunt surgery, as each of the evaluated in a small pilot study.28
primary iNPH symptoms has multiple
potential etiologies, and enlarged ven- Specialized Diagnostic Testing
tricles can be seen either with hy- The international guidelines recommend
drocephalus or with brain atrophy. tests of CSF hydrodynamics (tap test,
Predictive tests to determine the external lumbar drainage, and infusion
likelihood of shunt responsiveness are testing) to demonstrate either that the
recommended. The CSF tap test is a pre- patient has the potential to respond to
dictive test that easily can be performed shunt surgery or that the patient has ab-
at most neurologic centers. If multiple normal CSF hydrodynamics that are con-
comorbidities or differential diagnoses sistent with hydrocephalus.7Y9,24,29 The
make the diagnosis uncertain, referral tap test, also known as the large-volume
to specialized centers that can perform lumbar puncture (LP), will be described
ancillary tests (see the following section here. Infusion testing and external
on specialized diagnostic testing) can lumbar drainage will be described in
help to select patients with a high like- the following section on tertiary cen-
lihood of responding to shunt surgery. ters with expertise in complex iNPH.
The international and Japanese Tap test. The rationale for testing a
guidelines support shunt surgery as patient’s response to CSF removal is
effective treatment of iNPH, as does that doing so temporarily creates the
the American Academy of Neurology physiologic effect of a shunt for the pa-
(AAN) practice guideline.7Y9,24 Endo- tient. The hypothesis is that if the patient

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 KEY POINTS
has iNPH, a significant response to CSF CSF removal does not exclude shunt h If a patient has idiopathic
removal should be seen, and shunt responsiveness because the tap test is normal pressure
surgery should help. specific (range of 60% to 100% in var- hydrocephalus, a
Properly performing the tap test ious studies), rather than sensitive significant response to
rests on two principles.19 First, the pa- (range of 50% to 80%). External lumbar CSF removal should be
tient must be examined before and after drainage can be considered if iNPH is seen and shunt surgery
the LP so that the response to CSF re- still clinically suspected after a patient should help.
moval can be documented and quanti- has failed to improve after the tap test. h A ventriculoperitoneal
fied. Impaired gait is the symptom most shunt consists of three
likely to respond, and use of a standard- SHUNT BASICS parts: a proximal catheter,
ized evaluation of gait, with or without The purpose of a shunt is to divert CSF usually inserted in the
video recording or computer-assisted from the craniospinal CSF space to right lateral ventricle; a
assessment, is helpful. The baseline another anatomic space where the CSF distal catheter with its tip
assessment should be done immediately can be reabsorbed. The most common in the peritoneal cavity;
and a shunt valve
before the LP. The authors specifically configuration is a VP shunt. A VP shunt
between the proximal
recommend that a health care profes- consists of three parts (Figure 10-3): a
and distal catheters.
sional with the appropriate skills (eg, proximal catheter, usually inserted in
neurologist, nurse, or physical ther- the right lateral ventricle; a distal cath- h Several different makes
and models of adjustable
apist) assess and document the pa- eter with its tip in the peritoneal cavity;
shunts are available, and
tient’s gait before and after the LP, as and a shunt valve between the proximal
the devices for adjusting
relying only on the report of the patient and distal catheters. The valve consists them are not
or family is liable to be influenced by of a mechanism that opens when the interchangeable.
their desire to see improvement. pressure difference across the valve (ie,
Second, the volume of CSF removed between the ventricle and peritoneal
must be large enough to improve the cavity) exceeds the pressure required to
patient’s CSF hydrodynamics enough for open the valve. Once the valve opens,
the brain to respond and the symptoms CSF flows through the tubing. An alter-
to improve. The LP should be done nate configuration is a lumboperitoneal
with an 18- or 20-gauge spinal needle. shunt, in which the proximal catheter
Typical tap test protocols remove 30 mL is placed in the lumbar CSF space.
to 50 mL of CSF. The interval between Two types of shunt valves are widely
the LP and the formal follow-up exami- used: shunts with a fixed-valve opening
nation is usually between 2 and 4 hours. pressure and programmable shunts
The patient does not have to stay su- with variable valve opening pressure
pine after the LP, and our experience that can be changed via an external
is that headache and nausea after LP magnetic programming device. Several
are uncommon in the iNPH population. different makes and models of adjust-
We have patients lie down only if they able shunts are available, and the
develop adverse events and encour- devices for adjusting them are not
age them and their families to be active interchangeable. Flow through shunt
(eg, going for a snack or taking a walk) valves is unidirectional, preventing re-
after the LP, which enables them to flux into the ventricles. Some shunts
determine in realistic circumstances also have an antisiphon device that has
whether the patient’s gait has improved. a higher resistance in the vertical posi-
The same formal gait assessments tion to prevent overdrainage of CSF
should be performed before and after when patients are upright that can cause
the LP. If the response is significant, low-pressure symptoms or, in severe
shunt surgery can be recommended.30 circumstances, subdural fluid collections
However, the absence of response to or hematomas.
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 Normal Pressure Hydrocephalus

KEY POINT
h Some, but not all,
adjustable shunts are
susceptible to strong
external magnetic fields.

FIGURE 10-3 Lateral skull x-ray showing the three

components of a shunt: the proximal
catheter (yellow arrow), the valve
(red arrow), and the distal catheter
(blue arrow).

Depending on the design of the valve geon’s recommendation and the

mechanism, some, but not all, adjust- patient’s preference. No evidence sup-
able shunts are susceptible to strong ports the use of one specific make or
external magnetic fields (eg, MRI) or model of shunt over another29,35; how-
to weak external magnetic fields (eg, ever most tertiary centers with exper-
household magnets or magnets from tise in complex iNPH make use of
toys) that are brought within 1 to 2 mm shunts with adjustable settings. When
of the shunt valve mechanism, which patients with iNPH are selected for
can change the shunt setting.31Y33 A shunt surgery on the basis of testing
website for determining the safety of described in the international and
shunts, as well as other devices, in Japanese guidelines, the risk of shunt
MRI scanners is available at www. surgery is low in the context of the
mrisafety.com.34 Patients who have expected benefits, and most patients
MRI-susceptible shunts are not prohib- will proceed with shunt surgery.
ited from undergoing MRI scans; how- The goal of using a shunt to treat
ever, they should be seen soon after the iNPH is to improve the patient’s symp-
MRI to have the shunt setting checked toms and avoid serious complications,
and reset if necessary. Failure to do so such as subdural effusion or hematoma.
could result in either overdrainage if the Adjustable valves offer the advantage
shunt setting after the MRI is too low, or of being able to lower the pressure set-
in inadequate drainage and worsening ting incrementally until symptoms im-
of the iNPH symptoms if the shunt prove and to raise the pressure setting if
setting after the MRI is too high. low-pressure symptoms or complications
The choice of shunt valve and con- emerge. The introduction of adjustable
figuration depends on the neurosur- valves has dramatically lowered the need

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 KEY POINTS
for shunt revisions, and most complica- Overdrainage can be caused by a h Patients who have
tions can be handled by changing the shunt setting that is too low (if using had shunt surgery
shunt setting. Severe complications, such an adjustable shunt) or by a fixed valve should have periodic
as subdural hematoma with mass effect, with a setting that is too low. The main follow-up visits.
shunt infection, and shunt obstruction, symptom of overdrainage is headache h Although most
typically require neurosurgical interven- that worsens with sitting and standing neurologists have not
tion. Adjustable shunts can be used to and improves when lying down. Pa- been trained to provide
safely manage patients with iNPH who tients may also report altered hearing, longitudinal care of
need chronic anticoagulation.36 typically muffled.37 A subdural effusion patients with idiopathic
(hygroma) or hematoma can be seen normal pressure
LONGITUDINAL FOLLOW-UP on CT or MRI. Symptomatic patients hydrocephalus after
AFTER SHUNT SURGERY may benefit from raising the shunt shunt surgery, they can
Patients who have had shunt surgery setting (Figure 10-4). Thin subdural learn to do so.
should have periodic follow-up visits. effusions (2 mm to 5 mm) in asymp- h All symptoms in patients
Many neurosurgeons will see these pa- tomatic patients are usually not an with idiopathic normal
tients only for a postoperative wound indication for raising the shunt setting. pressure hydrocephalus
check and will not see them again un- The setting of adjustable shunts can improve after
less they have a shunt complication should be confirmed during the shunt surgery.
that requires surgery. Although most follow-up visit, provided the neurolo-
neurologists have not been trained to gist has the device appropriate for the
provide longitudinal care of patients patient’s shunt. Depending on the de-
with iNPH after shunt surgery, they gree of symptomatic recovery and the
can learn to do so. presence or absence of low-pressure
The follow-up of patients with a shunt signs and symptoms, the shunt setting
is similar to the follow-up of patients can be raised or lowered in small incre-
with parkinsonism or other chronic neu- ments or left unchanged. If the setting
rologic disorders. The interval history is changed (Current Procedural Ter-
should cover all three iNPH symptoms minology code 62252, reprogram-
of gait impairment, incontinence, and ming of programmable cerebrospinal
dementia. The neurologic examination shunt38) then follow-up in 2 to 3 months
should include cognitive screening (eg, to assess the response to the change is
MMSE or MoCA), gait evaluation, and indicated. Once patients have reached
a general neurologic examination. a stable degree of recovery without
All symptoms in iNPH can improve low-pressure symptoms, the interval
after shunt surgery. The cognitive im- between visits can be extended to 6 to
provement is not widely appreciated, 12 months.
but has been confirmed in multiple stud- Symptoms of shunt malfunction
ies and is more robust than the improve- should be explored, such as pain or dis-
ment seen with pharmacologic treatment comfort from the shunt components,
of degenerative dementias.14Y16 including abdominal pain. The exami-
Periodic brain imaging is recom- nation includes inspection and palpa-
mended to look for signs of overdrain- tion of the shunt, as rarely poor wound
age, such as subdural effusion or healing or dehiscence will be present,
hematoma, particularly in the first 6 to which requires immediate admission to
12 months after shunt surgery until it is the hospital and neurosurgical consul-
determined that the patient’s condition tation for possible shunt surgery be-
and the appearance of the scan are cause of the risk of shunt infection.
stable. In most instances, a CT scan Because shunt obstruction occurs in
without contrast suffices. 30% or more of patients with iNPH,
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 Normal Pressure Hydrocephalus

KEY POINT
h When patients who
have been treated with
shunts have worsening
symptoms, physicians
frequently presume that
the shunt is obstructed,
which is often incorrect.

FIGURE 10-4 Serial axial CT scans without contrast over a 6-week period showing the
evolution of enlarging bilateral subdural fluid collections (A, from January 3; B,
from January 7; C, from January 12) and resolution of the subdural fluid collections
after the adjustable shunt was placed at the highest setting (D, from February 16).

shunt obstruction symptoms should be When patients who have been treated
reviewed during clinic visits. It is not with a shunt have worsening symptoms,
possible to predict who will experience physicians frequently presume that the
shunt obstruction or when. The return shunt is obstructed, which is often
of iNPH symptoms is typically grad- incorrect because elderly patients may
ual, and it may be several weeks or worsen for other reasons, including
months before patients realize that worsening of comorbidities or emer-
they are getting worse. Shunt obstruc- gence of new diagnoses or conditions.
tion in iNPH is rarely an emergency. Typical clinical scenarios that are of
If shunt obstruction is detected and concern to patients are lagging symp-
treated, approximately 75% of patients tom recovery, transient worsening,
will once again improve.39 and insidious worsening.19

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 KEY POINTS
Some patients have recovery of only These centers typically have access to h Three typical clinical
one or two symptoms after shunt diagnostic tests that are not available scenarios of worsening
surgery, while other symptoms lag in general use, including external lum- symptoms are lagging
behind. In most circumstances, an- bar drainage, lumbar CSF infusion test- symptom recovery,
other disorder is responsible for the ing, tests to evaluate shunt patency, and transient worsening,
lagging symptom and should be in- specialized imaging approaches. and insidious worsening.
vestigated further. For example, a pa- h High-complexity patients
tient whose urinary symptoms do not Patient Flow at a Hydrocephalus with idiopathic normal
improve after shunt surgery may need Unit pressure hydrocephalus
to be referred to a urologist. Figure 10-5 illustrates the patient flow may be better served by
Some patients, after initial improve- at a tertiary clinic investigating pa- referral to tertiary centers
ment, will have transient worsening of tients for suspected iNPH. After inves- with expertise in complex
iNPH symptoms in association with tigation, about 60% of referred patients idiopathic normal
another illness (eg, urinary tract infec- had a diagnosis of probable or pos- pressure hydrocephalus.
tion) or with hospitalization or surgery. sible iNPH. A small portion had h Supplementary tests can
This pattern is similar to the worsening ventriculomegaly without iNPH symp- be used to include
of latent symptoms seen in many patients for surgery, but
toms, or had iNPH symptoms but a
neurologic disorders when patients not to exclude them.
normal radiologic examination. In
experience other illnesses. After the h Infusion testing for
about 10% of patients, secondary
underlying illness is identified and assessment of CSF
treated, the iNPH symptoms should causes of hydrocephalus were found.
hydrodynamics is
improve with time. About one-fourth had an alternate diag-
commonly used
Gradual worsening of symptoms nosis, such as parkinsonism, Alzheimer in Europe.
over weeks or months may indicate dementia, or vascular dementia.
h An increased resistance
shunt malfunction or the emergence CSF Infusion Testing to CSF outflow (Rout)
of a comorbidity. In this circumstance, is one of the most
Infusion testing for assessment of CSF
shunt malfunction should be investi- consistent findings
hydrodynamics is commonly used in
gated. Disconnection of the shunt in idiopathic
Europe to diagnose iNPH, but is rarely
components is easily detected by plain normal pressure
x-rays, although uncommon in the iNPH used in the United States or Canada. hydrocephalus research.
population. Palpating and depressing The CSF infusion test involves infusing
the shunt reservoir to check for Ringer lactate via one spinal needle
refilling is not helpful in distal shunt while simultaneously recording CSF
obstruction. A shunt patency study pressure via a second spinal needle.40,41
should be performed, w h i c h i s Several variables, such as intracranial
discussed in the following section. pressure (ICP), outflow resistance
(Rout), CSF formation rate, pulse pres-
TESTS AND SERVICES AVAILABLE sure curve,42 and dural venous pres-
AT TERTIARY CENTERS sure can be measured or indirectly
High-complexity patients (Table 10-2) calculated. Rout, or its inverse, CSF
may be better served by referral to ter- conductance, is a measure of the
tiary centers with experience in diagno- resistance to CSF resorption in the cen-
sis and management of complex adult tral nervous system. One of the most
hydrocephalus that utilize a multidis- consistent findings in iNPH research is
ciplinary team of specialists, including that patients have an increased resis-
neurologists, neurosurgeons, radiolo- tance to CSF outflow (Rout).43 Several
gists, and neuropsychologists, and pro- methods for infusion testing exist, and
vide a highly organized and protocolized the value and accuracy of Rout are
approach to the evaluation and treat- method dependent.40 Reference values
ment of iNPH and related disorders. for healthy elderly exist.41 Infusion

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 Normal Pressure Hydrocephalus

TABLE 10-2 High-Complexity Patients With Adult Hydrocephalus

b Patients with severe ventriculomegaly

b Patients who first received a shunt or endoscopic third ventriculostomy in
childhood or as young adults
b Patients who have congenital or childhood-acquired hydrocephalus but
were not treated
b Patients who require chronic anticoagulation
b Patients with severe neurologic impairment
b Patients with atypical presentations (eg, no gait impairment)
b Patients who need shunt adjustments
b Patients with shunt complications, including wound dehiscence or
suspected shunt infection, subdural hematoma in need of surgical
evacuation, or intraperitoneal complications

FIGURE 10-5 Flowchart illustrating the diagnostic workup at the

Department of Clinical Neuroscience, Umeå
University, Sweden, including diagnosis at discharge.
iNPH = idiopathic normal pressure hydrocephalus; NPH = normal
pressure hydrocephalus.

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 KEY POINTS
testing requires specialized equipment, predictive value and a high negative- h Attempts at ad hoc
which is commercially available in predictive value. The most frequent performance of external
Europe and other parts of the world,44 serious complication of external lumbar lumbar drainage in
but not the United States, and requires drainage is bacterial meningitis, seen in patients with idiopathic
considerable expertise on the part of 2% to 3% of patients.48,49 Because of normal pressure
the physicians who perform it. the potential risks and the need for hydrocephalus
specialized inpatient nursing, external are discouraged.
External Lumbar Drainage lumbar drainage should be performed h The presence of unstable
External lumbar drainage involves con- only by centers that have an organized intracranial pressure
tinuous CSF drainage and requires team and approach. Attempts at ad (predominantly B waves)
hospitalization. A spinal catheter is in- hoc performance of external lumbar in idiopathic normal
serted via a Tuohy needle (Figure 10-6) drainage are discouraged. pressure hydrocephalus
and connected to a sterile, closed sys- is well known.
tem for controlled CSF drainage at Intracranial Pressure Monitoring
approximately 10 mL/h (Case 10-1).45 Recording of ICP has been used as a
The patient’s gait should be examined diagnostic test for iNPH for 40 years.50
before the procedure, daily during The recordings in iNPH reveal wave-
CSF drainage, and after removal of form abnormalities similar to those
the catheter. Neuropsychological test- originally described for brain tumor
ing before and after external lumbar or acute injury, ie, so-called B waves
drainage may also be helpful. Most and A waves, particularly in sleep. The
publications have cited 72 hours of presence of unstable ICP (predomi-
CSF drainage, although some centers nantly B waves) in NPH is well known,
drain CSF for shorter periods. Exter- and the correlation with iNPH shunt
nal lumbar drainage is said to be responsiveness varies from 50% to
accurate, with both a high positive- 90%.51Y53 Most ICP monitoring has

FIGURE 10-6 Insertion of a 16-gauge spinal catheter via a 14-gauge Touhy needle for
external lumbar CSF drainage.

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 Normal Pressure Hydrocephalus

Case 10-1
An 82-year-old woman was referred for difficulty with gait, balance, bladder control, and cognition. She
had experienced gait trouble for ‘‘many years,’’ but it had been much worse over the past year. She had
problems getting in and out of seats, initiating gait, and turning, and she had festination. She used a
walker with wheels. Urinary symptoms included urgency, but sometimes her urine would not flow when
she was on the toilet, and she lost urine with coughing or straining. Cognitively, she had trouble finding
words, but managed her money, medications, and appointments, which her daughter confirmed. Her
medications included alprazolam, oxycodone, and tramadol. She was unable to live independently.
The Montreal Cognitive Assessment (MoCA) score was 14 out of 30, and the Tinetti scale score46
(a standardized gait and balance assessment) was variable from 12 out of 28 to 16 out of 28.
Motor examination revealed paratonia versus rigidity. Brain MRI scan (Figure 10-7) showed an Evans
ratio of 0.40, bilateral frontal atrophy, and possible disproportionately enlarged subarachnoid space
hydrocephalus (DESH).
She did not improve after cessation of alprazolam, oxycodone, and tramadol, and thus was
admitted to the hospital for external lumbar drainage. Over 3 days, 690 mL CSF was drained. The Tinetti scale
score improved from 5 to 10 out of 28 on admission to 21 to 25 out of 28 after external lumbar drainage.
The Timed Up and Go Test (TUG),47 a standardized assessment in which a patient is observed and timed
while arising from an arm chair, walking 3 meters, turning around, walking back, and sitting down
again, improved from 36.65 seconds to 16.25 seconds after external lumbar drainage. She was referred to
a neurosurgeon. A programmable ventriculoperitoneal shunt was inserted at a setting with an opening
pressure of approximately 115 mm H2O.

FIGURE 10-7 Imaging from the patient in Case 10-1. The Evans ratio is 0.40. The widening
of the sulci in the frontal lobes (A, B) suggests atrophy; however, the pattern
also raises the possibility of disproportionately enlarged subarachnoid space
hydrocephalus (DESH), particularly the widening of the sulci higher over the convexities
(B, arrows).

Three months after shunt surgery, she no longer needed a walker and only occasionally used a
cane. The MoCA score was 20 out of 30 and the Tinetti scale score was 25 out of 28, which was normal.
Because she was still improving, the shunt setting was not changed.
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 Continued from page 594
Nine months after shunt surgery, she was living in her own home part time and able to do light
housework and manage all of her affairs. The MoCA score was 24 out of 30 and the Tinetti scale score
was 22 out of 28.
Fourteen months after shunt surgery, she had passed a formal driving evaluation. She was living
independently. Her gait examination was described as cautious, but with no shuffling. Because her
condition was stable, she was seen annually for follow-up.
Comment. This case illustrates the evaluation and management of a patient with possible
idiopathic normal pressure hydrocephalus from the beginning to a sustained successful outcome
after shunt surgery.

been done with ventricular catheters or safely via lumbar catheter, and the
other intracranial devices.50,53 Elderly authors tend to reserve ICP monitoring
patients with obstructive hydrocepha- for patients whose gait impairment is so
lus may present with symptoms of iNPH. mild that it may be difficult to ascertain
In such cases, diagnostic ICP monitor- improvement with CSF drainage alone.45
ing via intracranial methods should be Recently, analysis of the amplitudes of
considered. Because most patients with the ICP pulse pressure has been pro-
iNPH have communicating hydroceph- posed as a predictive test in iNPH.
alus, ICP monitoring can be performed High pulse pressure amplitudes are

Case 10-2
A 77-year-old man was referred for evaluation of possible idiopathic normal
pressure hydrocephalus (iNPH) at a center that uses CSF infusion testing. The
investigation revealed a low CSF outflow conductance (6.2 mm3/s/kPa), which
is a typical finding in iNPH. (Normal values are above 10 mm3/s/kPa.) A shunt
with a fixed opening pressure and an antisiphon device was inserted.
At 3 and 12 months after surgery, he had a marked clinical improvement.
The conductance was increased, as expected (57 mm3/s/kPa and 59 mm3/s/kPa,
respectively), because the shunt, which is an alternate CSF outflow
channel, increases the measured conductance.
The patient’s gait and cognitive function deteriorated 36 months after
the shunt surgery. The conductance was reevaluated and was lower than
before (25 mm3/s/kPa), but still higher than the preoperative value. After
consideration, the original shunt valve was replaced with an adjustable
valve set at 120 mm H2O. However, the patient did not improve as expected.
Another CSF dynamic investigation was performed, showing CSF outflow
conductance results (7.7 mm3/s/kPa) that were the same as the preoperative
value, indicating that the shunt system was obstructed. The shunt was revised
again, after which the patient improved.
The patient’s iNPH symptoms once again worsened 57 months after the
original shunt surgery. Another CSF dynamic investigation revealed a high
conductance (33 mm3/s/kPa), consistent with a functioning shunt. The shunt
setting was lowered, but the patient did not improve, and the cause of his
worsening was attributed to his comorbidities.
Comment. This case illustrates how an infusion technique can be used
for patient selection, but also to assess postoperative shunt function.
Case modified with permission from Eklund A, et al, Med Biol Eng Comput.50 B 2004 Springer International
Publishing AG.

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 Normal Pressure Hydrocephalus

KEY POINT
h Pathologic CSF dynamics considered to predict good chances of key features on brain imaging, and
are an important part of improvement after surgery.54 A variant assessment of the clinical response to
the idiopathic normal of this method is the ICP pulsatility tap test. Evidence supports the use of
pressure hydrocephalus curve, which describes how the pulse shunt surgery to treat patients with
pathophysiology. amplitude changes while ICP is manip- iNPH, and when patients are properly
ulated to different levels during CSF selected, the benefit-to-risk ratio is
infusion testing.42 favorable. Neurologists have a role in
the longitudinal care of patients with
Shunt Patency Evaluation iNPH who have undergone shunt sur-
Either radionuclide shunt patency study gery, particularly in considering the
or CSF infusion testing can be used to differential diagnosis of any symptoms
assess shunt function.39,55 Radionuclide that may worsen after shunt surgery.
shunt patency study involves the injec- Tertiary centers with expertise in com-
tion of a small volume of radioisotope plex iNPH are available throughout
into the shunt reservoir. Once the the world.
radionuclide is injected, images of the
proximal system are obtained every REFERENCES
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53. Eide PK, Sorteberg W. Diagnostic intracranial 55. Eklund A, Lundkvist B, Koskinen LO, Malm J.
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 Review Article

Psychiatric Aspects
Address correspondence to
Dr Chiadi U. Onyike, Johns
Hopkins University, 600 N

of Dementia
Wolfe St, Meyer 279, Baltimore,
MD 21287, [email protected].
Relationship Disclosure:
Dr Onyike has received
personal compensation as Chiadi U. Onyike, MD, MHS
special issue editor for the
International Review of
Psychiatry and the Psychiatric
Clinics of North America and ABSTRACT
has given expert legal
testimony for the Paley Rothman Purpose of Review: The psychiatric aspects of dementia are increasingly recognized
law firm on disabilities related as significant contributors to distress, disability, and care burden, and, thus, are of
to frontotemporal dementia. increasing interest to practicing neurologists. This article examines how psychiatric
Dr Onyike receives research
funding from the Jane Tanger disorders are entwined with dementia and describes the predictive, diagnostic, and
Black Fund for Young-Onset therapeutic implications of the psychiatric symptoms of dementia.
Dementia Research, the Recent Findings: Psychiatric disorders, particularly depression and schizophrenia,
National Institute of Neurological
Disorders and Stroke, the are associated with higher risk for late-life dementia. Psychiatric phenomena also
National Institute on Aging, the define phenotypes such as frontotemporal dementia and dementia with Lewy bodies,
National Institutes of Health, cause distress, and amplify dementia-related disabilities. Management requires a
the Robert and Nancy Hall
family, and Tau Therapeutics. multidisciplinary team, a problem-solving stance, programs of care, and pharmacologic
Unlabeled Use of management. Recent innovations include model programs that provide structured
Products/Investigational problem-solving interventions and tailored in-home care.
Use Disclosure:
Dr Onyike discusses the
Summary: There is new appreciation of the complexity of the relationship between
unlabeled/investigational psychiatric disorders and dementia as well as the significance of this relationship for
indications and evidence for treatment, community services, and research.
efficacy and risks of
prescribing antidepressants,
antipsychotics, and other Continuum (Minneap Minn) 2016;22(2):600–614.
psychotropic agents for
treating psychiatric aspects of
dementia, as well as the
alternatives to making these INTRODUCTION and their predictive, diagnostic, and
prescriptions, which include
behavioral interventions, The coincidence of primary (ie, neuro- treatment implications.
care programs, caregiver
support and training, degenerative) dementia and psychiatric LINKS BETWEEN PSYCHIATRIC
environment modulation, and disorders is increasingly seen as a com- DISORDERS AND DEMENTIA
structured recreation.
mon occurrence and as a significant con- The earliest descriptions of the primary
* 2016 American Academy
of Neurology. tributor to distress, handicap, care needs, dementias included psychiatric distur-
and health costs. Psychiatric disorders bances alongside the cognitive and
have long been viewed as epiphenom- functional symptoms. Alois Alzheimer
ena that complicate dementias that are identified anxiety, hallucinations, delu-
‘‘essentially’’ cognitive disorders, but sions, and agitation amid confusion and
contemporary views suggest: (1) some dense impairments of memory, orienta-
psychiatric disorders are integral to the tion, and knowledge that would define
dementia phenotype, (2) dementia the illness named for him.1 His con-
may be foreshadowed by syndromes temporaries, Arnold Pick, Paul Sérieux,
such as major depression and schizo- and Joseph Dejerine, described mid-
phrenia and states such as apathy and life deterioration of conduct and lan-
irritability, and (3) many psychiatric guage, which are the first descriptions
disorders complicate the course of the of frontotemporal dementia (FTD).2Y4
dementia by amplifying or adding to From these beginnings, primary de-
distress and disability. This article mentias came to be viewed narrowly
examines the overlap between psychi- as cognitive disorders, but in the past
atric disorders and primary dementias 35 years, observations of the ubiquity

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 KEY POINTS
of psychiatric disorders in dementia although late-life variants of depression, h The majority of
and that patients experience one or anxiety, mania, and psychosis are rec- patients with dementia
more disturbances of mood, behavior, ognized. In contrast, primary demen- experience one or more
perception, and thought content have tias are generally conditions of midlife disturbances of mood,
been replicated numerous times.5Y9 and late life, although youth and young- behavior, perception,
Psychiatric symptoms in neurode- adult presentations occur. Psychiatric and thought content.
generative disease can arise from the disorders preceding cognitive dysfunc- h While most psychiatric
dementia phenotype, or from psychiat- tion and dementia have long been rec- states manifest as
ric disorders or psychological vulnerabil- ognized in schizophrenia, since Emil episodes, apathy
ity preceding the dementia. Additional Kraepelin described dementia praecox associated with
risk factors for development of psychi- as a chronic disintegration of cognition dementia is usually a
atric symptoms in neurodegenerative and conduct beginning in youth.18,19 persistent state.
disease include a family history of psy- Schizophrenia is now viewed as a het- h Primary psychiatric
chiatric illness, uncontrolled pain, and erogenous psychosis in which cognitive disorders usually
systemic illnesses that give rise to de-
dysfunction is common, and progres- develop in youth and
lirium. Nearly all community-dwelling early adulthood,
sive cognitive decline and dementia
elderly individuals with dementia will although first episodes
develop psychiatric symptoms within rare. Schizophrenia is believed to arise
from aberrant neurodevelopment, of depression, anxiety,
5 years, which commonly includes mania, and psychosis in
apathy, depression, anxiety, and, often, with deficiencies in dopamine and
midlife and in the
combinations of these and other symp- glutamate neurotransmission culmi-
elderly are recognized.
toms.10Y15 Predementia states such as nating in the disintegration of mental
function in early adulthood. Most cases h A subset of individuals
mild cognitive impairment (MCI) fea- with schizophrenia
ture psychiatric disorders, but less com- of schizophrenia feature static deficits
develop dementia in
monly than dementia.12,16 While most in attention, executive functions, and
later life, decades after
psychiatric states manifest as episodes, social reasoning from the outset, along- the onset of the
apathy associated with dementia is usu- side the illness-defining hallucinations psychotic state.
ally a persistent state,17 and its fre- and delusions. These cognitive disabil-
quency and severity increases along ities undermine treatment adherence
the continuum from prodrome (such and psychosocial adjustment.
as MCI) to advanced dementia.16,17 Only a minority of patients with
Psychosis in dementia sometimes per- schizophrenia develop dementia in
sists, especially in the phenotypes it later life (ie, decades after the onset
defines such as dementia with Lewy of the psychotic state).20 These patients
bodies (DLB).15 Some psychiatric dis- have dense impairments of memory
orders are wont to appear early in the
and executive functions, with relative
illness (such as apathy, anxiety, de-
sparing of language and visuospatial
pression, and irritability), whereas
other symptoms such as hallucina- functions.21 A recent 18-year observa-
tions, delusions, roaming, and abnor- tional study of a large Danish schizo-
mal feeding tend to appear later. As a phrenia cohort showed a greater than
general observation, psychiatric states twofold higher risk for dementia than
are more common in dementia clinics in the general population.22 The risk
and residential care settings than they was higher in midlife than in late life,
are in the community. an observation not easily explained by
Alzheimer disease (AD), where a
PSYCHIATRIC DISORDERS higher frequency in older members of
FORESHADOW COGNITIVE the cohort is expected. Neuropath-
DECLINE AND DEMENTIA ologic studies of cohorts and large se-
Primary psychiatric disorders usually ries have observed lower brain weight
develop in youth and early adulthood, in subjects who had schizophrenia
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 Psychiatric Aspects of Dementia

KEY POINT
h Depressive symptoms and dementia, compared to those who polar disorder.30,31 Whether the risk
have been associated had schizophrenia and no dementia.23 for dementia is greater for young-onset
with cognitive decline A more recent analysis showed that versus late-onset depression is still un-
and transitions to neuritic plaques and neurofibrillary settled as studies have yielded mixed
dementia in individuals tangles that did not meet the threshold results.30,32 Recent data from a Swedish
with mild cognitive for a formal AD diagnosis showed a cohort of military conscripts suggests
impairment and other positive correlation with dementia se- that depression in youth is associated
mild cognitive disorders. verity.24 Thus, dementia in schizophre- with a nearly twofold higher risk for
nia appears to be related primarily to young-onset dementia, 33 although
insidious brain atrophy and, for some, this finding has not been replicated.
a consequent lowering of the thresh- Whereas a causal relationship between
old for coincident neurodegeneration major depression and dementia has
to cause dementia. not been established, depressive symp-
It may be that some cases of schizo- toms may appear in the dementia
phrenia, a schizophreniform state, or prodrome (Case 11-1). Furthermore,
other psychotic presentations, are pro- depressive symptoms have been as-
dromes of a dementia. One study of sociated with cognitive decline and
progranulin (GRN) mutation carriers transitions to dementia in individuals
describes a family in which two sib- with MCI and other mild cognitive
lings manifested a classic schizophre- disorders (ie, states of cognitive dys-
nia phenotype and a third sibling had function that do not reach a thresh-
a typical FTD.25 It is also now increas- old for dementia, or match formal
ingly recognized that up to 20% of definitions for MCI). Psychiatric dis-
carriers of the C9ORF72 mutation orders are more frequently observed
associated with FTD and amyotrophic in elderly patients with MCI and other
lateral sclerosis experience psycho- mild cognitive disorders than in their
sis,26Y28 although it is still uncertain age-matched peers with normal cog-
what proportion present with primary nition, and these associations have
psychosis. Earlier clinicopathologic been linked to worse cognition and
analysis of a brain bank cohort has functional disabilities.16,34,35 Studies
suggested that schizophreniform and of community-based elderly indi-
other psychiatric presentations are viduals have shown associations
more likely in patients with FTD who between depression, apathy, and
are younger than 45 years of age, irritability/agitation, and transitions
whereas later-life presentations are from normal cognition to MCI, and
more likely to feature impairments of from MCI to dementia.36Y40 A recent
cognition and social conduct.29 meta-analysis reached the same con-
Cognitive dysfunction has been ob- clusions, showing that transitions
served in cases of remitted major from mild cognitive disorders to
depression and bipolar disorder, par- dementia are predicted by depres-
ticularly affecting attention, executive sion (in community samples) and
function, and memory, and depression apathy (in the clinic).41
appears to be associated with increased
risk for late-life dementia.30 The risk for PSYCHIATRIC PHENOMENA
dementia appears to be higher in in- AS DEFINING FEATURES
dividuals with more severe depressive OF DEMENTIA
symptoms and appears to be associated Although dementia syndromes are
with the frequency of admission to psy- widely viewed essentially as cognitive
chiatric wards for depression and bi- disorders, many of these are defined by
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 KEY POINT

Case 11-1 h Alzheimer disease

typically presents a
A 58-year-old man, who had formerly worked as a business manager,
variety of psychiatric
developed a severe major depression with anorexia and severe weight loss
symptoms, most
10 years prior to his presentation at the neuropsychiatry clinic. He did
commonly apathy,
not recover fully despite antidepressant therapy and, 3 years into his illness,
depression, anxiety,
developed irritability, religious passions, confusion, indecisiveness, and,
irritability, agitation,
intermittently, suicidal thoughts. Five years into the illness, symptoms emerged
and delusions.
of inattention, disorganization, and misreading of social cues. He became
talkative, loud, self-centered, and compulsive. In the last year, symptoms
included low mental acuity, inattention, lack of spontaneity, indifference,
inertia, inflexibility, literalness, rigid moralizing, slovenliness, jocularity,
irritability, impulsiveness, restlessness, and overeating. His behavior had
engendered conflict in his marriage and in his community. A neuropsychological
assessment ordered by his psychiatrist and performed in the month before
the current visit showed impairments in attention, executive functions, and
emotion recognition. He had no other significant past medical history, and
his current medications included paroxetine and lamotrigine. In the clinic, the
mental status examination showed paucity of thought, indifference, and
shallow affect. He did not have depressed mood, suicidal thoughts, anxiety,
paranoia, or hallucinations. Compulsive behavior was not observed.
Neurologic examination showed normal cranial nerve, motor, sensory, and
coordination testing. Upper and lower extremity reflexes, including
plantar responses, were normal. He did not have primitive reflexes. Brain
MRI showed mild bilateral orbitofrontal atrophy, and fluorodeoxyglucose
positron emission tomography (FDG-PET) imaging showed low uptake in
the left cerebral hemisphere that was worse in the left frontal lobe.
Comment. This case illustrates a psychiatric syndrome as the initial
presentation of a primary dementia: behavioral variant of frontotemporal
dementia. The case demonstrates the diagnostic misdirection, dysfunction,
and disability that psychiatric states can produce and shows the types of
diagnostic data that reveal the neurodegenerative origin of the illness. The
reader is also reminded that primitive reflexes are not reliable indicators
of frontal lobe dysfunction, as they may be absent in the early stages of
frontotemporal dementia.

psychiatric phenomena. AD presents a delusions, anxiety, and depression. Rapid

variety of these states, most commonly eye movement (REM) sleep behavior
apathy, depression, anxiety, irritability, disorder is also characteristic of these
agitation, and delusions. Hallucina- conditions42 and has been associated,
tions and mania are uncommon in AD.14 albeit less frequently, with progressive
Vascular dementia also presents many supranuclear palsy, corticobasal de-
of the same symptoms, but especially generation, FTD with parkinsonism that
apathy, depression, anxiety, and irrita- is caused by mutations in the gene for
bility. On the other hand, patients who microtubule-associated protein tau
have DLB or Parkinson disease de- (MAPT), and some forms of spinocer-
mentia (PDD) often experience visual ebellar ataxia. In these conditions, the
illusions, pareidolia (perception of REM sleep behavior disorder may be
ambiguous visual forms as meaningful the earliest symptom, constituting a
objects) and hallucinations, paranoia, prodrome that precedes the motor

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 Psychiatric Aspects of Dementia

KEY POINTS
h Cognitive deficits and syndrome or dementia syndrome by ered a rarity in FTD, was common in a
behavioral symptoms many years. Huntington disease fea- recently described neuropathology
are present in patients tures a triad of cognitive, affective, and cohort and may distinguish a subtype
with Huntington motor phenomena. The motor fea- of FTD caused by mutations in the
disease beginning tures, typically chorea, athetosis, tics, C9ORF72 gene, although the diagnos-
approximately 15 years bradykinesia, incoordination, and tic utility of this association has not
prior to motor diagnosis. ideomotor apraxias, are preceded by been examined. Visual illusions and
h The behavioral variant executive dysfunction, apathy, irri- hallucinations develop early in DLB
of frontotemporal tability, depression, and anxiety.43 and become florid, persistent, and,
dementia typically Such cognitive deficits and behavioral in many cases, associated with mis-
presents as a combination symptoms are present beginning identification, paranoia, delusions,
of socially offensive about 15 years prior to motor diag- and anxiety.26Y28,49 PDD manifests
behaviors, such as nosis.44 In asymptomatic Huntington illusions, hallucinations, paranoia,
indifference, impatience, disease mutation carriers, the earliest and delusions very late in the illness,
carelessness, insensitivity,
cognitive deficits are found in atten- usually many years after the de-
jocularity, intrusiveness,
tion, working memory, verbal learn- velopment of parkinsonism, subclini-
distractibility,
impulsiveness,
ing, verbal long-term memory, and cal cognitive dysfunction, anxiety, and
stereotyped behaviors, learning of random associations.45 depression. In PDD, visual hallucina-
compulsions, food Still, clinical diagnosis in Huntington tions, paranoia, and anxiety often
craving and gluttony, disease emphasizes the motor phe- arise as complications of dopaminer-
and slovenliness, and nomena and genetic testing; the gic therapy. REM sleep behavior dis-
many of these patients cognitive deficits and psychiatric order is a characteristic of DLB and
do not have noticeable phenomena lack the specificity for Parkinson disease that, when present
cognitive deficits until differential diagnosis but may facil- in advance of cognitive and motor
illness is established. itate early recognition in individu- dysfunction, facilitates the clinical
h Visual illusions and als who are known carriers of the diagnosis.42,50,51
hallucinations develop Huntington mutation or have a posi-
early in dementia with tive family history.46 IMPACTS OF PSYCHIATRIC
Lewy bodies and For some dementia syndromes, psy- DISORDERS ON DEMENTIA
become florid, persistent chiatric states are defining elements of Psychiatric disorders are frequently the
and, in many cases,
the illness and its diagnosis. Psychiatric main clinical focus because they bring
are associated
phenomena that define the dementia about distress directly and can exacer-
with misidentification,
paranoia, delusions,
syndrome are integrated into the diag- bate other morbidity. These states in-
and anxiety. nostic criteria for FTD and DLB, for crease the demands placed on relatives
example.47,48 To illustrate further, FTD and other caregivers and, thus, the
h Psychiatric symptoms in
is characterized by gross decline in levels of caregiver stress, and they also
dementia have been
linked to more severe
conduct (ie, the behavioral variant) or result in higher rates of resource utili-
cognitive and functional speech and language (the language zation.52 Psychiatric symptoms in de-
disabilities and faster variant). The behavioral variant of FTD mentia have also been linked to more
progression to severe typically presents as a combination of severe cognitive and functional disabil-
dementia and death. socially offensive behaviors, such as ities and faster progression to severe
indifference, impatience, carelessness, dementia and death.53,54 It has been
insensitivity, jocularity, intrusiveness, estimated, for example, that nearly
distractibility, impulsiveness, stereo- one-third of all dementia treatment
typed behaviors, compulsions, food costs are accounted for by psychiatric
craving and gluttony, and slovenliness, symptoms.55,56 These symptoms also
and many of these patients do not have shape the quality of life for many in-
noticeable cognitive deficits until illness dividuals with dementia. They are also
is established. Psychosis, once consid- major drivers of transfers to residential

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 KEY POINTS
care, where they cause higher mor- & Documenting disabilities is vital h Patients with apathy
bidity and strain on caregivers.57Y60 for planning treatments and appear passive,
rehabilitation and for securing disinterested, and aloof,
PSYCHIATRIC SYMPTOMS AND public assistance, disability benefits, but do not experience
DIAGNOSTIC CONSIDERATIONS and other resources. a sad or depressed
The clinical history is the linchpin The mental status examination in- mood. In contrast,
of the diagnostic examination of pa- cludes not only detailed cognitive test- depression is associated
tients presenting with cognitive or with a sad mood, low
ing, but also a systematic examination
self-worth, feelings of
behavioral symptoms, and interview- of each psychiatric domain (eg, con-
guilt, and pessimism.
ing a source who has an intimate duct, mood, thought processes, per-
knowledge of the patient (usually a cepts). (For more information on the h Psychometric instruments
mental status examination, refer to the are used to provide
spouse, a close relative or friend, or a
measurements of the
longtime caregiver) is imperative. The article ‘‘The Mental Status Examination
psychiatric phenomena
goal of taking the patient’s clinical in Patients With Suspected Dementia’’
and their correlates
history is to capture all symptoms, de- by Murray Grossman, MD, FAAN, and
(particularly cognitive
scribe how the syndrome has devel- David J. Irwin, MD, in this issue of profiles and functional
oped over time, and make contrasts Continuum.61) The examination pro- disabilities) that facilitate
vides a characterization of the psychi- differential diagnosis,
between the current state and the
atric status of the patient and captures judgment of severity,
patient’s lifelong cognitive capacity,
symptoms of diagnostic value and in- and monitoring of
temperament, conduct, and habits.
forms the therapeutic approach. temporal change and
The following are key elements of Separating apathy from depression treatment responses.
the clinical history: at the bedside is valuable, as the former
& Interviewing the source privately is a signal characteristic of many de-
facilitates candor and disclosure. mentia phenotypes and is often mis-
This author typically asks the taken for depression. Patients with
patient’s permission to speak with apathy appear passive, disinterested,
their source. and aloof, but do not experience a sad
& Developing the chronology of or depressed mood. In contrast, de-
symptoms defines the syndrome and pression is associated with a sad mood,
the place of psychiatric symptoms low self-worth, feelings of guilt, and
within the context of the disease. pessimism. Apathy is best treated with
& Cataloging the symptoms and their structured behavioral routines and
severity defines the degree of psychostimulants, but some cases have
disability and distress. responded to bupropion (other anti-
& Identifying preceding or concurrent depressants are ineffective).
psychiatric states helps clarify Quantitative assessments of symp-
whether the patient has a primary toms can supplement the clinical ex-
psychiatric disorder. amination for differential diagnosis,
& Describing the context in which monitoring, and research. Psychomet-
current psychiatric states ric instruments are used to provide
emerged may point to modifiable measurements of the psychiatric
environmental, behavioral, or phenomena and their correlates (par-
social factors. ticularly cognitive profiles and func-
& Interrogating other physiologic tional disabilities) that facilitate
systems allows detection of differential diagnosis, judgment of
systemic derangements (such as severity, and monitoring of temporal
thyroid dysfunction) that may change and treatment responses. Psy-
mimic psychiatric disorders. chometric measurements are based
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 Psychiatric Aspects of Dementia

KEY POINT
h A multidisciplinary team on self-reports, caregiver interviews, shadow the cognitive impairments; and
model involving or direct observations, and may be (3) syndromes defined by motor dys-
physicians, nursing, structured or semistructured. Since functions that usually overshadow
physical therapy, and self-reports are bedeviled by the loss cognitive and psychiatric phenomena,
other rehabilitative of self-monitoring and decisional ca- such as progressive supranuclear
services, as well as pacities in people with dementia, palsy and corticobasal degeneration.68
social work and measurements are usually sourced The alternative approach is to take
caregiver/family from caregiver interviews or direct a problem-solving stance, based on the
advocacy is often observations. Two classes of instru- understanding that some of the psy-
required for the optimal ments are used: standard psychiatric chiatric disturbances seen in demen-
management of
instruments adapted to dementia tia may be maladaptive reactions or
patients with psychiatric
practice and research objectives as patient-caregiver conflicts, rather than
disorders and dementia.
well as specially designed scales and symptoms of neurophysiologic distur-
questionnaires. The Neuropsychiatric bance. In this perspective, the psychiat-
Inventory (NPI),62 the most widely ric state is understood as arising from
used tool for measuring psychiat- the interplay of personal and environ-
ric phenomena in dementia, is a mental factors, implying that they can
semistructured screen-and-probe in- be extinguished or reshaped by behav-
terview of the patient’s spouse, care- ioral and environmental manipulations.
giver, or other source. It covers a
swarth of psychiatric states, and ver- PERSPECTIVES ON
sions have been developed for as- CLINICAL MANAGEMENT
sisted living and nursing home A multidisciplinary team model involv-
settings. The Neuropsychiatric Inven- ing physicians, nursing, physical ther-
tory Questionnaire (NPI-Q),63 a short apy, and other rehabilitative services,
version of the NPI, has found wide as well as social work and caregiver/
application in clinical practice and family advocacy is often required for
research. Numerous other tools for the optimal management of patients
measuring specific psychiatric phe- with psychiatric disorders and demen-
nomena in elderly individuals with tia. At the author’s institution, behavioral
dementia exist, such as the Geriatric care, case management, pharmacologic
Depression Scale and the Frontal Be- prescriptions, and physical, speech/
havioral Inventory for use in FTD.64Y67 language, and occupational therapy
At Johns Hopkins Hospital, we have are melded into an individualized treat-
described an algorithmic approach,68 in ment plan to relieve distress, provide
which the temporal clustering of cog- direction, promote adaptation, and
nitive, neuropsychiatric, and motor optimize quality of life.69 A healthy
symptoms and signs is used to define partnership with the patient and the
syndrome categories that facilitate dif- caregiver, and their education about
ferential diagnosis (Figure 11-1). The psychiatric symptoms, dementia, and
method classifies syndromes into: the interventions are vital for success.
(1) primarily cognitive syndromes, such The clinical formulation is the frame-
as the canonical (amnestic) AD phe- work for managing the psychiatric
notype and the primary progressive aspects of dementia. Where the for-
aphasias, in which the cognitive defi- mulation emphasizes specific disorders,
cits are the signal features; (2) predo- pharmacologic intervention specific to
minantly psychiatric syndromes such the underlying neurodegenerative dis-
as the behavioral variant of FTD and ease or psychiatric disorder may be in-
DLB, where psychiatric disorders over- dicated (ie, cholinesterase inhibitors for
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FIGURE 11-1 Algorithm for identifying the neurodegenerative types of dementia. The diagram shows how symptom clusters and
the syndromes they signify drive the differential diagnosis of dementia. Cognitive and motor syndromes define
pathways and, when complemented by psychiatric states (red text), may define specific dementia diagnoses
(such as the behavioral variant of frontotemporal dementia [bvFTD], frontotemporal dementia with amyotrophic lateral sclerosis
[FTD-ALS], and dementia with Lewy bodies [DLB]).
AD = Alzheimer disease; CJD = Creutzfeldt-Jakob disease; HD = Huntington disease; PCA = posterior cortical atrophy; PDD = Parkinson
disease dementia; PIA = progressive ideomotor apraxia; PLA = progressive logopenic aphasia; PNFA = progressive nonfluent
aphasia; PSP = progressive supranuclear palsy; SCA = spinocerebellar ataxia; SD = semantic dementia.
Reprinted with permission from Devineni B, Onyike CU, Psychiatr Clin North Am.68 www.sciencedirect.com/science/article/pii/S0193953X15000271. B 2015
Elsevier Inc.

AD or selective serotonin reuptake in- terventions directed at the environment, KEY POINT
hibitors [SSRIs] for depression). When their comfort, or the patient-caregiver h Where the clinical
problem solving is emphasized, psycho- relationship.70 The choice of approach formulation for
social approaches such as environment derives from careful analysis of the managing the psychiatric
aspects of dementia
remodeling, structured recreation, care- context of the psychiatric state. An-
emphasizes problem
giver education and training, and psy- other model views psychiatric states as
solving, psychosocial
chotherapy are more pertinent. One catastrophic reactions to frustration, approaches such as
commonly used psychosocial approach failure, or being thwarted, in which case, environment remodeling,
calls for formal analysis of the context simplifying tasks and providing direc- structured recreation,
and antecedents of the psychiatric state, tion and assistance can go a long way. caregiver education
so as to identify and remove (or man- Yet another approach is to examine the and training, and
age) precipitating factors. A patient patient-caregiver dyad for dysfunctional psychotherapy
who has exhibited agitated resistance interactions that will be corrected are pertinent.
of morning hygiene routines might through caregiver counseling and skill-
do much better when allowed to wake building training sessions. The efficacy
naturally or to eat first. The patient of structured skill-building programs
might also respond to nonspecific in- and tailored problem-solving methods

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 Psychiatric Aspects of Dementia

KEY POINT
h Typical and atypical for dementia care has been demon- (Figure 11-2), which requires that the
antipsychotic agents strated in formal trials that examined problem be specified (describe) along
are associated with a effects on psychiatric disorders and with the contexts, triggers, and modi-
high risk for mortality caregiver coping.71Y74 fiers (investigate), that a collaboration is
in patients who Pharmacologic interventions for psy- undertaken with the caregiver to devise
have dementia. chiatric symptoms in dementia mirror a program of care (create), and that the
standard psychiatric practice, albeit implementation and results are moni-
with more cautious dosing, and they tored (evaluate).52 The DICE approach
remain in need of the validation of is now part of the Centers for Medicare
formal clinical trials.70,75,76 The na- and Medicaid Services toolkit of non-
tionwide Clinical Antipsychotic Trials pharmacologic programs for dementia
of Intervention Effectiveness did not care, which hopefully will stimulate
demonstrate efficacy for treatment of broad implementation, dissemination,
dementia-related psychosis, agitation, and evaluation. Another innovation is
and aggression, although a secondary the Maximizing Independence (MIND)
analysis suggested the atypical agents at Home study, which has used multi-
may have value, but that any bene- disciplinary teams for home-based case
fits might be offset by worsening of management that consists of individu-
cognitive disabilities, somnolence, par- alized care planning with monitoring,
kinsonism, weight gain, metabolic de- links to local services, dementia-related
rangements, and death.77,78 In DLB and education, and caregiver skills building,
PDD, quetiapine and clozapine are the which resulted in far fewer transfers
only antipsychotics recommended from home to residential care and
given the higher risk of extrapyramidal higher quality-of-life ratings than usual
side effects with other antipsychotic care in the pilot study.91 A larger
medications. Other antipsychotic drugs follow-up study, now underway, is aimed
must be avoided in these patients as at demonstrating the efficacy and scal-
they may precipitate life-threatening ability of this program.
rigidity and autonomic dysfunction. Pharmacologic interventions are still
The atypical antipsychotics are associ- indicated in some cases, owing to the
ated with mortality from cardiovascular biological grounding of some of the
and cerebrovascular events (and other psychiatric symptoms of dementia; vi-
causes of mortality, including infectious sual hallucinations in DLB, for example,
causes) in patients who have demen- cannot be formulated as arising from a
tia.79,80 The risk is higher still with the caregiver’s mishandling of a situation, a
conventional agents.81Y85 Where these patient’s misunderstanding, misinter-
agents are prescribed, risk can be pretation, or overreaction, or other so-
mitigated by routine use of planned cial mishap. Psychiatric states such as
discontinuation trials, in line with evi- these warrant pharmacologic interven-
dence that most psychiatric states in tion when they cause distress, are offen-
dementia do not persist longer than sive, or bring about significant morbidity
3 to 6 months and results from discon- (such as when depression causes an-
tinuation trials that show benefit.14,86Y90 orexia, weight loss, and malnutrition).
The development of structured be- Thus, present-day research continues
havioral programs that can be readily the search for physiologic indices of
disseminated are now underway, which psychiatric states in dementia, with the
will facilitate intervention in the home. hope that biomarkers will lead to more
One innovation is the Describe, Inves- effective case recognition and physio-
tigate, Create, Evaluate (DICE) method logic targets for drug development.
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FIGURE 11-2 DICE (describe, investigate, create, and evaluate) approach to the examination, formulation, and management of
dementia-related behavioral problems. A two-part flow diagram is shown, illustrating the socially dynamic context of
the DICE approach (ie, the triad of patient, caregiver, and environment), the progression in its implementation, and the recursive
routines for managing high-acuity states. The bidirectional arrows in the triad emphasize the reciprocity of the dynamics that shape
many behavioral problems encountered in dementia care.
Modified with permission from Kales HC, et al, BMJ.70 www.bmj.com/content/350/bmj.h369. B 2015 British Medical Journal Publishing Group.

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 Psychiatric Aspects of Dementia

CONCLUSION Neurol Psychiatr Springer-Verlag

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 LIFELONG LEARNING IN NEUROLOGY ®
\

The Mental Status Examination in

Patients With Suspected Dementia
Grossman, Murray MD, FAAN; Irwin, David J. MD. Continuum (Minneap Minn).
April 2016; 22 (2 Dementia): 385Y403.

Abstract
Purpose of Review:
This article describes a comprehensive approach to the mental status examination and
diagnostic workup of patients suspected of having an emerging neurodegenerative dementia.
Key strategies for obtaining a history and bedside examination techniques are highlighted.
Recent Findings:
Classic descriptions of behavioral neurology syndromes were largely based on clinicopathologic
correlations of strategic lesions in stroke patients. While still very important, advances in
neuroimaging have expanded our armamentarium of cognitive evaluations to include
assessments of findings in nonstroke anatomic distributions of disease. These efforts support
comprehensive assessments of large-scale cerebral networks in cognitive neurology.
Summary:
A thorough and focused mental status examination is essential for the evaluation of patients with
cognitive symptoms. Selective use of laboratory testing and neuroimaging can aid in the
diagnosis of dementia by excluding non-neurodegenerative etiologies. Neurodegenerative
diseaseYspecific tests are in development and will enhance diagnosis and efforts for
disease-modifying therapy development.

Key Points
& The mental status examination is structured to probe each major cognitive domain
(attention, memory, language, visuospatial perception, executive functioning,
and social comportment).
& Cognitive function is mediated by large-scale networks or connectomes, where gray
matter nodes are interconnected by white matter tracts.
& Any gray matter node may contribute to multiple cognitive networks.

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 & While the assessment of a patient can reveal selective impairment of specific components
of the mental status examination, it is often the overall pattern of cognitive
performance across multiple components that is most informative.
& A single mental status examination obtains only a cross-sectional perspective of a
patient’s performance. A history of slow progression or observed longitudinal decline
on serial cognitive examination testing is required to make a diagnosis of a
neurodegenerative dementia.
& The neurologic history is an important component to determine the onset, tempo, and
associated features of the cognitive symptoms. These factors help direct the specific
features to focus on during examination.
& Each cognitive domain should be probed during the history, similar to a medical review
of symptoms.
& Differentiating age-associated memory decline from pathologic etiologies is challenging.
Mental status history should include details on the functional impact of problems
associated with aging and recognition of a problem by others.
& Visual-perceptual-spatial difficulties may be difficult to elicit through history.
Common examples include difficulty navigating a car, finding objects in the home,
recognizing faces or objects, or difficulty dressing.
& Detecting social and personality changes associated with neurodegenerative dementia
often requires a careful history from a reliable informant who spends significant time
with the patient.
& Social comportment is difficult to assess in the mental status examination and often
requires a thorough history from a reliable informant to be detected.
& It is important to inquire about activities of daily living to identify potential safety
issues that could result in morbidity and mortality from cognitive impairment.
& Screening cognitive instruments provide a brief sample of different cognitive domains
that can be useful to track patients longitudinally but do not substitute for a thorough
examination.
& Episodic memory is often tested by using list-learning tasks where a sequence of
words is repeated after several trials and then recalled after a brief delay. Recognition
is assessed through use of cues or semantic foils. Difficulty can be adjusted depending
on length of list and delay time.
& Nonverbal methods of testing memory, such as figure-recall tasks, are useful in patients
with significant left-hemispheric disease.
& Language dysfunction can be detected during the clinical examination through
identification of abnormal prosody, word-finding pauses, circumlocutions, grammatical
sophistication, and frank agrammatisms in spontaneous speech.
& Language comprehension should be performed on the single-word and sentence level.
Single-word comprehension can be assessed through word and object meaning and
sentence comprehension through repetition and verbal commands of sequenced tasks.
& Lexical comprehension should be assessed in parallel with assessment of object
meaning in semantic memory. This can be done by asking for the definition
of a single word or asking to name attributes of a word’s referent.
& Apraxia of speech refers to disruption of coordination of the motor speech apparatus
and should be distinguished from dysarthria, which is a dysfunction of the muscles
involved in speech.
& Grammatical comprehension can be assessed through use of simple questions of
‘‘who did what to whom’’ in sentences with increasing grammatical complexity
(ie, ‘‘The car that hit the truck was green. Who was hit?’’).

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 & Surface dyslexia is the reading of a sight (orthographically irregular) word that
requires semantic knowledge rather than phonetics for proper pronunciation, examples
of which include cough, choir, and pint.
& Executive impairment can cause impairments in construction tasks through poor
organization and omission of elements. In contrast, visuospatial impairments manifest
in spatial displacements and distortions on construction tasks.
& Visuospatial function can be assessed through construction of figures with varying
familiarity and complexity.
& Ideomotor apraxia is difficulty in demonstrating learned gestures. Transitive gestures
involve use of tools while intransitive gestures do not involve an implement.
& Higher-order parietal lobe functions include calculations, cortical sensation, left-right
discrimination, somatosensory maps (ie, limb position), and apraxia.
& Executive functioning involves mental manipulation of information and shifting
between tasks. These functions can be tested through an alternating sequence of written,
oral, or manual tasks.
& Working memory is the ability to hold and manipulate data. Assessment of the number
of digits recalled in reverse can be useful to test working memory.
& Social functioning and behavior difficulties should be considered in any patient who
has difficulties with social discourse, simple repetitive motor rituals, or inappropriate
behavior during the interview. A reliable informant should be obtained to gather
additional history.
& A major limitation in the development of meaningful treatment for neurodegenerative
diseases is that definitive diagnosis is obtained only at autopsy.
& Careful selection of ancillary laboratory and neuroimaging studies can be useful to
rule out common non-neurodegenerative etiologies of cognitive impairment.

Mild Cognitive Impairment

Petersen, Ronald C. PhD, MD. Continuum (Minneap Minn). April 2016;
22(2 Dementia): 404Y418.

Abstract
Purpose of Review:
As individuals age, the quality of cognitive function becomes an increasingly important topic.
The concept of mild cognitive impairment (MCI) has evolved over the past 2 decades to represent
a state of cognitive function between that seen in normal aging and dementia. As such, it is
important for health care providers to be aware of the condition and place it in the appropriate
clinical context.
Recent Findings:
Numerous international population-based studies have been conducted to document the
frequency of MCI, estimating its prevalence to be between 15% and 20% in persons 60 years
and older, making it a common condition encountered by clinicians. The annual rate in which
MCI progresses to dementia varies between 8% and 15% per year, implying that it is an
important condition to identify and treat. In those MCI cases destined to develop Alzheimer

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disease, biomarkers are emerging to help identify etiology and predict progression. However, not
all MCI is due to Alzheimer disease, and identifying subtypes is important for possible treatment
and counseling. If treatable causes are identified, the person with MCI might improve.
Summary:
MCI is an important clinical entity to identify, and while uncertainties persist, clinicians need
to be aware of its diagnostic features to enable them to counsel patients. MCI remains an active
area of research as numerous randomized controlled trials are being conducted to develop
effective treatments.

Key Points
& The Key Symposium criteria for mild cognitive impairment accomplished two goals:
(1) to broaden the classification scheme beyond memory, and (2) to recognize that mild
cognitive impairment could result from a variety of etiologies and not just Alzheimer
disease.
& Traditionally, amnestic mild cognitive impairment is the typical prodromal stage of
dementia due to Alzheimer disease, but other phenotypes can also lead to this type of
dementia, such as logopenic aphasia, posterior cortical atrophy (also known as the visual
variant), or a frontal lobeYdysexecutive presentation of Alzheimer disease.
& Not all mild cognitive impairment is early Alzheimer disease.
& The criteria for mild cognitive impairment due to Alzheimer disease developed by the
National Institute on Aging and the Alzheimer’s Association essentially adopted the
Key Symposium criteria while making some of the diagnostic features more explicit.
These criteria also added biomarkers for underlying Alzheimer disease pathophysiology
in an attempt to refine the underlying etiology and, hence, predict outcome.
& In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, for the
general category of neurocognitive disorders, the criteria now include a predementia
phase called mild neurocognitive disorder.
& The construct of prodromal Alzheimer disease evolved from the accumulating literature
that had developed regarding the observation that amnestic mild cognitive impairment,
when paired with certain biomarkers, approximated the condition of Alzheimer disease.
In fact, the proponents believed that a certain type of amnestic mild cognitive impairment
coupled with biomarkers for the presence of amyloid or amyloid and tau constituted the
earliest symptomatic stages of the Alzheimer disease process.
& The multiple sets of criteria referring to mild cognitive impairment actually contain many
of the same elements and are quite similar to the original Key Symposium criteria.
& Numerous international studies have been completed involving several thousand
subjects, and these studies tend to estimate the overall prevalence of mild cognitive
impairment in the 12% to 18% range in persons over the age of 60 years.
& The Mayo Clinic Study of Aging followed subjects 70 years and older for a median
of 5 years and found the progression rate of mild cognitive impairment to be in
the 5% to 6% per year range.
& Mild cognitive impairment is not meant to reflect lifelong low cognitive function; rather,
it is meant to reflect a change for this individual person.
& In mild cognitive impairment, the patient’s daily function is largely preserved.
& Several studies have indicated that individuals with mild cognitive impairment who have
a positive amyloid positron emission tomography scan are more likely to progress rapidly,
which is confirmed by data from the Alzheimer’s Disease Neuroimaging Initiative.

* 2016 American Academy of Neurology.

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 & The National Institute on Aging and the Alzheimer’s Association divided the Alzheimer
disease spectrum into three overlapping areas: preclinical Alzheimer disease in which
individuals are clinically normal but possess biomarker evidence for the Alzheimer
disease process, mild cognitive impairment due to Alzheimer disease whereby individuals
meet the clinical criteria for mild cognitive impairment and have varying levels of biomarker
specificity for Alzheimer disease, and AD dementia in which individuals meet clinical
criteria for dementia and similarly have varying degrees of biomarker support.
& The spectrum of neurocognitive disorder, as defined by the Diagnostic and Statistical
Manual of Mental Disorders, Fifth Edition, is divided into mild neurocognitive
disorder, which is very similar to mild cognitive impairment, and major neurocognitive
disorder, which is very similar to dementia.
& Currently, there are no accepted pharmacologic treatments for mild cognitive impairment
approved by the US Food and Drug Administration, the European Medicines Agency,
or the Pharmaceuticals and Medical Devices Agency in Japan.
& Lifestyle modifications and other nonpharmacologic therapies have also been
investigated, and there is a suggestion that some of these modifications or therapies, such
as aerobic exercise, may be effective at reducing the rate of progression from mild
cognitive impairment to dementia.
& Criticism has been raised regarding the boundaries of the condition of mild cognitive
impairment with respect to differentiating it from changes of cognitive aging and
also differentiating it from dementia.

Alzheimer Disease
Apostolova, Liana G. MD, MS, FAAN. Continuum (Minneap Minn). April 2016;
22(2 Dementia): 404Y434.

Abstract
Purpose of Review:
This article discusses the recent advances in the diagnosis and treatment of Alzheimer
disease (AD).
Recent Findings:
In recent years, significant advances have been made in the fields of genetics, neuroimaging,
clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our
ability to visualize amyloid pathology in the living human brain. The newly revised criteria
for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the
underlying pathology. Guidelines for the responsible use of amyloid positron emission
tomography (PET) have been developed, and the clinical and economic implications of amyloid
PET imaging are actively being explored.
Summary:
Our improved understanding of the clinical onset, progression, neuroimaging, pathologic
features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and
future therapeutic interventions.

* 2016 American Academy of Neurology.

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Key Points
& Alzheimer disease prevalence is rapidly increasing.
& Although age is the greatest risk factor for the development of Alzheimer disease, old age
is not sufficient, in and of itself, to cause Alzheimer disease.
& Memory impairment is the most pervasive feature of Alzheimer disease.
& Neuropsychiatric comorbidities often present the most pressing therapeutic needs
due to the psychological and physical strain they place on the family and caregivers
of patients with Alzheimer disease.
& Several less common Alzheimer disease variants should be recognized, which include
frontal variant of Alzheimer disease, posterior cortical atrophy, and logopenic variant
primary progressive aphasia due to Alzheimer disease.
& The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria no
longer require the presence of memory impairment for the diagnosis of neurodegenerative
dementia to be established.
& The National Institute on Aging and Alzheimer’s Association criteria for probable
Alzheimer dementia recognize the diagnostic utility of disease biomarkers.
& Amyloid positron emission tomography imaging allows the detection of moderate to
severe amyloid deposition in the brain.
& Amyloid positron emission tomography scans are only appropriate if the scan results are
expected to alter clinical management.
& The APOE4 genotype should be considered a risk factor that is neither sufficient nor
necessary for Alzheimer disease development.
& The search for other gene variants that may affect risk of Alzheimer disease is
ongoing.
& Amyloid deposition is thought to begin20 years prior to development of clinical
symptoms.
& Vital importance should be placed on coordinating care among physicians, nurse
practitioners, and social workers, and instituting appropriate oversight and safety
precautions when patients have functional impairment and poor judgment.
& Treatment with acetylcholinesterase inhibitors should be considered in patients with
mild to moderate Alzheimer disease per the American Academy of Neurology practice
guidelines for dementia.
& Memantine is US Food and Drug Administration approved for the moderate to severe
stages of Alzheimer disease.
& The first line of treatment for behavioral and neuropsychiatric symptoms of Alzheimer
disease are nonpharmacologic modalities.

Lewy Body Dementias: Dementia With

Lewy Bodies and Parkinson Disease
Dementia
Gomperts, Stephen N., MD, PhD. Continuum (Minneap Minn). April 2016;
22(2 Dimentia): 435Y463.

* 2016 American Academy of Neurology.

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Abstract
Purpose of Review:
This article provides an overview of the clinical features, neuropathologic findings, diagnostic
criteria, and management of dementia with Lewy bodies (DLB) and Parkinson disease
dementia (PDD), together known as the Lewy body dementias.

Recent Findings:
DLB and PDD are common, clinically similar syndromes that share characteristic
neuropathologic changes, including deposition of !-synuclein in Lewy bodies and neurites
and loss of tegmental dopamine cell populations and basal forebrain cholinergic populations,
often with a variable degree of coexisting Alzheimer pathology. The clinical constellations of
DLB and PDD include progressive cognitive impairment associated with parkinsonism,
visual hallucinations, and fluctuations of attention and wakefulness. Current clinical diagnostic
criteria emphasize these features and also weigh evidence for dopamine cell loss measured
with single-photon emission computed tomography (SPECT) imaging and for rapid eye
movement (REM) sleep behavior disorder, a risk factor for the synucleinopathies. The timing
of dementia relative to parkinsonism is the major clinical distinction between DLB and PDD,
with dementia arising in the setting of well-established idiopathic Parkinson disease (after at least
1 year of motor symptoms) denoting PDD, while earlier cognitive impairment relative to
parkinsonism denotes DLB. The distinction between these syndromes continues to be an active
research question. Treatment for these illnesses remains symptomatic and relies on both
pharmacologic and nonpharmacologic strategies.

Summary:
DLB and PDD are important and common dementia syndromes that overlap in their clinical
features, neuropathology, and management. They are believed to exist on a spectrum of Lewy
body disease, and some controversy persists in their differentiation. Given the need to optimize
cognition, extrapyramidal function, and psychiatric health, management can be complex and
should be systematic.

Key Points
& Deposition of >-synuclein is the hallmark neuropathologic finding of the
synucleinopathies, which include dementia with Lewy bodies, Parkinson disease, and
multiple system atrophy. The Lewy body dementias include dementia with Lewy bodies
and Parkinson disease dementia.
& The Lewy body dementias are the second most common neurodegenerative dementia,
after Alzheimer disease.
& In dementia with Lewy bodies, >-synuclein pathology is observed beyond the brainstem
in limbic and neocortical regions. In contrast, in Parkinson disease, >-synuclein pathology
is first observed in the brainstem, in association with extrapyramidal impairment, and
appears to spread with progression of disease to involve limbic and neocortical regions.
& Amyloid deposition is common and variably present in dementia with Lewy bodies
and Parkinson disease dementia.
& Early dementia, visual hallucinations, fluctuations of attention and arousal, and the
motor manifestations of parkinsonism characterize dementia with Lewy bodies.

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 & Due to neuroleptic sensitivity in dementia with Lewy bodies, D2 receptor
antagonists such as typical and most atypical neuroleptics are dangerous and
contraindicated.
& Rapid eye movement sleep behavior disorder, impairment of olfaction, chronic
constipation, and neuroleptic sensitivity are common in dementia with Lewy bodies and
Parkinson disease. These features may precede the development of typical clinical
symptoms in these illnesses.
& Clinical diagnostic criteria for dementia with Lewy bodies have better specificity than
sensitivity.
& Early anterograde amnesia is the sine qua non of Alzheimer disease. Hallucinations
and parkinsonism can arise late in the course of Alzheimer disease. Early additional
cognitive features and the early appearance of hallucinations, parkinsonism, and
fluctuations of attention or arousal point to dementia with Lewy bodies.
& Parkinson disease hastens cognitive decline and is a risk factor for dementia.
& Parkinson disease medications can impair cognition. This is particularly true of
trihexyphenidyl and the dopamine agonists but can be seen in all agents at
sufficient dose.
& The relative timing of dementia and parkinsonism defines the clinical distinction
between dementia with Lewy bodies and Parkinson disease dementia.
& Dementia with Lewy bodies and Parkinson disease dementia can be distinguished
from multiple system atrophy, progressive supranuclear palsy, and corticobasal
syndrome on the basis of their clinical features. However, no firm biomarkers have
been developed that can predict a pathologic diagnosis.
& It is generally advisable to make single changes in treatment systematically and
serially, starting at low dose and tackling the most severe problem first. This simple
strategy accounts for the frequent sensitivity to medications in dementia with
Lewy bodies and allows for straightforward interpretation of the effects of
manipulations.
& The marked loss of acetylcholine neurons in dementia with Lewy bodies and
Parkinson disease dementia likely underlies the efficacy of acetylcholinesterase
inhibitors in these illnesses.
& In Parkinson disease dementia, it is often useful to streamline the medication regimen
in the service of cognition.
& When psychosis in dementia with Lewy bodies or Parkinson disease dementia requires
medical treatment, acetylcholinesterase inhibitors, quetiapine, and clozapine can be
useful. However, the latter two agents require caution, given their risk of significant
and severe adverse reactions.
& Physical therapy, occupational therapy, and home safety evaluations are valuable treatments
for motor impairments in dementia with Lewy bodies and Parkinson disease dementia.
& Medical and nonmedical strategies exist to manage rapid eye movement sleep
behavior disorder.
& Given its prevalence, dementia with Lewy bodies is likely to be a common cause of
mild cognitive impairment.

Frontotemporal Dementias
Finger, Elizabeth C. MD, FRCPC. Continuum (Minneap Minn). April 2016;
22(2 Dementia): 464Y489.

* 2016 American Academy of Neurology.

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Abstract
Purpose of Review:
This article reviews the common behavioral and cognitive features of frontotemporal
dementia (FTD) and related disorders as well as the distinguishing clinical, genetic, and
pathologic features of the most common subtypes.
Recent Findings:
Advances in clinical phenotyping, genetics, and biomarkers have enabled improved
predictions of the specific underlying molecular pathology associated with different presentations
of FTD. Evaluation of large international cohorts has led to recent refinements in diagnostic
criteria for several of the FTD subtypes.
Summary:
The FTDs are a group of neurodegenerative disorders featuring progressive deterioration of
behavior or language and associated pathology in the frontal or temporal lobes. Based on
anatomic, genetic, and neuropathologic categorizations, the six clinical subtypes of FTD or
related disorders are: (1) behavioral variant of FTD, (2) semantic variant primary progressive
aphasia, (3) nonfluent agrammatic variant primary progressive aphasia, (4) corticobasal
syndrome, (5) progressive supranuclear palsy, and (6) FTD associated with motor neuron disease.
Recognition and accurate diagnoses of FTD subtypes will aid the neurologist in the
management of patients with FTD.

Key Points
& Frontotemporal dementia classically affects adults in their fifties to sixties, although cases
have been reported from 30 to more than 90 years of age.
& The prevalence of frontotemporal dementia is likely underestimated due to lack
of recognition and diagnosis of the frontotemporal dementia syndromes by
non-neurologists.
& Behavioral variant of frontotemporal dementia is defined by the gradual onset and
progression of changes in behavior, including disinhibition, loss of empathy, apathy, and
may include hyperorality and perseverative or compulsive behaviors.
& Patients with frontotemporal dementia may exhibit psychotic features early in the disease
course, including visual or auditory hallucinations and bizarre or somatic delusions.
& Standard neurocognitive testing in behavioral variant of frontotemporal dementia
classically demonstrates deficits in executive function tasks, with relative sparing in
memory and visuospatial domains.
& Consideration of qualitative aspects of performance during neurocognitive testing,
such as impulsive behaviors and error types, may be more helpful than raw scores in
detecting behavioral variant of frontotemporal dementia.
& Consideration of the patient’s baseline personality, life events, and relationship factors
that may influence behavior, and the caregiver’s perspective on behaviors, is necessary
for accurate diagnosis of behavioral variant frontotemporal dementia.
& The hallmark symptom of semantic variant primary progressive aphasia is the loss of
word meaning.
& Atrophy of the dominant anterior temporal pole is the characteristic finding in semantic
variant primary progressive aphasia.

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 & Hallmark features of nonfluent agrammatic variant primary progressive aphasia include
nonfluent speech with word-finding difficulties, circumlocutions, stuttering, and
grammatical errors with relative preservation of comprehension.
& Approximately 20% of patients with progressive supranuclear palsy first present with
frontotemporal dementia symptoms including behavioral changes or progressive
language deficits.
& Most commonly, patients with progressive supranuclear palsy demonstrate cognitive
slowing and poorer performance on timed tests of executive function and verbal fluency.
& In patients presenting with primary apraxia of speech, progressive supranuclear palsy
is the most common underlying pathology.
& Patients with corticobasal degeneration may first present with behavioral changes,
executive function deficits, or language features consistent with early frontal lobe
pathology.
& Frontotemporal dementia symptoms are found in approximately 30% of patients
diagnosed with amyotrophic lateral sclerosis.
& Approximately 40%of frontotemporal dementia cases are associated with an autosomal
dominant pattern of inheritance, with remaining cases considered sporadic.
& A genetic mutation may be found in approximately 6% of patients with no family history
of frontotemporal dementia; thus, referral to a genetic counselor for consideration of
genetic testing may be considered for all patients presenting with frontotemporal
dementia.
& Abnormal accumulations of tau or TDP-43 account for the majority of pathologically
confirmed cases of frontotemporal dementia, with FUS inclusions most common in the
remaining 10%.
& CSF biomarkers may help to distinguish between frontotemporal dementia and
Alzheimer disease, but at present there are no validated biomarkers that can reliably
distinguish patients with frontotemporal dementia from controls or other non-Alzheimer
disease dementias.

Vascular Cognitive Impairment

Smith, Eric MD, MPH. Continuum (Minneap Minn). April 2016; 22(2 Dementia): 490Y509.

Abstract
Purpose of Review:
This article provides a diagnostic framework for vascular cognitive impairment, discusses
prevalence and relationships to other neurodegenerative pathologies, and provides advice on
diagnostic workup and management.
Recent Findings:
Vascular cognitive impairment is the second most common cause of cognitive impairment
and frequently coexists with other neurodegenerative neuropathologies. Three new diagnostic
criteria have been published recently; common diagnostic elements include the need to classify
cognitive impairment as mild cognitive impairment or dementia and to link the cognitive
impairment to evidence of clinically significant cerebrovascular disease. Vascular cognitive

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impairment may be further subclassified into poststroke vascular cognitive impairment and
nonstroke vascular cognitive impairment, most commonly caused by cerebral small vessel
disease, which may only be recognized on neuroimaging.

Summary:
Vascular cognitive impairment is a potentially treatable common cause of cognitive impairment,
progression of which may be slowed or halted by secondary prevention of vascular disease.

Key Points
& Diagnostic criteria for vascular cognitive impairment are based on the presence of
cognitive impairment and vascular disease as well as a clinical judgment that the vascular
disease is causing the impairment.
& The term vascular cognitive impairment encompasses all severity of cognitive impairment
caused by vascular disease, including mild cognitive impairment and dementia.
& Vascular cognitive impairment may be subclassified as poststroke vascular cognitive
impairment, which refers to the direct immediate consequence of clinical stroke, or as
nonstroke vascular cognitive impairment, which is most commonly caused by cerebral
small vessel disease.
& Vascular cognitive impairment has many vascular causes. The cause of the vascular
disease should be identified so that further progression or recurrence can be prevented.
& The clinical assessment for vascular cognitive impairment can be conceived as a
three-stage process that includes the following steps: (1) assess for cognitive impairment;
(2) assess the presence, severity, and cause of vascular disease; and (3) assess whether
the vascular disease is sufficient to cause the impairment, in whole or in part.
& Cerebrovascular disease should be diagnosed by history, examination, and diagnostic
testing, including neuroimaging.
& Neuroimaging provides useful evidence of the presence, location, and severity of
cerebrovascular disease.
& Because cerebrovascular disease is common and can be incidental, clinical judgment
is needed in individual patients to determine whether cerebrovascular lesions are
sufficient to cause cognitive impairment in the affected individual.
& In poststroke vascular cognitive impairment, the link between stroke and subsequent
vascular cognitive impairment should be readily apparent.
& Location, as well as size and severity, must be taken into account when considering the
cognitive consequences of infarcts and other cerebrovascular lesions.
& The diagnosis of nonstroke vascular cognitive impairment should be supported by the
presence of diffuse, severe cerebrovascular disease.
& Microinfarcts are asubstrate for vascular cognitive impairment, but are only visible at
autopsy because they are too small to see on MRI.
& Although patients with vascular cognitive impairment often exhibit impairments in
executive function and processing speed, other cognitive domains may also be affected.
& Motor signs that may accompany vascular cognitive impairment include frontal gait
disorder, lower body parkinsonism, apathy, depression, urinary incontinence, spasticity,
hyperreflexia, and frontal release signs.
& Cerebral amyloidangiopathy is an important cause of vascular cognitive impairment, with
effects that are independent of the degree of accompanying Alzheimer disease pathology.

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 & Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy is the most common inherited monogenic cause of vascular
cognitive impairment.
& Vascular cognitive impairment is the second most common cause of cognitive impairment
and frequently coexists with other neurodegenerative pathologies as mixed dementia.
& Vascular cognitive impairment accounts for up to one-third of dementia risk.
& Patient and caregiver support to maintain quality of life and prolong community living are
important aspects of vascular cognitive impairment management.
& Acetylcholinesterase inhibitors have a modest beneficial effect in vascular cognitive
impairment.
& The most important component of vascular cognitive impairment management is
identifying and treating the underlying cerebrovascular processes that lead to brain injury.
& Patients with vascular cognitive impairment with stroke should be treated according
to secondary prevention guidelines for stroke.
& Careful control of vascular risk factors may be an important component of dementia
prevention.

Rapidly Progressive Dementia

Geschwind, Michael D. MD, PhD. Continuum (Minneap Minn). April 2016;
22(2 Dementia): 510Y537.

Abstract
Purpose of Review:
This article presents a practical and informative approach to the evaluation of a patient with a
rapidly progressive dementia (RPD).
Recent Findings:
Prion diseases are the prototypical causes of RPD, but reversible causes of RPD might mimic
prion disease and should always be considered in a differential diagnosis. Aside from prion
diseases, the most common causes of RPD are atypical presentations of other neurodegenerative
disorders, curable disorders including autoimmune encephalopathies, as well as some infections,
and neoplasms. Numerous recent case reports suggest dural arterial venous fistulas sometimes
cause RPDs.
Summary:
RPDs, in which patients typically develop dementia over weeks to months, require an alternative
differential than the slowly progressive dementias that occur over a few years. Because of
their rapid decline, patients with RPDs necessitate urgent evaluation and often require an
extensive workup, typically with multiple tests being sent or performed concurrently.
Jakob-Creutzfeldt disease, perhaps the prototypical RPD, is often the first diagnosis many
neurologists consider when treating a patient with rapid cognitive decline. Many conditions
other than prion disease, however, including numerous reversible or curable conditions, can
present as an RPD. This chapter discusses some of the major etiologies for RPDs and offers
an algorithm for diagnosis.

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Key Points
& In most larger rapidly progressive dementia series, the most common causes of rapidly
progressive dementia are nonprion neurodegenerative diseases, prion diseases, and
autoimmune/antibody-mediated encephalopathies.
& Sending the CSF biomarkers 14-3-3, total tau, and neuron-specific enolase is always
recommended, not necessarily as diagnostic tests for prion disease, because they are not,
but rather as markers of rapid neuronal injury. If these biomarkers are elevated, they
help confirm the history of a rapidly progressive neurologic condition.
& The use of a mnemonic device, such as VITAMINS (vascular, infectious, toxic-metabolic,
autoimmune, malignancy, iatrogenic, neurodegenerative, and systemic), when evaluating
a patient with rapidly progressive dementia can help the clinician consider many diverse
etiologies for such conditions.
& Any patient in whom Wernicke encephalopathy is a consideration should be urgently
treated with empiric thiamine replacement.
& In sporadic Jakob-Creutzfeldt disease, there is usually relative sparing of the perirolandic
cortex on fluid-attenuated inversion recovery and diffusion-weighted imaging MRI,
particularly in comparison to adjacent cortex.

Autoimmune Encephalopathies and

Dementias
McKeon, Andrew MD. Continuum (Minneap Minn). April 2016; 22(2 Dementia): 538Y558.

Abstract
Purpose of Review:
This article describes the methods of diagnosis and management of autoimmune
encephalopathies and dementias. The expedited distinction of autoimmune encephalopathies
and dementias from neurodegenerative disorders is important because treatment is most effective
at the early stage of illness.
Recent Findings:
The spectrum of antibody biomarkers of treatable autoimmune encephalopathies continues to
broaden and now includes antibodies targeting glutamate receptors (N-methyl-D-aspartate [NMDA]
and >-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), F-aminobutyric acid A
and B (GABA-A and GABA-B) receptors, glycine receptors, potassium channel complexes
(Kv1, which includes leucine-rich, glioma inactivated 1 [LgI1], contactin-associated proteinlike
2 [CASPR2], and unknown specificity, and Kv4.2, which includes dipeptidyl-peptidase
6 [DPPX]), and glutamic acid decarboxylase 65 (GAD65). Early treatment of certain autoimmune
encephalopathies with rituximab or cyclophosphamide improves outcome when corticosteroids,
IV immunoglobulin (IVIg), and plasma exchange have proven ineffective.
Summary:
Despite the progress made in diagnostics, in many instances, patients with
immunotherapy-responsive encephalopathies and dementias are seronegative for

* 2016 American Academy of Neurology.

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encephalitis-specific antibodies. Other clues to an autoimmune cause include a subacute
symptom onset, rapid progression, personal history of autoimmunity or cancer, an inflammatory
CSF, non-neural antibodies detected in serum, and a response to immunotherapy.

Key Points
& The clinical manifestations of neurologic autoimmunity are diverse (including
encephalopathy) and are often multifocal.
& In the absence of detection of an encephalitis-specific antibody (eg, leucine-rich,
glioma inactivated 1 or N-methyl-D-aspartate receptor antibody), a history of autoimmune
disease or seropositivity for other autoantibodies (organ-specific or nonYorgan-specific
autoantibodies) are risk factors for an autoimmune encephalopathy.
& Detection of a neuralspecific autoantibody serves as a marker of neurologic
autoimmunity.
& A profile of neuralspecific autoantibodies may aid the identification of a paraneoplastic
encephalopathic disorder.
& Neurologic improvement after immunotherapy may be diagnostically informative of
autoimmune encephalopathy.
& In many instances, the diagnosis of autoimmune encephalopathy is based on clinical
improvements obtained with immunotherapy. Therefore, baseline objective clinical,
electrophysiologic, radiologic, and neuropsychological testing provides reference points
for evaluating clinical improvement with immunotherapies.
& Patients with an autoimmune neurologic disorder may have a background of having a
relatively common systemic autoimmune disease or may have several first-degree
relatives affected by common systemic autoimmune diseases.
& Autoimmune encephalopathic symptoms are almost always of subacute onset (ie, evolving
over days to weeks).
& Limbic encephalitis classically presents with altered mood, memory, and personality
as well as delirium and focal seizures of mesial temporal origin, with or without
secondary generalization.
& Autoimmune dementia phenotypes may resemble Jakob-Creutzfeldt disease, which,
classically, is a rapidly progressive neurodegenerative disorder accompanied by ataxia
and myoclonus.
& Central nervous system infection and other inflammatory central nervous system
disorders are major differential diagnostic considerations when evaluating patients with
rapidly progressive cognitive decline and an inflammatory spinal fluid.
& N-Methyl-D-aspartate receptor encephalitis often has a stereotyped course evolving from
a psychiatric-predominant phenotype to encephalopathy, seizures, and hyperkinetic
movement disorders.
& Presenting symptoms of brainstem encephalitis include eye movement disorders, other
cranial neuropathies, nausea, vertigo, postural instability, and parkinsonism.
& Caution is advised regarding making a diagnosis of Hashimoto encephalopathy
(also known as steroid-responsive encephalopathy associated with autoimmune
thyroiditis) in patients with cognitive symptoms (without objective abnormalities) and
thyroid autoimmunity, which is common in the general population.
& Other inflammatory disorders that can cause a dementia phenotype, but are of unknown
cause, include central nervous system vasculitis, sarcoidosis, and multiple sclerosis.
& Where possible, a more detailed neuropsychological profile should be obtained to
document mild abnormalities not detectable by bedside testing and to exclude potential
confounders (such as mood disorders and the side effects of psychoactive medications).

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 & Imaging of the brain can provide both structural and functional clues to an autoimmune
cause for encephalopathy.
& EEG is also helpful for documenting functional abnormalities in patients with
autoimmune encephalitis.
& Objectifying the cognitive abnormalities through clinical examination, cognitive testing,
imaging, and EEG is critical to the diagnosis of autoimmune encephalopathy and
provides a baseline for treatment.
& Normal results of MRI, CSF testing, and antibody testing do not exclude an autoimmune
encephalopathy diagnosis, but normal findings in all three make the diagnosis unlikely.
& In a paraneoplastic context, the autoantibody profile may narrow the search for cancer.
& In patients in whom a response to immunotherapy is documented, maintenance treatment
for 6 to 9 months (depending on severity) is usually required.
& Prophylaxis against opportunistic infection and osteoporosis and monitoring for
hypertension and diabetes mellitus should be undertaken in patients taking
corticosteroids.

Adult-Onset Leukoencephalopathies
Renaud, Deborah L. MD. Continuum (Minneap Minn). April 2016; 22(2 Dementia): 559Y578.

Abstract
Purpose of Review:
This article describes the clinical, genetic, and radiographic features of inherited
leukoencephalopathies presenting in adulthood.
Recent Findings:
In recent years, the molecular basis for several inherited leukoencephalopathies, presenting
exclusively in adults, has been discovered. Inherited leukoencephalopathies, previously
described in children, have been found to have milder or later onset forms presenting in adults.
Summary:
Although individually rare, inherited leukoencephalopathies are important to consider in the
differential diagnosis of cognitive decline. Patients with inherited leukoencephalopathies
frequently present to multiple sclerosis and dementia clinics. Clinical and radiographic features
can be used to guide investigations in these patients.

Key Points
& Leukoencephalopathies are disorders that selectively involve the white matter of
the brain.
& Acute demyelination secondary to acquired causes of leukoencephalopathy is generally
asymmetric and nonconfluent.
& Chronic demyelination associated with inherited leukoencephalopathies is more
commonly bilateral, symmetric, and confluent in distribution.

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 & Cognitive impairment affects 40% to 70% of patients with multiple sclerosis and is
more common and more severe in secondary progressive multiple sclerosis than
in relapsing remitting multiple sclerosis.
& Psychiatric manifestations, personality change, and slowly progressive cognitive
decline are frequently seen early in the clinical presentation of adult-onset
leukoencephalopathies and generally precede the diagnosis of a leukoencephalopathy.
& The evaluation for metachromatic leukodystrophy should include both the
measurement of sulfatides in the urine as well as the arylsulfatase A enzyme activity
in white blood cells.
& MRI in Krabbe disease may demonstrate bilateral white matter involvement or may be
normal even in the presence of significant neurologic signs.
& Men with X-linked adrenoleukodystrophy may develop the cerebral form of the disease
without preceding neurologic features of adrenomyeloneuropathy.
& The adult-onset form of Alexander disease presents with bulbar signs (dysphagia,
dysarthria, and dysphonia), spastic paraplegia, ataxia, and other neurologic features,
including palatal myoclonus/tremor, autonomic dysfunction, and sleep disturbance.
& Xanthomas are an important clue that may lead to the diagnosis of cerebrotendinous
xanthomatosis. Early treatment can prevent the development of progressive neurologic
decline.
& Leukoencephalopathies associated with small vessel vasculopathy predispose patients
to ischemic and hemorrhagic strokes and are associated with vascular cognitive
impairment.
& Adult-onset autosomal dominant leukodystrophy is associated with autonomic
dysfunction, presenting as bladder and bowel dysfunction and orthostatic hypotension,
followed by slowly progressive pyramidal and cerebellar features.
& The majority of patients with adult polyglucosan body disease due to mutations in
GBE1 have been of Ashkenazi Jewish descent; however, panethnic cases have
been described.
& Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia should be
considered in the differential diagnosis of frontotemporal dementia.

Diagnosis and Treatment of Idiopathic

Normal Pressure Hydrocephalus
Williams, Michael A. MD, FAAN; Malm, Jan MD, PhD. Continuum (Minneap Minn).
April 2016; 22(2 Dementia): 579Y599.

Abstract
Purpose of Review:
This article provides neurologists with a pragmatic approach to the diagnosis and treatment
of idiopathic normal pressure hydrocephalus (iNPH), including an overview of: (1) key
symptoms and examination and radiologic findings; (2) use of appropriate tests to determine
the patient’s likelihood of shunt responsiveness; (3) appropriate referral to tertiary centers with
expertise in complex iNPH; and (4) the contribution of neurologists to the care of patients
with iNPH following shunt surgery.

* 2016 American Academy of Neurology.

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Recent Findings:
The prevalence of iNPH is higher than previously estimated; however, only a fraction of persons
with the disorder receive shunt surgery. iNPH should be considered as a diagnosis for
patients with unexplained symmetric gait disturbance, a frontal-subcortical pattern of cognitive
impairment, and urinary urge incontinence, whose MRI scans show enlarged ventricles and
whose comorbidities are not sufficient to explain their symptoms. Physiologically based tests,
such as the tap test (largevolume lumbar puncture) or temporary spinal catheter insertion for
external lumbar drainage with gait testing before and after CSF removal, or CSF infusion testing
for measurement of CSF outflow resistance, can reliably identify patients who are likely to
respond to shunt surgery. Properly selected patients have an 80% to 90% chance of responding
to shunt surgery, and all symptoms can improve following shunt surgery. Longitudinal care
involves investigating the differential diagnosis of any symptoms that either fail to respond to
shunt surgery or that worsen after initial improvement from shunt surgery.
Summary:
Neurologists play an important role in the identification of patients who should be evaluated
for possible iNPH. With contemporary diagnostic tests and treatment with programmable shunts,
the benefit-to-risk ratio of shunt surgery is highly favorable. For more complex patients,
tertiary centers with expertise in complex iNPH are available throughout the world.

Key Points
& Spasticity, hyperreflexia, and other upper motor neuron findings are atypical in patients
with idiopathic normal pressure hydrocephalus.
& The features of gait impairment in patients with idiopathic normal pressure hydrocephalus
can be difficult to distinguish from those of neurodegenerative disorders with motor
involvement, such as parkinsonism or dementia with Lewy bodies.
& Neuroimaging with either CT or MRI is required for the diagnosis of idiopathic normal
pressure hydrocephalus.
& An Evans ratio of more than 0.3 indicates large ventricles, and a ratio of more than
0.33 indicates very large ventricles, but is not specific for idiopathic normal
pressure hydrocephalus.
& Gait impairment is typically either the first or worst symptom in patients with idiopathic
normal pressure hydrocephalus.
& Attempts to investigate acutely hospitalized patients for idiopathic normal pressure
hydrocephalus are fraught with the risk of misattribution.
& Identification of comorbidities is an essential part of the clinical management of
idiopathic normal pressure hydrocephalus.
& The presence of comorbidities does not exclude the possibility of idiopathic normal
pressure hydrocephalus; however, comorbidities do influence the prognosis after
shunt surgery.
& The international and Japanese guidelines support shunt surgery as effective treatment
of idiopathic normal pressure hydrocephalus, as does the American Academy of
Neurology practice guideline.
& If a patient has idiopathic normal pressure hydrocephalus, a significant response to
CSF removal should be seen and shunt surgery should help.
& A ventriculoperitoneal shunt consists of three parts: a proximal catheter, usually inserted
in the right lateral ventricle; a distal catheter with its tip in the peritoneal cavity; and a
shunt valve between the proximal and distal catheters.

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 & Several different makes and models of adjustable shunts are available, and the devices
for adjusting them are not interchangeable.
& Some, but not all, adjustable shunts are susceptible to strong external magnetic fields.
& Patients who have had shunt surgery should have periodic follow-up visits.
& Although most neurologists have not been trained to provide longitudinal care of patients
with idiopathic normal pressure hydrocephalus after shunt surgery, they can learn to do so.
& All symptoms in patients with idiopathic normal pressure hydrocephalus can improve
after shunt surgery.
& When patients who have been treated with shunts have worsening symptoms, physicians
frequently presume that the shunt is obstructed, which is often incorrect.
& Three typical clinical scenarios of worsening symptoms are lagging symptom recovery,
transient worsening, and insidious worsening.
& High-complexity patients with idiopathic normal pressure hydrocephalus may be
better served by referral to tertiary centers with expertise in complex idiopathic normal
pressure hydrocephalus.
& Supplementary tests can be used to include patients for surgery, but not to exclude them.
& Infusion testing for assessment of CSF hydrodynamics is commonly used in Europe.
& An increased resistance to CSF outflow (Rout) is one of the most consistent findings
in idiopathic normal pressure hydrocephalus research.
& Attempts at ad hoc performance of external lumbar drainage in patients with idiopathic
normal pressure hydrocephalus are discouraged.
& The presence of unstable intracranial pressure (predominantly B waves) in idiopathic
normal pressure hydrocephalus is well known.
& Pathologic CSF dynamics are an important part of the idiopathic normal pressure
hydrocephalus pathophysiology.

Psychiatric Aspects of Dementia

Onyike, Chiadi U. MD, MHS. Continuum (Minneap Minn). April 2016;
22(2 Dementia): 600Y614.

Abstract
Purpose of Review:
The psychiatric aspects of dementia are increasingly recognized as significant contributors to
distress, disability, and care burden, and, thus, are of increasing interest to practicing neurologists.
This article examines how psychiatric disorders are entwined with dementia and describes the
predictive, diagnostic, and therapeutic implications of the psychiatric symptoms of dementia.
Recent Findings:
Psychiatric disorders, particularly depression and schizophrenia, are associated with higher risk
for late-life dementia. Psychiatric phenomena also define phenotypes such as frontotemporal
dementia and dementia with Lewy bodies, cause distress, and amplify dementia-related
disabilities. Management requires a multidisciplinary team, a problem-solving stance, programs
of care, and pharmacologic management. Recent innovations include model programs that
provide structured problem-solving interventions and tailored in-home care.

* 2016 American Academy of Neurology.

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Summary:
There is new appreciation of the complexity of the relationship between psychiatric disorders
and dementia as well as the significance of this relationship for treatment, community services,
and research.

Key Points
& The majority of patients with dementia experience one or more disturbances of mood,
behavior, perception, and thought content.
& While most psychiatric states manifest as episodes, apathy associated with dementia is
usually a persistent state.
& Primary psychiatric disorders usually develop in youth and early adulthood, although
first episodes of depression, anxiety, mania, and psychosis in midlife and in the elderly
are recognized.
& A subset of individuals with schizophrenia develop dementia in later life, decades after
the onset of the psychotic state.
& Depressive symptoms have been associated with cognitive decline and transitions
to dementia in individuals with mild cognitive impairment and other mild
cognitive disorders.
& Alzheimer disease typically presents a variety of psychiatric symptoms, most commonly
apathy, depression, anxiety irritability, agitation, and delusions.
& Cognitive deficits and behavioral symptoms are present in patients with Huntington
disease beginning approximately 15 years prior to motor diagnosis.
& The behavioral variant of frontotemporal dementia typically presents as a combination
of socially offensive behaviors, such as indifference, impatience, carelessness,
insensitivity, jocularity, intrusiveness, distractibility, impulsiveness, stereotyped
behaviors, compulsions, food craving and gluttony, and slovenliness, and many of these
patients do not have noticeable cognitive deficits until illness is established.
& Visual illusions and hallucinations develop early in dementia with Lewy bodies and
become florid, persistent and, in many cases, are associated with misidentification,
paranoia, delusions, and anxiety.
& Psychiatric symptoms in dementia have been linked to more severe cognitive and
functional disabilities and faster progression to severe dementia and death.
& Patients with apathy appear passive, disinterested, and aloof, but do not experience a
sad or depressed mood. In contrast, depression is associated with a sad mood, low
self-worth, feelings of guilt, and pessimism.
& Psychometric instruments are used to provide measurements of the psychiatric
phenomena and their correlates (particularly cognitive profiles and functional disabilities)
that facilitate differential diagnosis, judgment of severity, and monitoring of temporal
change and treatment responses.
& A multidisciplinary team model involving physicians, nursing, physical therapy, and
other rehabilitative services, as well as social work and caregiver/family advocacy is often
required for the optimal management of patients with psychiatric disorders and dementia.
& Where the clinical formulation for managing the psychiatric aspects of dementia
emphasizes problem solving, psychosocial approaches such as environment remodeling,
structured recreation, caregiver education and training, and psychotherapy are pertinent.
& Typical and atypical antipsychotic agents are associated with a high risk for mortality
in patients who have dementia.

* 2016 American Academy of Neurology.

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

 Ethical Issues

Ethical Considerations
Address correspondence to
Dr Serge Gauthier, Douglas
Hospital, McGill Centre for

for the Use of

Studies in Aging, 6825
LaSalle Boulevard, Verdun,
QC H4H 1R3, Canada,
[email protected].

Next-Generation Relationship Disclosure:

Dr Gauthier receives personal
compensation for serving on

Alzheimer Drugs in the scientific advisory boards

of AFFiRiS, Eli Lilly and
Company, and Hoffmann-La

Symptomatic and
Roche Ltd; for serving as chair
of the scientific advisory
board of TauRx Therapeutics;

At-Risk Patients
and as a lecturer for Ever
Pharma and Schwabe,
Williamson & Wyatt.
Dr Gauthier serves as an
editorial board member of
Serge Gauthier, CM, MD, FRCPC; Pedro Rosa-Neto, MD, PhD; Alzheimer’s & Dementia: The
Joseph S. Kass, MD, JD, FAAN Journal of The Alzheimer’s
Association, Current Medical
Research & Opinion,
Dementia and Geriatric
ABSTRACT Cognitive Disorders, Eurasian
Journal of Medicine, European
This article presents a case in which a patient with mild Alzheimer disease requests Neurology, and the World
a prescription for a newly developed Alzheimer disease drug, after which the Journal of Biological
patient’s daughter inquires about its potential usefulness as a prevention strategy Psychiatry. Dr Gauthier
receives research funding
for herself. The article discusses the physician’s responsibility to balance the ethical as site principal investigator
principles of beneficence, nonmaleficence, and respect for patient autonomy when of the Eli Lilly and Company
evaluating requests for medications from patients with neurocognitive disease as and Hoffmann-La Roche Ltd,
and receives funding for this
well as from asymptomatic but at-risk patients. work from the Canadian
Institutes of Health Research
Continuum (Minneap Minn) 2016;22(2):615–618. and the Canadian Consortium
on Neurodegeneration in Aging
as chair of the Ethical, Legal,
and Social Issues advisory
committee. Dr Gauthier
Case receives book royalties from
Cambridge University Press.
Note: This is a hypothetical case and drug. Dr Rosa-Neto receives grant
A 75-year-old woman presented to the memory clinic for her annual support from the Alzheimer’s
follow-up visit, accompanied by her 50-year-old daughter. The patient had Association. Dr Kass has
received personal
been diagnosed with mild, symptomatic Alzheimer disease (AD) 4 years compensation for expert
prior and had been stable on donepezil 10 mg/d for the past 2 years. The testimony in legal cases
patient had a strong family history of AD. She lived independently, but her involving personal injury,
defamation, and malpractice.
daughter advised her about her finances and phoned her daily, reminding Unlabeled Use of
her to take her donepezil. At the follow-up visit, her Mini-Mental State Products/Investigational
Examination (MMSE) score was 24 out of 30. Use Disclosure:
Drs Gauthier, Rosa-Neto, and
At the conclusion of the examination, the patient asked whether a Kass report no disclosures.
recently approved drug for AD would be useful for her condition. The * 2016 American Academy
patient’s daughter then asked whether she should begin taking the drug of Neurology.
herself to try to prevent onset of neurocognitive symptoms because of her
strong family history of AD. The daughter provided the neurologist with a
printout of information she had located on the Internet describing the
medication as a monthly IV medication costing thousands of dollars per dose
to be used only in patients with biomarker evidence of amyloid pathology.
During clinical trials, 5% of patients developed either cerebral edema or
intracerebral hemorrhage.

Continuum (Minneap Minn) 2016;22(2):615–618 www.ContinuumJournal.com 615

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 Next-Generation Alzheimer Drugs

DISCUSSION
This case, while about a hypothetical patient and drug, is realistic considering
the pace of research in Alzheimer disease (AD) for asymptomatic at-risk indi-
viduals1 and individuals with prodromal symptoms,2 mild cognitive impair-
ment due to AD,3 or mild dementia due to AD.4 Neurologists may soon be
facing such clinical and ethical dilemmas with their patients who have AD. Any
time physicians recommend a new therapeutic intervention, they must engage
their patients in an informed consent process. Adult patients with decision-
making capacity (or surrogates, acting on the patient’s behalf, if patients lack
capacity) have a right to self-determination. Patients must be apprised of the
risks and benefits of a proposed therapy and given adequate information to
decide whether the proposed intervention aligns with their personal values.
Shared decision making is often appropriate and allows the physician to guide
the patient to make the choice most compatible with the patient’s values and
desires. This shared decision-making model eschews paternalism, respects patient
autonomy, and acknowledges that patients typically desire some guidance from
their physicians in making sense of the information that must be considered for
a truly informed decision. In addition to respecting a patient’s autonomy rights,
physicians must also consider the dual effects of beneficence and nonma-
leficence. Beneficence calls on physicians to act to propose interventions that
promote patients’ well-being, while nonmaleficence requires physicians to
minimize patient harm.
Although traditionally recommendations for therapy come from physicians,
physicians are now routinely managing the expectations of patients who re-
search therapies on the Internet. Neurologists must grapple with the same
ethical considerations regardless of the source of the request for therapy.
Additionally, neurologists must remember that they are their patients’ fidu-
ciaries and must always act in their patients’ best interests. Especially when a
request for a given therapy comes from the patient, the physician must resist the
urge to act paternalistically and dismiss the request outright. However, the
physician need not concede to the demands of a patient in the false belief that
a patient’s right to autonomy trumps sound clinical judgment. Physicians are
not acting paternalistically when they refuse to give in to a patient’s medically
unreasonable request. Like all therapies, the requested therapy must be medically
appropriate, meeting the demands of beneficence by maximizing benefit and the
demands of nonmaleficence by minimizing harm.
In this hypothetical case, the patient’s request and her daughter’s request
present quite different ethical challenges. The patient’s request is truly a routine
matter of clinical judgment. If the US Food and Drug Administration (FDA)
approved this new (hypothetical) medication for people like this patient who
have mild AD, then the issue is really about ethical demands on a physician
when providing informed consent for a therapy with which the physician has no
experience. When proposing a new therapy unfamiliar to the physician, the
demands of medical professionalism, which include the physician’s fiduciary
obligations to work in the patient’s best interest, require the physician to
consult peer-reviewed publications and pay particular attention to inclusion
and exclusion criteria used in phase 3 trials as well as to the efficacy and safety
data of the new medication as compared to placebo. The physician should explain
to the patient that there may be insufficient postmarketing data to establish safety
616 www.ContinuumJournal.com April 2016

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

beyond the length of the study and in patients whose demographics and medical
comorbidities differ from the studied population.
This particular hypothetical drug also requires expensive diagnostic tests as
part of the patient selection process. Thus, if the patient meets the clinical
criteria for using this therapy, she may be an appropriate candidate for this newly
approved therapy. The informed consent process would have to include an
honest and thorough review of the not-insignificant risks associated with this
therapy. Even if the patient possesses decision-making capacity, the patient should
be encouraged to involve her daughter in the informed consent process since this
treatment requires marshaling considerable cognitive and material resources, and
the patient appears to rely on her daughter considerably. If the neurologist deems
the patient lacking in capacity for this decision, the patient should still assent to the
intervention even while the patient’s surrogate decision maker provides consent.
The daughter’s request for a preventive treatment using this therapy would
be considerably more complicated if the FDA did not approve this therapy for
people like her, who have a strong family history of AD, but who currently do
not exhibit symptoms of the disease. Although they may prescribe medications
off-label, physicians, as their patients’ fiduciaries, must ensure that their thera-
peutic recommendations meet the same ethical and clinical standards as on-label
prescribing. However, clinicians at the vanguard of off-label prescribing of
recently approved medications typically will not possess robust evidence sup-
porting the therapy’s off-label use. The more serious the risk of harm from an
intervention and the less well-founded is the evidence of benefit, the less
prudent it would be for a physician to recommend such off-label treatment.
Thus, the risks of harm of nonintervention must be considerably greater than
the risks for active intervention in order to warrant recommending a relatively
untested therapy.

CONCLUSION
Although the patient’s request for the (theoretical) new medication may be
reasonable, the neurologist should not concede to the daughter’s request at this
time, even if the daughter has the financial resources to pay out-of-pocket for
this costly intervention. If new data emerge from high-quality trials suggesting
that this treatment is effective in preventing AD in presymptomatic at-risk people,
the physician should reconsider this request at that point. The neurologist may
probe to see if the daughter is interested in participating in a trial for at-risk people,
and she can be referred to an appropriate research center. Additionally, the
encouraging results of nonpharmacologic interventions combining physical
activity, cognitive training, optimal nutrition, and medical care over 2 years in the
Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and
Disability (FINGER) study provide strategies to stave off the onset of dementia.5
Similar studies are underway in North America and Europe.6 Some countries,
such as Australia, are already implementing national plans to prevent AD based
on interventional epidemiology data.7 The daughter in this case should be
educated about these nonpharmacologic interventions.

ACKNOWLEDGMENTS
Drs Gauthier and Rosa-Neto receive funding from the Canadian Institutes of Health
Research and the Canadian Consortium on Neurodegeneration in Aging.
Continuum (Minneap Minn) 2016;22(2):615–618 www.ContinuumJournal.com 617

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 Next-Generation Alzheimer Drugs

REFERENCES
1. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s
disease: recommendations from the National Institute on Aging-Alzheimer’s Association
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement
2011;7(3):280Y292. doi:10.1016/j.jalz.2011.03.003.

2. Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s
disease: the IWG-2 criteria. Lancet Neurol 2014;13(6):614Y629. doi:10.1016/S1474-4422(14)70090-0.

3. Albert MS, DeKosky ST, Dickson D, et al. The diagnosis of mild cognitive impairment due to
Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement
2011;7(3):270Y279. doi:10.1016/j.jalz.2011.03.008.

4. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s
disease: recommendations from the National Institute on Aging-Alzheimer’s Association
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement
2011;7(3):263Y269. doi:10.1016/j.jalz.2011.03.005.
5. Ngandu T, Lehtisalo J, Solomon A, et al. A 2 year multidomain intervention of diet, exercise,
cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in
at-risk elderly people (FINGER): a randomized controlled trial. Lancet. 2015;385(9984):2255Y2263.
doi:10.1016/S0140-6736(15)60461-5.
6. Fougère B, Vellas B, Delrieu J et al. The road ahead to cure and prevent Alzheimer’s disease:
implementing prevention into primary care. J Prev Alz Dis 2015;2(3):199Y211.
7. Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s
disease: an analysis of population-based data. Lancet Neurol 2014;13(8):788Y794.
doi:10.1016/S1474-4422(14)70136-X.

618 www.ContinuumJournal.com April 2016

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 Practice Issues

Caregiver Stress
Address correspondence to
Dr Amy E. Sanders,
State University of New York

and the Patient

Upstate Medical
University, 750 East Adams St,
Jacobsen Hall 1012,
Department of Neurology,

With Dementia Syracuse, NY 13210,

[email protected].
Relationship Disclosure:
Dr Sanders served as an
Amy E. Sanders, MD, MS, FAAN expert medical witness for
Gilreath Law Firm.
Unlabeled Use of
Products/Investigational
ABSTRACT Use Disclosure:
Dr Sanders reports no disclosure.
Informal caregivers (often, but not exclusively, family members) are essential to the
* 2016 American Academy
clinical care of a patient with dementia. Most caregivers are untrained and unpaid. of Neurology.
As a result, caregivers often experience stress caused by the caregiving experience;
they are the ‘‘invisible second patients’’ in dementia care. Clinicians can help
caregivers by supporting them in their role and by referring them to additional
resources for support.

Continuum (Minneap Minn) 2016;22(2):619–625.

Case
An 81-year-old man presented with symptoms of escalating memory loss
experienced for the past 18 months. A retired geologist, he first became
concerned about his memory when he misplaced his favorite soil sampling
kit, only to find it several months later at the bottom of the laundry hamper.
In his spare time, he had long enjoyed directing a barbershop quartet, but
had begun to note more recently that he was having trouble harmonizing,
and for the 3 months prior to presentation, he specifically expressed
difficulty remembering the lyrics to well-known songs. The week before
he came to the office, he woke up at midnight, thought it was morning,
and went to the supermarket to shop, only to find it dark and closed.
The patient previously had been diagnosed with hypertension and
osteoarthritis. He was a widower and lived alone; his eldest daughter lived
locally with her own family. The patient stated that his daughter would
likely be the one to ‘‘help me out, if I should ever need it.’’ His daughter
did not attend the diagnostic visit, citing conflict with her job as a small-business
owner with small children of her own. The patient was diagnosed with
probable Alzheimer disease after a thorough workup, including a caregiver
interview, a neuropsychological evaluation, screening laboratory testing, and
structural brain neuroimaging.

DISCUSSION
A consequence of all diseases that cause dementia is the inevitable total dependence
of the patient upon a caregiver. In most cases, the primary caregiver for the patient
with dementia is an informal one, without specific training or resources to manage
the relentless and exhausting job. Caregiver burden is therefore common in the care
of patients with dementia, which can lead to disastrous outcomes for patient and
caregiver alike.

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 Caregiver Stress

Caregiving is the process of caring for another person’s health needs. A

synthesis of data collected by the Alzheimer’s Association suggests that 65% of
caregivers of people with Alzheimer disease and other dementias are women;
21% are 65 years old and older; 40% had some college education or had received
a degree; 64% were currently employed, a student, or a homemaker; and 71%
were married or in a long-term relationship.1 According to data from the National
Alliance for Caregiving and the American Association for Retired Persons
analyzed by the Alzheimer’s Association, white caregivers are more likely to be
caring for a parent than African American or Hispanic caregivers; however,
African American and Hispanic caregivers, on average, spend more hours weekly
engaged in caregiving than white caregivers and are more likely to experience
high levels of burden from the caregiving role (57% in African American and
45% in Hispanic versus 33% in white individuals). This care comes at a high
cost. The Alzheimer’s Association estimates that in 2014, unpaid caregivers
provided 17.7 billion hours of care, valued at approximately $220 billion. Higher
health care costs for caregivers were estimated at more than $9 billion.1

Case Continued
The patient was started on donepezil monotherapy, titrated from 5 to
10 mg/d, and did well for the ensuing 2 years. When his daughter
finally accompanied him to an appointment, she sat quietly for much of the
visit, but occasionally sighed loudly or shook her head as though she
disagreed with statements from her father. Finally, when asked if there was
anything else that needed to be discussed, the daughter exclaimed, ‘‘Well, he
can’t find the bathroom anymore, and last week he urinated in the coat
closet. I try to help him get to the right place, and he hits me! Frankly, I don’t
have time for this! Can’t you prescribe him something?’’

In formal and theoretical terms, caregiver stress has been defined as the
unequal exchange of assistance among people who stand in close relationship
to one another, resulting in emotional and physical stress on the caregiver.2
According to data from the Behavioral Risk Factor Surveillance System reported
by Anderson and colleagues,3 older (more than 65 years of age) caregivers appear
to be more resilient in the caregiving role than their younger (ages 18 to 64)
counterparts, reporting significantly less mental distress and dissatisfaction with
life, even in the face of poorer personal health and more physical distress. Studies
investigating factors related to caregiver burden report that burden is inversely
related to cognitive function in the person with dementia, with caregiver burden
rising as cognitive ability in the care recipient declines. Caregiver burden is seen
when caring for all stages of patients with Alzheimer disease with behavioral issues.
Caregiver burden is also seen when caring for patients with mild to moderate
Alzheimer disease with impairment in instrumental activities of daily living.4
Neurologists and other clinicians providing primary care to patients with de-
mentia should consider the patient-caregiver relationship as a dyad, one in which
the caregiver often functions as a secondary patient.5 The underlying psychody-
namic relationship between the patient and caregiver, and the caregiver’s intrinsic
personality traits, contribute in important ways to the caregiving experience. Some
caregivers experience the caregiver role in a predominantly positive way, but many

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do not (Practice Table 1).6,7 Caregiver burnout can lead to dire outcomes. A
recent systematic review of risk factors for elder abuse in community-dwelling
older adults found that the highest odds for abuse were associated with family
disharmony and low levels of social support.8

PRACTICE TABLE 1 Positive and Negative Outcomes for the Caregiver

of Caring for Individuals With Dementia

b Positive Outcomes
Sense of personal accomplishment
Fostering family togetherness
Satisfaction of helping others
b Negative Outcomes
Stress and burden
Anxiety (new or increased)
Sleep deprivation and other disruptions of good sleep hygiene
Depression
Decreased participation in recreation, work, or self-care
Social isolation
Financial hardship
Declining physical health
Increased risk of cognitive decline7

More than 100 clinical instruments are available to assess caregiver stress and
burdens. The original and modified Zarit Burden Interview (Practice Table 29Y11)
is considered by dementia researchers to be the most useful.12 Numerous Internet
resources are available to help guide and support family and other informal
caregivers (refer to the useful website section at the end of this article). Local
organizations, such as senior centers, may have adult day care programs that
offer the person with dementia a chance to be social and the opportunity to
participate in planned and supervised activities designed to promote well-being,
such as music and exercise. Senior centers or other local services for older adults
may also offer support groups, providing caregivers with a safe place to meet
and develop a mutual support system. Local organizations may also be able to
provide initial links to aging resources, including those for transportation and
elder care legal advice. Finally, nursing homes may have respite care available,
providing caregivers with a temporary rest from caregiving, while the person with
dementia continues to receive care in a safe environment. A clinician who is
familiar with the scope of challenges that can confront caregivers and is willing to
spend time providing caregiver guidance is a valuable resource.
Caregiver stress often occurs when a patient exhibits noncognitive neuro-
psychiatric symptoms. Some of these behaviors are vegetative, such as apathy
and depression, and many involve patient behavioral challenges. These

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

 Caregiver Stress

PRACTICE TABLE 2 Screening and Short Zarit Burden Interview for

Caregivers of Cognitively Impaired Adultsa,b

Screening Short
Version Version
Do You FeelI Question Question
1. that because of the time you spend with your relative ! !
that you don’t have enough time for yourself?
2. stressed between caring for your relative and trying ! !
to meet other responsibilities (work/family)?
3. angry when you are around your relative? !
4. that your relative currently affects your relationship !
with family members or friends in a negative way?
5. strained when you are around your relative? ! !
6. that your health has suffered because of your !
involvement with your relative?
7. that you don’t have as much privacy as you would like !
because of your relative?
8. that your social life has suffered because you are !
caring for your relative?
9. that you have lost control of your life since your !
relative’s illness?
10. uncertain what to do about your relative? ! !
11. you should be doing more for your relative? !
12. you could do a better job in caring for your !
relative?
a
Original Zarit Burden Interview printed in Zarit SH, et al, New York University Press.9 Screening and
short versions reprinted from Bédard M, et al, Gerontologist.10 gerontologist.oxfordjournals.org/
content/41/5/652.full.pdf?ck=nck. B 2001 The Gerontological Society of America.
b
Answers are scored Never (0), Rarely (1), Sometimes (2), Quite Frequently (3), Nearly Always (4), and
scores are summed. The total score of the short version of the Zarit Burden Interview will range
from 0 to 48. Epidemiologic comparative effectiveness studies reported a mean (standard deviation)
of 15.1 (10) in caregivers for people with dementia.11

behaviors can arise from disorders of thought (eg, delusions, hallucinations),

disorders of mood (eg, irritability, emotional lability, depression, apathy, or out-
bursts), or disorders of activity (eg, agitation, verbal or physical aggression, socially
inappropriate behaviors, wandering, purposeless hyperactivity, repetitive behav-
iors, impulsivity, and others).13 The DICE (describe, investigate, create, and evaluate)
approach helps the caregiver evaluate the problem in a constructive, organized, and
fruitful manner.14 (For more information on the DICE approach, refer to Figure 11-2
in the article ‘‘Psychiatric Aspects of Dementia’’ by Chiadi U. Onyike, MD, MHS,
in this issue of Continuum.15) In this approach, caregivers are asked first to
describe the problematic behavior. In the case in this article, the patient was
getting lost at night and mistaking another room for the bathroom. Next, the
caregiver and clinician together can investigate potential causes contributing to the
undesirable behavior. The third step is to create a treatment plan, which, in this

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case, included a brainstorming session with the patient, caregiver, and clinician.
These sessions may yield a creative, yet simple, solution. Finally, a solution is
proposed that can then be evaluated. Collaboration demonstrates to the caregiver
that solutions are being explored, allows the clinician to model problem-solving
behavior, and increases buy-in from patient and caregiver.

Case Continued
The DICE (describe, investigate, create, and evaluate) approach was proposed
to the patient and the caregiver. The daughter was asked to evaluate the
situation at home, and she noted that the patient’s bedroom is at one end
of a hallway, and the bathroom at the other end. A plan was initiated to
install a series of night lights in the hallway and in the bathroom so that
the way would always be illuminated.

CONCLUSION
In patients with dementia, the severity and rate of progression of cognitive
and behavioral symptoms are idiosyncratic, making it difficult to predict the
nature of the challenges that a given patient and his or her caregiver will ex-
perience. There will be challenges, and helping to guide the caregiver and
patient dyad through the difficult times is an essential aspect of providing good
clinical care for the patient with dementia.

USEFUL WEBSITES
The following websites are useful resources for family and other informal care-
givers of individuals with dementia.
Alzheimer’s Association. The Alzheimer’s Association provides information on
local chapters and national offices, support groups, educational resources, as
well as a 24-hour helpline.
www.alz.org
Alzheimer’s Disease Education and Referral Center. Part of the National
Institutes of Health National Institute on Aging, the Alzheimer’s Disease
Education and Referral Center provides individuals with Alzheimer disease and
their caregivers with caregiving tip sheets and links to the National Institute on
Aging resources and Eldercare locator.
www.nia.nih.gov/alzheimers
Alzheimer’s Foundation. The Alzheimer’s Foundation provides caregiving tip
sheets and access to online support groups and caregiver training.
www.alzfdn.org
The Association for Frontotemporal Degeneration. The Association for
Frontotemporal Degeneration provides information on caregiver support
groups as well as tip sheets for caregivers, patients, and physicians on behavioral

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

 Caregiver Stress

techniques that can be helpful in dealing with some of the most challenging
behaviors in patients with frontotemporal degeneration.
www.theaftd.org
Caregiver Action Network. The Caregiver Action Network offers situation-
specific caregiver education such as to new caregivers and individuals who care
for their aging parents while raising their own children.
www.caregiveraction.com
Family Caregiving Alliance. The Family Caregiving Alliance provides education
materials for caregivers as well as information on caregiver policy and advocacy.
www.caregiver.org
Homewatch Caregivers. Homewatch Caregivers provides tip sheets and additional
education resources to those caring for patients with dementia.
www.homewatchcaregivers.com
Lewy Body Dementia Association. The Lewy Body Dementia Association
supports those affected by Lewy body dementia, their families, and their caregivers,
and is dedicated to raising awareness and promoting scientific advances.
www.lbda.org
Strength for Caring. Strength for Caring provides caregiver education and
information on care for the caregiver.
www.strengthforcaring.com

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(published online ahead of print May 1, 2014). Nurs Forum. doi:10.1111/nuf.12090.
3. Anderson LA, Edwards VJ, Pearson WS, et al. Adult caregivers in the United States:
characteristics and differences in well-being, by caregiver age and caregiving status. Prev Chronic
Dis 2013;10:E135. doi:10.5888/pcd10.130090.
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several cognitive stages of Alzheimer’s disease. Geriatr Gerontol Int 2014;14(suppl 2):45Y55.
doi:10.1111/ggi.12260.
5. Brodaty H, Donkin M. Family caregivers of people with dementia. Dialogues Clin Neurosci
2009;11(2):217Y228.
6. Zarit SH. Positive aspects of caregiving: more than looking on the bright side. Aging Ment Health
2012;16(6):673Y674. doi:10.1080/13607863.2012.692768.
7. Vitaliano PP, Murphy M, Young HM, et al. Does caring for a spouse with dementia promote
cognitive decline? A hypothesis and proposed mechanisms. J Am Geriatr Soc 2011;59(5):900Y908.
doi:10.1111/j.1532-5415.2011.03368.x.
8. Johannesen M, LoGiudice D. Elder abuse: a systematic review of risk factors in
community-dwelling elders. Age Ageing 2013;42(3):292Y298. doi:10.1093/ageing/afs195.
9. Zarit SH, Orr N K, Zarit JM. The hidden victims of Alzheimer’s disease: families under stress.
New York, NY: New York University Press, 1985.
10. Bédard M, Molloy DW, Squire L, et al. The Zarit Burden Interview: a new short version and
screening version. Gerontologist 2001;41(5):652Y657. doi: 10.1093/geront/41.5.652.

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11. Higginson IJ, Gao W, Jackson D, et al. Short-form Zarit caregiver burden interviews were valid in
advanced conditions. J Clin Epidemiol 2010;63(5):535Y542. doi:10.1016/j.jclinepi.2009.06.014.
12. Van Durme T, Macq J, Jeanmart C, Gobert M. Tools for measuring the impact of informal
caregiving of the elderly: a literature review. Int J Nurs Stud 2012;49(4):490Y504. doi:10.1016/
j.ijnurstu.2011.10.011.
13. Odenheimer G, Borson S, Sanders AE, et al. Quality improvement in neurology: dementia
management quality measures. Neurology 2013;81(17):1545Y1549. doi:10.1212/
WNL.0b013e3182a956bf .
14. Kales HC, Gitlin LN, Lyketsos CG. Management of neuropsychiatric symptoms of dementia in
clinical settings: recommendations from a multidisciplinary expert panel. J Am Geriatr Soc
2014;62(4):762Y769. doi:10.1111/jgs.12730.
15. Onyike CU. Psychiatric aspects of dementia. Continuum (Minneap Minn) 2016;
22(2 Dementia):600Y614.

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 Practice Issues

Coding for Dementia

Address correspondence to
Dr Bruce H. Cohen, 215 W
Bowery St, CPB 4400, Akron,
OH 44087,
[email protected]. Bruce H. Cohen, MD, FAAN; Peter D. Donofrio, MD, FAAN
Relationship Disclosure:
Dr Cohen has received
personal compensation from
the American Academy of
Neurology for educational
speaking engagements, has Accurate coding is an important function of neurologic practice. This contribution to
served as an expert consultant Continuum is part of an ongoing series that presents helpful coding information
for the Division of Vaccine
Compensation and the
along with examples related to the issue topic. Tips for diagnosis coding, Evaluation
United States Department of and Management coding, procedure coding, or a combination are presented,
Justice and Health & Human depending on which is most applicable to the subject area of the issue.
Services, and serves on the
speakers bureau of the
United Mitochondrial Disease
Foundation. Dr Cohen serves
on the editorial boards of
Mitochondrian and Pediatric INTRODUCTION
Neurology, serves as content Current Procedural Terminology (CPT) is a publication of the American
editor for Motive Medical
Intelligence, and has received Medical Association, which is updated yearly, and lists all the five-digit codes
personal compensation and definitions for all Evaluation and Management (E/M) codes and procedural
and travel expenses as a
consultant for Stealth codes used to care for patients.1 The E/M codes make up a small component of
BioTherapeutics. Dr Cohen CPT and are the codes that are used in delivering cognitive services. Specifically,
receives research funding
from the National Institutes the majority of E/M coding used by doctors who care for patients with dementia
of Health (GG006326-03), are ambulatory codes, which are used for the care delivered in the office setting.
and Dr Cohen’s institution
has received compensation
In general, the E/M codes require no special technology. In addition to the new
for his lectures at Courtagen and established office visit codes, some new CPT codes are available that are
Life Sciences, Inc, and relevant to providers caring for patients with dementia.
Transgenomic, Inc, and for
his expert witness testimony The International Classification of Diseases, Tenth Revision, Clinical Modi-
in various court cases. fication (ICD-10-CM) is the classification for medical coding supported by the
Dr Cohen’s institution has
also received research Centers for Medicare & Medicaid Services (CMS) and the National Center for
support from Edison Health Statistics.2 The ICD-10-CM is the United States modification of the tenth
Pharmaceuticals, Inc, Raptor
Pharmaceuticals, Reata revision of the World Health Organization’s International Statistical Classifica-
Pharmaceuticals, Inc, and tion of Diseases and Related Health Problems (whose short-form name is
Stealth BioTherapeutics, and
Dr Cohen has also received
International Classification of Diseases, Tenth Revision [ICD-10]), and replaced
travel expense reimbursement the International Classification of Diseases, Ninth Revision, Clinical Modifica-
from these entities.
Dr Donofrio has served on
tion (ICD-9-CM) on October 1, 2015.2,3 Chapter 6 of the ICD-10-CM contains the
the scientific advisory board codes for diseases of the nervous system (codes G00 to G99), with the Alzheimer
of and as a consultant for disease codes contained in the G30 grouping. The G31 grouping contains ‘‘Other
Baxter, CSL Behring, and
UCB, Inc, and has served on degenerative diseases of nervous system, not elsewhere classified,’’ and the G32
the editorial board of Muscle group contains ‘‘Other degenerative disorders of nervous system in diseases
& Nerve.
Unlabeled Use of classified elsewhere.’’ The G30 and G31 codes will be used most often when
Products/Investigational coding for illnesses related to dementia. Refer to Coding Table 1 for a list of
Use Disclosure:
Drs Cohen and Donofrio
useful codes in this category.
report no disclosures. Caring for patients with dementia provides a considerable clinical challenge
* 2016 American Academy that directly impacts all the most complex aspects of both the ICD-10-CM and
of Neurology.
CPT code sets. Initial evaluation requires an extensive review of any comorbid
conditions, medical conditions that can mimic or contribute to dementia, and
the medical and neuropsychological evaluation that is necessary to establish the
correct diagnosis. Subsequent visits are complicated by discussions regarding
disease progression and possible therapy to treat cognitive or behavioral
manifestations, skilled nursing care, palliative care, and end-of-life planning. The

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CODING TABLE 1 International Classification of Diseases, Tenth
Revision, Clinical Modification Codes for Dementia

G30 Alzheimer disease

G30.0 Alzheimer disease with early onset
G30.1 Alzheimer disease with late onset
G30.8 Other Alzheimer disease
G30.9 Alzheimer disease, unspecified
G31 Other degenerative disease of nervous system, not elsewhere classified
G31.0 Frontotemporal dementia
G31.01 Pick disease
G31.09 Other frontotemporal dementia
G31.1 Senile degeneration of brain, not elsewhere classified
G31.2 Degeneration of the nervous system due to alcohol
G31.8 Other specified degenerative diseases of nervous system
G31.81 Alpers disease
G31.82 Leigh disease
G31.83 Dementia with Lewy bodies
G31.84 Mild cognitive impairment, so stated
G31.85 Corticobasal degeneration
G31.89 Other specified degenerative diseases of the nervous system
G31.9 Degenerative disease of nervous system, unspecified
G32 Other degenerative disorders of nervous system in diseases classified
elsewhere)
G32.0 Subacute combined degeneration of spinal cord in diseases
classified elsewhere
G32.8 Other specified degenerative disorders of nervous system in
diseases classified elsewhere
G32.81 Cerebellar ataxia in diseases classified elsewhere
G32.89 Other specified degenerative disorders of nervous system
in diseases classified elsewhere
F01 Vascular dementia
Code first the underlying physiologic condition or sequelae of
cerebrovascular disease.
F01.5 Vascular dementia
F01.50 Vascular dementia without behavioral disturbance
F01.51 Vascular dementia with behavioral disturbance
Continued on page 628

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 Coding for Dementia

CODING TABLE 1 International Classification of Diseases, Tenth

Revision, Clinical Modification Codes for Dementia
Continued from page 627

F02 Dementia in other diseases classified elsewhere

Code first the underlying physiological condition
F02.8 Dementia in other diseases classified elsewhere
F02.80 Dementia in other diseases classified elsewhere without
behavioral disturbance
F02.81 Dementia in other diseases classified elsewhere with
behavioral disturbance
F03 Unspecified dementia
F03.9 Unspecified dementia
F03.90 Unspecified dementia without behavioral disturbance
Dementia NOS
F03.91 Unspecified dementia with behavioral disturbance

patient is often attended by an elderly spouse who may also have medical or
cognitive issues, leading to visits lasting longer than what has been scheduled.
Patients with dementia are usually insured by Medicare, which tends to be
reimbursed at a lower rate than commercial insurance, so any practice with a
large number of patients with dementia cannot function under the same
budgetary constraints as with other practices. In general, caring for patients with
dementia does not require procedural technology that tends to be reimbursed
at a higher level. Because of all these factors, the providers that care for patients
with dementia face a difficult challenge for financial solvency. This means that
providers caring for patients with this illness must be accurate with their coding
in order to charge properly for services delivered and not have claims rejected
because of erroneous coding practices.

Case 1
A 67-year-old woman presented because of memory difficulties. The family
relayed memory, but no behavior problems, specifying ‘‘there are good days
and bad days.’’ One year before presentation, the patient became lost on her
way home, and she had stopped driving except to go to work, the bank, and
the grocery store. Over the recent months, her children noticed that their
mother’s usual animated and lengthy conversations had become brief and
lacked emotion. She had spent her life working as a bookkeeper for the
family’s dry cleaning business, and employees had recently noted errors in
their paychecks. Her past medical history was notable for hypothyroidism,
hypercholesterolemia, type 2 diabetes mellitus, and a painful neuropathy
attributed to her diabetes mellitus, which was treated with levothyroxine,
simvastatin, metformin, and gabapentin. Her family history was unremarkable.
Continued on page 629

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 Continued from page 628
The remainder of a 10-organ review of systems was negative. Her heart
rate, blood pressure, and temperature were normal. The general physical
examination, including cardiovascular elements, was normal. Her speech
was slow with loss of normal prosody but there were no paraphasic errors.
She was able to name most objects, and her memory was two out of
three at 5 minutes. Her general fund of information for history and jazz
music (her passion) was normal but she was not able to name the current
president, the governor of her state, or its capitol, citing ‘‘congress controls
our government anyway.’’ Her Mini-Mental State Examination (MMSE) score
was 25 out of 30 points, with the patient appearing to be fully engaged in
the task. The remainder of the 25-element neurologic examination was
normal. There were no historical elements to suggest depression. The
physician informed the patient and her family that her memory problems
could at best be the result of an underlying ‘‘fixable’’ medical condition
such as a vitamin deficiency or a slow-growing benign brain tumor, or the
problem could be the result of a dementing condition such as the early
stages of Alzheimer disease. The physician wanted to order tests and then
decide about further plans. The duration of the visit was 60 minutes, and
the physician spent 25 minutes performing the history and examination,
with the remaining 35 minutes discussing the differential diagnosis of
cognitive impairment in the elderly.

DISCUSSION
Although the physician suspects Alzheimer disease, because no specific
diagnosis can be determined at this time, the G30 codes (representing the
various Alzheimer disease codes) are probably not the best choice to use when
coding for this patient. When dementia is known but the etiology is not, the
ICD-10-CM code best used in this case is F03.90.

F03.90 Unspecified dementia without behavioral disturbance

Refer to Coding Table 1 for a list of related codes. Case 1 did not state if the
patient’s visit was with her primary care provider or if she was being seen for
the first time by a new provider or by a specialist, functioning as a consultant. If
this patient’s visit was with her primary care provider, the best CPT code choice
would be 99215, a level 5 established patient visit. If the visit were coded based
on ‘‘bullets,’’ the comprehensive medical history and comprehensive physical
examination, using the 1997 neurologic single system examination, would default
this visit to the highest level of intensity.4 Furthermore, the medical decision
making involves a life-altering diagnosis, a visit type of the highest risk, and would
be viewed again as the highest level of intensity. Although this visit was
60 minutes in duration, if the provider performed the same elements in
30 minutes (less than the typical 40 minutes assigned to this visit), the 99215
code would still be justified on the basis of the work performed and docu-
mented. If the visit were to be coded based on counseling and/or coordina-
tion of care, also referred to as time-based billing, the visit would also be

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 Coding for Dementia

coded as a 99215 because over 50% of the total time of the visit was spent
educating the patient and family about the illness. If counseling and coor-
dination of care is chosen for the 99215 code, the visit must be a minimum of
40 minutes, with greater than 50% of the time spent performing counseling
and coordination of care issues. In this case, the visit duration was 60 minutes,
35 of which were spent performing this task. There is no code available for a
visit that runs 20 minutes longer than specified by CPT, and the physician does
not receive extra reimbursement for this time.
If the physician had not provided care to that patient in over 3 years, such as
a consulting neurologist, CMS would consider this a new patient visit. Although
consult codes (99241 to 99245) remain a part of CPT, in 2010 CMS stopped
paying for these codes for Medicare patients, so this patient would need to be
billed as a new patient using the codes 99201 to 99205. Many commercial carriers
and some Medicaid carriers do accept the consult codes, so if the patient was
referred for a consultation, those codes could be applied. Sixty minutes is the
typical time spent to complete elements for a 99205 code and also is the minimum
time required if counseling and coordination of care are used to support time-
based billing. For the same reasons given for the previous discussion about the
established patient, this patient’s office visit would qualify for a 99205 code, the
highest level in the ambulatory new patient codes (60-minute visit with a 25-point
comprehensive history and examination and complex medical decision making
or 35 minutes spent counseling and coordinating care).

Case 1 Continued
After her initial visit, where several tests had been ordered, the patient
returned for a follow-up visit to discuss the results and further considerations
for care. The thyroid-stimulating hormone (TSH), vitamin B12 levels,
hemoglobin A1c, and cholesterol were normal. A brain MRI showed only
mild volume loss. No additional symptoms were reported. The only
examination performed during the patient’s second visit was a cursory
cardiac examination and the observation of the patient’s affect and
language function. The patient and family declined further evaluation.
Following a brief discussion, the physician told the family the diagnosis
was likely mild late-onset Alzheimer disease, suggested treatment with
rivastigmine, and scheduled a return visit in 3 months. The visit duration
was 15 minutes, and the physician spent 10 minutes performing counseling
for the diagnosis and management. Following the physician leaving the
office, the registered nurse spent 20 minutes going over the medication and
side effects with the family and offered advice and comfort.

DISCUSSION
Because the physician diagnosed Alzheimer disease, the best code choices are
the following from ICD-10-CM:

G30.1 Alzheimer disease with late onset

F02.80 Dementia in other diseases classified elsewhere without behavioral disturbance

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 By definition, late onset is used for those with symptom onset after age 65. If
the symptom onset was before age 65, then G30.0 (Alzheimer disease with early
onset) would be the best choice. All dementia etiology codes require a second
manifestation code from Chapter 5 of ICD-10-CM, describing dementia with or
without behavioral disturbance. Because this was an established ambulatory
visit, the CPT code set would be the 99211 to 99215 codes. Despite the gravity
of the diagnosis, only a problem-focused history was obtained along with a
focused examination. This was justified as the choice of the extent of history
and physical examination is at the discretion of the physician performing the
service and should be commensurate with the nature of the chief complaint and
presenting problem. The physician should not perform an overly extensive
history or examination just to ‘‘up-code,’’ and the choice on the second visit not
to perform a more extensive history or physical examination was justified. In
this case, the extent of both the history and physical examination were by
definition, ‘‘problem focused,’’ the lowest level available. The medical decision
making is composed of three elements: number of diagnostic and management
options, data review, and risk of morbidity and mortality. Although the
determination of any of these elements is subjective, one could argue there were
limited diagnostic and therapeutic decisions during this office visit, the data
complexity was moderate, and the risk of morbidity and mortality was high. The
rule is that the lower of the highest two levels determines the overall level of
medical decision making, which, in this case, would be moderate. Determining
the correct code for this case is challenging and likely would be CPT code
99213 based on bullets and level of medical decision making.

99213 Office or other outpatient visit for the evaluation and management of an
established patient, which requires at least two of these three components:
h An expanded problem-focused history;
h An expanded problem-focused examination;
h Medical decision making of low complexity.
CPT B 2014 American Medical Association. All rights reserved. CPT is a registered trademark of
the American Medical Association.

Given the majority of this visit was spent providing counseling to the patient,
a 99213 code could be justified based on this time (15-minute visit with 10 minutes
spent in counseling and coordination of care). Although the registered nurse
spent a considerable amount of time with the family, time spent by any nurs-
ing services (registered nurse or licensed practical nurse) or office staff cannot
be used by the provider in selecting a level of service for office-based E/M codes.

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 Coding for Dementia

Case 1 Continued
The patient continued to be followed with biannual appointments.
During the last few years, her memory and language function deteriorated,
and she stopped working. Although she was safe at home and
participated in family events, she could no longer cook or plan family
events. She had a myocardial infarction following surgery for noninvasive
bladder cancer. The patient reiterated to her husband over the years
that she did not want any ‘‘heroics’’ or to be ‘‘hooked up to tubes’’ if she
became ill. The husband felt that the physician who cared for her and
made her diagnosis of Alzheimer disease was best able to talk to his wife,
to direct them to the right choices, and possibly even fill out the forms.
At her 10th follow-up visit, the patient was accompanied by her husband
and daughter. The total duration of the visit was 50 minutes, and during
that time the physician assessed the patient to be competent to make
these decisions, and with no objection from family members, paperwork
for end-of-life planning, including health care power of attorney and
advance directives, were completed and signed. No physical examination
was performed outside the questions asked to assess competency.

DISCUSSION
In this case the ICD-10-CM code choices would remain the same:

G30.1 Alzheimer disease with late onset

F02.80 Dementia in other diseases classified elsewhere without behavioral
disturbance

The proper CPT code(s) would be 99497 and 99499.

99497 Advance care planning including the explanation and discussion of advance
directives such as standard forms (with completion of such forms, when
performed), by the physician or other qualified health care professional; first
30 minutes, face-to-face with the patient, family member(s), and/or surrogate.
99499 Unlisted evaluation and management service.
CPT B 2014 American Medical Association. All rights reserved. CPT is a registered trademark of
the American Medical Association.

The 99499 code is an add-on code to the 99497 when another 30 minutes of
time is spent after the initial 30 minutes spent for the 99497 code. Because
more than one-half of the 30 minutes was spent (in this case, 20 minutes past
the 30 minutes required for the initial code), the 99499 code is allowed.

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 Case 2
A 72-year-old man presented because of his family’s concern over increasing
episodes of confusion. The patient’s wife reported that the first episode had
occurred at least 3 years ago when she found his cell phone placed in the
recharging dock of the home phone, while he had instead taken that home
phone handset with him on a drive to the hardware store. Since that time there
had been dozens of similar occurrences, but over the last 3 months, he had
episodes of leaving his home at night and being found by neighbors wandering
up and down the street. He had become uncharacteristically argumentative
and seemingly had trouble recognizing familiar faces. His past medical history
was notable for obesity and gout, which had been treated with allopurinol.
His family history was unremarkable. The remainder of a 10-organ review of
systems was negative. His heart rate, blood pressure, and temperature were
normal. The general physical examination, including cardiovascular elements,
was normal. His speech was well articulated and did not show any paraphasic
errors. He was able to name objects, but had delayed naming when shown
pictures of his eight grandchildren. His memory was three out of three at
5 minutes. His general fund of information was normal. The Mini-Mental State
Examination (MMSE) score was 26 out of 30. The thyroid-stimulating hormone
(TSH), vitamin B12 level, hemoglobin A1c, and cholesterol were normal. A brain
MRI showed only mild volume loss. In addition to all the testing performed
in Case 1, the neurologist asked that the patient be evaluated by a geriatric
psychologist for the purpose of investigating the possibility of depression.
That evaluation was performed, and the patient had no evidence of a mood
disturbance or other psychiatric illness. The neurologist, who had expertise
in neuropsychological testing, asked the patient to come to the office for the
purpose of performing additional cognitive testing. At that visit, 1 hour of
standardized cognitive, memory, and language testing was performed, and
the report preparation time was 1 additional hour. This testing determined
that the patient likely was experiencing the early signs of dementia.

DISCUSSION
The Mini-Mental State Examination (MMSE) is considered part of a standard
neurologic examination and cannot be used to justify the CPT 96118 code
(neuropsychological testing). When a physician or psychologist performs face-
to-face neuropsychological testing that goes beyond the informal testing (such
as the MMSE) done as part of the neurologic examination, the code 96118 can
be used. This is a code that is time based, and one unit of 96118 can be billed
for test administration, review of computerized testing, and report preparation
by the physician or psychologist. This can also be used to interpret and report
on testing done by technicians or by computer. In this case, two units of
service were performed and, therefore, 96118 ! 2 can be billed.

96118 Neuropsychological testing (eg, Halstead-Reitan Neuropsychological Battery,

Wechsler Memory Scales, and Wisconsin Card Sorting Test), per hour of the
psychologist’s or physician’s time, both face-to-face time administering tests to
the patient and time interpreting these test results and preparing the report.
CPT B 2014 American Medical Association. All rights reserved. CPT is a registered trademark of
the American Medical Association.

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 Coding for Dementia

Case 3
An 89-year-old woman with a history of mild congestive heart failure
and anxiety, treated with digoxin and clonazepam, presented with a
several-week history of worsening anxiety as well as frequent awakenings
at night with behavioral disturbances. She lived with her great nephew
and, until recently, was able to prepare meals, clean the house, and care
for all of her activities of daily living. Her family reported that she was now
commonly confused about dates, time, and facts about current events.
Past history, social history, medications, family history, and a 10-system
review of systems was performed. A full physical examination was
performed and documented. On examination, the patient recalled two
out of three words at 5 minutes. Her speech content was generally
normal, although there were times when she was mumbling words and
phrases that were not understandable. She did not know the day of the
week, day of the month, her wedding anniversary, or the name of her
deceased husband. The general physical examination was normal aside
from a kyphotic posture that has been present for at least 20 years.
She had mild shuffling gait, also long standing, but no tremor or
bradykinesia. Deep tendon reflexes were increased in the arms and at
the knees and absent at the ankles. Toes were extensor on plantar
stimulation. Sensation to vibration was reduced at the toes and ankles.
At the conclusion of this visit, the physician thought her illness was
consistent with a dementia but wanted to order tests to make sure there
were no treatable conditions or conditions that would require a decision
about how to move forward with her medical and social care, such as a
malignant brain tumor. The duration of this office visit was 35 minutes.

DISCUSSION
Because the etiology of the dementia is not known, the ICD-10-CM code F03.91
is the most appropriate to use for this patient.

F03.91 Unspecified dementia with behavioral disturbance

The other neurologic findings, including the shuffling gait, hyperreflexia

in the arms, and absent reflexes in the legs, represent findings that could be
used to justify additional medical testing, so the other code choice that
would be reasonable could include ICD-10-CM code R26.89.

R26.89 Other abnormalities of gait and mobility

The best choice for the E/M code would be established CPT care code 99214,
as the history and examination are high complexity and the medical decision
making is moderately high complexity. The physician could bill the same code if
35 minutes were spent with the patient and more than 50% was expended in
counseling and coordination of care.

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 99214 Office or other outpatient visit for the evaluation and management of
an established patient, which requires at least two of these three
key components:
h A detailed history;
h A detailed examination;
h Medical decision making of moderate complexity.
CPT B 2014 American Medical Association. All rights reserved. CPT is a registered trademark of
the American Medical Association.

Case 3 Continued
A brain MRI showed moderate cerebral atrophy and microvascular disease
changes. The thyroid-stimulating hormone (TSH) and free T4 were normal.
The complete blood cell count showed a hemoglobin of 8.9 g/dL (normal
range is 12 mg/dL to 15 mg/dL), and the mean corpuscular volume was
elevated at 110 fL (normal range 80 fL to 100 fL). The vitamin B12 level
was low at 176 pg/mL (normal range 200 pg/mL to 900 pg/mL), and the
methylmalonic acid level was elevated at 2.1 mmol/L (normal range
0.08 mmol/L to 0.56 mmol/L). The physician reviewed these laboratory tests
and decided the proper management would be institution of vitamin B12
injections. The physician saw the patient the next day. An examination was
not performed. The physician told the patient and her family the ‘‘good
news’’ that she had a potentially treatable dementia and relayed that the
treatment may or may not be effective considering her age and how long
the vitamin B12 deficiency may have been present. The physician instructed
the patient to come in monthly for a vitamin B12 shot, after a loading dose of
weekly vitamin B12 for several weeks. The total face-to-face time with the
patient was 20 minutes. The patient remained in the examination room
after the doctor left and the nurse came in moments later to give the
patient her first IM injection of cyanocobalamin and spent 15 minutes with
the family going over information on fact sheets about pernicious anemia.

DISCUSSION
The correct ICD-10-CM code choices at this visit would be very different than
for the first visit.

E53.8 Deficiency of other specified B group vitamins

G32.0 Subacute combined degeneration of spinal cord in diseases classified elsewhere

The E/M CPT coding for this visit would be 99213 as the total face time was
20 minutes, all of which was spent in counseling and coordination of care.
There is no means to code for the nurse’s time as it is provided on the same
day as the visit to the primary care doctor.

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 Coding for Dementia

Case 3 Continued
The patient returned 2 months later for a monthly vitamin B12 injection,
scheduled as a nurse-only visit. The family told the nurse the episodes of
confusion were improved after the loading doses of vitamin B12. Before the
vitamin B12 was administered at the visit, the nurse stepped out of the
examination room and pulled the doctor aside to give him the good news.
The doctor replied, ‘‘Great, let’s keep giving her the vitamin B12.’’ The nurse
went back into the room and gave the patient another vitamin B12 injection
and scheduled the patient to return in a month for another injection.

DISCUSSION
The best ICD-10-CM code at this point would again be the following:

E53.8 Deficiency of other specified B group vitamins

G32.0 Subacute combined degeneration of spinal cord in diseases classified
elsewhere

The only E/M CPT code that could be used in this case would be 99211,
which is reserved for a nursing visit and would be used for this visit because the
doctor did not see the patient on this day.

CONCLUSION
Caring for patients with cognitive problems is heavily weighted toward E/M ser-
vices and is additionally challenging because the illness itself requires extra time to
provide these services. The use of time-based billing is often the best way for the
provider to properly bill for their services and, therefore, the provider should be
well-versed on these requirements. The proper ICD-10-CM code may change
between visits, especially as the etiology of the illness is identified. The underlying
cause of the dementia (or other associated conditions), once identified, should
be listed first, with the sequelae, including dementia, following.

REFERENCES
1. American Medical Association. Current procedural terminology (CPT) 2015. Chicago: American
Medical Association Press, 2015.
2. Centers for Medicare & Medicaid Services, National Center for Health Statistics. International
classification of diseases, tenth revision, clinical modification (ICD-10-CM). www.cdc.gov/nchs/icd/
icd10cm.htm. Updated October 29, 2015. Accessed February 6, 2016.
3. Centers for Medicare & Medicaid Services, National Center for Health Statistics. International
classification of diseases, ninth revision, clinical modification (ICD-9-CM). www.cdc.gov/nchs/icd/
icd9cm.htm. Updated June 18, 2013. Accessed February 6, 2016.
4. Department of Health and Human Services, Centers for Medicare and Medicaid Services.
Evaluation and management services guide: 1997 documentation guidelines for evaluation and
management services. www.cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/
MLNProducts/downloads/referenceII.pdf. Accessed February 5, 2016.

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Participants may earn up to 12 AMA PRA Category
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 Self-Assessment and CME

Postreading
Self-Assessment and
CME Test
Douglas J. Gelb, MD, PhD, FAAN; Joseph E. Safdieh, MD, FAAN

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) tomeet 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.
A faxable scorecard is available only upon request to subscribers who do
not have computer access or to nonsubscribers who have purchased
single back issues (send an email to [email protected]).
Participants who complete the Postreading Self-Assessment and CME
Test and issue evaluation online at www.aan.com/continuum/cme may earn
up to 12 AMA PRA Category 1 Creditsi toward SA-CME. Participants have
up to 3 years from the date of publication to earn CME credits. No SA-CME
will be awarded for this issue after April 30, 2019.

b 1. Which of the following cognitive deficits is most typical of idiopathic

normal pressure hydrocephalus?
A. anomia
B . auditory hallucinations
C. delirium
D. slow processing
E . visual agnosia
b 2. A 61-year-old man with a clinical syndrome of behavioral variant of
frontotemporal dementia dies in a car accident and undergoes autopsy.
What is the most likely pathologic finding?
A. amyloid plaques
B . FUS inclusions
C. Lewy bodies
D. microglial proliferation
E . tau inclusions

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 Postreading Test

b 3. Which of the following would be standard initial treatment for a 22-year-old

woman who has acute encephalopathy and an abnormal titer of N-methyl-D-
aspartate receptor (NMDA) antibody, but no evidence of ovarian teratoma?
A. azathioprine
B . high-dose IV corticosteroids
C. mycophenolate mofetil
D. rituximab
E . total abdominal hysterectomy and bilateral oophorectomy

b 4. The presence of which of the following features would be most helpful in

distinguishing between dementia due to mitochondrial disease and
Jakob-Creutzfeldt disease?
A. cardiomyopathy
B . extrapyramidal symptoms
C. MRI findings
D. presence of a family history
E . visual symptoms
b 5. A 66-year-old man presents with 3 years of personality changes, anxiety,
and cognitive impairment. He also reports frequently seeing ‘‘small colorful
animals’’ on his kitchen table. His wife reports that there are days when he is
extremely anxious and confused and other days where he is much improved
and closer to his prior baseline. She has also been sleeping in a separate bed
from him for the past 10 years because he kicks out in his sleep in a ‘‘violent
way.’’ Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . dementia with Lewy bodies
C. depression with psychotic features
D. frontotemporal dementia
E . Huntington disease

b 6. Which of the following components of the Mini-Mental State Examination

(MMSE) is most likely be abnormal early in the disease course of
Alzheimer disease?
A. construction of intersecting pentagons
B . delayed recall
C. following three-step commands
D. repetition
E . serial 7’s
b 7. A 76-year-old woman suddenly lost control of the left side of her body
while watching television, and a head CT scan shows a right parietal
hemorrhage. Which of the following MRI sequences would be most
useful when looking for evidence of prior hemorrhage to support
the diagnosis of cerebral amyloid angiopathy?
A. diffusion-weighted imaging (DWI)
B . fluid-attenuated inversion recovery (FLAIR)
C. susceptibility-weighted imaging (SWI)
D. T1-weighted imaging with and without contrast
E . T2-weighted imaging

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b 8. Which of the following deficits would be most consistent with the
diagnosis of mild cognitive impairment (MCI)?
A. difficulty dressing
B . frequently getting lost driving to work
C. inability to manage personal finances
D. inability to operate home appliances
E . regularly forgetting names of casual acquaintances
b 9. Which of the following diagnostic test abnormalities is more common in
dementia with Lewy bodies than it is in Alzheimer disease?
A. hippocampal atrophy on MRI scan
B . increased levels of tau protein in spinal fluid
C. lateralized periodic discharges on EEG
D. reduced dopamine transporter levels on single-photon emission computed
tomography (SPECT) scan
E . temporoparietal hypometabolism on fluorodeoxyglucose positron
emission tomography (FDG-PET) scan
b 10. A 28-year-old woman stopped going to work because of recurrent
headaches and nausea. After several unproductive emergency department
visits over the course of 2 weeks, she retreated to her apartment and stopped
interacting via telephone or social media. Her roommate offered to make
some meals for her, but she refused to eat anything except ramen noodles.
After another week, she would not even eat that and screamed at her
roommate, accusing him of trying to poison her. She became increasingly
agitated over the next 2 days, so her roommate called for an ambulance. She
was admitted to the inpatient psychiatric service, and over the next 2 days
became progressively less responsive. This clinical course is most consistent
with the syndrome associated with which of the following antibodies?
A. antineuronal nuclear antibody-1 (ANNA-1, anti-Hu)
B . ganglionic acetylcholine receptor antibody
C. glutamic acid decarboxylase 65 (GAD65) antibody
D. N-methyl-D-aspartate (NMDA) receptor antibody
E . voltage-gated potassium channel (VGKC) complex antibody
b 11. A 35-year-old woman presents for evaluation of cognitive impairment.
She was diagnosed with depression with psychotic features 2 years ago.
Antidepressants have helped her mood somewhat, but she has continued
to demonstrate progressive behavioral changes. Over the course of the
past year, she has developed worsening cognitive function as well as gait
impairment. Past medical history includes cholecystitis. Examination
demonstrates disinhibition, frontal release signs, impaired recall, spasticity
in the extremities, and hyperreflexia. Brain MRI reveals frontal-predominant
confluent symmetrical T2 hyperintensity in the periventricular white matter.
Which of the following is the most likely diagnosis?
A. adrenoleukodystrophy
B . Alexander disease
C. Krabbe disease
D. metachromatic leukodystrophy
E . multiple sclerosis

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 Postreading Test

b 12. Which of the following cognitive domains is most likely to be impaired in

early Alzheimer disease?
A. distant memories
B . episodic memory
C. procedural memory
D. semantic memory
E . working memory

b 13. A 32-year-old man presents for evaluation of dysarthria and dysphagia.

His symptoms began 1 year ago and have been progressively worsening. Over
the past 6 months he has also experienced gait disturbance as well as sleep
disturbance. His father had a similar illness and died in his forties. Neurologic
examination demonstrates spastic dysarthria, exaggerated jaw jerk, spastic
paraparesis with hyperactive deep tendon reflexes, and palatal myoclonus.
Brain MRI demonstrates medullary atrophy as well as bilateral T2 changes
in the dentate nuclei and middle cerebellar peduncles. Which of the following
is the most likely diagnosis?
A. adrenoleukodystrophy
B . Alexander disease
C. cerebrotendinous xanthomatosis
D. Krabbe disease
E . metachromatic leukodystrophy

b 14. A 77-year-old man presents for evaluation of memory loss and behavioral
changes. His symptoms started 2 years ago and have been progressively
worsening. He frequently loses his wallet and keys, accuses others of stealing
misplaced items, repeats questions often in a conversation and is no longer
able to manage the household finances. On examination, his Mini-Mental
State Examination (MMSE) score is 24 out of 30 with points lost for
orientation and recall (0 out of 3). MRI of the brain demonstrates mild diffuse
atrophy. Vitamin B12 level and thyroid-stimulating hormone (TSH) are
normal. Which of the following findings would most likely be seen on a
fluorodeoxyglucose positron emission tomography (FDG-PET) scan of the
brain in this patient?
A. frontal hypometabolism
B . global hypometabolism
C. normal study
D. occipital hypometabolism
E . temporoparietal hypometabolism
b 15. A patient with idiopathic normal pressure hydrocephalus is most likely to
have which of the following findings on neurologic examination?
A. anisocoria
B . areflexia
C. cogwheel rigidity at the wrists
D. gait initiation failure
E . unilateral Babinski sign

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b 16. Which of the following cognitive functions is more often abnormal in the
early stages of Alzheimer disease than in the early stages of dementia with
Lewy bodies?
A. attention
B . executive function
C. language comprehension
D. recent memory
E . visuospatial skill

b 17. Which of the following most accurately summarizes the current situation
with respect to the use of cholinesterase inhibitors to delay or prevent the
progression from mild cognitive impairment (MCI) to Alzheimer disease or
other forms of dementia?
A. not proven to be effective in delaying or preventing development
of dementia
B . proven to be effective in delaying development of dementia, but not
preventing it, and approved by the US Food and Drug Administration
(FDA) for this indication
C. proven to be effective in delaying development of dementia, but not
preventing it, but not approved by the FDA for this indication
D. proven to reduce the risk of developing dementia, and approved by the
FDA for this indication
E . proven to reduce the risk of developing dementia, but not approved by
the FDA for this indication

b 18. A beneficial effect on cognition in patients with dementia with Lewy

bodies has been demonstrated most convincingly for which of the following
classes of medications?
A. anticholinergics
B . cholinesterase inhibitors
C. D2 receptor agonists
D. D2 receptor antagonists
E . N-methyl-D-aspartate (NMDA) receptor agonists

b 19. A 29-year-old man presents for evaluation of rapidly progressive

cognitive decline. He was well until 9 months ago when he developed
significant gait instability with associated spasticity in the lower extremities
as well as significant difficulty with visual processing. Over the past few
months he has developed frequent seizures and cognitive dysfunction.
Neurologic examination demonstrates disorientation to time and place,
poor recall, inability to name objects, poor construction, and spasticity in the
limbs with hyperreflexia and significant gait impairment. Brain MRI reveals
confluent symmetrical T2 hyperintensity in the periventricular white matter,
predominantly in the parieto-occipital white matter. Which of the following
clinical features is also likely to be present in this patient?
A. adrenal insufficiency
B . cataracts
C. cholecystitis
D. liver failure
E . migraine with atypical aura

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 Postreading Test

b 20. A 56-year-old man presents for evaluation of behavioral changes. His

wife reports that the patient has become a ‘‘different person’’ over the past
2 years. He used to be a very calm and pleasant person, but over that period
of time he has become ‘‘nasty.’’ He curses in public, spits on the bus, and
makes unwanted sexual advances toward women. He has also been less
able to complete tasks at work and was recently given a formal warning from
his employer that he is at risk of losing his job if he does not change his
behavior and meet deadlines. During the neurologic examination he calls
the neurologist ‘‘honey’’ and ‘‘gorgeous,’’ and he asks if he can use the reflex
hammer to ‘‘hit the doctor back.’’ The patient’s Mini-Mental State Examination
(MMSE) score is 30 out of 30. MRI of the brain demonstrates right frontal lobe
atrophy. Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . behavioral variant of frontotemporal dementia
C. corticobasal degeneration
D. Lewy body disease
E . primary progressive aphasia

b 21. A 72-year-old man presents for evaluation of recent-onset cognitive decline.

His children note that his symptoms started after his wife died unexpectedly
3 months ago. He has been unable to manage his finances and has left the stove
on multiple times over the past few months, causing his neighbors to call the
fire department after smelling gas. His children do not think he has worsened
over the past 3 months. He reports, ‘‘My wife took care of all that stuff. I miss
her.’’ On examination, the patient’s Mini-Mental State Examination (MMSE)
score is 22 out of 30, with points lost for orientation and recall (0 out of 3).
His neurologic examination is otherwise normal. Brain MRI demonstrates
moderate global atrophy as well as hippocampal atrophy and enlargement of
the temporal horns of the lateral ventricles. Which of the following is the most
likely diagnosis?
A. Alzheimer disease
B . frontotemporal dementia
C. idiopathic normal pressure hydrocephalus
D. Jakob-Creutzfeldt disease
E . limbic encephalitis

b 22. Which of the following clinical features would provide the most compelling
reason to search for an alternative explanation for a patient’s symptoms
other than idiopathic normal pressure hydrocephalus?
A. normal bladder control
B. normal bowel control
C. normal cognition
D. normal gait
E. patient awareness of symptoms

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b 23. A 57-year-old right-handed woman presents for evaluation of progressive language
disturbances over the past 2 years. She works as a customer service representative
and initially had difficulty understanding what customers were discussing with
her on the phone. She would often ask what words meant, such as ‘‘what is a
computer’’ and would have difficulty thinking of words, sometimes describing
what she was trying to say but not saying the actual word. The symptoms progressed
and she eventually lost her job. She also developed difficulty at home completing
tasks and would look at a magazine but ask ‘‘what am I reading?’’ Examination
demonstrates a Mini-Mental State Examination (MMSE) score of 18 out of 30 with
significant difficulty understanding what is asked. She called a watch ‘‘that thing that
tells time’’ and a pen ‘‘that thing that makes notes.’’ MRI of the brain demonstrates
left temporal atrophy. Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . behavioral variant of frontotemporal dementia
C. nonfluent agrammatic variant primary progressive aphasia
D. progressive supranuclear palsy
E . semantic variant primary progressive aphasia

b 24. A 17-year-old girl presents for evaluation of cognitive decline and

behavioral changes. Her symptoms developed 2 years ago and have been
worsening since then. Over the past few months she has also developed
balance problems and difficulty walking. She has a history of a cataract that
was removed at age 13. Examination reveals soft tissue masses on the Achilles
tendons bilaterally, behavioral disinhibition, 2 out of 3 recall, bilateral limb
dysmetria, spasticity in the lower extremities, and impaired tandem gait.
Brain MRI demonstrates periventricular white matter changes as well as
T2 signal changes in the dentate nucleus and globus pallidus bilaterally.
Which of the following is the most likely diagnosis?
A. adrenoleukodystrophy
B . Alexander disease
C. cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
D. cerebrotendinous xanthomatosis
E . metachromatic leukodystrophy

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 Postreading Test

b 25. A 78-year-old woman with a 4-year history of progressive decline in

cognitive function has a profile on neuropsychological testing notable for
prominent deficits in executive function and processing speed and
mild-to-moderate deficits in episodic memory. She has a history of diabetes,
hypertension, hyperlipidemia, coronary artery disease, and atrial fibrillation,
and she takes insulin, lisinopril, hydrochlorothiazide, atorvastatin, and
warfarin. There is no known family history of dementia. In addition to her
abnormal mental status, her neurologic examination is notable only for
diffuse hyperreflexia, symmetric in the lower extremities but greater in the
left upper extremity than the right. MRI is notable for multiple areas of
increased T2 and fluid-attenuated inversion recovery (FLAIR) signal scattered
throughout the subcortical white matter of both cerebral hemispheres,
consistent with chronic small vessel ischemic changes. Which of the following
diagnoses is most likely?
A. cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
B . frontotemporal dementia
C. multiple sclerosis
D. nonstroke vascular cognitive impairment
E . poststroke vascular cognitive impairment

b 26. In a patient with mild cognitive impairment (MCI), which of the following
test results is associated with an increased risk of developing Alzheimer
disease dementia?
A. high levels of amyloid-$42 (A"42) in CSF
B . homozygosity for apolipoprotein (APOE) (2
C. low levels of tau protein in CSF
D. medial temporal lobe atrophy on MRI
E . occipital lobe hypometabolism on fluorodeoxyglucose positron emission
tomography (FDG-PET)
b 27. A 57-year-old man presents for evaluation of rapidly progressive dementia.
He had been well until 12 weeks ago, when he started developing
progressively worsening confusion and memory loss as well as headaches.
He has been unable to work or even leave the house alone over the past
month because he has been getting lost frequently. On examination, he is
disoriented to time and place, cannot perform serial 7’s, has 0 out of 3 recall
after 3 minutes, and has an unsteady gait. MRI of the brain demonstrates
confluent bilateral white matter hyperintensities with enlarged blood vessels
noted over the hemispheric surface. What is the most likely diagnosis?
A. cerebral amyloid angiopathy
B. cerebral vasculitis
C. cerebroretinal microangiopathy with calcifications and cysts
D. dural arteriovenous fistula (DAVF)
E. venous sinus thrombosis

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b 28. In a 50-year-old woman with limbic encephalitis and positive serum titers
for antineuronal nuclear antibody-1 (ANNA-1 or anti-Hu), which of the
following primary tumors is most likely?
A. breast adenocarcinoma
B. Hodgkin lymphoma
C. ovarian teratoma
D. renal cell carcinoma
E. small cell lung carcinoma

b 29. Dementia with Lewy bodies is differentiated from Parkinson disease

dementia on the basis of which of the following clinical features?
A. age of onset
B. ideas of reference
C. presence of hallucinations
D. severity of dementia
E. timing of dementia onset relative to the onset of parkinsonism

b 30. Immunotherapy is most likely to be effective in patients who have

encephalopathy associated with which of the following antibodies?
A. antineuronal nuclear antibody-1 (ANNA-1, anti-Hu)
B. antineuronal nuclear antibody-2 (ANNA-2, anti-Ri)
C. glutamic acid decarboxylase 65 (GAD65) antibody
D. Purkinje cell cytoplasmic antibody type 2 (PCA-2)
E. voltage-gated potassium channel (VGKC) complex antibody
b 31. A 67-year-old man presents for evaluation of personality and behavioral
changes experienced over the past year. His spouse notes that he has
become very disinhibited over that period of time, often ‘‘saying whatever
comes to his mind, like he has no filter.’’ At baseline, he was known to
be a very polite, soft-spoken man. He is still driving to work every day
and paying his bills, but a number of his employees have quit recently due
to his inappropriate behavior. Which of the following mental status
assessments is most likely to correlate with this symptom complex?
A. construction of intersecting pentagons
B. reading comprehension
C. serial 7’s
D. short-term recall
E. Stroop test
b 32. Which of the following treatments has the best benefit-to-risk profile for
the treatment of idiopathic normal pressure hydrocephalus?
A. acetazolamide
B. endoscopic third ventriculostomy
C. optic nerve sheath fenestration
D. topiramate
E. ventriculoperitoneal shunt

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 Postreading Test

b 33. Which of the following conditions is most likely in a 34-year-old woman

with headaches, rapid cognitive decline, episodes of abrupt change in vision,
and sudden hearing loss?
A. dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis
B. Jakob-Creutzfeldt disease
C. N-methyl-D-aspartate (NMDA) antibody encephalitis
D. steroid-responsive encephalopathy associated with autoimmune thyroiditis
E. Susac syndrome

b 34. Which of the following patterns of CSF amyloid-$ (A$) and tau is most
consistent with the diagnosis of Alzheimer disease?
A. elevated A$ and tau
B. elevated A$42, reduced total tau (t-tau) and phosphorylated tau (p-tau)
C. elevated t-tau and p-tau, reduced A$42
D. normal A$42, t-tau, and p-tau
E. reduced A$42, t-tau, and p-tau

b 35. In a patient who has had a ventriculoperitoneal shunt for idiopathic

normal pressure hydrocephalus, which of the following is the most common
symptom of overdrainage?
A. cognitive decline
B. headache that is worse when lying down
C. headache that is worse when standing
D. urinary urgency that is worse when lying down
E. urinary urgency that is worse when standing

b 36. Which of the following psychiatric conditions is associated with an

increased risk of conversion from mild cognitive impairment to dementia?
A. anxiety
B. conversion disorder
C. depression
D. eating disorder
E. mania
b 37. An abnormality of which of the following mental status tests would
provide the strongest evidence of impaired executive function?
A. confrontation naming
B. performance on alternating pattern tasks
C. recall of a drawn figure
D. sentence comprehension
E. writing single words to dictation

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b 38. A 65-year-old man presents for evaluation of memory loss. His wife has
noticed that over the past year he has often been repeating questions in
conversation. She also has taken over the grocery shopping because he
would often purchase the same items multiple times in a day. The patient
has no medical history and takes no medications. There is no family history
of neurologic disease. On examination, his Mini-Mental State Examination
(MMSE) score is 23 out of 30, with points lost for orientation and recall
(0 out of 3). Vitamin B12 level and thyroid-stimulating hormone (TSH) are
normal. What is the most appropriate next step in diagnosis?
A. amyloid positron emission tomography (PET) scan
B. APOE genotyping
C. CSF analysis for amyloid and tau
D. fluorodeoxyglucose positron emission tomography (FDG-PET) scan of
the brain
E . MRI of the brain
b 39. A 61-year-old right-handed woman presents with a 1-year history of
progressive language difficulty. She notes that it is ‘‘hard to get it out.’’
Her family reports that she has been experiencing difficulty expressing her
thoughts and that her speech has become very fragmentary. Her husband
does think she understands what he is saying. On examination she can easily
name a pen and watch but cannot name a cactus or hammock. She called
a hammock ‘‘theIumIyou knowI.between treesIrest.’’ She can follow
three-step commands. MRI demonstrates no mass lesions but bifrontal
atrophy is noted. What is the most likely diagnosis?
A. Alzheimer disease
B. behavioral variant of frontotemporal dementia
C. nonfluent agrammatic variant primary progressive aphasia
D. progressive supranuclear palsy
E . semantic variant primary progressive aphasia

b 40. A 34-year-old woman presents for evaluation of a rapidly progressive

dementia. She has been experiencing progressively deteriorating cognitive
function over the past 11 months and is no longer able to care for herself.
She has also been experiencing diarrhea, bloating, joint aches, weight loss,
and night sweats. On examination, she is disoriented to time and place,
cannot spell ‘‘world’’ backward, has 0 out of 3 recall after 3 minutes, and
is noted to have abnormal rhythmic facial and eye movements. Brain
MRI is normal. Which of the following infectious agents is most likely to
be causative here?
A. Aspergillus
B. Borrelia burgdorferi
C. herpes simplex virus
D. human immunodeficiency virus (HIV)
E. Tropheryma whippelii

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 Self-Assessment and CME

Postreading
Self-Assessment and
CME Test—Preferred
Responses
Douglas J. Gelb, MD, PhD, FAAN; Joseph E. Safdieh, MD, FAAN

Following are the preferred responses to the questions in the Postreading

Self-Assessment and CME Test in this Continuum issue. The questions and
answer options are repeated, and the preferred response is given, followed
by an explanation and a reference with which you may seek more specific
information. You are encouraged to review the responses and explanations
carefully to evaluate your general understanding of the course material.
The comments and references included with each question are intended
to encourage independent study.
Participants who complete the Postreading Self-Assessment and CME Test
and issue evaluation online at www.aan.com/continuum/cme may earn
up to 12 AMA PRA Category 1 CreditsTM toward SA-CME. Participants have
up to 3 years from the date of publication to earn CME credits. No SA-CME will
be awarded for this issue after April 30, 2019.

b 1. Which of the following cognitive deficits is most typical of idiopathic

normal pressure hydrocephalus?
A. anomia
B . auditory hallucinations
C. delirium
D. slow processing
E . visual agnosia

The preferred response is D (slow processing). The most prominent

cognitive deficits in patients with idiopathic normal pressure hydrocephalus
are usually slow processing and difficulty with problem solving and retrieval
of memories, with relatively intact recognition memory. Anomia, agnosia,
and hallucinations are uncommon, and patients only develop delirium if
another disorder is superimposed. For more information, refer to page 582
of the Continuum article ‘‘Diagnosis and Treatment of Idiopathic Normal
Pressure Hydrocephalus.’’

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b 2. A 61-year-old man with a clinical syndrome of behavioral variant of
frontotemporal dementia dies in a car accident and undergoes autopsy. What
is the most likely pathologic finding?
A. amyloid plaques
B. FUS inclusions
C. Lewy bodies
D. microglial proliferation
E . tau inclusions

The preferred response is E (tau inclusions). On neuropathologic

examination, the most common abnormality in behavioral variant
of frontotemporal dementia is abnormal accumulations of either tau or
TDP-43. FUS accumulations are less common but also occur. Amyloid
plaques are more typical in Alzheimer disease but can occur with normal
aging. Lewy bodies are seen in Parkinson disease and the Lewy body dementias.
Microglial proliferation is a nonspecific finding in various central nervous system
infectious and inflammatory conditions. For more information, refer to
page 479 of the Continuum article ‘‘Frontotemporal Dementias.’’

b 3. Which of the following would be standard initial treatment for a

22-year-old woman who has acute encephalopathy and an abnormal titer
of N-methyl-D-aspartate receptor (NMDA) antibody, but no evidence of
ovarian teratoma?
A. azathioprine
B . high-dose IV corticosteroids
C. mycophenolate mofetil
D. rituximab
E . total abdominal hysterectomy and bilateral oophorectomy

The preferred response is B (high-dose IV corticosteroids). The standard

treatment protocol for autoimmune encephalopathy has an acute
component and a chronic component. High-dose IV corticosteroids are
usually the first step in acute therapy. Azathioprine, mycophenolate mofetil,
and rituximab may eventually be used in the chronic therapy regimen,
but they do not act as rapidly as steroids. Although ovarian teratomas should
be removed if present, and they may be difficult to detect, a total
abdominal hysterectomy and bilateral oophorectomy would be an overly
aggressive approach in a 22-year-old with no known teratoma. For more
information, refer to pages 552 and 554 of the Continuum article
‘‘Autoimmune Encephalopathies and Dementias.’’

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 Postreading Test—Preferred Responses

b 4. The presence of which of the following features would be most helpful in

distinguishing between dementia due to mitochondrial disease and
Jakob-Creutzfeldt disease?
A. cardiomyopathy
B . extrapyramidal symptoms
C. MRI findings
D. presence of a family history
E . visual symptoms

The preferred response is A (cardiomyopathy). Mitochondrial disease can

manifest with an acute dementia, as can Jakob-Creutzfeldt disease. Both
conditions can be associated with visual symptoms, extrapyramidal
symptoms, and a positive family history. Although in most cases, MRI should
be able to differentiate Jakob-Creutzfeldt disease from mitochondrial
myopathy, encephalopathy, lactic acidosis, and strokelike episodes syndrome
(MELAS), sometimes, although rarely, MRI findings of MELAS can have
overlapping features with Jakob-Creutzfeldt disease. Cardiomyopathy is
a well described consequence of mitochondrial disease but is not well
described in Jakob-Creutzfeldt disease. For more information, refer to
page 533 of the Continuum article ‘‘Rapidly Progressive Dementia.’’

b 5. A 66-year-old man presents with 3 years of personality changes, anxiety,

and cognitive impairment. He also reports frequently seeing ‘‘small colorful
animals’’ on his kitchen table. His wife reports that there are days when he is
extremely anxious and confused and other days where he is much improved
and closer to his prior baseline. She has also been sleeping in a separate bed
from him for the past 10 years because he kicks out in his sleep in a ‘‘violent
way.’’ Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . dementia with Lewy bodies
C. depression with psychotic features
D. frontotemporal dementia
E . Huntington disease

The preferred response is B (dementia with Lewy bodies). The key features
in this case suggestive of this diagnosis include fluctuations of cognition,
visual hallucinations, and the longstanding sleep behavior suggestive of
premorbid rapid eye movement (REM) sleep behavior disorder. All of these
are features of dementia with Lewy bodies. Alzheimer disease is unlikely to
manifest with REM sleep behavior disorder, and visual hallucinations would
be unusual early in the course. There is no reported history of depression in
this patient. Frontotemporal dementia may be associated with personality
changes, but the visual hallucinations and REM sleep behavior disorder are
inconsistent with this diagnosis. No chorea is reported in this patient, and visual
hallucinations are not a typical feature of Huntington disease. For more
information, refer to pages 602Y604 of the Continuum article ‘‘Psychiatric
Aspects of Dementia.’’

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b 6. Which of the following components of the Mini-Mental State
Examination (MMSE) is most likely be abnormal early in the disease
course of Alzheimer disease?
A. construction of intersecting pentagons
B . delayed recall
C. following three-step commands
D. repetition
E . serial 7’s

The preferred response is B (delayed recall). The MMSE is a bedside

cognitive examination that tests a number of modalities including
orientation, registration, delayed recall, serial 7’s (or other attention task),
and various components of language and construction. In early Alzheimer
disease, episodic memory is the predominant impaired domain, which
would most commonly be tested with delayed recall of three words after
a brief time delay. As the disease progresses, patients with Alzheimer disease
will develop dysfunction in multiple cognitive domains, but memory is
generally the earliest to be impacted. For more information, refer to
pages 385Y387 of the Continuum article ‘‘The Mental Status Examination
in Patients With Suspected Dementia.’’

b 7. A 76-year-old woman suddenly lost control of the left side of her body
while watching television, and a head CT scan shows a right parietal
hemorrhage. Which of the following MRI sequences would be most useful
when looking for evidence of prior hemorrhage to support the diagnosis
of cerebral amyloid angiopathy?
A. diffusion-weighted imaging (DWI)
B . fluid-attenuated inversion recovery (FLAIR)
C. susceptibility-weighted imaging (SWI)
D. T1-weighted imaging with and without contrast
E . T2-weighted imaging

The preferred response is C (susceptibility-weighted imaging [SWI]). A

patient with a single lobar, cortical, or cortico-subcortical hemorrhage
and focal or disseminated superficial siderosis satisfies the modified Boston
criteria for probable cerebral amyloid angiopathy. Hemorrhage-sensitive
sequences such as SWI greatly facilitate the demonstration of superficial
siderosis. For more information, refer to Table 6-3 and page 501 of the
Continuum article ‘‘Vascular Cognitive Impairment.’’

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 Postreading Test—Preferred Responses

b 8. Which of the following deficits would be most consistent with the diagnosis
of mild cognitive impairment (MCI)?
A. difficulty dressing
B . frequently getting lost driving to work
C. inability to manage personal finances
D. inability to operate home appliances
E . regularly forgetting names of casual acquaintances

The preferred response is E (regularly forgetting names of casual

acquaintances). The feature that distinguishes MCI from dementia is that
the patient’s daily function is impaired in dementia but spared in MCI.
A person who regularly forgets the names of casual acquaintances can still
function in daily life, whereas people who frequently get lost when driving
to work, have difficulty dressing, or are unable to manage personal
finances or operate home appliances have functional deficits that are too
great to be consistent with MCI. For more information, refer to
pages 409Y410 of the Continuum article ‘‘Mild Cognitive Impairment.’’

b 9. Which of the following diagnostic test abnormalities is more common in

dementia with Lewy bodies than it is in Alzheimer disease?
A. hippocampal atrophy on MRI scan
B. increased levels of tau protein in spinal fluid
C. lateralized periodic discharges on EEG
D. reduced dopamine transporter levels on single-photon emission computed
tomography (SPECT) scan
E. temporoparietal hypometabolism on fluorodeoxyglucose positron emission
tomography (FDG-PET) scan

The preferred response is D (reduced dopamine transporter levels on

single-photon emission computed tomography [SPECT] scan).
Reduced dopamine transporter levels on SPECT scan are typical of both
dementia with Lewy bodies and Parkinson disease, and this test has a 90%
to 100% specificity for differentiating these conditions from Alzheimer
disease. Hippocampal atrophy on MRI scan, increased spinal fluid levels of
tau protein, and temporoparietal hypometabolism on FDG-PET scan are
all typical of Alzheimer disease. Lateralized periodic discharges are not typical
of either Alzheimer disease or dementia with Lewy bodies. For more
information, refer to pages 444 and 446Y447 of the Continuum article
‘‘Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson
Disease Dementia.’’

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b 10. A 28-year-old woman stopped going to work because of recurrent
headaches and nausea. After several unproductive emergency department
visits over the course of 2 weeks, she retreated to her apartment and stopped
interacting via telephone or social media. Her roommate offered to make
some meals for her, but she refused to eat anything except ramen noodles.
After another week, she would not even eat that and screamed at her
roommate, accusing him of trying to poison her. She became increasingly
agitated over the next 2 days, so her roommate called for an ambulance. She
was admitted to the inpatient psychiatric service, and over the next 2 days
became progressively less responsive. This clinical course is most consistent
with the syndrome associated with which of the following antibodies?
A. antineuronal nuclear antibody-1 (ANNA-1, anti-Hu)
B . ganglionic acetylcholine receptor antibody
C. glutamic acid decarboxylase 65 (GAD65) antibody
D. N-methyl-D-aspartate (NMDA) receptor antibody
E . voltage-gated potassium channel (VGKC) complex antibody

The preferred response is D (N-methyl-D-aspartate [NMDA] receptor

antibody). The NMDA receptor antibody is associated with a stereotyped
disorder that often evolves in stages, starting with headache, fever, or nausea,
then prominent psychiatric symptoms and behavioral changes including
social withdrawal and stereotyped behavior, and eventually reduced
responsiveness. For more information, refer to pages 544Y545 of the
Continuum article ‘‘Autoimmune Encephalopathies and Dementias.’’

b 11. A 35-year-old woman presents for evaluation of cognitive impairment.

She was diagnosed with depression with psychotic features 2 years ago.
Antidepressants have helped her mood somewhat, but she has continued
to demonstrate progressive behavioral changes. Over the course of the past
year, she has developed worsening cognitive function as well as gait
impairment. Past medical history includes cholecystitis. Examination
demonstrates disinhibition, frontal release signs, impaired recall, spasticity
in the extremities, and hyperreflexia. Brain MRI reveals frontal-predominant
confluent symmetrical T2 hyperintensity in the periventricular white matter.
Which of the following is the most likely diagnosis?
A. adrenoleukodystrophy
B. Alexander disease
C. Krabbe disease
D. metachromatic leukodystrophy
E . multiple sclerosis

The preferred response is D (metachromatic leukodystrophy). While all

of the choices listed can cause a white matter syndrome, there are some
clues in the case that suggest the diagnosis of metachromatic leukodystrophy,
which is caused by arylsulfatase A deficiency. Adult-onset cases present with
slow-onset psychiatric, behavioral, and cognitive changes and may be
associated with spasticity or peripheral neuropathy. Cholecystitis is

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 Postreading Test—Preferred Responses

an important non-neurologic manifestation of metachromatic leukodystrophy.

MRI findings are typical of most leukodystrophies with bilateral symmetrical
T2 changes in the white matter, usually more frontally located in
metachromatic leukodystrophy. Adrenoleukodystrophy is X-linked and
would not be expected to cause this degree of impairment in females.
Krabbe disease rarely presents in adulthood and when it does, cognitive
and psychiatric symptoms appear later. Alexander disease usually presents
with bulbar dysfunction in adults. For more information, refer to page 566
of the Continuum article ‘‘Adult-Onset Leukoencephalopathies.’’

b 12. Which of the following cognitive domains is most likely to be impaired in

early Alzheimer disease?
A. distant memories
B . episodic memory
C. procedural memory
D. semantic memory
E . working memory

The preferred response is B (episodic memory). In Alzheimer disease,

memory is generally the first cognitive domain that is impacted. Specifically,
the type of memory affected in early Alzheimer disease is episodic memory,
specifically for recent events. Patients often lose objects and repeat
questions in a conversation. Distant memories are relatively spared early in
the disease. Procedural memory for task performance becomes impaired later.
Working memory and semantic memory are actually often preserved until
late in the disease course. For more information, refer to page 420 of the
Continuum article ‘‘Alzheimer Disease.’’

b 13. A 32-year-old man presents for evaluation of dysarthria and dysphagia.

His symptoms began 1 year ago and have been progressively worsening. Over
the past 6 months he has also experienced gait disturbance as well as sleep
disturbance. His father had a similar illness and died in his forties. Neurologic
examination demonstrates spastic dysarthria, exaggerated jaw jerk, spastic
paraparesis with hyperactive deep tendon reflexes, and palatal myoclonus.
Brain MRI demonstrates medullary atrophy as well as bilateral T2 changes in
the dentate nuclei and middle cerebellar peduncles. Which of the following
is the most likely diagnosis?
A. adrenoleukodystrophy
B . Alexander disease
C. cerebrotendinous xanthomatosis
D. Krabbe disease
E . metachromatic leukodystrophy

The preferred response is B (Alexander disease). Alexander disease is an

autosomal dominant condition caused by toxic gain of function mutation in
the GFAP gene. The adult-onset form of the disease differs from other
forms and manifests with progressive bulbar dysfunction as well as other
features including ataxia, spasticity, ocular motility disturbances, palatal
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 myoclonus, and sleep disturbance. MRI features are different than other
leukodystrophies, with adult forms demonstrating medullary atrophy and
changes in the dentate nuclei and middle cerebellar peduncles. The
positive family history in the patient’s father suggests an autosomal
dominant mode of transmission, consistent with Alexander disease.
Adrenoleukodystrophy is X-linked so cannot be transmitted to a male by
his father. Krabbe disease and metachromatic leukodystrophy are
autosomal recessive. Cerebrotendinous xanthomatosis can also cause
palatal myoclonus and dentate changes and also would be expected to
cause white matter changes with psychiatric and cognitive manifestations,
but is autosomal recessive. For more information, refer to page 570 of
the Continuum article ‘‘Adult-Onset Leukoencephalopathies.’’

b 14. A 77-year-old man presents for evaluation of memory loss and behavioral
changes. His symptoms started 2 years ago and have been progressively
worsening. He frequently loses his wallet and keys, accuses others of stealing
misplaced items, repeats questions often in a conversation and is no longer
able to manage the household finances. On examination, his Mini-Mental
State Examination (MMSE) score is 24 out of 30 with points lost for
orientation and recall (0 out of 3). MRI of the brain demonstrates mild diffuse
atrophy. Vitamin B12 level and thyroid-stimulating hormone (TSH) are
normal. Which of the following findings would most likely be seen on a
fluorodeoxyglucose positron emission tomography (FDG-PET) scan of the
brain in this patient?
A. frontal hypometabolism
B . global hypometabolism
C. normal study
D. occipital hypometabolism
E . temporoparietal hypometabolism

The preferred response is E (temporoparietal hypometabolism). This

patient presents with a progressive cognitive disorder with predominant
memory symptoms. He also demonstrates behavioral changes and accuses
others of stealing items he has misplaced. The most likely diagnosis is
Alzheimer disease, based on the age of onset and the predominance of
memory symptoms. FDG-PET in a patient with Alzheimer disease is most
likely to demonstrate hypometabolism in the temporal and parietal lobes.
Occipital hypometabolism is usually associated with Lewy Body disease.
Frontal hypometabolism is usually associated with frontotemporal dementia.
For more information, refer to page 424 of the Continuum article
‘‘Alzheimer Disease.’’

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 Postreading Test—Preferred Responses

b 15. A patient with idiopathic normal pressure hydrocephalus is most likely to

have which of the following findings on neurologic examination?
A. anisocoria
B . areflexia
C. cogwheel rigidity at the wrists
D. gait initiation failure
E . unilateral Babinski sign

The preferred response is D (gait initiation failure). Patients with idiopathic

normal pressure hydrocephalus typically have a gait disorder that can include
a variety of parkinsonian features, such as difficulty initiating gait, shuffling,
tripping, falling, festination, retropulsion, anteropulsion, or difficulty with
turns. Other than problems with gait, balance, and cognition, patients’
examinations are normal. For more information, refer to pages 581Y582 of
the Continuum article ‘‘Diagnosis and Treatment of Idiopathic Normal
Pressure Hydrocephalus.’’

b 16. Which of the following cognitive functions is more often abnormal in

the early stages of Alzheimer disease than in the early stages of dementia with
Lewy bodies?
A. attention
B . executive function
C. language comprehension
D. recent memory
E . visuospatial skill

The preferred response is D (recent memory). The dominant feature

early in the course of Alzheimer disease is usually impaired recent
memory, primarily the encoding of memory. In contrast, memory loss is
more variable in dementia with Lewy bodies, and, when present, the
problem is often one of memory retrieval, rather than encoding. Early in
the course of dementia with Lewy bodies, problems with attention, executive
function, and visuospatial skills usually dominate. Language is typically
spared early in the course of both Alzheimer disease and dementia with
Lewy bodies. For more information, refer to page 440 of the Continuum
article ‘‘Lewy Body Dementias: Dementia With Lewy Bodies and Parkinson
Disease Dementia.’’

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b 17. Which of the following most accurately summarizes the current situation
with respect to the use of cholinesterase inhibitors to delay or prevent
the progression from mild cognitive impairment (MCI) to Alzheimer
disease or other forms of dementia?
A. not proven to be effective in delaying or preventing development
of dementia
B. proven to be effective in delaying development of dementia, but not
preventing it, and approved by the US Food and Drug Administration
(FDA) for this indication
C. proven to be effective in delaying development of dementia, but not
preventing it, but not approved by the FDA for this indication
D. proven to reduce the risk of developing dementia, and approved by the
FDA for this indication
E . proven to reduce the risk of developing dementia, but not approved by the
FDA for this indication

The preferred response is A (not proven to be effective in delaying or

preventing development of dementia). No medications have been proven
to be effective in delaying or preventing progression from MCI to
dementia, and no medications have been approved by the FDA for this
indication. For more information, refer to page 414 of the Continuum
article ‘‘Mild Cognitive Impairment.’’

b 18. A beneficial effect on cognition in patients with dementia with Lewy

bodies has been demonstrated most convincingly for which of the following
classes of medications?
A. anticholinergics
B . cholinesterase inhibitors
C. D2 receptor agonists
D. D2 receptor antagonists
E . N-methyl-D-aspartate (NMDA) receptor agonists

The preferred response is B (cholinesterase inhibitors). Donepezil

(a cholinesterase inhibitor) has been shown to be effective in treating
cognition in a randomized controlled trial of patients with dementia with
Lewy bodies. Anticholinergic medications can cause increased confusion in
patients with dementia. D2 receptor agonists may exacerbate hallucinations
in patients with Parkinson disease or dementia with Lewy bodies, and
D2 receptor antagonists may exacerbate parkinsonism or cause neuroleptic
malignant syndrome. The NMDA receptor antagonist, memantine, has been
shown to have beneficial cognitive effects in Alzheimer disease in large
clinical trials. Although small clinical studies support the use of memantine in
dementia with Lewy bodies, no large clinical trials have been conducted to
confirm its efficacy. For more information, refer to pages 449 and 456Y457
of the Continuum article ‘‘Lewy Body Dementias: Dementia With Lewy
Bodies and Parkinson Disease Dementia.’’

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 Postreading Test—Preferred Responses

b 19. A 29-year-old man presents for evaluation of rapidly progressive

cognitive decline. He was well until 9 months ago when he developed
significant gait instability with associated spasticity in the lower extremities as
well as significant difficulty with visual processing. Over the past few months
he has developed frequent seizures and cognitive dysfunction. Neurologic
examination demonstrates disorientation to time and place, poor recall,
inability to name objects, poor construction, and spasticity in the limbs with
hyperreflexia and significant gait impairment. Brain MRI reveals confluent
symmetrical T2 hyperintensity in the periventricular white matter,
predominantly in the parieto-occipital white matter. Which of the following
clinical features is also likely to be present in this patient?
A. adrenal insufficiency
B . cataracts
C. cholecystitis
D. liver failure
E . migraine with atypical aura

The preferred response is A (adrenal insufficiency). The patient presents

with a rapidly progressive white matter syndrome manifesting with
parieto-occipital involvement on imaging. Clinically, he developed cognitive
impairment with visual processing disturbances as well as seizures and
spastic paraparesis. The most likely diagnosis in this patient is adult-onset
adrenoleukodystrophy, which is X-linked and occurs in males with a
mutation in the ABCD1 gene. Of patients with adrenoleukodystrophy,
90% have associated adrenal insufficiency. Cataracts can be associated with
cerebrotendinous xanthomatosis. Cholecystitis can be associated with
metachromatic leukodystrophy. Liver failure is not associated with any
specific leukodystrophy but can occur in Wilson disease. Migraine with
atypical aura can be associated with cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
For more information, refer to pages 567 and 569 of the Continuum article
‘‘Adult-Onset Leukoencephalopathies.’’

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b 20. A 56-year-old man presents for evaluation of behavioral changes. His wife
reports that the patient has become a ‘‘different person’’ over the past
2 years. He used to be a very calm and pleasant person, but over that period
of time he has become ‘‘nasty.’’ He curses in public, spits on the bus, and
makes unwanted sexual advances toward women. He has also been less able
to complete tasks at work and was recently given a formal warning from
his employer that he is at risk of losing his job if he does not change his
behavior and meet deadlines. During the neurologic examination he calls the
neurologist ‘‘honey’’ and ‘‘gorgeous,’’ and he asks if he can use the reflex
hammer to ‘‘hit the doctor back.’’ The patient’s Mini-Mental State Examination
(MMSE) score is 30 out of 30. MRI of the brain demonstrates right frontal
lobe atrophy. Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . behavioral variant of frontotemporal dementia
C. corticobasal degeneration
D. Lewy body disease
E . primary progressive aphasia

The preferred response is B (behavioral variant of frontotemporal

dementia). The patient presents with a progressive behavioral syndrome
manifested by disinhibition. His personality dramatically changed from calm
and pleasant to inappropriate. The symptoms are clearly impairing both his
social and occupational functioning. The most likely diagnosis is behavioral
variant of frontotemporal dementia, and the right frontal atrophy on brain
MRI is also supportive of the diagnosis. Alzheimer disease can certainly manifest
with behavioral changes, but memory loss would also be expected. Lewy body
disease can manifest with psychosis but not dramatic behavioral changes
without other symptoms. There is no language involvement in this patient
to suggest primary progressive aphasia. For more information, refer to
page 465 of the Continuum article ‘‘Frontotemporal Dementias.’’

b 21. A 72-year-old man presents for evaluation of recent-onset cognitive

decline. His children note that his symptoms started after his wife died
unexpectedly 3 months ago. He has been unable to manage his finances and
has left the stove on multiple times over the past few months, causing his
neighbors to call the fire department after smelling gas. His children do not
think he has worsened over the past 3 months. He reports, ‘‘My wife took
care of all that stuff. I miss her.’’ On examination, the patient’s Mini-Mental
State Examination (MMSE) score is 22 out of 30, with points lost for
orientation and recall (0 out of 3). His neurologic examination is otherwise
normal. Brain MRI demonstrates moderate global atrophy as well as
hippocampal atrophy and enlargement of the temporal horns of the lateral
ventricles. Which of the following is the most likely diagnosis?
A. Alzheimer disease
B . frontotemporal dementia
C. idiopathic normal pressure hydrocephalus
D. Jakob-Creutzfeldt disease
E . limbic encephalitis

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 Postreading Test—Preferred Responses

The preferred response is A (Alzheimer disease). In many series, a nonprion

neurodegenerative disease is the most common diagnosis in patients
presenting with a true or an apparent rapidly progressive dementia. In some
cases, symptoms at first are slowly progressive, and the family only recognizes
the extent of cognitive impairment when it becomes more severe. It is likely that
this patient had symptoms for longer than reported but were not necessarily
apparent to his children because his wife took care of the household tasks.
Frontotemporal dementia would manifest with behavioral changes.
Jakob-Creutzfeldt disease and limbic encephalitis can manifest with a rapidly
progressive dementia but would progress more rapidly. Idiopathic normal
pressure hydrocephalus is unlikely as there is no mention of abnormal gait or
urinary incontinence. For more information, refer to page 532 of the
Continuum article ‘‘Rapidly Progressive Dementia.’’

b 22. Which of the following clinical features would provide the most
compelling reason to search for an alternative explanation for a patient’s
symptoms other than idiopathic normal pressure hydrocephalus?
A. normal bladder control
B . normal bowel control
C. normal cognition
D. normal gait
E . patient awareness of symptoms

The preferred response is D (normal gait). Gait deficits are nearly universal
among patients with idiopathic normal pressure hydrocephalus. Cognitive
deficits and problems with sphincter control are less consistently present.
Patients who have incontinence are usually aware of it and concerned about
it. For more information, refer to page 582 of the Continuum article
‘‘Diagnosis and Treatment of Idiopathic Normal Pressure Hydrocephalus.’’

b 23. A 57-year-old right-handed woman presents for evaluation of progressive

language disturbances over the past 2 years. She works as a customer service
representative and initially had difficulty understanding what customers were
discussing with her on the phone. She would often ask what words meant, such
as ‘‘what is a computer’’ and would have difficulty thinking of words, sometimes
describing what she was trying to say but not saying the actual word. The
symptoms progressed and she eventually lost her job. She also developed
difficulty at home completing tasks and would look at a magazine but ask ‘‘what
am I reading?’’ Examination demonstrates a Mini-Mental State Examination
(MMSE) score of 18 out of 30 with significant difficulty understanding what is
asked. She called a watch ‘‘that thing that tells time’’ and a pen ‘‘that thing that
makes notes.’’ MRI of the brain demonstrates left temporal atrophy. Which of
the following is the most likely diagnosis?
A. Alzheimer disease
B . behavioral variant of frontotemporal dementia
C. nonfluent agrammatic variant primary progressive aphasia
D. progressive supranuclear palsy
E . semantic variant primary progressive aphasia

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 The preferred response is E (semantic variant primary progressive aphasia).
The patient presents with a neurodegenerative pattern of progressive
language impairment. Specifically, she seems to be losing the meaning of
her speech. She has difficulty assigning meanings to words, specifically
demonstrating impaired single-word comprehension. This is consistent with
semantic variant primary progressive aphasia. The dominant temporal lobe
atrophy is also supportive. In nonfluent agrammatic variant primary
progressive aphasia, the problem is more in expressive speech than
understanding the content of speech. Alzheimer disease can certainly
involve language but single-word comprehension is typically spared.
Behavioral variant of frontotemporal dementia can also involve language but
the predominant symptoms would be behavioral with spared single-word
comprehension. For more information, refer to pages 469Y472 of the
Continuum article ‘‘Frontotemporal Dementias.’’

b 24. A 17-year-old girl presents for evaluation of cognitive decline and

behavioral changes. Her symptoms developed 2 years ago and have been
worsening since then. Over the past few months she has also developed
balance problems and difficulty walking. She has a history of a cataract that
was removed at age 13. Examination reveals soft tissue masses on the Achilles
tendons bilaterally, behavioral disinhibition, 2 out of 3 recall, bilateral limb
dysmetria, spasticity in the lower extremities, and impaired tandem gait.
Brain MRI demonstrates periventricular white matter changes as well as T2
signal changes in the dentate nucleus and globus pallidus bilaterally. Which of
the following is the most likely diagnosis?
A. adrenoleukodystrophy
B. Alexander disease
C. cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
D. cerebrotendinous xanthomatosis
E . metachromatic leukodystrophy

The preferred response is D (cerebrotendinous xanthomatosis). The

patient has a clinical syndrome most consistent with cerebrotendinous
xanthomatosis, a rare autosomal recessive disorder caused by mutations in
the gene for mitochondrial sterol 27-hydroxylase. Juvenile cataracts and
tendon xanthomas (especially in the Achilles tendon) are clues to the
diagnosis. Patients present with early psychiatric manifestations and later
develop neurologic manifestations such as ataxia and upper motor neuron
signs like this patient manifests. Treatment with chenodeoxycholic acid
may prevent neurologic deterioration. For more information, refer to
page 570 of the Continuum article ‘‘Adult-Onset Leukoencephalopathies.’’

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 Postreading Test—Preferred Responses

b 25. A 78-year-old woman with a 4-year history of progressive decline in

cognitive function has a profile on neuropsychological testing notable for
prominent deficits in executive function and processing speed and
mild-to-moderate deficits in episodic memory. She has a history of diabetes,
hypertension, hyperlipidemia, coronary artery disease, and atrial fibrillation,
and she takes insulin, lisinopril, hydrochlorothiazide, atorvastatin, and
warfarin. There is no known family history of dementia. In addition to her
abnormal mental status, her neurologic examination is notable only for
diffuse hyperreflexia, symmetric in the lower extremities but greater in the
left upper extremity than the right. MRI is notable for multiple areas of
increased T2 and fluid-attenuated inversion recovery (FLAIR) signal scattered
throughout the subcortical white matter of both cerebral hemispheres,
consistent with chronic small vessel ischemic changes. Which of the following
diagnoses is most likely?
A. cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
B. frontotemporal dementia
C. multiple sclerosis
D. nonstroke vascular cognitive impairment
E . poststroke vascular cognitive impairment

The preferred response is D (nonstroke vascular cognitive impairment).

This patient has multiple vascular risk factors, relatively greater impairment
in executive function and processing speed than in episodic memory, reflex
asymmetry, and neuroimaging findings suggestive of multiple small infarcts.
All of these features are consistent with vascular cognitive impairment. Her
symptoms did not begin abruptly in the setting of a clinical stroke, and, in
fact, she has no history of clinically evident stroke, so her presentation is
most consistent with nonstroke vascular cognitive impairment. For more
information, refer to pages 493, 495Y496, and 500 of the Continuum article
‘‘Vascular Cognitive Impairment.’’

b 26. In a patient with mild cognitive impairment (MCI), which of the following
test results is associated with an increased risk of developing Alzheimer
disease dementia?
A. high levels of amyloid-"42 (A"42) in CSF
B. homozygosity for apolipoprotein (APOE) (2
C. low levels of tau protein in CSF
D. medial temporal lobe atrophy on MRI
E . occipital lobe hypometabolism on fluorodeoxyglucose positron emission
tomography (FDG-PET)

The preferred response is D (medial temporal lobe atrophy on MRI). In

patients with MCI, biomarkers associated with an increased likelihood of
developing Alzheimer disease dementia include medial temporal lobe
atrophy on MRI, temporoparietal hypometabolism on FDG-PET, diffuse uptake
on amyloid positron emission tomography (PET), low levels of A"42 in CSF,
high levels of tau protein in CSF, and the presence of the (APOE) (4 haplotype.
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 For more information, refer to pages 411Y412 of the Continuum article
‘‘Mild Cognitive Impairment.’’

b 27. A 57-year-old man presents for evaluation of rapidly progressive dementia.

He had been well until 12 weeks ago, when he started developing
progressively worsening confusion and memory loss as well as headaches.
He has been unable to work or even leave the house alone over the past month
because he has been getting lost frequently. On examination, he is disoriented
to time and place, cannot perform serial 7’s, has 0 out of 3 recall after 3 minutes,
and has an unsteady gait. MRI of the brain demonstrates confluent bilateral
white matter hyperintensities with enlarged blood vessels noted over the
hemispheric surface. What is the most likely diagnosis?
A. cerebral amyloid angiopathy
B . cerebral vasculitis
C. cerebroretinal microangiopathy with calcifications and cysts
D. dural arteriovenous fistula (DAVF)
E . venous sinus thrombosis

The preferred response is D (dural arteriovenous fistula [DAVF]).

Although uncommon, DAVF can cause a rapidly progressive dementia and
is important to diagnose because it can be treated. Patients usually progress
over the course of weeks to months, and the disease can manifest with
confusion and memory loss as well as seizures, gait instability, headaches, or
focal neurologic deficits. MRI demonstrates white matter hyperintensities and
enlarged blood vessels over the surface of the cortex. The diagnosis can be
confirmed with cerebral angiography. All of the other choices are vascular
processes and may also be associated with rapidly progressive dementia but
would have different imaging features. For more information, refer to page 522
of the Continuum article ‘‘Rapidly Progressive Dementia.’’

b 28. In a 50-year-old woman with limbic encephalitis and positive serum titers
for antineuronal nuclear antibody-1 (ANNA-1 or anti-Hu), which of the
following primary tumors is most likely?
A. breast adenocarcinoma
B . Hodgkin lymphoma
C. ovarian teratoma
D. renal cell carcinoma
E . small cell lung carcinoma

The preferred response is E (small cell lung carcinoma). About 90% of

patients with limbic encephalitis and ANNA-1 (anti-Hu) have small cell
carcinoma, usually of the lung. For more information, refer to Table 8-2 and
pages 542Y544 of the Continuum article ‘‘Autoimmune Encephalopathies
and Dementias.’’

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 Postreading Test—Preferred Responses

b 29. Dementia with Lewy bodies is differentiated from Parkinson disease

dementia on the basis of which of the following clinical features?
A. age of onset
B. ideas of reference
C. presence of hallucinations
D. severity of dementia
E . timing of dementia onset relative to the onset of parkinsonism

The preferred response is E (timing of dementia onset relative to the onset

of parkinsonism). The cognitive profile in Parkinson disease dementia
considerably overlaps that in dementia with Lewy bodies. Hallucinations are
common in Parkinson disease dementia, and they are a core feature of
dementia with Lewy bodies. Neither condition involves ideas of reference,
which are often present in schizophrenia. The two conditions display the
same spectrum of severity of dementia. By definition, the onset of
parkinsonism (and, in fact, established Parkinson disease) precedes the
onset of dementia in patients with Parkinson disease dementia, whereas in
patients who have dementia with Lewy bodies, dementia usually begins
before the onset of parkinsonism, and at the latest it begins 1 year after the
onset of parkinsonism. For more information, refer to Table 4-1, Table 4-4,
and pages 442 and 444 of the Continuum article ‘‘Lewy Body Dementias:
Dementia With Lewy Bodies and Parkinson Disease Dementia.’’

b 30. Immunotherapy is most likely to be effective in patients who have

encephalopathy associated with which of the following antibodies?
A. antineuronal nuclear antibody-1 (ANNA-1, anti-Hu)
B . antineuronal nuclear antibody-2 (ANNA-2, anti-Ri)
C. glutamic acid decarboxylase 65 (GAD65) antibody
D. Purkinje cell cytoplasmic antibody type 2 (PCA-2)
E . voltage-gated potassium channel (VGKC) complex antibody

The preferred response is E (voltage-gated potassium channel [VGKC]

complex antibody). The prognosis is generally better for patients who have
encephalopathy associated with antibodies targeting neural surface antigens
than for patients who have encephalopathy associated with antibodies
targeting intracellular antigens. Of the antibodies listed, only the VGKC complex
antibody targets neural surface antigens. For more information, refer to page 552
of the Continuum article ‘‘Autoimmune Encephalopathies and Dementias.’’

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b 31. A 67-year-old man presents for evaluation of personality and behavioral
changes experienced over the past year. His spouse notes that he has
become very disinhibited over that period of time, often ‘‘saying whatever
comes to his mind, like he has no filter.’’ At baseline, he was known to be a
very polite, soft-spoken man. He is still driving to work every day and paying
his bills, but a number of his employees have quit recently due to his
inappropriate behavior. Which of the following mental status assessments is
most likely to correlate with this symptom complex?
A. construction of intersecting pentagons
B. reading comprehension
C. serial 7’s
D. short-term recall
E . Stroop test
The preferred response is E (Stroop test). The Stroop test is a test of
executive function designed to assess inhibitory control. The patient is asked
to read names of colors (eg, green, blue, red) that are printed in a different
color than denoted by the word (eg, the word ‘‘green’’ printed in blue ink).
Patients with impulse control problems will have difficulty with this task
since they may impulsively say the color of the font when asked to read the
word, or vice versa. Construction of intersecting pentagons tests parietal
visuospatial function. Reading comprehension tests language. Short-term recall
tests memory and serial 7’s test attention and calculation ability. For more
information, refer to page 398 of the Continuum article ‘‘The Mental Status
Examination in Patients With Suspected Dementia.’’

b 32. Which of the following treatments has the best benefit-to-risk profile for
the treatment of idiopathic normal pressure hydrocephalus?
A. acetazolamide
B. endoscopic third ventriculostomy
C. optic nerve sheath fenestration
D. topiramate
E . ventriculoperitoneal shunt

The preferred response is E (ventriculoperitoneal shunt). Medications,

endoscopic third ventriculostomy, and optic nerve sheath fenestration have
not been shown to be effective for the treatment of idiopathic normal
pressure hydrocephalus. All symptoms of the condition can improve after
shunt surgery. For more information, refer to pages 586 and 589 of
the Continuum article ‘‘Diagnosis and Treatment of Idiopathic Normal
Pressure Hydrocephalus.’’

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 Postreading Test—Preferred Responses

b 33. Which of the following conditions is most likely in a 34-year-old woman with
headaches, rapid cognitive decline, episodes of abrupt change in vision,
and sudden hearing loss?
A. dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis
B . Jakob-Creutzfeldt disease
C. N-methyl-D-aspartate (NMDA) antibody encephalitis
D. steroid-responsive encephalopathy associated with autoimmune thyroiditis
E . Susac syndrome

The preferred response is E (Susac syndrome). Susac syndrome is

characterized by a triad of rapidly progressive encephalopathy, branch retinal
artery occlusions, and hearing loss. For more information, refer to page 546
of the Continuum article ‘‘Autoimmune Encephalopathies and Dementias.’’

b 34. Which of the following patterns of CSF amyloid-" (A") and tau is most
consistent with the diagnosis of Alzheimer disease?
A. elevated A" and tau
B . elevated A"42, reduced total tau (t-tau) and phosphorylated tau (p-tau)
C. elevated t-tau and p-tau, reduced A"42
D. normal A"42, t-tau, and p-tau
E . reduced A"42, t-tau, and p-tau

The preferred response is C (elevated t-tau and p-tau, reduced A"42). In

patients with Alzheimer disease, pathologic A" deposition in the brain tissue
begins early in the disease course and is associated with decline in CSF A"42.
CSF t-tau and p-tau levels rise in Alzheimer disease secondary to
neurodegeneration of tau-containing neurons. Therefore, in patients with
Alzheimer disease, CSF levels of A" are reduced, and CSF levels of both
t-tau and p-tau are elevated. For more information, refer to page 426 of
the Continuum article ‘‘Alzheimer Disease.’’

b 35. In a patient who has had a ventriculoperitoneal shunt for idiopathic

normal pressure hydrocephalus, which of the following is the most common
symptom of overdrainage?
A. cognitive decline
B . headache that is worse when lying down
C. headache that is worse when standing
D. urinary urgency that is worse when lying down
E . urinary urgency that is worse when standing

The preferred response is C (headache that is worse when standing).

The main symptom of shunt overdrainage is headache that worsens with
sitting or standing and improves when lying down. For more information,
refer to page 589 of the Continuum article ‘‘Diagnosis and Treatment
of Idiopathic Normal Pressure Hydrocephalus.’’

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b 36. Which of the following psychiatric conditions is associated with an
increased risk of conversion from mild cognitive impairment to dementia?
A. anxiety
B . conversion disorder
C. depression
D. eating disorder
E . mania

The preferred response is C (depression). Multiple studies have demonstrated

an association between depression and progressive cognitive decline. It is
not clear if depression is causative, but depression may be a prodromal
symptom of dementia, and the presence of depression or apathy raises the
risk of conversion from normal cognition and mild cognitive impairment
to dementia. For more information, refer to page 602 of the Continuum
article ‘‘Psychiatric Aspects of Dementia.’’

b 37. An abnormality of which of the following mental status tests would

provide the strongest evidence of impaired executive function?
A. confrontation naming
B . performance on alternating pattern tasks
C. recall of a drawn figure
D. sentence comprehension
E . writing single words to dictation

The preferred response is B (performance on alternating pattern tasks).

Alternating tasks can be relatively simple or complex, but they all require
the subject to shift attention from one motor program to another in a
purposeful way corresponding to specified goals. Abnormal performance on
these tests suggests impaired executive function. Executive function is less
relevant to the other tasks listed. For more information, refer to
pages 397Y398 of the Continuum article ‘‘The Mental Status Examination
in Patients With Suspected Dementia.’’

b 38. A 65-year-old man presents for evaluation of memory loss. His wife has
noticed that over the past year he has often been repeating questions in
conversation. She also has taken over the grocery shopping because he
would often purchase the same items multiple times in a day. The patient has
no medical history and takes no medications. There is no family history of
neurologic disease. On examination, his Mini-Mental State Examination
(MMSE) score is 23 out of 30, with points lost for orientation and recall (0 out
of 3). Vitamin B12 level and thyroid-stimulating hormone (TSH) are normal.
What is the most appropriate next step in diagnosis?
A. amyloid positron emission tomography (PET) scan
B. APOE genotyping
C. CSF analysis for amyloid and tau
D. fluorodeoxyglucose positron emission tomography (FDG-PET) scan of the brain
E . MRI of the brain

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 Postreading Test—Preferred Responses

The preferred response is E (MRI of the brain). The patient has a syndrome
of progressive cognitive dysfunction with significant amnestic features
suggestive of Alzheimer disease. The American Academy of Neurology
practice parameter for the evaluation of a patient with dementia recommends
structural brain imaging as a standard part of the workup. MRI or CT of the
head can be performed, but MRI is preferred as it can demonstrate atrophy
patterns and white matter signal abnormalities more accurately than CT.
The other tests listed can all assist in the diagnosis of Alzheimer disease but
are not part of the current standard recommendations. Amyloid PET is reasonable
to consider due to the relatively young onset of symptoms in the patient but
is not the next step, nor is it readily covered by insurance plans. APOE
genotyping is unlikely to add much as the pretest probability of Alzheimer
disease is already quite high. CSF analysis is invasive and is not the next step,
although it can be considered for atypical cases of dementia. FDG-PET
may demonstrate temporal or parietal hypometabolism but would not be
expected to change management in this case. For more information, refer
to pages 423Y424 of the Continuum article ‘‘Alzheimer Disease.’’

b 39. A 61-year-old right-handed woman presents with a 1-year history of

progressive language difficulty. She notes that it is ‘‘hard to get it out.’’
Her family reports that she has been experiencing difficulty expressing her
thoughts and that her speech has become very fragmentary. Her husband
does think she understands what he is saying. On examination she can easily
name a pen and watch but cannot name a cactus or hammock. She called
a hammock ‘‘theIumIyou knowIbetween treesIrest.’’ She can follow
three-step commands. MRI demonstrates no mass lesions but bifrontal
atrophy is noted. What is the most likely diagnosis?
A. Alzheimer disease
B . behavioral variant of frontotemporal dementia
C. nonfluent agrammatic variant primary progressive aphasia
D. progressive supranuclear palsy
E . semantic variant primary progressive aphasia

The preferred response is C (nonfluent agrammatic variant primary

progressive aphasia). The patient presents with a neurodegenerative pattern
of progressive language impairment. Specifically, she seems to be losing
the ability to express herself fluently and has halting, hesitant speech with no
difficulty understanding or following commands. This is most consistent
with the nonfluent agrammatic form of primary progressive aphasia.
Semantic variant primary progressive aphasia manifests with loss of meaning
of words but relatively intact fluency. Alzheimer disease can involve
language, but relatively later in the disease, grammar is typically spared,
and memory impairment would be expected early. Behavioral variant of
frontotemporal dementia can also involve language but the predominant
symptoms would be behavioral. For more information, refer to page 473
of the Continuum article ‘‘Frontotemporal Dementias.’’

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b 40. A 34-year-old woman presents for evaluation of a rapidly progressive
dementia. She has been experiencing progressively deteriorating cognitive
function over the past 11 months and is no longer able to care for herself.
She has also been experiencing diarrhea, bloating, joint aches, weight
loss, and night sweats. On examination, she is disoriented to time and place,
cannot spell ‘‘world’’ backward, has 0 out of 3 recall after 3 minutes, and
is noted to have abnormal rhythmic facial and eye movements. Brain MRI
is normal. Which of the following infectious agents is most likely to be
causative here?
A. Aspergillus
B . Borrelia burgdorferi
C. herpes simplex virus
D. human immunodeficiency virus (HIV)
E . Tropheryma whippelii

The preferred response is E (Tropheryma whippelii). Although rare,

Whipple disease (due to infection with Tropheryma whippelii) is important
to recognize as it a treatable cause of rapidly progressive dementia.
Whipple disease should be suspected when a patient manifests with
gastrointestinal symptoms (especially chronic diarrhea), systemic symptoms
(fever, arthralgia) and neurologic involvement, which may include
cognitive impairment as well as hemiparesis, seizures, or ataxia. Diagnosis
can be made with CSF or blood polymerase chain reaction (PCR), or with
intestinal biopsy, immunohistochemistry and PCR. HIV dementia is also an
important consideration in any patient with a rapidly progressive dementia
but is less likely in this patient, especially given the associated features, which
are highly suggestive of Whipple disease. For more information, refer to
pages 524Y525 of the Continuum article ‘‘Rapidly Progressive Dementia.’’

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 Self-Assessment and CME

Patient Management
Address correspondence to
Dr Elizabeth C. Finger, LHSC
Parkwood Institute, 550

Problem
Wellington Road, London,
ON N6C 0A7, Canada,
[email protected].
Relationship Disclosure:
Dr Finger has received Elizabeth C. Finger, MD, FRCPC
personal compensation as a
speaker for Western University
and receives grant support
from the Canadian Institutes of
Health Research for this work The following Patient Management Problem was chosen to reinforce the
as well as grant funding from subject matter presented in the issue. It emphasizes decisions facing the
the Alzheimer Society of
Canada, the Ministry of practicing physician. As you read through the case you will be asked to
Research and Innovation, complete 12 questions regarding history, examination, diagnostic evaluation,
Ontario Brain Institute, and
the Weston Foundation. therapy, and management. For each item, select the single best response.
Dr Finger has provided expert To obtain CME credits for this activity, subscribers must complete this Patient
legal testimony for the Ontario
Court of Justice.
Management Problem online at www.aan.com/continuum/cme. A tally
Unlabeled Use of sheet is provided with this issue to allow the option of marking answers
Products/Investigational before entering them online. A faxable scorecard is available only upon
Use Disclosure:
Dr Finger discusses the request to subscribers who do not have computer access or to non-
unlabeled/investigational use subscribers who have purchased single back issues (send an email to
of antipsychotic medications [email protected]).
for behavioral management in
dementia. Upon completion of the Patient Management Problem, participants may earn
* 2016 American Academy up to 2 AMA PRA Category 1 Creditsi. Participants have up to 3 years from
of Neurology.
the date of publication to earn CME credits. No CME will be awarded for
this issue after April 30, 2019.

Learning Objectives
Upon completion of this activity, the participant will be able to:
& Discuss the differential diagnosis of patients presenting with progressive
cognitive impairment
& Discuss the diagnosis and management of cognitive and behavioral
symptoms in patients with Alzheimer disease

Case
A 57-year-old man is referred by his family doctor for memory deficits. He
reports some forgetfulness, such as forgetting where he put his keys or
trouble recalling people’s names, but generally feels his memory is ‘‘not too
bad for a guy [his] age.’’ During the interview, the patient’s wife attempts
to contradict his answers to some of the physician’s questions, which appears
to agitate the patient. Following the interview and examination of the
patient, the patient’s family is interviewed separately to discuss any concerns
they may have. The patient’s spouse then reports that the family first noticed
changes in the patient’s memory beginning 3 years ago. He began to miss
dental appointments, forgot to pick up their daughter from swim practice, and
got lost on a few occasions when driving in their home town. The changes
started gradually but have progressed. They now find he repeats questions and
stories multiple times within a few minutes, is confused when attempting to
complete projects at home or pay the bills, and has accused family members of
Continued on page 675

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 Continued from page 674
stealing his wallet. He has not experienced any hallucinations. He was recently
laid off from his job as a welder. He drives and has had no accidents or tickets in
the past 3 years. He smokes 10 cigarettes and drinks two beers per day. He has
no significant past medical history and takes no medications.

b 1. Given the patient’s history, what is the most likely working diagnosis?
A. Alzheimer disease
B . autoimmune encephalopathy
C. dementia with Lewy bodies
D. frontotemporal dementia
E . vascular cognitive impairment

A working diagnosis of Alzheimer disease is considered. The patient’s neurologic

examination shows full extraocular movements with normal vertical saccades,
normal axial and appendicular tone, no tremor, no bradykinesia, normal
ideomotor praxis and stereognosis bilaterally, and normal gait. On the
Mini-Mental State Examination (MMSE), he scores 22 out of 30, losing points
for orientation, recall, and attention.

b 2. In addition to neuroimaging, which of the following is the next appropriate

step in the workup of this patient?
A. amyloid positron emission tomography (PET) scan
B . EEG
C. further cognitive testing and assessment of function
D. lumbar puncture
E . polysomnogram
b 3. On further cognitive testing, a patient with mild Alzheimer disease would be
expected to demonstrate which of the following patterns of performance?
A. impaired episodic memory, mild anomia, mild deficits on executive
function tests
B . impaired executive functions, impaired letter fluency worse than category
fluency, impaired retrieval
C. impaired grammar, deficits in comprehension, impaired calculations
D. impaired recall of recently learned information, grammar deficits,
preserved visuospatial abilities
E . impaired single-word comprehension, preserved fluency, preserved
visuospatial skills

The Alzheimer’s Disease Assessment ScaleVCognitive Subscale (ADAS-Cog)

is administered. The patient shows difficulties learning a list of words, with
just 5 out of 10 recalled immediately after three trials and, following a delay,
he recalls only 2 out of 10 words. He is able to copy a circle but makes mistakes
when drawing a cube. He follows all commands and names only 8 out of 12 items
correctly. He is oriented to the year but not the month or day of the week.

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 Patient Management Problem

b 4. Which of the following additional measures or historical features would be

most important to obtain in this patient?
A. history of exposure to ticks
B. retrieval of patient’s driving record from the department of motor
vehicles/ministry of transportation
C. screening for depression and other neuropsychiatric symptoms
D. screening for risk factors for syphilis
E . vaccination history

The patient’s family doctor has recently checked his complete blood cell
count, electrolytes including magnesium, calcium, and phosphorus, liver
function tests, and vitamin B12 levels, which were within normal limits.

b 5. Additional routine laboratory workup should include which of the

following blood tests?
A. antinuclear antibody
B. C-reactive protein
C. erythrocyte sedimentation rate
D. thyroid-stimulating hormone (TSH)
E . venereal disease research laboratory (VDRL)
b 6. Which is the most appropriate imaging test to order at this time?
A. amyloid PET
B . CT angiography of head and neck
C. CT scan of the brain
D. fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain
E . MRI scan of the brain

The patient’s laboratory blood work returns normal. The MRI demonstrates
bilateral hippocampal atrophy and widening of the sylvian fissures, but
no other structural lesions. At a follow-up visit, a diagnosis of probable
Alzheimer disease is made and discussed with the patient and caregiver.

b 7. Which of the following treatments should be initiated at this time?

A. a cholinesterase inhibitor
B. coconut oil
C. ginkgo biloba
D. memantine
E. vitamin E
b 8. When counseling the patient and family prior to prescribing a cholinesterase
inhibitor, which of the following should be discussed as the most common
side effect?
A. bradycardia
B . gastrointestinal symptoms
C. liver abnormalities
D. rash
E . seizures

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 Prior to completion of the follow-up visit, driving privileges are discussed
with the patient and his family in light of a diagnosis of Alzheimer disease
and his performance on the cognitive testing.

b 9. Which of the following factors best predicts a patient’s driving abilities?

A. caregiver’s rating of patient’s driving as safe
B. history of crashes in the past 5 years
C. lack of reduction of patient’s driving mileage or situational avoidance
D. neuropsychological testing scores
E. patient’s self-reported driving abilities

At the next visit the patient’s spouse and adult children ask if his illness
could be hereditary and if they and the patient can be tested for genetic
risks. The patient’s father had ‘‘dementia’’ with onset around age 55. The
family recalls that he became angry and stopped recognizing family members.
He went into a nursing home and died around age 70. A paternal uncle had
depression and also developed dementia in his late fifties. The patient’s
mother lived to age 86 and died of a myocardial infarction.

b 10. To address the family’s question about heritability, what is the next
appropriate step?
A. reassurance that familial early-onset Alzheimer disease is rare
B. referral of the patient and family for genetic counseling
C. screening of the family members for early-onset Alzheimer disease
gene mutations
D. testing for apolipoprotein E (APOE) genotype
E . testing of the patient for presenilin 1 (PSEN1), amyloid-" precursor protein
(APP), and presenilin 2 (PSEN2) mutations

After genetic counseling, the patient elects to undergo genetic testing and
is found to carry an Alzheimer diseaseYcausing mutation in the PSEN1
gene. The patient’s adult children, who are asymptomatic, inquire about
the possibility of genetic testing for themselves. A referral is made for
genetic counseling for all interested asymptomatic family members to
further consider the potential consequences of genetic testing. One year
later the patient is unable to operate appliances at home, prepare meals,
or manage his medications without assistance. He can dress and feed
himself independently. His MMSE score in clinic is 16 out of 30.

b 11. The patient’s disease severity is now best classified as which of the following?
A. mild
B . moderate
C. prodromal
D. severe
E . terminal

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 Patient Management Problem

At the next visit 6 months later, the patient’s spouse appears rather
distressed and notes that he has become more dependent and requires
near complete supervision at home due to wandering tendencies. She is
tearful and reports poor sleep as she is fearful he may fall or wander when
he awakens in the middle of the night.

b 12. Which of the following represent important management approaches for

these behaviors?
A. prescription of an antidepressant for the caregiver
B. prescription of a sleep aid for the caregiver
C. prescription of a sleep medication for the patient
D. prescription of quetiapine for wandering behavior
E . referral of the patient to a day program

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 Self-Assessment and CME

Patient Management
Address correspondence to
Dr Elizabeth C. Finger, LHSC
Parkwood Institute, 550

Problem—Preferred
Wellington Road, London,
ON N6C 0A7, Canada,
[email protected].

Responses
Relationship Disclosure:
Dr Finger has received
personal compensation as a
speaker for Western University
and receives grant support
Elizabeth C. Finger, MD, FRCPC from the Canadian Institutes of
Health Research for this work
as well as grant funding from
the Alzheimer Society of
Canada, the Ministry of Research
and Innovation, Ontario Brain
Following are the preferred responses for the Patient Management Problem Institute, and the Weston
in this Continuum issue. The case, questions, and answer options are re- Foundation. Dr Finger has
provided expert legal testimony
peated, and the preferred response is given, followed by an explanation and for the Ontario Court of Justice.
a reference with which you may seek more specific information. You are Unlabeled Use of
encouraged to review the responses and explanations carefully to evaluate Products/Investigational
Use Disclosure:
your general understanding of the material. The comment and references Dr Finger discusses the
included with each question are intended to encourage independent study. unlabeled/investigational use
of antipsychotic medications
To obtain CME credits for this activity, subscribers must complete this for behavioral management
Patient Management Problem online at www.aan.com/continuum/cme. in dementia.
Upon completion of the Patient Management Problem, participants may * 2016 American Academy
of Neurology.
earn up to 2 AMA PRA Category 1 CreditsTM. Participants have up to 3 years
from the date of publication to earn CME credits. No CME will be awarded
for this issue after April 30, 2019.

Learning Objectives
Upon completion of this activity, the participant will be able to:
& Discuss the differential diagnosis of patients presenting with progressive
cognitive impairment
& Discuss the diagnosis and management of cognitive and behavioral
symptoms in patients with Alzheimer disease

Case
A 57-year-old man is referred by his family doctor for memory deficits. He
reports some forgetfulness, such as forgetting where he put his keys or
trouble recalling people’s names, but generally feels his memory is ‘‘not
too bad for a guy [his] age.’’ During the interview, the patient’s wife
attempts to contradict his answers to some of the physician’s questions,
which appears to agitate the patient. Following the interview and
examination of the patient, the patient’s family is interviewed separately
to discuss any concerns they may have. The patient’s spouse then reports
that the family first noticed changes in the patient’s memory beginning
3 years ago. He began to miss dental appointments, forgot to pick up their
daughter from swim practice, and got lost on a few occasions when driving
in their home town. The changes started gradually but have progressed.
Continued on page 680

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 PMP—Preferred Responses

Continued from page 679

They now find he repeats questions and stories multiple times within a few
minutes, is confused when attempting to complete projects at home or pay
the bills, and has accused family members of stealing his wallet. He has not
experienced any hallucinations. He was recently laid off from his job as a
welder. He drives and has had no accidents or tickets in the past 3 years. He
smokes 10 cigarettes and drinks two beers per day. He has no significant past
medical history and takes no medications.

b 1. Given the patient’s history, what is the most likely working diagnosis?
A. Alzheimer disease
B . autoimmune encephalopathy
C. dementia with Lewy bodies
D. frontotemporal dementia
E . vascular cognitive impairment

The preferred response is A (Alzheimer disease). The patient’s initial

forgetfulness as described by the family is suggestive of amnestic mild
cognitive impairment. Over time, his symptoms progressed to indicate that
his memory impairments and deficits in executive functioning (difficulty
completing projects) and navigation impacted his daily functioning,
consistent with progression to dementia. The gradual onset and progression
of deficits in short-term memory and navigation are most commonly
associated with Alzheimer disease.1 Repetitiousness, misplacing objects, and
accusing others of stealing one’s possessions when they are misplaced
around the home are all hallmark symptoms of memory deficits in Alzheimer
disease. Vascular cognitive impairment would typically be associated with a
stepwise decline. Dementia with Lewy bodies may present with alterations in
level of arousal, parkinsonism, and visual hallucinations. While patients
with frontotemporal dementia may have memory deficits, this is not typically
the predominant feature, and navigational deficits in frontotemporal
dementia are rare.

1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s
disease: recommendations from the National Institute on Aging-Alzheimer’s Association
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement
2011;7(3):263Y269. doi:10.1016/j.jalz.2011.03.005.

A working diagnosis of Alzheimer disease is considered. The patient’s

neurologic examination shows full extraocular movements with normal
vertical saccades, normal axial and appendicular tone, no tremor, no
bradykinesia, normal ideomotor praxis and stereognosis bilaterally, and
normal gait. On the Mini-Mental State Examination (MMSE), he scores
22 out of 30, losing points for orientation, recall, and attention.

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b 2. In addition to neuroimaging, which of the following is the next appropriate
step in the workup of this patient?
A. amyloid positron emission tomography (PET) scan
B . EEG
C. further cognitive testing and assessment of function
D. lumbar puncture
E . polysomnogram

The preferred response is C (further cognitive testing and assessment of

function). The MMSE is a screening test for cognitive impairment. More
detailed objective measurement of cognitive deficits and activities of daily
living is necessary to confirm the deficits reported by the patient or family
members and to aid in staging the severity of deficits.1 Sleep apnea may
result in excessive daytime somnolence, contributing to cognitive deficits;
thus, taking the patient’s history should include screening questions for sleep
apnea and, if present, consideration of referral for a formal sleep study.
Lumbar puncture and EEG are indicated in the workup of a rapidly progressive
dementia. While the patient’s presentation is typical for Alzheimer disease,
CSF amyloid-" (A") and tau measurements could be considered given the early
age of onset (younger than 65 years of age), although CSF analysis may be
most helpful in diagnostically challenging cases (ie, patients presenting with
mixed features of frontotemporal dementia and Alzheimer disease). Similarly,
amyloid PET may be useful in differentiating Alzheimer disease from
frontotemporal dementia and may be considered in patients with early-onset
disease if the results are expected to change disease management. In this
patient, although the age of onset was before age 65 years, the patient’s
features and course were typical for Alzheimer disease and, thus, lumbar
puncture and amyloid PET imaging were not indicated.2

1. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1143Y1153. doi:10.1212/WNL.56.9.1143.
2. Gauthier S, Patterson C, Chertkow H, et al. Recommendations of the 4th Canadian Consensus
Conference on the Diagnosis and Treatment of Dementia (CCCDTD4). Can Geriatr J
2012;15(4):120Y126. doi:10.5770/cgj.15.49.

b 3. On further cognitive testing, a patient with mild Alzheimer disease would

be expected to demonstrate which of the following patterns of performance?
A. impaired episodic memory, mild anomia, mild deficits on executive
function tests
B . impaired executive functions, impaired letter fluency worse than category
fluency, impaired retrieval
C. impaired grammar, deficits in comprehension, impaired calculations
D. impaired recall of recently learned information, grammar deficits,
preserved visuospatial abilities
E . impaired single-word comprehension, preserved fluency, preserved
visuospatial skills

The preferred response is A (impaired episodic memory, mild anomia, mild

deficits on executive function tests). Patients with Alzheimer disease
demonstrate early deficits in episodic memory, often manifested by impaired

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 PMP—Preferred Responses

recall of recently learned information.1 In the early stages of the disease,

encoding and consolidation are impaired while retrieval is relatively preserved.
Executive function tasks are often impaired early on in Alzheimer disease, and
some patients may demonstrate mild anomia. Category fluency is typically
impaired while letter fluency may be preserved. Deficits on visuospatial tasks are
common. Grammar is typically preserved in patients with Alzheimer disease,
including in the logopenic aphasia variant of primary progressive aphasia typically
associated with Alzheimer disease pathology.1 Single-word comprehension
is preserved in Alzheimer disease, but is a classic deficit in semantic dementia.
1. Weintraub S, Wicklund AH, Salmon DP. The neuropsychological profile of Alzheimer disease.
Cold Spring Harb Perspect Med 2012;2(4):a006171. doi:10.1101/cshperspect.a006171.

The Alzheimer’s Disease Assessment ScaleVCognitive Subscale (ADAS-Cog)

is administered. The patient shows difficulties learning a list of words,
with just 5 out of 10 recalled immediately after three trials and, following
a delay, he recalls only 2 out of 10 words. He is able to copy a circle but makes
mistakes when drawing a cube. He follows all commands and names only
8 out of 12 items correctly. He is oriented to the year but not the month or
day of the week.

b 4. Which of the following additional measures or historical features would be

most important to obtain in this patient?
A. history of exposure to ticks
B . retrieval of patient’s driving record from the department of motor
vehicles/ministry of transportation
C. screening for depression and other neuropsychiatric symptoms
D. screening for risk factors for syphilis
E . vaccination history
The preferred response is C (screening for depression and other
neuropsychiatric symptoms). Assessment of a patient with cognitive
complaints should include screening for depression and other
neuropsychiatric symptoms, which can be associated with deficits in
attention, concentration, and working memory.1 Patients with impairments in
frontal lobe functions or memory may have impaired insight or recollection
of these symptoms; thus, collection of collateral history from a
knowledgeable informant is essential. A review of neuropsychiatric symptoms
including agitation, wandering, impulsivity, delusions, hallucinations, anxiety,
depression, and insomnia should be reviewed at each visit as these symptoms
may inform the diagnosis and often impact quality of life for patients and
caregivers and thus require management when possible.2 Delusions of theft
and infidelity are common in patients with Alzheimer disease, and anxiety and
depression are common in patients with Alzheimer disease and dementia
with Lewy bodies. Additionally, screening for safety-related behaviors such as
wandering, use of the stove, presence of guns, or use of other dangerous
equipment or tools in the home is indicated at each visit. Physicians are not
required to obtain official driving records but confirmation of the patients’
driving history within the past 5 years, including difficulties with navigation,
accidents, or tickets from a reliable informant, is critical.

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 1. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1143Y1153. doi:10.1212/WNL.56.9.1143.
2. Hogan DB, Bailey P, Black S, et al. Diagnosis and treatment of dementia: 4. Approach to
management of mild to moderate dementia. CMAJ 2008;179(8):787Y793.
doi:10.1503/cmaj.070803.

The patient’s family doctor has recently checked his complete blood cell
count, electrolytes including magnesium, calcium, and phosphorus, liver
function tests, and vitamin B12 levels, which were within normal limits.

b 5. Additional routine laboratory workup should include which of the

following blood tests?
A. antinuclear antibody
B . C-reactive protein
C. erythrocyte sedimentation rate
D. thyroid-stimulating hormone (TSH)
E . venereal disease research laboratory (VDRL)

The preferred response is D (thyroid-stimulating hormone [TSH]). Patients

presenting with cognitive complaints should be screened with a complete
blood cell count, electrolytes including calcium levels, liver function tests, TSH,
and vitamin B12 level to rule out these reversible causes of dementia. VDRL,
human immunodeficiency virus (HIV), or other infection screening is
indicated only for patients with risk factors.1 Inflammatory markers such as
erythrocyte sedimentation rate, C-reactive protein, or antinuclear antibody
would be indicated for patients with a history suggestive of a rapidly progressive
dementia or other autoimmune disease risk factors or symptoms.2
1. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1143Y1153. doi:10.1212/WNL.56.9.1143.
2. Geschwind MD. Rapidly progressive dementia: prion diseases and other rapid dementias.
Continuum (Minneap Minn) 2010;16(2 Dementia):31Y56. doi:10.1212/01.CON.0000368211.
79211.4c.

b 6. Which is the most appropriate imaging test to order at this time?

A. amyloid PET
B . CT angiography of head and neck
C. CT scan of the brain
D. fluorodeoxyglucose positron emission tomography (FDG-PET) of the brain
E . MRI scan of the brain

The preferred answer is E (MRI scan of the brain). A structural imaging study is
indicated for patients presenting with cognitive deficits to rule out a structural
etiology such as a tumor or normal pressure hydrocephalus. MRI is preferred,
as white matter lesions and microhemorrhages such as those seen in cerebral
amyloid angiopathy, either of which may contribute to cognitive impairment,
1,2
may be better visualized on MRI. For patients unable to undergo MRI, CT
imaging is a reasonable substitute. FDG-PET and amyloid PET may help
specifically to differentiate Alzheimer disease from frontotemporal dementia
but are not routinely indicated in the diagnostic workup of patients
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 PMP—Preferred Responses

presenting with cognitive impairment. There is no specific role for vascular

imaging in the initial workup of cognitive impairment.
1. Feldman HH, Jacova C, Robillard A, et al. Diagnosis and treatment of dementia: 2. Diagnosis.
CMAJ 2008;178(7):825Y836. doi:10.1503/cmaj.070798.
2. Harper L, Barkhof F, Scheltens P, et al. An algorithmic approach to structural imaging in
dementia. J Neurol Neurosurg Psychiatry 2014;85(6):692Y698. doi:10.1136/jnnp-2013-306285.

The patient’s laboratory blood work returns normal. The MRI demonstrates
bilateral hippocampal atrophy and widening of the sylvian fissures, but
no other structural lesions. At a follow-up visit, a diagnosis of probable
Alzheimer disease is made and discussed with the patient and caregiver.

b 7. Which of the following treatments should be initiated at this time?

A. a cholinesterase inhibitor
B. coconut oil
C. ginkgo biloba
D. memantine
E. vitamin E
The preferred answer is A (a cholinesterase inhibitor). The cholinesterase
inhibitors donepezil, galantamine, and rivastigmine are typically indicated
for symptomatic treatment of cognitive impairment in mild to moderate
Alzheimer disease. Donepezil and the high-dose rivastigmine patch (13.3 mg
every 24 hours) are approved by the US Food and Drug Administration (FDA)
for use in severe Alzheimer disease. These medications have been associated
with a modest improvement in cognition in a portion of patients with
Alzheimer disease. While there have been case reports published suggesting
benefit of coconut oil in Alzheimer disease, controlled trials are ongoing, and
there is insufficient evidence to date to recommend this as therapy. Trials of
vitamin E and ginkgo biloba have failed to show a benefit in Alzheimer disease.
Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has also
been approved for use in moderate to severe Alzheimer disease. While
memantine appears safe as monotherapy or when added to a cholinesterase
inhibitor, evidence of a modest benefit is equivocal in moderate to severe
Alzheimer disease1 and meta-analysis suggests there is not a benefit in
patients with mild Alzheimer disease.2 Thus, some recent guidelines support
the use of memantine in moderate and severe Alzheimer disease, and others
suggest there is insufficient evidence to support or refute use of memantine
in moderate to severe Alzheimer disease.3

1. Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe

Alzheimer’s disease. N Engl J Med 2012;366(10):893Y903. doi:10.1056/NEJMoa1106668.
2. Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of
memantine in mild Alzheimer disease. Arch Neurol 2011;68(8):991Y998. doi:10.1001/
archneurol.2011.69.
3. Gauthier S, Patterson C, Chertkow H, et al. Recommendations of the 4th Canadian Consensus
Conference on the Diagnosis and Treatment of Dementia (CCCDTD4). Can Geriatr J 2012;15(4):
120Y126. doi:10.5770/cgj.15.49.

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b 8. When counseling the patient and family prior to prescribing a
cholinesterase inhibitor, which of the following should be discussed as the
most common side effect?
A. bradycardia
B. gastrointestinal symptoms
C. liver abnormalities
D. rash
E. seizures

The preferred answer is B (gastrointestinal symptoms). On average, the

cholinesterase inhibitors are associated with an approximate 20% incidence
of gastrointestinal side effects including nausea, with approximately 5% of
patients experiencing more severe nausea, vomiting, or diarrhea.1 A less
common but more serious adverse reaction to the cholinesterase inhibitors
is bradycardia, which can be life threatening.2 Thus, measurement of pulse
and assessment of cardiac symptoms is indicated before initiation.
Less common and less serious side effects of this class include vivid
dreams, including nightmares, and persistent rhinorrhea. Other possible side
effects due to cholinergic effects include seizures, worsening of urinary
obstruction in patients with prostatic hyperplasia or urinary outlet obstruction,
or exacerbation of asthma. As many patients will not show a favorable response
to this class of medications, response to treatment should be assessed
after a few months.3 If no favorable response is observed, discontinuation
is recommended, and a trial of an alternate agent in the class can
be considered.
1. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1154Y1166. doi:10.1212/WNL.56.9.1154.
2. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with
dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern
Med 2009;169(9):867Y873. doi:10.1001/archinternmed.2009.43.
3. Gauthier S, Patterson C, Chertkow H, et al. Recommendations of the 4th Canadian Consensus
Conference on the Diagnosis and Treatment of Dementia (CCCDTD4). Can Geriatr J
2012;15(4):120Y126. doi:10.5770/cgj.15.49.

Prior to completion of the follow-up visit, driving privileges are discussed

with the patient and his family in light of a diagnosis of Alzheimer disease
and his performance on the cognitive testing.

b 9. Which of the following factors best predicts a patient’s driving abilities?

A. caregiver’s rating of patient’s driving as safe
B . history of crashes in the past 5 years
C. lack of reduction of patient’s driving mileage or situational avoidance
D. neuropsychological testing scores
E . patient’s self-reported driving abilities

The preferred answer is B (history of crashes in the past 5 years). There is

level C evidence that a history of crashes in the past 5 years or traffic citations

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 PMP—Preferred Responses

in the past 3 years are associated with an increased risk of future crashes.1
Caregivers’ ratings of patients’ driving as unsafe is a predictor of unsafe driving,
but the opposite, caregivers’ judgment of patients’ driving as safe, has not
been found to be reliably associated with safe driving performance. A
reduction in driving mileage or situational avoidance has been associated
with increased risk of unsafe driving, but a lack of reduction or avoidance has
not. The presence of impulsive or aggressive personality characteristics has
been associated with unsafe driving risk. While neuropsychological testing
generally has not been highly predictive of driving risk, an MMSE score or 24 or
less may be somewhat useful in identifying patients possibly at increased risk of
unsafe driving.1 Studies of driving in patients with dementia have tended to
collapse the groups across all causes of dementia and, thus, have weighted the
results toward patients with Alzheimer disease. The few studies conducted in
patients with frontotemporal dementia consistently indicate that the risk of
unsafe driving is high even in early stages of disease, while there are no studies
specifically in patients with dementia with Lewy bodies.2,3
1. Iverson DJ, Gronseth GS, Reger MA, et al. Practice parameter update: evaluation and
management of driving risk in dementia: report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2010;74(16):1316Y1324. doi:10.1212/
WNL.0b013e3181da3b0f.
2. de Simone V, Kaplan L, Patronas N, et al. Driving abilities in frontotemporal dementia patients.
Dement Geriatr Cogn Disord 2007;23(1):1Y7. doi:10.1159/000096317.
3. Fujito R, Kamimura N, Ikeda M, et al. Comparing the driving behaviours of individuals with
frontotemporal lobar degeneration and those with Alzheimer’s disease [published online ahead
of print March 3, 2015]. Psychogeriatrics. doi:10.1111/psyg.12115.

At the next visit the patient’s spouse and adult children ask if his illness
could be hereditary and if they and the patient can be tested for genetic
risks. The patient’s father had ‘‘dementia’’ with onset around age 55. The
family recalls that he became angry and stopped recognizing family members.
He went into a nursing home and died around age 70. A paternal uncle had
depression and also developed dementia in his late fifties. The patient’s
mother lived to age 86 and died of a myocardial infarction.

b 10. To address the family’s question about heritability, what is the next
appropriate step?
A. reassurance that familial early-onset Alzheimer disease is rare
B . referral of the patient and family for genetic counseling
C. screening of the family members for early-onset Alzheimer disease
gene mutations
D. testing for apolipoprotein E (APOE) genotype
E . testing of the patient for presenilin 1 (PSEN1), amyloid-" precursor protein
(APP), and presenilin 2 (PSEN2) mutations

The preferred answer is B (referral of the patient and family for genetic
counseling). A referral for genetic counseling is recommended for symptomatic
testing for patients with possible familial early-onset Alzheimer disease and
is essential for individuals considering predictive testing. The patient’s
presentation with probable Alzheimer disease prior to age 60 and likely
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 history of early-onset dementia in his father raise the possibility of an
autosomal dominant early-onset familial Alzheimer disease. Autosomal
dominant mutations are a rare cause of Alzheimer disease overall; however,
in kindreds with three family members across three generations affected
before age 60, the probability of identifying an autosomal mutation is
approximately 86%.1 The most common genetic mutation associated with
familial early-onset Alzheimer disease is PSEN1, followed by mutations in APP.
APOE4 status is associated with a higher risk of developing Alzheimer
disease but the presence is not diagnostic and, thus, symptomatic and
predictive genetic testing of APOE genotype is not recommended.

1. Loy CT, Schofield PR, Turner AM, Kwok JB. Genetics of dementia. Lancet 2014;383(9919):
828Y840. doi:10.1016/S0140-6736(13)60630-3.

After genetic counseling, the patient elects to undergo genetic testing and is
found to carry an Alzheimer diseaseYcausing mutation in the PSEN1 gene.
The patient’s adult children, who are asymptomatic, inquire about the
possibility of genetic testing for themselves. A referral is made for genetic
counseling for all interested asymptomatic family members to further
consider the potential consequences of genetic testing. One year later
the patient is unable to operate appliances at home, prepare meals, or
manage his medications without assistance. He can dress and feed
himself independently. His MMSE score in clinic is 16 out of 30.

b 11. The patient’s disease severity is now best classified as which of

the following?
A. mild
B . moderate
C. prodromal
D. severe
E . terminal

The preferred response is B (moderate). Staging of dementia severity can be

accomplished through clinical interview of activities of daily living, through
standardized measures assessing functional activities such as the Clinical
Dementia Rating scale or the Dementia Severity Rating Scale, or estimated
through cognitive screens such as the MMSE. Patients in moderate stages of
Alzheimer disease have difficulties with instrumental activities of daily living
(eg, managing the finances and shopping) but are able to perform basic
activities of daily living (eg, dressing, feeding, and toileting). MMSE ratings
between 11 and 20 are generally considered to be associated with
moderate-stage Alzheimer disease. Assessment of disease severity at onset
and at least annually is considered a best practice to guide patient
management and council family members and caregivers on prognosis and
anticipated course of symptoms.1
1. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: diagnosis of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1143Y1153. doi:10.1212/WNL.56.9.1143.

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 PMP—Preferred Responses

At the next visit 6 months later, the patient’s spouse appears rather distressed
and notes that he has become more dependent and requires near complete
supervision at home due to wandering tendencies. She is tearful and reports
poor sleep as she is fearful he may fall or wander when he awakens in the
middle of the night.

b 12. Which of the following represent important management approaches for

these behaviors?
A. prescription of an antidepressant for the caregiver
B . prescription of a sleep aid for the caregiver
C. prescription of a sleep medication for the patient
D. prescription of quetiapine for wandering behavior
E . referral of the patient to a day program
The preferred response is E (referral of the patient to a day program).
Caregivers of patients with dementia are at high risk of depression, caregiver
burnout, and medical problems. As the patient’s dementia advances,
maintaining options for caregiver respite is critical for the well-being of the
patient and caregiver. Referrals to local day care programs for patients with
dementia, Alzheimer society for social work and caregiver support groups,
and other community organizations for care relief are essential for caregivers.1
Prescription sleep aids are associated with only a mean increase of 15 minutes
of increased sleep per night and are associated with an increased risk of hip
fractures and pneumonia in elderly patients.2 Neuroleptic medications may be
required for aggression or psychosis in dementia but are typically not effective
for wandering behaviors, which are better treated with nonpharmacologic
strategies including redirection and safety door locks or alarms. Neuroleptic
medications are associated with increased cardiovascular morbidity and
mortality and cerebrovascular events in patients with dementia.

1. Doody RS, Stevens JC, Beck C, et al. Practice parameter: management of dementia
(an evidence-based review). Report of the Quality Standards Subcommittee of the American
Academy of Neurology. Neurology 2001;56(9):1154Y1166. doi:10.1212/WNL.56.9.1154.
2. McMillan JM, Aitken E, Holroyd-Leduc JM. Management of insomnia and long-term use of
sedative-hypnotic drugs in older patients. CMAJ 2013;185(17):1499Y1505. doi:10.1503/
cmaj.130025.

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 Dementia

INDEX
* 2016 American Academy of
simultagnosia, 396, 421 Neurology. All rights reserved.
visual, 395, 396, 421, 471c, 472
Agranulocytosis, clozapine-induced, 451t, 458
Agraphia, 396, 421
Page numbers in boldface type indicate major AHA/ASA. See American Heart Association/American
discussions. Letters after page numbers refer to Stroke Association
the following: c = case study; f = figure; ALDP gene mutations, 563t
r = reference; t = table. Alexander disease, 560, 562t, 569Y570, 571f,
576rY577r
Alien limb phenomenon, 475c, 476, 477t, 478
A ALS. See Amyotrophic lateral sclerosis
AA. See Alzheimer’s Association Alternating patterns tasks, 391c, 397Y398
AAN. See American Academy of Neurology Alzheimer, Alois, 600
A". See Amyloid-" Alzheimer disease (AD), 419Y431, 431rY434r
ABCD1 gene mutations, 563t, 566Y567 age-related prevalence of, 419
ACE (Addenbrooke Cognitive Examination), 393 atypical variants of, 419, 421
Acetazolamide, in idiopathic normal pressure frontal variant, 421
hydrocephalus, 586, 597r logopenic aphasia, 421
Acetylcholine loss, Lewy body dementias and, posterior cortical atrophy, 421
435, 436, 449, 459t, 460, 461r cerebral amyloid angiopathy and, 429, 501Y502
Acetylcholinesterase inhibitors (AChEIs). See also clinical presentation of, 420Y421
specific drugs coding for, 627t
adverse effects of, 429Y430, 449 cognitive decline in, 419, 420, 422, 423,
for Alzheimer disease, 429Y430, 434r, 606Y607 431rY434r, 440
memantine and, 430 diagnosis of, 402r
in frontotemporal dementia, 484Y485 amyloid PET imaging, 399, 402r, 424Y426,
in Lewy body dementias, 449, 450t, 451t, 456 425f, 427c, 428c
in mild cognitive impairment, 414, 416r biomarkers, 423Y426
in vascular cognitive impairment, 505 CSF analysis, 399Y400, 402rY403r, 426, 447
Acidurias neuroimaging, 424Y425, 424fY425f
glutaric aciduria type 1, 564t neurologic examination, 421
L-2-hydroxyglutaric aciduria, 564t at referral centers for rapidly progressive
3-methylglutaconic aciduria type 1, 564t dementia, 513t, 514Y515, 514t
Activities of daily living, assessment of, 392, 400 diagnostic criteria for, 421Y423, 422t
AD. See Alzheimer disease differential diagnosis of, 399
ADAMS (Aging, Demographics, and Memory vs. frontotemporal dementia, 400, 401r, 535r
Study), 419Y420, 431r epidemiology of, 419Y420
ADC maps. See Apparent diffusion coefficient maps family history of, 428
Addenbrooke Cognitive Examination (ACE), 393 genetics of, 426Y429
ADDTC (Alzheimer’s Disease Diagnostic and apolipoprotein E4 genotype, 420, 426Y427
Treatment Centers), 490 autosomal dominant variants, 428Y429
Adenine kinase 5 receptor encephalopathy, 535r mild cognitive impairment due to, 404,
ADNI (Alzheimer’s Disease Neuroimaging 410, 416r
Initiative), 402r, 411, 417r criteria for, 406Y407, 413Y414
Adrenoleukodystrophy, X-linked, 559, 562t, 563t, diagnosis of, 402r
566Y567, 569, 576r management of, 411
Adrenomyeloneuropathy, 567, 569, 569f mental status examination for, 386cY387c
Adult-onset autosomal dominant leukodystrophy, mortality due to, 419, 421
565t, 573Y574, 574f neuropathology of, 429
Adult-onset leukoencephalopathy with axonal vascular cognitive impairment and, 490, 504
spheroids and pigmented glia (ALSP), 575, 578r neuropsychiatric symptoms of, 420Y421, 603
Adult polyglucosan body disease, 565t, 574Y575, 577r anxiety, 420, 427c, 430, 603
Affect, flat, 392, 465, 468c apathy, 420, 603, 610r
Aging, Demographics, and Memory Study depression, 421, 427c, 430, 603, 613r
(ADAMS), 419Y420, 431r irritability, 420, 421, 430, 603
AGNA (antiglial/neuronal nuclear; SOX1) psychosis, 421, 600, 601Y602, 603
antibody, 542t preclinical, 404
Agnosia, 582 prodromal, 399, 407, 408f, 413, 424f
finger, 397, 421 risk factors for, 420
prosopagnosia, 472 treatment of, 429Y431

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 Dementia

acetylcholinesterase inhibitors, 429Y430, Appropriate Use Criteria for, 425Y426, 427c,

606Y607 428c, 433r
for behavioral symptoms, 430Y431 to differentiate frontotemporal dementia from
ethical considerations for use of Alzheimer disease, 469, 470f
next-generation drugs, 615Y617, 615c, 618r lack of insurance coverage for, 425
future therapies, 431 in Lewy body dementias, 460
memantine, 430 to predict progression of mild cognitive
Alzheimer’s Association (AA), 623 impairment to dementia, 412f
data on caregivers of patients with dementia, 620 rationale for use of, 426
NIA/AA criteria for dementia syndrome and Amyotrophic lateral sclerosis (ALS), 387, 392, 399
probable Alzheimer disease, 422, 423t, 432r behavioral changes in, 392
NIA/AA criteria for mild cognitive impairment cognitive impairments in, 401r, 402r
due to Alzheimer disease, 406, 413, 415r, 416r differential diagnosis of, 399
Alzheimer’s Disease Cooperative Study, 414 frontotemporal dementia and (FTD-ALS), 478
Alzheimer’s Disease Diagnostic and Treatment phosphorylated tau as biomarker for, 403
Centers (ADDTC), 490 treatment in prodromal stage of, 399
Alzheimer’s Disease Education and Referral ANNA-1 (antineuronal nuclear antibody type 1;
Center, 623 anti-Hu) antibody, 542t, 544, 548f, 556, 557r
Alzheimer’s Disease Neuroimaging Initiative ANNA-2 (antineuronal nuclear antibody type 2;
(ADNI), 402r, 411, 417r anti-Ri) antibody, 542t, 545
Alzheimer’s Foundation, 623 ANNA-3 (antineuronal nuclear antibody type 3)
American Academy of Neurology (AAN) antibody, 542t
acceptance of construct of mild cognitive Anosognosia, 421
impairment, 414 Anti-Hu antibody (ANNA-1), 542t, 544, 548f,
guidelines for dementia management, 433r 556, 557r
guidelines for diagnostic evaluation of dementia, Anti-Ri antibody (ANNA-2), 542t, 545
423, 432r Antibody testing, 550Y551, 550f
American Association of Retired Persons, 620 Anticholinergic agents, 514
American Heart Association/American Stroke adverse cognitive effects of, 547t
Association (AHA/ASA), 495 avoiding in Lewy body dementias, 456, 457t
criteria for vascular cognitive impairment, 490, Anticholinergic effects of drugs
491tY492t, 493, 499 antipsychotics, 430
recommendations for management of vascular bladder antispasmodics, 455t
cognitive impairment, 504, 505 SSRIs, 430
American Parkinson Disease Association, 460 tricyclic antidepressants, 451t
!-Amino-3-hydroxy-5-methyl-5-isoxazolepropionic trospium, 455t
acid (AMPA) receptor antibody, 535r, 538, Antidepressants. See also specific drugs and classes
543t, 557r in Alzheimer disease, 430
+-Aminobutyric acid A and B (GABA-A and for anxiety, 453t
GABA-B) receptor antibody, 535r, 538, 543t, for apathy, 451t, 605
550f, 551, 557r cognitive impairment induced by, 547t
for depression, 430, 452t, 603c
AMPA (!-amino-3-hydroxy-5-methyl-
in Lewy body dementias, 451t, 453tY454t, 457t
5-isoxazolepropionic acid) receptor antibody,
tricyclic, 451t, 457t
535r, 538, 543t, 557r
use in autoimmune encephalopathies, 539c
Amphetamine, 454t, 547t
Antiglial/neuronal nuclear (AGNA; SOX1)
Amphiphysin antibody, 542t, 551, 558r
antibody, 542t
Amyloid-" (A")
Antineuronal nuclear antibody type 1 (ANNA-1;
in Alzheimer disease, 429, 431r, 433r, 481, 504 anti-Hu) antibody, 542t, 544, 548f, 556, 557r
future therapies for, 431 Antineuronal nuclear antibody type 2 (ANNA-2;
in cerebral amyloid angiopathy, 501 anti-Ri) antibody, 542t, 545
CSF levels of, 399, 402rY403r Antineuronal nuclear antibody type 3 (ANNA-3)
in Alzheimer disease, 426 antibody, 542t
to predict progression of mild cognitive Antipsychotics. See also specific drugs
impairment to dementia, 412 adverse effects of, 430, 451t
in Lewy body dementias, 460 in elderly patients with dementia, 430Y431,
therapies targeting, 399 434r, 451t
Amyloid PET imaging neuroleptic sensitivity in dementia with Lewy
in Alzheimer disease, 399, 402r, 411, 420, bodies, 438, 439t
424Y426, 425f, 427c, 428c QTc interval prolongation, 451t, 453t, 454t, 458

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 in Alzheimer disease, 430, 434r in dementia with Lewy bodies, 437, 440, 448, 460
Clinical Antipsychotic Trials of Intervention in Parkinson disease dementia, 444, 448, 460
Effectiveness, 434r, 608, 613r ARSA gene mutations, 563t
in frontotemporal dementia, 484 Arsenic toxicity, 525
in Lewy body dementias, 448c, 451t, 453t, 454t, Arteriovenous fistulae
457, 458, 608 dural, rapidly progressive dementia due to,
Anxiety, 388, 398, 547t, 600, 601, 634c 518, 519t, 522, 522f, 536r
in Alzheimer disease, 420, 427c, 430, 603 vascular cognitive impairment and, 494t
among caregivers of patients with dementia, 621t Arylsulfatase A deficiency, 566
coffee-exacerbated, 454t Ashkenazi Jews, 574
in frontotemporal dementia, 603c, 604 Aspergillosis, 519t, 524
in Huntington disease, 604 Association for Frontotemporal Degeneration,
in Lewy body dementias, 445t, 448c, 603, 604 623Y624
medications for, 430, 454t Ataxia
in mild cognitive impairment, 410 autosomal recessive spastic ataxia with
in NMDA receptor encephalitis, 545 leukoencephalopathy, 564t
in progressive supranuclear palsy, 475 childhood ataxia with central hypomyelination/
in semantic variant primary progressive vanishing white matter disease, 562t
aphasia, 470c fragile X-associated tremor/ataxia syndrome, 565t
in Wernicke encephalopathy, 476c leukoencephalopathy with, 562t
Apathy, 392, 600, 601, 602, 610r, 621Y622 Attention deficits
in Alzheimer disease, 420, 603, 610r in adrenoleukodystrophy, 567
differentiating from depression, 605 in Alzheimer disease, 410, 440
in frontotemporal dementia, 410, 465, 466t, assessment for, 386, 391c, 393
468, 468c, 485t in dementia with Lewy bodies, 410, 435, 437,
in Huntington disease, 604 438, 439t, 440, 444.448, 460
in Lewy body dementias, 441c, 445t, 446t, 451t in depression, 602
medications for, 451t, 485t, 605 in frontotemporal dementia, 468cY469c.
in progressive supranuclear palsy, 473, 476 484, 603c
in vascular cognitive impairment, 500, 503c, 603 in Huntington disease, 604
Aphasia induced by dopamine replacement agents, 444
logopenic, 406, 421, 607f in mild cognitive impairment, 409
primary progressive, 469Y473 (See also Primary in Parkinson disease dementia, 435, 442, 443t,
progressive aphasia) 444, 445t, 446t, 448, 460
in progressive supranuclear palsy, 476 in schizophrenia, 601
Apolipoprotein E4 (APOE4) genotype in vascular cognitive impairment, 491t, 497
Alzheimer disease and, 420, 426Y427, 433r AUH gene mutations, 564t
prediction of progression of mild cognitive Autoimmune encephalopathies and dementias,
impairment, 411Y412, 417r 538Y556, 539c, 541, 544c, 546c, 556rY558r
dementia with Lewy bodies and, 449 clinical and serologic spectrum of, 542Y546
APP gene mutations, 428 autoimmune dementia, 510, 521t,
Apparent diffusion coefficient (ADC) maps in 530Y532, 537r, 544
rapidly progressive dementia, 530, 534 brainstem encephalitis, 545
extrapontine myelinolysis, 530c, 531f DPPX encephalitis, 545
hypoglycemic encephalopathy, 528c, 529f limbic encephalitis, 542Y544
Wernicke encephalopathy, 526, 527f NMDA receptor encephalitis, 544Y545
Appetite changes, in Alzheimer disease, 421 other types, 545Y546
Apraxia(s), 402r SREAT, 545Y546
assessment for, 396Y397 clinical examination and cognitive testing for,
definition of, 396 547Y551
limb, 397, 477t antibody testing, 542t, 543t, 550Y551
orobuccal, 389c, 397, 477t CSF analysis, 549Y550
Apraxia of speech, 395, 397, 487r electrophysiology, 549
in corticobasal syndrome, 476, 478 neuroimaging, 547Y549, 548f, 549f
in nonfluent agrammatic variant primary diagnostic clues to, 538Y539, 540Y542, 540t
progressive aphasia, 473, 473t, 477t clinical features, 540Y541
in progressive supranuclear palsy, 475, 475t, detection of neural-specific
476, 487r autoantibodies, 541, 542t, 543t
Arousal level identifying a paraneoplastic disorder, 541
assessment of, 393 improvement after immunotherapy, 541

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 Dementia

personal/family history of autoimmunity, in Huntington disease, 604

541Y542 in Lewy body dementias
risk factors, 541 dementia with Lewy bodies, 437, 441c
differential diagnosis of, 546, 547t Parkinson disease dementia, 442, 445t, 448c
epidemiology of, 540 treatment of, 452t, 458
oncologic significance of, 551Y552 in progressive supranuclear palsy, 475t
treatment of, 538, 552Y556 Bradyphrenia, 441c, 442, 445t
acute therapy, 552Y555 Brain injury, 387, 420, 479, 505, 507r
algorithm for, 554f Brainstem encephalitis, 545
cancer treatment, 556 Bupropion, 451t, 605
chronic therapy, 555Y556 Buspirone, 453t
immunotherapy agents, 552, 553t bvFTD. See Frontotemporal dementia, behavioral
Autonomic dysfunction variant
antipsychotic-induced, 608
in autoimmune encephalopathies, 542t, 543t, C
545, 546c, 555 C9ORF72 gene mutations, 465, 468, 468c, 476,
in inherited leukoencephalopathies, 561, 562t, 478, 479, 479t, 480, 480t, 483, 485t, 486, 486r,
564t, 565t, 575 487r, 532, 602, 604
adult-onset Alexander disease, 570 CAA. See Cerebral amyloid angiopathy
adult-onset autosomal dominant CADASIL (cerebral autosomal dominant
leukodystrophy, 573Y574, 577r arteriopathy with subcortical infarcts and
in Lewy body dementias leukoencephalopathy), 494t, 502, 565t,
dementia with Lewy bodies, 438, 439t 571Y572, 572f, 573f, 577r
Parkinson disease dementia, 445t Calculation ability, assessment of, 397
putative brain substrates for, 459t California Encephalitis Project, 524, 536r
treatment of, 455t Canadian Consensus Conference on the Diagnosis
Azathioprine, for autoimmune encephalopathies, and Treatment of Dementia (2012), 505
539c, 553t, 555, 558r Capgras syndrome, 437
CARASIL (cerebral autosomal recessive
B arteriopathy with subcortical infarcts and
Balamuthia mandrillaris infection, 519t, 524, leukoencephalopathy), 502, 565t, 573
525, 536r Carbidopa/levodopa, for parkinsonism
Behavioral disinhibition adverse cognitive effects of, 444
in Alzheimer disease, 421 in frontotemporal dementia, 484
assessment for, 390Y392, 398 in Lewy body dementias, 450t, 452t, 456, 457
in behavioral variant of frontotemporal dementia, dementia with Lewy bodies, 438, 441c, 458
465, 466t Parkinson disease, 437Y438, 444, 448c
medications for, 484, 485t Cardiovascular effects of drugs
in progressive supranuclear palsy, 475 acetylcholinesterase inhibitors, 429, 450t, 456
Behavioral functioning assessment, 390Y392, atypical antipsychotics, 430, 451t, 453t, 454t, 458
390cY391c, 398 Caregiver Action Network, 624
Behavioral Risk Factor Surveillance System, 620 Caregiver Distress Scale, 432r
Benson figure, 396 Caregiver stress, 388, 619Y624, 619c, 620c, 623c
Benzodiazepines, 547t assessment instruments for, 621, 622t
avoiding in Lewy body dementias, 457t definition of, 620
for REM sleep behavior disorder, 458 demographics of caregivers of patients with
Biomarkers dementia, 620
for Alzheimer disease, 423Y426, 433r due to patient’s neuropsychiatric symptoms,
for frontotemporal dementia, 480Y481 420, 421, 604Y605
to predict progression of mild cognitive management of, 606Y608, 612r, 613r
impairment to dementia, 412Y413 patients with Alzheimer disease and, 420, 421,
testing for, 399Y400, 401, 402rY403r 429, 431
Bipolar disorder, 602 patients with dementia with Lewy bodies and,
Bisacodyl, 456t 438, 458
Bismuth toxicity, 525Y526 patients with frontotemporal dementia and,
Bladder antispasmodics, 455t 468cY469c, 481, 484
Bradycardia, acetylcholinesterase patients with Parkinson disease dementia
inhibitorYinduced, 429, 450t, 456 and, 442
Bradykinesia patients with vascular cognitive impairment
in corticobasal syndrome, 478 and, 504

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 positive and negative outcomes of caregiving, Cerebral folate deficiency, 564t
621t Cerebroretinal microangiopathy with
quality of life and, 612r, 613r calcifications and cysts, 519t, 523, 561t
useful websites related to, 623Y624 Cerebrospinal fluid (CSF) analysis, 399Y400,
value of care provided by unpaid caregivers, 620 402rY403r
Caregivers as source of patient information, 398, in Alzheimer disease, 399Y400, 402rY403r, 426,
442, 469, 481, 606 433r, 447, 518
Case studies for differentiation from frontotemporal
Appropriate Use Criteria for amyloid PET dementia, 480Y481, 482, 484
imaging, 427c, 428c in autoimmune encephalopathies, 549Y550
autoimmune encephalopathy, 539c, 544c, 546c in CNS or intravascular lymphoma, 533
behavioral variant of frontotemporal dementia, in dementia with Lewy bodies, 447
390cY391c, 468cY469c in Jakob-Creutzfeldt disease, 518
caregiver stress, 619c, 620c, 623c in mild cognitive impairment, 411
cerebral amyloid angiopathy, 503c to predict progression to dementia, 412, 417r
coding for dementia, 628cY630c, 632cY636c in Parkinson disease, 400, 402rY403r
dementia with Lewy bodies, 441c in rapidly progressive dementia, 515Y518,
ethical considerations for use of next-generation 516tY517t
drugs in Alzheimer disease, 615c Cerebrospinal fluid (CSF) infusion testing, 579,
hypoglycemic encephalopathy, 528cY530c 591Y593
idiopathic normal pressure hydrocephalus, Cerebrospinal fluid (CSF) tap test, 579, 586Y587,
593cY595c 596, 597t, 598t
mental status examination Cerebrotendinous xanthomatosis, 560, 561t, 565t,
executive function, 390cY391c 570, 577r
language deficits, 389c Cerebrovascular disease. See also Stroke
memory impairment, 386cY387c autopsy studies of, 502, 504, 507r
metachromatic leukodystrophy, 567cY568c neuroimaging for detection of, 399, 495,
mild cognitive impairment, 405c.411c 496fY499f, 497, 498c, 499Y500, 499c
amnestic type, 386cY387c silent, 493
Parkinson disease dementia, 448c vascular cognitive impairment and, 490,
primary progressive aphasia 491tY492t, 493, 495Y500
nonfluent agrammatic variant, 389c, 474cY475c coding for, 627t
semantic variant, 470cY471c secondary prevention of, 504, 505, 507
psychiatric disorders and dementia, 603c Chief complaint, 388, 631
vascular cognitive impairment, 498c, 499c Childhood ataxia with central hypomyelination/
Wernicke encephalopathy, 526cY528c vanishing white matter disease, 562t
CASPR2 (contactin-associated proteinlike 2) Circumlocutions, 394, 470c, 473
antibody, 538, 543t, 551, 556r Citalopram, 430, 452t, 453t, 468c, 484,
Category naming fluency, 397 485t, 539c
CBD, CBS. See Corticobasal degeneration/ CLCN2 gene mutations, 562t
corticobasal syndrome Clinical Antipsychotic Trials of Intervention
Centers for Disease Control and Prevention, 512, 525 Effectiveness, 434r, 608, 613r
Centers for Medicare & Medicaid Services (CMS), Clinical Dementia Rating Scale, 466t
626, 630 Clonazepam, 454t, 634c
Central nervous system lupus, 520t, 550, 557r Clozapine, 608
Central nervous system vasculitis, 513t, 514, 519t, adverse effects of, 451t, 458
520t, 522, 531Y532, 546, 547t in Lewy body dementias, 451t, 454t, 457Y458
Cerebral amyloid angiopathy (CAA), 493, 494t, CMS (Centers for Medicare & Medicaid Services),
500, 501Y502, 503c, 503f, 505, 508r 626, 630
Alzheimer disease and, 429, 501Y502 Cobalamin C disease, 561t, 564t
modified Boston criteria for, 501t Cockayne syndrome, 561t, 562t, 564t
rapidly progressive dementia due to, 518, 519t, Coding for dementia, 626Y636, 627tY628t,
523, 523f, 536r 628cY630c, 632cY636c, 636r
Cerebral autosomal dominant arteriopathy with Coffee, 451t, 454t
subcortical infarcts and leukoencephalopathy Cognitive effects of drugs
(CADASIL), 494t, 502, 565t, 571Y572, 572f, anticholinergic agents, 547t
573f, 577r antipsychotics, 430
Cerebral autosomal recessive arteriopathy with dopamine replacement agents, 444, 456Y457
subcortical infarcts and leukoencephalopathy Cognitive impairment. See also specific dementias
(CARASIL), 502, 565t, 573 and encephalopathies

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 Dementia

in adult-onset leukoencephalopathies, 560Y561 Constipation, in Lewy body dementias, 438, 458

age-related, 420 treatment of, 456t
in Alzheimer disease, 419, 420, 422, 423, Contactin-associated proteinlike 2 (CASPR2)
431rY434r, 440 antibody, 538, 543t, 551, 556r
in autoimmune encephalopathies, 547 Corticobasal degeneration (CBD)/corticobasal
in behavioral variant of frontotemporal syndrome (CBS), 402r, 464, 474Y476
dementia, 467 alien limb syndrome and, 476
in cerebral amyloid angiopathy, 501Y502 behavioral changes in, 392
in corticobasal degeneration, 476 clinical features of, 440
in corticobasal syndrome, 440 differentiation from Lewy body dementias,
depression and, 602 447, 448
in idiopathic normal pressure hydrocephalus, neuroimaging in, 478
579, 582 neurologic examination in, 476Y478
in Lewy body dementias neuropsychological testing in, 475f, 478
dementia with Lewy bodies, 435, 436Y437, phenotypic presentations of, 476, 477t
438, 439t, 440 Corticosteroids
medications for, 449, 450t, 456Y457 for autoimmune encephalopathies, 532,
Parkinson disease dementia, 435, 436, 539c, 546c
442Y444, 443t, 444t, 448c acute therapy, 552Y555, 553t, 554f
major and mild neurocognitive impairment in chronic therapy, 555Y556
DSM-5, 413, 421Y422, 422t Hashimoto encephalopathy (SREAT),
medications for, 429Y430 545Y546, 557r
acetylcholinesterase inhibitors, 429Y430 lack of response to, 538, 552
memantine, 430 paraneoplastic encephalitis, 556
mental status examination for, 385Y401, avoiding before brain biopsy for CNS
401rY403r lymphoma, 533
in metachromatic leukodystrophy, 567c for cerebral amyloid angiopathy, 523, 523f
mild, 404Y415, 415rY418r CPT (Current Procedural Terminology) codes,
in multiple sclerosis, 560 598r, 626Y636, 636r
pace of progression of, 387 CRMP-5 (collapsin response mediator protein-5)
in progressive supranuclear palsy, 440, 476 antibody, 542t, 550
vascular, 490Y507, 507rY509r CSF. See Cerebrospinal fluid
COL4A1 gene mutations, 502, 561t, 565t, 573 CSF1R gene mutations, 565t, 575, 578r
Collapsin response mediator protein-5 (CRMP-5) CT. See Computed tomography
antibody, 542t, 550 Current Procedural Terminology (CPT) codes,
Color processing, assessment of, 396 598r, 626Y636, 636r
Comprehension deficits Cyclophosphamide, for autoimmune
assessment for, 389, 389c, 394, 395, 397 encephalopathies, 538, 553t, 555, 556
in metachromatic leukodystrophy, 567c CYP27A1 gene mutations, 565t, 570
in nonfluent agrammatic variant primary
progressive aphasia, 389c, 401r, 473, 473t, 477t D
in Parkinson disease dementia, 445t DAP12 gene mutations, 564t
in semantic variant primary progressive aphasia, Darifenacin, 455t
470, 470cY471c, 472, 472t DARS2 gene mutations, 564t
Computed tomography (CT) DAT (dopamine transporter), in Lewy body
in Alzheimer disease, 424 dementias, 438, 439t, 447, 463r
in behavioral variant of frontotemporal DAVF (dural arteriovenous fistula), 518, 519t, 522,
dementia, 465 522f, 536r
in cerebrovascular disease, 495 Daytime sleepiness, 437, 440, 445t, 446t
to detect neoplasm, 533 treatment of, 454t
in idiopathic normal pressure hydrocephalus, Dejerine, Joseph, 600
580, 582 Delusions, 600, 601, 603, 622
after shunt surgery, 589, 590f in Alzheimer disease, 421, 600, 603
in rapidly progressive dementia, 517t, 518 in dementia with Lewy bodies, 437, 439t, 604
Computed tomography (CT) angiography in extrapontine myelinolysis, 530c
in cerebrovascular disease, 498c in frontotemporal dementia
in vascular etiologies of rapidly progressive behavioral variant, 465
dementia, 522 with C9ORF72 mutation, 532
Computerized cognitive test batteries, 387 in frontotemporal dementiaYmotor neuron
COMT gene mutations, 449 disease, 478

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 induced by dopamine replacement agents, 444 Describe, Investigate, Create, Evaluate (DICE)
medications for, 449, 451t, 457 approach to dementia-related behavioral
in NMDA receptor encephalitis, 545 problems, 608, 609f, 622Y623, 623c
in Parkinson disease dementia, 442, 445t, 446t, DESH (disproportionately enlarged subarachnoid
448c, 604 space hydrocephalus), 582Y583, 594c, 594f
Dementia with Lewy bodies (DLB), 402r, Dexamethasone, for cerebral amyloid angiopathy,
435Y442, 441c, 460rY463r 523f
clinical features of, 436Y438 Diagnostic and Statistical Manual of Mental
associated symptoms, 438 Disorders, Fifth Edition (DSM-5), 416r, 432r
autonomic impairment, 438 major depression in, 446t
cognitive symptoms, 436Y437 major neurocognitive impairment in, 413,
fluctuations of attention and arousal, 437 421Y422, 422t
neuroleptic sensitivity, 438 mild neurocognitive impairment in, 406Y407,
neuropsychiatric symptoms, 437, 603, 604 407f, 408f, 413, 421Y422, 422t, 427c, 428c
parkinsonian motor signs, 437Y438 vascular cognitive impairment in, 490,
REM sleep behavior disorder, 438 491tY492t, 493
diagnostic criteria for, 438Y442, 439tY440t DICE (Describe, Investigate, Create, Evaluate)
diagnostic studies in, 444Y447 approach to dementia-related behavioral
EEG, 399 problems, 608, 609f, 622Y623, 623c
differential diagnosis of, 447Y448 Diencephalic angioencephalopathy, subacute,
genetics of, 449 519t, 523, 524f, 536r
mild cognitive impairment preceding, 458Y459 Differential diagnosis of neurodegenerative
neuropathology of, 435Y436 diseases, 387, 398Y400. See also specific
rapidly progressive, 514 disorders
symptomatic treatment in, 449Y458, 450tY457t Diffusion-weighted imaging (DWI)
for cognitive impairment, 449, 456Y457 in cerebral small vessel disease, 496f
guidelines for, 449 in rapidly progressive dementia, 530
medications to avoid, 457t extrapontine myelinolysis, 530c, 531c
for parkinsonism, 458 hypoglycemic encephalopathy, 528cY530c,
for psychosis, 457Y458 529f
for REM sleep behavior disorder, 458 MELAS, 534f
timing of dementia relative to parkinsonism in, thiamine deficiency, 526, 526cY528c, 527f
435, 436 vascular causes, 522
treatment in prodromal stage, 399 Dipeptidyl-peptidase 6 (DPPX) antibody, 538,
Demyelination, 499, 502, 515, 559, 560, 566 543, 545, 546c, 550f, 557r
Depression, 388, 398, 547t, 600, 601, 602, Diphenhydramine, 457t
603c, 611r Disease-modifying therapies, 385, 388, 399, 401,
in Alzheimer disease, 421, 427c, 603, 613r 425, 459, 502
treatment of, 430 Disproportionately enlarged subarachnoid space
in autoimmune encephalopathies, 546 hydrocephalus (DESH), 582Y583, 594c, 594f
NMDA receptor encephalitis, 543t, 545 DLB. See Dementia with Lewy bodies
in caregivers of patients with dementia, Docusate, 456t
621Y622, 621t Donepezil
cognitive impairment and, 602 for Alzheimer disease, 429, 433r, 456, 615c, 620c
differentiation from apathy, 605 in Lewy body dementias, 449, 450t
in Huntington disease, 604 in mild cognitive impairment, 414, 416r
in idiopathic normal pressure hydrocephalus, in vascular cognitive impairment, 505
582, 585t, 597r Dopamine agonists/dopamine replacement
in Lewy body dementias, 603 adverse cognitive effects of, 444, 456Y457
dementia with Lewy bodies, 439t avoiding in Lewy body dementias, 457t
Parkinson disease dementia, 443t, 445t, conditions with lack of response to, 448
448c, 604 for Parkinson disease dementia, 442
treatment of, 452t psychiatric symptoms induced by, 442, 444,
in mild cognitive impairment, 410, 602 457, 604
in multiple sclerosis, 560 use in frontotemporal dementia, 484, 485t
in progressive supranuclear palsy, 476 Dopamine antagonists, avoiding in Lewy body
in semantic variant primary progressive dementias, 457t
aphasia, 470c Dopamine loss
treatment of, 607, 608 Lewy body dementias and, 435, 436, 438, 459,
in vascular cognitive impairment, 500, 603 459t, 460

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 Dementia

schizophrenia and, 601 Evans ratio or index, in idiopathic normal pressure

Dopamine transporter (DAT), in Lewy body hydrocephalus, 582, 583f
dementias, 438, 439t, 447, 463r Executive dysfunction
DPPX (dipeptidyl-peptidase 6) antibody, 538, 543, in Alzheimer disease, 406, 419, 420, 421, 423t, 428c
545, 546c, 550f, 557r assessment for, 385, 387, 387c, 389c, 390,
DSM-5. See Diagnostic and Statistical Manual of 390cY391c, 397Y398
Mental Disorders, Fifth Edition in autoimmune encephalopathies, 543t
Dural arteriovenous fistula (DAVF), 518, 519t, in corticobasal degeneration, 476, 478
522, 522f, 536r in depression and bipolar disorder, 602
DWI. See Diffusion-weighted imaging in extrapontine myelinolysis, 530c
Dysarthria in frontotemporal dementia, 485t
in adult-onset Alexander disease, 570 behavioral variant, 390cY391c, 466c, 467, 603c
in bismuth toxicity, 526 with motor neuron disease, 478
in cerebral amyloid angiopathy, 523 in Huntington disease, 604
distinction from apraxia of speech, 395 in idiopathic normal pressure hydrocephalus, 582
in extrapontine myelinolysis, 531c in Lewy body dementias, 436, 438, 439t, 442,
in IgLONS5 autoimmune encephalopathy, 543t 445t, 446t, 447, 448c
poststroke, 495 effects of excessive dopamine replacement
in progressive supranuclear palsy, 476 on, 444
in subacute diencephalic angioencephalopathy, in multiple sclerosis, 560
524 in nonfluent agrammatic variant of primary
Dyslexia, surface, 395, 472t progressive aphasia, 389c
Dysmyelination, 559 in progressive supranuclear palsy, 476
Dystonia in schizophrenia, 601
in corticobasal syndrome, 447, 477t, 478 social deficits and, 398
jaw, in brainstem encephalitis, 545, 557r in vascular cognitive impairment, 483Y494,
in NMDA receptor encephalitis, 545 491t, 500
in Richardson syndrome, 476 visual-perceptual-spatial deficits and, 396
working memory and, 398
E Exercise, 621
E/M (Evaluation and Management) codes, 626, in Alzheimer disease, 429
631, 634, 635, 636, 636r in Lewy body dementias, 452t
Echolalia, 392, 567c in mild cognitive impairment, 414
Echopractic behavior, 392 to prevent cognitive decline, 506, 509r, 618r
EEG. See Electroencephalogram External lumbar drainage, for idiopathic normal
EIF2B1 gene mutations, 562t pressure hydrocephalus, 593, 593f
EIF2B2 gene mutations, 562t Extrapontine myelinolysis, 530, 530cY531c, 531f
EIF2B3 gene mutations, 562t
EIF2B4 gene mutations, 562t F
EIF2B5 gene mutations, 562t Fabry disease, 561t, 563t, 566
Electroencephalogram (EEG), 399 Face processing, assessment of, 396
in autoimmune encephalopathies, 539c, 543, Family Caregiving Alliance, 624
544c, 546c, 549, 550, 554f, 557r Financial judgment deficits, 390c, 392
in Lewy body dementias, 439t, 444 Finger agnosia, 397, 421
in metachromatic leukodystrophy, 567c Fludrocortisone, 455t
in rapidly progressive dementia, 515, 517t, Fluoxetine, 452t, 485t
526c, 537r Fluvoxamine, 485t, 489r
MELAS, 534f FMR1 gene mutations, 565t
in vascular cognitive impairment, 505 FOLR1 gene mutations, 564t
Electrolyte abnormalities, 528 Frontal Behavioral Inventory, 398, 402r, 482,
Encephalitis. See also specific types 606, 613r
rapidly progressive dementia due to, 514, 519t, Frontal behavioral-spatial syndrome, 477t
523Y525 Frontotemporal dementia (FTD), 401r, 464Y486,
ERCC6 gene mutations, 564t 486rY489r
ERCC8 gene mutations, 564t age at onset of, 464
Escitalopram, 448c, 452t, 453t age-related prevalence of, 465
Ethical considerations for use of next-generation behavioral variant (bvFTD), 390cY391c, 464,
drugs in Alzheimer disease, 615Y617, 615c, 618r 465Y469, 468cY469c
Evaluation and Management (E/M) codes, 626, diagnosis of, 469
631, 634, 635, 636, 636r diagnostic criteria for, 466tY467t

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 neuroimaging in, 391c, 391f, 468Y469, 469f differential diagnosis of, 585tY586t
neurologic examination in, 465, 467 evaluation of, 587
neuropsychiatric symptoms of, 602, 603c, 604 after shunt surgery, 589, 593, 594cY595c, 595
neuropsychological testing in, 467Y468 in Krabbe disease, 566
vs. phenocopy syndrome, 400, 403r, 469, 486r in Lewy body dementias
symptoms of, 392, 465 dementia with Lewy bodies, 437, 441c
caregivers of patients with, 484 Parkinson disease dementia, 442, 448c
coding for, 627t treatment of, 452t, 458
CSF and serum biomarkers for, 480Y481 in metachromatic leukodystrophy, 566, 567cY568c
diagnostic workup for, 481Y484 in progressive supranuclear palsy, 475t, 476
differential diagnosis of, 399, 400 in vascular cognitive impairment, 491t, 495,
adult-onset leukoencephalopathy with axonal 499c, 500, 522
spheroids and pigmented glia, 575, 578r !-Galactosidase deficiency, 566
Alzheimer disease, 400, 401r, 486r, 535r Galantamine
disorders related to, 464, 473Y478 for Alzheimer disease, 429, 434r
corticobasal syndrome, 464, 476Y478 in Lewy body dementias, 450t
progressive supranuclear palsy, 464, in mild cognitive impairment, 416r
473Y476 in vascular cognitive impairment, 505
epidemiology of, 464Y465 GALC gene mutations, 563t
historical descriptions of, 600 Ganglionic acetylcholine receptor antibody,
management of, 484Y486 543t, 545
medications, 484Y486, 485t Gastrointestinal effects of acetylcholinesterase
supportive management and follow-up inhibitors, 429, 449, 450t
assessments, 484 GBA gene mutations, 449
with motor neuron disease (FTD-ALS), 464, 478 GBE1 gene mutations, 565t, 574
neuropathology of, 479Y480, 482f, 483f GCDH gene mutations, 564t
nonfluent agrammatic variant primary Generalized anxiety disorder, 410
progressive aphasia, 464, 473, 474cY475c Genetics. See also specific genes
prognosis for, 478 of adult-onset leukoencephalopathies, 559,
rapidly progressive, 514Y515, 514t, 532 560, 562, 562tY565t
risk factors for, 478Y479 of Alzheimer disease, 426Y429, 433r
environmental, 479 of frontotemporal dementia, 479, 479t, 480t, 488r
genetic, 479, 479t, 480t of Lewy body dementias, 449
semantic variant primary progressive aphasia, Geriatric Depression Scale, 606, 613r
464, 469Y472, 470cY471c Gerstmann syndrome, 421
subtypes of, 464 GFAP gene mutations, 562t, 569, 570, 577r
TDP-43 protein in, 400 Gibbs, Clarence J., 511
Frontotemporal Dementia Rating Scale, 482 GJC2 gene mutations, 564t
Frontotemporal lobar degeneration (FTLD), 470f GLA gene mutations, 563t
definition of, 464 GLB1 gene mutations, 563t
gene mutations associated with, 480tY481t, 488r Global Deterioration Scale, 404Y405
neuropathologic classification of, 482f Globoid cell leukodystrophy (Krabbe disease),
FTD. See Frontotemporal dementia 559, 560, 561tY563t, 565, 566, 576r
FTLD. See Frontotemporal lobar degeneration Glutamic acid decarboxylase 65 (GAD65)
FUCA1 gene mutations, 563t antibody, 513t, 538, 542t, 552
Fucosidosis, 563t, 565 Glycine receptor antibody, 538, 543t, 545, 557r
Functional Activities Questionnaire, 466t GM1 gangliosidosis, 560, 561t, 563t, 565
Functional assessment, 409Y410 GM2 gangliosidosis, 561t, 563t, 566
GRN gene mutations, 468, 468c, 476, 479, 479t,
G 480, 480t, 481, 483f, 488r, 602, 611r
GABA-A and GABA-B (+-aminobutyric acid A and B)
receptor antibodies, 538, 543t, 550f, 551, 557r H
GAD65 (glutamic acid decarboxylase 65) Hallucinations, 582, 600, 601, 603c, 622
antibody, 513t, 538, 542t, 552 in Alzheimer disease, 421, 440, 600, 603
Gait impairment, 597r, 634c in autoimmune encephalopathies, 543t, 546c
coding for, 634 in behavioral variant of frontotemporal
in extrapontine myelinolysis, 530c dementia, 465
in frontotemporal dementia, 484 in extrapontine myelinolysis, 530c
in idiopathic normal pressure hydrocephalus, in frontotemporal dementiaYmotor neuron
579, 580, 581Y582, 581f, 584, 597r disease, 478

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 Dementia

induced by dopamine replacement agents, in behavioral variant of frontotemporal dementia,

444, 458 465, 466t
in Lewy body dementias, 435, 436, 460, 603 medications for, 485t
dementia with Lewy bodies, 436, 437, 439t, Hypersexuality, 391
440, 441c, 447, 448, 463r, 604, 608 Hypoglycemic encephalopathy, 514, 520t, 528,
medications for, 449, 451t, 457 528cY530c, 529f
Parkinson disease dementia, 442, 445t, 446t,
447, 448, 448c, 604 I
putative brain substrates for, 459t ICD-10. See International Classification of
in toxic-metabolic encephalopathy, 525 Diseases, Tenth Revision
Haloperidol, 614r ICP. See Intracranial pressure
use in Lewy body dementias, 438, 448c, 457t IgLON family member 5 (IgLON5) antibody, 543t,
Hashimoto encephalopathy (SREAT), 513t, 520t, 551, 558r
544c, 545Y546 Immunotherapy for autoimmune encephalopathies,
HDLS (hereditary diffuse leukoencephalopathy 552Y556, 553t
with spheroids), 565t, 575, 577rY578r acute therapy, 552Y555
Head injury, 387, 420, 479, 505, 507r algorithm for, 554f
Headache chronic therapy, 555Y556
in autoimmune encephalopathies, 540t, 546 Impulsivity, 603, 622
limbic encephalitis, 544 in Alzheimer disease, 421
NMDA receptor encephalitis, 545 in frontotemporal dementia, 465, 466t, 467,
in CADASIL, 572 468, 468cY469c, 484, 604
after CSF shunt surgery, 589 in Parkinson disease, 392, 401r
due to dural arteriovenous fistula, 522 Infectious etiologies of rapidly progressive
due to venous sinus thrombosis, 522 dementia, 514, 519t, 523Y525
IVIg-induced, 553t metagenomic deep sequencing for identification
after lumbar puncture, 426, 587 of, 525
in retinal vasculopathy with cerebral Informant Questionnaire on Cognitive Decline in
leukodystrophy, 573 the Elderly (IQCODE), 497, 507r
in subacute diencephalic angioencephalopathy, Inhibitory control, assessment of, 398
523, 524f iNPH. See Normal pressure hydrocephalus,
Hemoglobin A1c, 505, 506, 630c, 633c idiopathic
HEPACAM gene mutations, 562t Insight, limited, 388, 390, 392, 398
Hereditary diffuse leukoencephalopathy with in Alzheimer disease, 421
spheroids (HDLS), 565t, 575, 577rY578r in frontotemporal dementia, 410, 481
Herpes simplex virus infection, 519t, in metachromatic leukodystrophy, 567c
523Y524, 547t Insomnia. See Sleep disturbances
HEX gene mutations, 563t International Classification of Diseases, Tenth
Hippocampus Revision (ICD-10), 507r, 636r
in Alzheimer disease, 386c, 422Y423, 423t, ICD-10-CM codes for dementia, 626Y636
428c, 432r, 433r, 444, 582 vascular cognitive impairment in, 490
in autoimmune encephalopathies, 539c, 543, 550f International Society of Vascular Behavioral and
in rapidly progressive dementias, 530c Cognitive Disorders (Vas-Cog) criteria for
in vascular cognitive impairment, 494t vascular cognitive impairment, 490, 491tY492t,
HIV (human immunodeficiency virus) disease, 493, 499
413, 512, 514, 515, 519t, 524, 536r, 547t Intracranial pressure (ICP), in idiopathic normal
Homewatch Caregivers, 624 pressure hydrocephalus, 581f
HTRA1 gene mutations, 502, 565t, 573 monitoring of, 593Y596, 598rY599r
Human immunodeficiency virus (HIV) disease, Intravenous immunoglobulin (IVIg), for
413, 512, 514, 515, 519t, 524, 536r, 547t autoimmune encephalopathies, 538,
Huntington disease, 513t, 604, 607f, 612r 552Y555, 553t
Hydrocephalus Involuntary movements, 398, 581
disproportionately enlarged subarachnoid IQCODE (Informant Questionnaire on Cognitive
space, 582Y583, 594c, 594f Decline in the Elderly), 497, 507r
idiopathic normal pressure, 579Y596, Irritability, 600, 601, 602, 603c, 622
596rY599r in Alzheimer disease, 420, 421, 430, 603
Hyperglycemia, 520t, 528 in autoimmune encephalopathy, 546c
corticosteroid-induced, 553t, 556 in Huntington disease, 604
Hyperoral behavior, 392 medications for, 430, 484

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IVIg (intravenous immunoglobulin), for autoimmune adult-onset autosomal dominant
encephalopathies, 538, 552Y555, 553t leukodystrophy, 573Y574, 574f
adult polyglucosan body disease, 574Y575
J Alexander disease, 560, 562t, 569Y570, 571f,
Jakob-Creutzfeldt disease (JCD), 510 576rY577r
CSF analysis in, 518 with axonal spheroids and pigmented glia,
differential diagnosis of 575, 577r
mitochondrial disorders, 533 clinical approach to, 560
in referral centers for rapidly progressive dementia in multiple sclerosis and, 560Y561
dementia, 510Y515, 511f, 514t dysmyelination and demyelination in, 559
Wernicke encephalopathy, 526cY528c, 527f eye abnormalities in, 561t
time from onset to dementia in, 514 forms of, 561Y562, 562tY565t
Judgment of Line Orientation test, 401r genetics of, 559, 560, 562, 562tY565t
lysosomal storage diseases, 560, 562, 563t,
K 565Y566, 576r
Kokmen Short Test of Mental Status, 417r, Krabbe disease (globoid cell leukodystrophy),
544c, 547 559, 560, 561tY563t, 565, 566, 576r
Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy, 559, 560,
559, 560, 561tY563t, 565, 566, 576r 561tY563t, 565, 566, 567cY568c, 568f, 576r
Kraepelin, Emil, 601 macrocephaly in, 560
Kv1 (potassium channel complex) antibodies, mitochondrial disorders, 560, 561t, 562,
538, 551, 556r 563tY564t, 576r
with peripheral neuropathy, 562t
L peroxisomal disorders, 560, 561tY563t, 566Y567
L2HGDH gene mutations, 564t with small vessel vasculopathy, 570Y573
Laboratory studies, 385, 388, 399Y400, 401, CADASIL, 494t, 502, 565t, 571Y572, 572f,
402rY403r. See also Cerebrospinal fluid analysis 573f, 577r
in adult-onset leukoencephalopathies, 560 CARASIL, 502, 565t, 573
antibody testing, 550Y551, 550f COL4A1-related disorders, 502, 561t,
in metachromatic leukodystrophy, 567c 565t, 573
in rapidly progressive dementia, 515Y518, X-linked adrenoleukodystrophy and
516tY517t adrenomyeloneuropathy, 559, 562t, 563t,
Labrune syndrome, 561t 566Y567, 569, 576r
Lactulose, 456t Levetiracetam, 539c
Language deficits Levodopa. See also Carbidopa/levodopa
in Alzheimer disease, 420 in progressive supranuclear palsy, 475t
assessment for, 388Y390, 389c, 394Y396 Lewy, Frederick, 435
in corticobasal degeneration, 476 Lewy bodies, 435Y436
in mild cognitive impairment, 409 Lewy Body Dementia Association, 460, 624
in Parkinson disease dementia, 442 Lewy body dementias, 435Y460, 460rY463r. See
in progressive supranuclear palsy, 475Y476 also Dementia with Lewy bodies; Parkinson
in semantic variant primary progressive disease dementia
aphasia, 470Y471, 472 clinical features of, 436, 460
Laxatives, 456t neuropsychiatric symptoms, 603, 604
Lead toxicity, 525 dementia with Lewy bodies, 436Y442
Leucine-rich, glioma inactivated 1 (LgI1) diagnostic studies for, 444, 447
antibody, 538, 539c, 540, 541, 543t, 544, 551, differential diagnosis of, 447Y448, 448c
552, 556r, 557r at referral centers for rapidly progressive
Leukodystrophy, 559, 565t dementia, 514Y515, 514t
adult-onset autosomal dominant, 573Y574, 574f genetics of, 449
definition of, 559 neuropathology of, 435Y436
globoid cell (Krabbe disease), 559, 560, Parkinson disease dementia, 442Y447
561tY563t, 565, 566, 576r rapidly progressive, 514
metachromatic, 559, 560, 561tY563t, 565, 566, symptomatic treatment in, 449Y458, 450tY456t
567cY568c, 568f, 576r for cognitive impairment, 449, 456Y457
pigmented orthochromatic, 575, 577r guidelines for, 449
X-linked adrenoleukodystrophy, 559, 562t, medications to avoid, 457t
563t, 566Y567, 569, 576r for parkinsonism, 458
Leukoencephalopathies, adult-onset, 559Y575, for psychosis, 457Y458
575rY578r for REM sleep behavior disorder, 458

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 Dementia

trends affecting diagnosis and management of, behavioral variant, 391c, 391f, 465
458Y460 in hypoglycemic encephalopathy, 539f
mechanisms for dementia and in idiopathic normal pressure hydrocephalus,
disease-modifying treatment trials, 580, 582Y584, 583f
459Y460, 459t after shunt surgery, 589
mild cognitive impairment preceding in Jakob-Creutzfeldt disease, 530, 534
dementia with Lewy bodies, 458Y459 in limbic encephalitis, 538
preclinical synucleinopathies, 458 in metachromatic leukodystrophy, 567c, 568f
useful websites related to, 460 in mild cognitive impairment, 410, 411.412f
LgI1 (leucine-rich, glioma inactivated 1) antibody, in multiple system atrophy, 447
538, 539c, 540, 541, 543t, 544, 551, 552, in Parkinson disease dementia, 448c
556r, 557r in primary progressive aphasia
Lifestyle modifications, in mild cognitive nonfluent agrammatic variant, 474f
impairment, 411, 411c, 414 semantic variant, 471c, 471f
Limbic encephalitis, autoimmune, 514, 520t, 535r, in progressive supranuclear palsy, 447, 478, 478f
542Y544, 548f, 556rY557r in rapidly progressive dementia, 517t
antibodies associated with, 538, 542t, 543t vascular etiologies, 522
clinical features of, 538, 540Y541 in subacute diencephalic angioencephalopathy,
LMNB1 gene mutations, 565t, 573 524f
Logopenic aphasia, 406, 421, 607f in Wernicke encephalopathy, 526c, 527f
LRRK2 gene mutations, 449 Magnetic resonance spectroscopy, 517t, 533, 534f
Lyme disease, 512, 519t, 524 Magnetic resonance venography (MRV), 517t, 522
Lymphoma, 548 MAPT gene mutations, 449, 468, 468c, 476, 479,
Hodgkin, 543t 479t, 480t, 482f, 483f, 603
immunosuppressant-induced, 553t MARS2 gene mutations, 564t
intravascular, 520, 522, 532, 533 Mayo Clinic Study of Aging, 408, 409, 417r
non-Hodgkin, 542t MCI. See Mild cognitive impairment
primary central nervous system, 513t, 520t, MCOLN1 gene mutations, 563t
524, 532Y533, 535r, 547t, 559 Megalencephalic leukoencephalopathy with
serum markers for, 516t, 533 subcortical cysts, 562t
Lysosomal storage diseases, 560, 562, 563t, MELAS (mitochondrial myopathy, encephalopathy,
565Y566, 576r lactic acidosis, and strokelike episodes
syndrome), 520t, 521t, 533, 534f, 547t, 548
M Melatonin, 448c, 453t, 454t, 458
Ma1 and Ma2 antibodies, 542t, 545, 557r Memantine
Macrocephaly, 560, 562t, 564t adverse effects of, 430
Magnetic resonance angiography (MRA), 517t, for Alzheimer disease, 429, 430, 434r
522, 522f in frontotemporal dementia, 485, 489r
Magnetic resonance imaging (MRI) in Lewy body dementias, 448c, 450t, 456
in adult-onset Alexander disease, 570, 571f in vascular cognitive impairment, 505
in adult-onset autosomal dominant Memory deficits
leukodystrophy, 574, 574f in Alzheimer disease, 419, 420, 440
in adult-onset leukoencephalopathies, 560, 575r in behavioral variant of frontotemporal
in adult-onset leukoencephalopathy with dementia, 467
axonal spheroids and pigmented glia, 575 in dementia with Lewy bodies, 436, 440
in adult polyglucosan body disease, 574 in metachromatic leukodystrophy, 567c
in Alzheimer disease, 424, 424f in mild cognitive impairment, 405Y406, 405c,
in autoimmune encephalopathies, 547Y549, 548f 406f, 410
in cerebral adrenoleukodystrophy, 569, 569f in semantic variant primary progressive
in cerebral amyloid angiopathy, 501, 503c, aphasia, 472
503f, 523f testing for, 385, 386cY387c, 388, 393Y394
in cerebrotendinous xanthomatosis, 570 working memory, 398
in cerebrovascular disease/vascular cognitive in vascular cognitive impairment, 500
impairment, 399, 495, 496fY499f, 497, 498c, Mental status examination, 385Y401, 386cY387c,
499Y500, 499c, 504, 507r 401rY403r, 605. See also Mini-Mental State
in CNS vasculitis, 532 Examination
to distinguish demyelination from caveats for administration of, 387
dysmyelination, 559 chief complaint, 388
in extrapontine myelinolysis, 531f cognitive domains of, 386, 393Y398, 400
in frontotemporal dementia, 482 attention, 393

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 executive functioning, 397Y398 determining etiology, 410
language, 394Y396 functional assessment, 409Y410
memory, 393Y394 medical comorbidities, 410
social functioning and behavior, 398 mental status examination, 386cY387c, 409
visual-perceptual-spatial functioning, 396Y397 neuroimaging and laboratory studies, 410Y411
differential diagnosis and ancillary testing for depression in, 410, 602
neurodegenerative disease, 388, 398Y400 due to Alzheimer disease, 386cY387c, 404, 410
factors affecting, 387Y388 criteria for, 406Y407, 413Y414
in mild cognitive impairment, 386cY387c diagnosis of, 402r
coding for, 633 management of, 411
cognitive functions targeted by, 385 due to Parkinson disease, 402r, 442, 443t
neurologic history, 387, 388Y392, 400 multiple terminologies for, 405Y407
activities of daily living, 392 preceding dementia with Lewy bodies, 458Y459
executive functioning, 390, 390cY391c predictors of progression to dementia,
language, 388Y390, 389c 411Y413, 432r
memory, 386cY387c, 388 prevalence of, 404, 407Y409
social and personality changes, 390Y392, rate of progression to dementia, 404
390cY391c treatment of, 399, 404, 411, 414, 434r
visual-perceptual-spatial performance, 390 Mini-Mental State Examination (MMSE), 393,
screening tests for, 393, 409, 547 401r. See also Mental status examination
tailoring of, 387 in Alzheimer disease, 430, 615c
Mental status history, 387, 387c, 388, 390 early-onset, 428c
Mercury toxicity, 525 mild, 427c
Metabotropic glutamate receptor 5 (mGluR5) in autoimmune encephalopathies, 547
antibody, 543t coding for, 629c, 633
Metachromatic leukodystrophy, 559, 560, in frontotemporal dementia
561tY563t, 565, 566, 567cY568c, 568f, 576r behavioral variant, 468c
Metagenomic deep sequencing, 525 semantic variant, 471c
N-Methyl-D-aspartate (NMDA) receptor in idiopathic normal pressure hydrocephalus,
antagonist. See Memantine 582
N-Methyl-D-aspartate (NMDA) receptor after shunt surgery, 589
encephalitis, 525, 538, 541, 543t, 544Y545, language deficits on, 389c
548f, 557r, 558r memory impairment on, 386c
antibody testing for, 550, 550f in metachromatic leukodystrophy, 567c
treatment of, 552, 555, 556 in vascular cognitive impairment, 495
Methylenetetrahydrofolate reductase deficiency, Mirtazapine, 453t
564t Mitochondrial disorders, 537r, 547t, 548
Methylphenidate, 454t with leukoencephalopathies, 560, 561t, 562,
Methylprednisolone, for autoimmune 563tY564t, 576r
encephalopathies, 539c, 544c, 546c, 552, with rapidly progressive dementia, 520t, 521t,
553t, 554 533, 537r, 547t, 548
mGluR5 (metabotropic glutamate receptor 5) Mitochondrial myopathy, encephalopathy, lactic
antibody, 543t acidosis, and strokelike episodes syndrome
Michael J. Fox Foundation for Parkinson’s (MELAS), 520t, 521t, 533, 534f, 547t, 548
Research, 460 Mitochondrial neurogastrointestinal
Microdeletion syndromes, 565t encephalopathy syndrome, 562t, 563t
Midodrine, 455t MLC1 gene mutations, 562t
Mild cognitive impairment (MCI), 404Y415, MMACHC gene mutations, 564t
415rY418r MMSE. See Mini-Mental State Examination
amnestic vs. nonamnestic, 405Y406, 408f, 409 MoCA. See Montreal Cognitive Assessment
clinical construct of, 404Y407, 405c Modafinil, 454t
clinical acceptance of, 414Y415 Montreal Cognitive Assessment (MoCA), 393,
comparison of criteria, 407, 408f 401r, 417r, 507r
DSM-5 criteria, 406, 407f, 408f in autoimmune encephalopathies, 547
historical aspects of concept, 404Y405 in behavioral variant of frontotemporal
Key Symposium criteria, 405Y406, 406fY408f dementia, 468c
NIA/AA criteria, 406 in cerebral amyloid angiopathy, 503c
temporal evolution of, 407, 407f in dementia with Lewy bodies, 441c
clinical evaluation of, 409Y411, 411c in idiopathic normal pressure hydrocephalus,
cognitive concern, 409 582, 594cY595c

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 Dementia

after shunt surgery, 589, 594c Navajo neurohepatopathy, 563t

in mild cognitive impairment, 408 Navon figure, 396
in vascular cognitive impairment, 494Y495, 499c Neoplastic causes of rapidly progressive dementia,
Morvan syndrome, 541, 556r 520t, 532Y533
MPV17 gene mutations, 563t Neural networks, 385
MRA (magnetic resonance angiography), 517t, Neuritic plaques, 400, 429, 436, 602, 611r
522, 522f Neurofibrillary tangles, 400, 429, 436, 459t, 502,
MRI. See Magnetic resonance imaging 602, 611r
MRV (magnetic resonance venography), 517t, 522 Neuroimaging, 385, 388, 399Y400, 401. See also
MS. See Multiple sclerosis specific imaging modalities
MSA. See Multiple system atrophy in Alzheimer disease, 424Y425, 424fY425f
MTHFR gene mutations, 564t in autoimmune encephalopathies, 547Y549,
Mucolipidosis type IV, 561t, 563t 548f, 549f
Multiple sclerosis (MS) in cerebral amyloid angiopathy, 501, 503c, 503f
CSF analysis in, 550 in cerebrovascular disease/vascular cognitive
dementia in, 513t, 514, 546, 547t, 559, 560, 576r impairment, 399, 495, 496fY499f, 497, 498c,
differential diagnosis of 499Y500, 499c, 504
adult polyglucosan body disease, 574 in corticobasal degeneration, 478
Susac syndrome, 548 in frontotemporal dementia, 482
incidence of, 580, 596r behavioral variant, 391c, 391f, 468Y469, 469f
Multiple sulfatase deficiency, 563t in idiopathic normal pressure hydrocephalus,
Multiple system atrophy (MSA), 438, 448, 458, 462r 580, 582Y584, 583f
differential diagnosis of, Lewy body dementias, after shunt surgery, 589, 590f
447, 448 in Lewy body dementias, 444, 447
Lewy body pathology in, 435, 436 in mild cognitive impairment, 410Y411, 412f
rapidly progressive dementia due to, 514, 514t in multiple system atrophy, 447
Mycophenolate mofetil, for autoimmune in primary progressive aphasia
encephalopathies, 539c, 546c, 553t, 555Y556 nonfluent agrammatic variant, 473, 474f
semantic variant, 471c, 471f, 472
N in progressive supranuclear palsy, 447,
Nasu-Hakola disease, 564t 476, 478f
National Alliance for Caregiving, 620 in rapidly progressive dementia, 515, 517t, 518
National Center for Health Statistics, 626 Neuroleptic malignant syndrome, 438
National Institute of Neurological Disorders and Neuroleptic sensitivity, in dementia with Lewy
Stroke-Association Internationale pour la bodies, 438, 439t
Recherche et l’Enseignement en Neurosciences Neuroleptics. See Antipsychotics
(NINDS-AIREN) criteria for vascular cognitive Neuroleptospirosis, 525
impairment, 490, 491tY492t, 507t Neurologic examination, 385
National Institute on Aging/Alzheimer’s in Alzheimer disease, 421
Association (NIA/AA) criteria in corticobasal syndrome, 476Y478
for dementia syndrome and probable in frontotemporal dementia, 482
Alzheimer disease, 422, 423t, 432r behavioral variant, 465Y467, 603c
for mild cognitive impairment due to in idiopathic normal pressure hydrocephalus,
Alzheimer disease, 406, 413, 415r, 416r 580, 581Y582
National Multiple Sclerosis Society, 580 after shunt surgery, 589
National Parkinson Foundation, 460 mental status examination, 385Y401
National Prion Disease Pathology Surveillance in metachromatic leukodystrophy, 567c
Center (NPDPSC), 512, 513t in Parkinson disease dementia, 446t
Nausea/vomiting in primary progressive aphasia
in brainstem encephalitis, 545 nonfluent agrammatic variant, 473
drug-induced semantic variant, 472
acetylcholinesterase inhibitors, 449 in progressive supranuclear palsy, 476
azathioprine, 553t in vascular cognitive impairment, 499c, 500
carbidopa/levodopa, 452t Neurologic history, 387, 388Y392, 400
cyclophosphamide, 553t activities of daily living, 392
mycophenolate mofetil, 553t executive functioning, 390, 390cY391c
after lumbar puncture, 587 language, 388Y390, 389c
in NMDA receptor encephalitis, 545 memory, 386cY387c, 388
rapidly progressive dementias with, 526c, social and personality changes, 390Y392,
530c, 533 390cY391c

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 visual-perceptual-spatial performance, 390 differential diagnosis of, 584, 585tY586t
Neuronal ceroid lipofuscinosis, 566 epidemiology of, 579Y580
Neuropathology pathophysiology of, 581f
of Alexander disease, 569 prevalence of, 579Y580
of Alzheimer disease, 429, 432r, 433r, 434r rapidly progressive dementia due to, 514, 514t
cognitive impairments and neural networks, role of comorbiditites in, 584Y586z
385Y386, 401r shunt surgery for, 579, 587Y589, 588f
of corticobasal degeneration, 476 adjustable valves for, 588Y589
of frontotemporal dementia, 479Y480, 482f, 483f choice of shunt valves for, 587Y588
behavioral variant, 391c, 391f, 468Y469, 469f evaluating shunt patency, 596
of Lewy body dementias, 435Y436, 435Y456, indications for, 586
459Y460, 459t longitudinal follow-up after, 589Y591, 590f
Parkinson disease dementia, 400, 401r, 402r purpose of, 587, 588
of semantic variant primary progressive specialized diagnostic testing for, 586Y587
aphasia, 470, 472 symptoms of shunt malfunction, 589Y590
vascular pathology of vascular cognitive worsening of symptoms after, 590Y591
impairment, 493, 494t tests and services at tertiary centers for, 591Y596
Neuropsychiatric Inventory (NPI), 398, 402r, 606 CSF infusion testing, 591Y593
Neuropsychiatric Inventory Questionnaire external lumbar drainage, 593, 593f
(NPI-Q), 606 for high-complexity patients, 591, 592t
Neuropsychiatric symptoms. See Psychiatric intracranial pressure monitoring, 593Y596
disorders patient flow at a hydrocephalus unit, 591, 592f
Neuropsychological testing, 388, 400, 626, 633c shunt patency evaluation, 596
in Alzheimer disease, 427c, 619c NOTCH3 gene mutations, 502, 565t, 571, 572c
early-onset, 428c NPDPSC (National Prion Disease Pathology
in autoimmune encephalopathies, 541, 544c, 547 Surveillance Center), 512, 513t
in behavioral variant of frontotemporal NPH. See Normal pressure hydrocephalus,
dementia, 466t, 467Y468, 603r idiopathic
coding for, 633 NPI (Neuropsychiatric Inventory), 398, 402r, 606
in corticobasal syndrome, 478 NPI-Q (Neuropsychiatric Inventory
in dementia with Lewy bodies, 441c Questionnaire), 606
in idiopathic normal pressure hydrocephalus, Nutritional deficiencies, 526
593, 597r
in mild cognitive impairment, 408, 409, 411c, O
415, 427c Occupational therapy, 606
in mild Parkinson disease dementia, 443t in frontotemporal dementia, 484
in progressive supranuclear palsy, 476 in Lewy body dementias, 441c, 448c, 452t, 458
in semantic variant primary progressive Olanzapine, 430, 457t, 485t, 489r
aphasia, 472 Olfactory abnormality, 438, 458, 542t
in vascular cognitive impairment, 495, 500, 508r Organic acidemias, 564t
NIA. See National Institute on Aging Orthostatic hypotension
NIA/AA criteria. See National Institute on in adult-onset autosomal dominant
Aging/Alzheimer’s Association criteria leukodystrophy, 574
Niacin deficiency, 526, 537r in adult polyglucosan body disease, 574
NINDS-AIREN (National Institute of Neurological antipsychotic-induced, 430, 451t, 457t
Disorders and Stroke-Association in dementia with Lewy bodies, 438
Internationale pour la Recherche et
l’Enseignement en Neurosciences) criteria P
for vascular cognitive impairment, 490, Paraneoplastic processes, 388
491tY492t, 507t with autoimmune encephalopathy, 518, 541,
NMDA receptor. See N-Methyl-D-aspartate receptor 548f, 551Y552, 557r, 558r
Normal pressure hydrocephalus, idiopathic antibody testing for, 550
(iNPH), 579Y596, 593cY595c, 596rY599r treatment of, 556
age at onset of, 579 with rapidly progressive dementia, 513t,
clinical evaluation of, 579, 580Y584 517Y518, 520t, 532
diagnostic criteria, 580 Parkinson, James, 442
neuroimaging, 580, 582Y584, 583f Parkinson disease (PD), 387
neurologic examination and typical behavioral changes in, 392
symptoms, 579, 581Y582 CSF analysis in, 400
typical presentations, 580Y581 differential diagnosis of, 399

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 Dementia

mild cognitive impairment due to, 402r, 442, 443t in autoimmune encephalopathies, 538, 542t
neuropathology of, 435 limbic encephalitis, 542, 544
treatment in prodromal stage of, 399 in frontal behavioral-spatial syndrome, 477t
Parkinson disease dementia (PDD), 435Y436, in frontotemporal dementia, 465, 466t, 469,
442Y444, 460rY463r 482, 532
cognitive deficits in, 442 in Parkinson disease dementia, 445t
diagnostic criteria for, 444, 445tY446t in vascular cognitive impairment, 491t
diagnostic studies for, 444Y447 PET. See Positron emission tomography
differential diagnosis of, 444, 447Y448 PEX gene mutations, 563t
genetics of, 449 Phenocopy syndrome, 400, 403r, 469, 486r
neuropathology of, 435Y436 Philadelphia Brief Assessment of Cognition
neuropsychiatric symptoms of, 603, 604 (PBAC), 401r
psychosis, 442Y444, 445t, 446t, 447, 448, Physical therapy, 606
448c, 604 in frontotemporal dementia, 484
rapidly progressive, 514 in idiopathic normal pressure hydrocephalus, 587
risk factors for, 442, 444t in Lewy body dementias, 441c, 448c, 452t, 458
symptomatic treatment in, 449Y458, 450tY457t Pick, Arnold, 600
for cognitive impairment, 449, 456Y457 Pigmented orthochromatic leukodystrophy
guidelines for, 449 (POLD), 575, 577r
medications to avoid, 457t Plasma exchange, for autoimmune
for parkinsonism, 458 encephalopathies, 538, 539c, 546c, 552, 553t,
for psychosis, 457Y458 554, 556
for REM sleep behavior disorder, 458 PLP1 gene mutations, 564t
timing of dementia relative to parkinsonism in, POLD (pigmented orthochromatic
435, 436 leukodystrophy), 575, 577r
Parkinsonian tauopathies, 440, 447 POLG gene mutations, 563t
Parkinsonism, 486r Polycystic lipomembranous osteodysplasia with
in Alzheimer disease, 421, 440 sclerosing leukoencephalopathy, 564t
in corticobasal syndrome, 447 Polyethylene glycol, 456t
in dementia with Lewy bodies, 421, 436, Positron emission tomography (PET)
437Y438, 439t, 440, 447, 453t in Alzheimer disease, 417r, 424.424f, 432r
in fragile X-associated tremor/ataxia syndrome, amyloid imaging (See Amyloid PET imaging)
565t in autoimmune encephalopathies, 549f
medications for, 453t, 458 for cancer detection, 552
in Parkinson disease dementia, 436, 448c, 486r in corticobasal syndrome, 447Y448
in progressive supranuclear palsy, 447 to detect neoplasm, 533
putative brain substrates for, 459t in frontotemporal dementia, 400, 482, 486r
timing of dementia relative to, 435, 436 behavioral variant, 465, 468, 603c
useful websites related to, 460 in Lewy body dementias, 438, 439t, 444, 446Y447
Paroxetine, 485t, 603c in mild cognitive impairment, 410Y411
PBAC (Philadelphia Brief Assessment of to predict progression to dementia, 412, 412f
Cognition), 401r in posterior cortical atrophy, 447, 462r
PCA-1 (Purkinje cell cytoplasmic antibody type 1), in rapidly progressive dementia, 517t, 518
552 Posterior cortical atrophy, 402r, 406, 421, 447,
PCA-2 (Purkinje cell cytoplasmic antibody type 2), 462r, 607f
542t Potassium channel complex (Kv1) antibodies,
PD. See Parkinson disease 538, 551, 556r
PDD. See Parkinson disease dementia PPA. See Primary progressive aphasia
Pelizaeus-Merzbacher disease, 561t, 562t, 564t Prednisone, 539c, 546c, 555
Pelizaeus-MerzbacherYlike disease, 561t, 564t Presenilin gene mutations, 428
Peroxisomal disorders, 560, 561tY563t, 566Y567 Primary progressive aphasia (PPA), 469Y473
Perseverative behavior, 391c, 392, 397 behavioral changes in, 392
in behavioral variant frontotemporal dementia, differential diagnosis of, 400, 401r
465, 466t, 468 nonfluent agrammatic variant, 389c, 401r, 464,
medications for, 485t 473, 474cY475c
in metachromatic leukodystrophy, 567c diagnostic criteria for, 473t
Personality changes neuroimaging in, 473, 474f
in adult-onset leukoencephalopathies, 560 neurologic examination in, 473
in Alzheimer disease, 420, 421, 423t symptoms of, 473
assessment for, 390Y392, 390cY391c, 398 semantic variant, 464, 469Y472, 470cY471c

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 diagnostic criteria for, 472t Purkinje cell cytoplasmic antibody type 2 (PCA-2),
neuroimaging in, 471c, 471f, 472 542t
neurologic examination in, 472 Pyridostigmine, 455t
neuropsychological testing in, 472
symptoms of, 469Y472 Q
Prion diseases, 399, 510, 518. See also QTc interval, 448c
Jakob-Creutzfeldt disease drug-induced prolongation of, 451t, 453t,
findings from referral centers for rapidly 454t, 458
progressive dementia, 510Y515, Quetiapine
511f, 514t adverse effects of, 451t
Progressive supranuclear palsy (PSP), 464, in Alzheimer disease, 430
473Y476, 487r in frontotemporal dementia, 485t
clinical features of, 392, 440, 473Y476, 475t in Lewy body dementias, 448c, 451t, 453t, 454t,
differentiation from Lewy body dementias, 457, 458, 608
447, 448
neuroimaging in, 476 R
neurologic examination in, 473Y476 Race/ethnicity
neuropsychological testing in, 476 adult polyglucosan body disease and, 574
Richardson syndrome, 447, 475t, 476 Alzheimer disease and, 420, 431r, 433r
Prosody disorders, 394, 395, 629c of caregivers of patients with dementia, 613r, 620
Prosopagnosia, 472 mental status examination and, 387
PSAP gene mutations, 563t Rapid eye movement (REM) sleep behavior
PSEN1 and PSEN2 gene mutations, 428 disorder, 435, 438, 439t, 440, 441c, 448, 448c,
PSP. See Progressive supranuclear palsy 458, 463r, 535r, 603Y604, 612r
Psychiatric disorders, 600Y610, 610rY614r. See putative brain substrates for, 459t
also specific disorders treatment of, 454t, 457t, 458
in adult-onset leukoencephalopathies, 560 Rapidly progressive dementia (RPD), 510Y535,
in Alzheimer disease, 420Y421, 432r, 601Y602, 535rY537r
603 diagnostic approach to, 510, 515Y518
treatment of, 430Y431 initial screening evaluation, 515Y518,
in behavioral variant of frontotemporal 516tY517t
dementia, 602, 603c, 604 differential diagnosis by etiologic category,
caregiver stress due to, 420, 421, 604Y605 518Y533, 519tY521t
management of, 606Y608, 612r, 613r algorithm for, 521f
clinical management of, 606Y608, 609f autoimmune, 515, 530Y532
DICE approach, 608, 609f, 622Y623, 623c infectious, 523Y525
psychotropic medications, 608 (See also neoplastic, 532Y533
specific drugs and classes) neurodegenerative, 532
cognitive decline and dementia foreshadowed systemic/structural, 533
by, 601Y602 toxic-metabolic, 525Y530, 526cY531c, 527f,
as defining features of dementia, 602Y604, 603f 529f, 531f
in dementia with Lewy bodies, 437 vascular, 518, 522Y523, 522fY524f
in Huntington disease, 604 VITAMINS mnemonic, 518
impacts on dementia, 604Y605 findings from referral centers for, 510Y515,
in Lewy body dementias, 437, 603, 604 511f, 513t, 514t
links with dementia, 600Y601 Rasagiline, for Parkinson disease, 448c
symptoms and diagnosis of, 605Y606, 607f Reading ability, assessment of, 389, 389c, 395Y396
Psychosis. See also Delusions; Hallucinations Reflexes/reflex testing, 634, 634c
in Alzheimer disease, 421, 600, 601Y602, 603 in Alzheimer disease, 421
in frontotemporal dementia, 465, 484, 602 in autoimmune encephalopathy, 546c
in Lewy body dementias, 435, 436, 460, 603 in frontotemporal dementia, 465, 467, 468c,
dementia with Lewy bodies, 436, 437, 439t, 472, 603
440, 441c, 447, 448, 463r, 601, 604, 608 in idiopathic normal pressure hydrocephalus,
medications for, 449, 451t, 457Y458 581
Parkinson disease dementia, 442Y444, 445t, in leukoencephalopathies, 560, 561, 575
446t, 447, 448, 448c, 604 metachromatic leukodystrophy, 567c
putative brain substrates for, 459t in vascular cognitive impairment, 495, 499c, 500
schizophrenia, 567, 600, 601Y602, 611r REM sleep behavior disorder. See Rapid eye
Purkinje cell cytoplasmic antibody type 1 (PCA-1), movement sleep behavior disorder
552 Remethylation cycle disorders, 564t

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 Dementia

Repetitive behaviors, 392, 622 hypoglycemia, 528, 530c

in behavioral variant of frontotemporal venous sinus thrombosis, 522
dementia, 391c, 398, 465, 466t Whipple disease, 524
in progressive supranuclear palsy, 475 Selective serotonin reuptake inhibitors (SSRIs)
Respiratory chain defects, mitochondrial, 561t, 563t adverse effects of, 430
Respite care, 621 for apathy in Lewy body dementias, 451t
Retinal vasculopathy with cerebral leukodystrophy, for behavioral symptoms in frontotemporal
573 dementia, 469, 484, 485t, 489r
Rey-Osterrieth figure, 386c, 386f, 396, 401r for depression in Alzheimer disease, 430,
Richardson syndrome, 475t, 476 607, 613r
differentiation from Lewy body dementias, 447 Semantic dementia. See Primary progressive
Rigidity aphasia, semantic variant
antipsychotic-induced, 608 Senna, 456t
in autoimmune encephalopathies, 543t, 545 Sérieux, Paul, 600
in corticobasal syndrome, 476, 477t, 478 Serotonin norepinephrine reuptake inhibitors
in nonfluent agrammatic variant primary (SNRIs), for apathy in Lewy body
progressive aphasia, 475c dementias, 451t
in Parkinson disease, 442, 443t, 448c Sertraline, 451t, 452t, 453t, 485t
treatment of, 452t Shoplifting, 392
in progressive supranuclear palsy, 475t, Short Test of Mental Status, 409, 417r, 544c, 547
476, 477t Simultagnosia, 396, 421
Risperidone, 430, 457t, 485t, 489r Single-photon emission computed tomography
Ritualistic behaviors, 392, 466t (SPECT), 432r, 462r
Rituximab, for autoimmune encephalopathies, in Alzheimer disease, 424, 432r
538, 546c, 553t, 555 in frontotemporal dementia, 482
Rivastigmine behavioral variant, 465, 467t, 468
for Alzheimer disease, 429, 434r in Lewy body dementias, 435, 438, 439t, 440,
for Lewy body dementias, 449, 450t, 456 441c, 444, 446Y447
for mild cognitive impairment, 416r in metachromatic leukodystrophy, 567c
transdermal, 449, 450t Sjögren syndrome, 541
Rofecoxib, 416r Sleep disturbances, 388
Ropinirole, for Parkinson disease, 448c in adult-onset Alexander disease, 570
RPD. See Rapidly progressive dementia in Alzheimer disease, 421, 440
RRM2B gene mutations, 563t among caregivers of patients with dementia, 621t
in autoimmune encephalopathies, 541, 543t,
S 545, 546, 546c, 551, 558r
Sarcoidosis, 514, 518, 521t, 546, 547t, 548 medications for, 454t
Schizophrenia, 567, 600, 601Y602, 611r. See also methylprednisolone-induced, 553t
Psychosis in mild cognitive impairment, 411
Seizures REM sleep behavior disorder, 435, 438, 439t,
adult-onset leukoencephalopathies with 440, 441c, 448, 448c, 458, 463r, 535r,
adult-onset leukoencephalopathy with axonal 603Y604, 612r
spheroids and pigmented glia, 565t, 575 putative brain substrates for, 459t
cerebrotendinous xanthomatosis, 570 treatment of, 454t, 457t, 458
COL4A1-related disorders, 573 sleep apnea, 411, 458, 543t, 546c, 547t, 585t
metachromatic leukodystrophy, 567c in toxic-metabolic encephalopathies, 525
X-linked adrenoleukodystrophy, 567 Social functioning
autoimmune encephalopathies with, 542t, assessment of, 390Y392, 390cY391c, 398
543t, 547, 557r in frontotemporal dementia, 399, 465, 466t
antiepileptic drug therapy for, 552 SOX1 (AGNA) antibodies, 542t
DPPX encephalitis, 545 SPECT. See Single-photon emission computed
global hypermetabolism and, 549 tomography
limbic encephalitis, 538, 542, 544 Speech therapy, in Lewy body dementias, 448c,
NMDA receptor encephalitis, 545 452t
EEG detection of, 444, 515 SREAT (steroid-responsive encephalopathy
rapidly progressive dementias with, 518, 521t, associated with autoimmune thyroiditis;
528, 533, 538 Hashimoto disease), 513t, 520t, 544c, 545Y546
cerebroretinal microangiopathy, 523 SSRIs. See Selective serotonin reuptake inhibitors
dural arteriovenous fistula, 522 Status epilepticus, 399, 557r
extrapontine myelinolysis, 530c nonconvulsive, 515, 521t, 547t

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Steroid-responsive encephalopathy associated Timed Up and Go (TUG) test, 594c
with autoimmune thyroiditis (SREAT; Tinetti scale score, 598r
Hashimoto disease), 513t, 520t, 544c, 545Y546 in idiopathic normal pressure hydrocephalus,
Strength for Caring, 624 594c
Stroke, 385 after shunt surgery, 594cY595c
due to leukoencephalopathies associated with Toxic-metabolic processes, 388, 399, 537r, 547t
small vessel vasculopathy, 570 adult-onset leukoencephalopathy due to, 559
CADASIL, 572, 572c differentiation from Parkinson disease
CARASIL, 573 dementia, 444
collagen type IV, !-1Yrelated disorders, 573 fluctuations of attention and arousal in, 437, 440
pace of progression of cognitive impairment rapidly progressive dementia due to, 514, 515,
after, 387 519tY520t, 525Y530
prevalence of dementia after, 431r Trazodone, 453t, 484, 485t, 489r
rapidly progressive dementia after, 518, 522, 533 TREM2 gene mutations, 564t
vascular cognitive impairment after, 490, Tremor
491t, 493, 495, 497Y498, 498c, 506, in adult-onset Alexander disease, 570
507rY509r, 536r in autoimmune encephalopathies, 540t, 547
management of, 504Y505 in corticobasal syndrome, 478
stroke recurrence and, 505 in fragile X-associated tremor/ataxia syndrome,
Stroop task, 398 565t
Stuttering, 473, 474c in Lewy body dementias
Subacute diencephalic angioencephalopathy, dementia with Lewy bodies, 437, 441c
519t, 523, 524f, 536r medication-induced worsening of, 452tY454t,
Substantia nigra 456
in cerebrotendinous xanthomatosis, 570 Parkinson disease dementia, 442, 445t, 448c
in Parkinson disease, 435, 461r treatment of, 444, 452t
SUMF1 gene mutations, 563t in toxic-metabolic encephalopathies, 525, 526
Sundowning, 421 TREX1 gene mutations, 561t, 565t
!-Synuclein Trihexyphenidyl, 444, 456, 457t
CSF level of, 400, 403r, 447 Trospium, 455t
in Lewy bodies, 435, 461r TUG (Timed Up and Go) test, 594c
in Lewy body dementias, 435, 436, 447, 449, TYMP gene mutations, 563t
459, 460, 463r
mutations of gene for, 449, 462r U
in Parkinson disease, 400, 402r, 403r Urinary symptoms/incontinence
in preclinical synucleinopathies, 458 in dementia with Lewy bodies, 438
therapies targeting, 399, 460 in idiopathic normal pressure hydrocephalus,
Synucleinopathies, 435, 438, 448, 462r, 535r 579, 582, 584, 591, 594c
preclinical, 458 medications for, 455t
Systemic lupus erythematosus, 514, 541 in progressive supranuclear palsy, 477t
in vascular cognitive impairment, 491t, 495, 500
T Utilization behavior, 392
Tangential speech, 391c, 392, 471c, 472, 567c
Tau protein V
in Alzheimer disease, 429, 433r Vas-Cog (International Society of Vascular
future therapies for, 431 Behavioral and Cognitive Disorders) criteria for
CSF analysis for, 399, 400, 402rY403r, 426 vascular cognitive impairment, 490, 491tY492t,
PET scan, to predict progression of mild 493, 499
cognitive impairment to dementia, 412, 412f Vascular cognitive impairment (VCI), 490Y507,
therapies targeting, 399 507rY509r
Tauopathies, 400, 440, 447, 449, 482f, 483f, 487r, classification of, 490Y493, 491tY492t
513t, 551 coding for, 627t
Tay-Sachs disease, 563t diagnosis and diagnostic testing for, 493Y500
TDP-43 protein cerebrovascular disease, 495Y496, 496f
in amyotrophic lateral sclerosis, 400 cognitive impairment, 493Y495
in frontotemporal dementia, 400, 470f, at referral centers for rapidly progressive
479Y480, 479tY481t, 481, 482f, 483f, 486 dementia, 514Y515, 514t
Thiamine deficiency, 526, 526cY528c, 527f, 537r relationship between cerebrovascular disease
Thyroid function tests, 516t, 528 and cognitive impairment, 496Y500, 497t,
Thyroiditis, autoimmune, 520t, 541, 545Y546, 557r 498c, 499c

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 Dementia

diagnostic criteria for, 490 specialized diagnostic testing for, 586Y587

management of, 504Y506 symptoms of shunt malfunction, 589Y590
neuropathology of, 493, 494t, 502Y504 worsening of symptoms after, 590Y591
Alzheimer pathology and, 490, 504 VGKC (voltage-gated potassium channel)
neuropsychiatric symptoms of, 603 antibodies, 538, 539c, 540, 541, 543t, 544, 551,
nonatherosclerotic and nonarteriolosclerotic 555, 556r
causes of, 500Y502 Viral encephalitis, 514, 515, 519t, 523Y524
cerebral amyloid angiopathy, 501Y502, 501t, Visual agnosia, 395, 396, 421, 471c, 472
503c, 505 Visual-perceptual-spatial deficits
monogenic inherited disorders: CADASIL in Alzheimer disease, 420
and CARASIL, 502 assessment for, 390, 396Y397
nonstroke-related, 490, 506 in corticobasal degeneration, 476
poststroke, 490, 491t, 493, 495, 497Y498, 498c, in Lewy body dementias, 436, 442
506, 507rY509r, 536r Vitamin B3 deficiency, 526, 537r
management of, 504Y505 Vitamin B6 deficiency, 526, 526cY528c, 527f, 537r
rapidly progressive dementia, 518, 522, 533 Vitamin B12 deficiency, 526, 528
stroke recurrence and, 505 Vitamin E, for mild cognitive impairment, 414, 416r
prevalence of, 490, 502 VITAMINS mnemonic for rapidly progressive
prevention of, 506 dementias, 518
Vascular etiologies of rapidly progressive Voltage-gated potassium channel (VGKC)
dementia, 518, 519t, 522Y523, 522fY524f antibodies, 538, 539c, 540, 541, 543t, 544, 551,
cerebral amyloid angiopathy, 523, 523f 555, 556r
cerebroretinal microangiopathy, 523 VP shunt. See Ventriculoperitoneal shunt surgery
dural arteriovenous fistula, 518, 522, 522f
subacute diencephalic angioencephalopathy, W
523, 524f Wernicke encephalopathy, 526, 526cY528c, 527f,
venous sinus thrombosis, 522Y523 537r
Vasculitis, CNS, 513t, 514, 519t, 520t, 522, Western Aphasia Battery, 471c, 474c
531Y532, 546, 547t Whipple disease, 516t, 519t, 524Y525, 536t, 547t
VCI. See Vascular cognitive impairment World Health Organization, 626
Venlafaxine XR, 452t, 453t Writing difficulty
Venous sinus thrombosis, 522Y523, 536r assessment for, 389, 389c, 395, 396
Ventriculoperitoneal (VP) shunt surgery, for in corticobasal syndrome, 475f, 478
idiopathic normal pressure hydrocephalus, spatial deficits and, 396
579, 587Y589, 588f, 597rY598r
adjustable valves for, 588Y589 X
choice of shunt valves for, 587Y588 X-linked adrenoleukodystrophy, 559, 562t, 563t,
evaluating shunt patency, 596 566Y567, 569, 576r
indications for, 586
longitudinal follow-up after, 589Y591, 590f Z
purpose of, 587, 588 Zarit Burden Interview, 621, 622t

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 ® Dementia
List of Abbreviations
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MISSION AND VISION EDITOR’S OFFICE AChEI Acetylcholinesterase inhibitor IM Intramuscular
Mission Statement: Continuum: Lifelong Learning in Neurology aids neurology professionals throughout Steven L. Lewis, MD, FAAN AD Alzheimer disease iNPH Idiopathic normal pressure hydrocephalus
their careers in improving the clinical care of patients and in demonstrating continued competency. Department of Neurological Sciences ADAMS Aging, Demographics, and Memory Study IQCODE Informant Questionnaire on Cognitive
Rush University Medical Center ADAS-Cog Alzheimer’s Disease Assessment Decline in the Elderly
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EDITOR-IN-CHIEF* Send your comments directly to the executive LP Lumbar puncture
Stroke Association
editor at [email protected] MCI Mild cognitive impairment
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Contact Member Services with all CME-related ALS Amyotrophic lateral sclerosis MELAS Mitochondrial myopathy, encephalopathy,
Rush University Medical Center, Chicago, Illinois lactic acidosis, and strokelike episodes
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Editor-in-Chief of Continuum: Lifelong Learning in Neurology, section co-editor for continuing medical Phone: 612-928-6000 or 800-879-1960 mGluR5 Metabotropic glutamate receptor 5
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AND MEDICOLEGAL ISSUES* Shannon M. Kilgore, MD, FAAN
Amanda F. Doering CTE Chronic traumatic encephalopathy PD Parkinson disease
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Joseph S. Kass, MD, JD, FAAN Senior Program Manager PDD Parkinson disease dementia
Ben Taub General Hospital, Baylor College of DAVF Dural arteriovenous fistula PERM Progressive encephalomyelitis with rigidity
Kerry H. Levin, MD, FAAN Debra K. Zoellner DESH Disproportionately enlarged subarachnoid and myoclonus
Medicine, Houston, Texas space hydrocephalus
Cleveland, Ohio Production Editor PET Positron emission tomography
DICE Describe, investigate, create, and evaluate PiB Pittsburgh compound B
Rebecca Oster Bach DLB Dementia with Lewy bodies
ASSOCIATE EDITOR OF PRACTICE* Aaron E. Miller, MD, FAAN Production Editor DNA Deoxyribonucleic acid
PIGD Postural instability gait disorder
New York, New York POLD Pigmented orthochromatic leukodystrophy
Anna D. Hohler, MD, FAAN Missy Render DPPX Dipeptidyl-peptidase 6
PPA Primary progressive aphasia
Boston University Medical Campus, Senior Administrator DSM-IV Diagnostic and Statistical Manual of Mental
Alejandro A. Rabinstein, MD, FAAN Disorders, Fourth Edition PRES Posterior reversible encephalopathy
Boston, Massachusetts syndrome
Rochester, Minnesota CME INFORMATION DSM-5 Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition PSP Progressive supranuclear palsy
The American Academy of Neurology Institute is DWI Diffusion-weighted imaging P-tau Phosphorylated tau
ASSOCIATE EDITOR OF CODING* Erik K. St. Louis, MD, FAAN accredited by the Accreditation Council for Continuing ECG Electrocardiogram REM Rapid eye movement
Laura B. Powers, MD, FAAN Rochester, Minnesota Medical Education to provide continuing medical EEG Electroencephalogram RNA Ribonucleic acid
Dr Powers is retired from private practice. education for physicians. ELISA Enzyme-linked immunosorbent assay RPD Rapidly progressive dementia
Allison L. Weathers, MD, FAAN The American Academy of Neurology Institute
E/M Evaluation and Management [codes] RPR Rapid plasma reagin
Chicago, Illinois EMG Electromyography RT-QuIC Real-time quaking induced conversion
designates this enduring material for a maximum of FDA US Food and Drug Administration SD Standard deviation
ASSOCIATE EDITOR OF CHILD NEUROLOGY* 12 AMA PRA Category 1 CreditsTM upon completion FDG-PET Fluorodeoxyglucose positron emission SOX1 Sex-determining region Y box 1
Jonathan W. Mink, MD, PhD, FAAN of the Postreading Self-Assessment and CME Test tomography SPECT Single-photon emission computed tomography
EX OFFICIO* (approved by the American Board of Psychiatry and FINGER Finnish Geriatric Intervention Study to
University of Rochester Medical Center, SREAT Steroid-responsive encephalopathy
A. Gordon Smith, MD, FAAN Neurology as self-assessment, CME [SA-CME] credit Prevent Cognitive Impairment and Disability associated with autoimmune thyroiditis
Rochester, New York
Salt Lake City, Utah toward part 2 of their Maintenance of Certification FLAIR Fluid-attenuated inversion recovery SSRI Selective serotonin reuptake inhibitor
Program); and a maximum of 2 AMA PRA Category 1
FTD Frontotemporal dementia SWI Susceptibility-weighted imaging
FTD-MND Frontotemporal dementia–motor neuron TPMT Thiopurine methyltransferase
ASSOCIATE EDITOR OF NEUROIMAGING* CreditsTM upon completion of the Patient Management disease
Problem. Physicians should claim only the credit FTLD Frontotemporal lobar degeneration TSH Thyroid-stimulating hormone
Laszlo Mechtler, MD, FAAN PAST EDITORS-IN-CHIEF commensurate with the extent of their participation GABA-A J-Aminobutyric acid A T-tau Total tau
Dent Neurologic Institute, Amherst, New York Elliott L. Mancall, MD, FAAN (1993–2002) in the activity. GABA-B J-Aminobutyric acid B UCSF University of California, San Francisco
GAD65 Glutamic acid decarboxylase 65 Vas-Cog International Society of Vascular Behavioural
Per AMA PRA guidelines, only US and licensed and Cognitive Disorders
Aaron E. Miller, MD, FAAN (2003–2012) GRE Gradient recalled echo
international physicians may be awarded AMA PRA HDLS Hereditary diffuse leukoencephalopathy VDRL Venereal disease research laboratory [test]
PHARMACOTHERAPEUTICS REVIEWER*
Category 1 Credit transcripts. The AAN will issue with spheroids VGKC Voltage-gated potassium channel
Marketa Marvanova, PharmD, PhD, CGP, BCPP certificates of participation to non-MD and non-DO HIV Human immunodeficiency virus VITAMINS Vascular, infectious, toxic-metabolic,
North Dakota State University College of Health FOUNDING PROGRAM DIRECTOR health professionals indicating that the activity was ICD-9-CM International Classification of Diseases, autoimmune, malignancy, iatrogenic,
Professions, Fargo, North Dakota Theodore L. Munsat, MD, FAAN designated for AMA PRA Category 1 Credits. Ninth Revision, Clinical Modification neurodegenerative,
ICD-10 International Classification of Diseases, and systemic
Tenth Revision VP Ventriculoperitoneal [shunt]

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