Continuum: Lifelong Learning in Neurology—Cerebrovascular Disease, Volume 23, Issue 1,

February 2017

Issue Overview

Cerebrovascular Disease February 2017;23(1)

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 Cerebrovascular Disease
issue, participants will be able to:

 Describe the epidemiology of ischemic stroke and its associated risk factors and summarize
the best evidence for managing stroke risk factors for prevention of recurrent stroke

 Perform key elements in the bedside evaluation of the patient with acute stroke, including the
focused stroke history, essential aspects of the bedside examination, and initial brain
imaging, and recognize anatomic stroke syndromes and common mimics

 Discuss the main indications and contraindications of acute reperfusion therapies for
ischemic stroke

 Diagnose and manage transient ischemic attack and minor stroke and distinguish high-risk
transient ischemic attacks from more benign transient events

 Discuss common early and late medical complications following acute ischemic stroke

 Discuss the comprehensive evaluation of cardioembolic stroke and outline current

management options

 Evaluate and manage patients with large artery atherosclerotic occlusive disease of the head
and neck

 Discuss the risk factors, recurrence risk, evaluation, and outcomes of arterial ischemic stroke
in children and young adults

 Discuss the natural history of and general management and treatment options for unruptured
intracranial aneurysms and vascular malformations of the brain

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

 Recognize key historical and clinicoradiographic features of inherited and uncommon causes
of stroke

 Discuss the natural history of stroke as well as established pharmacologic and

nonpharmacologic rehabilitative strategies in the acute, subacute, and chronic phases of
stroke

 List recommended steps for practical conflict mediation in situations in which surrogates of
patients with severe stroke request life-prolonging treatment thatclinicians believe I s
potentially inappropriate

 Recognize the usefulness of telestroke and its potential to improve acute stroke care in
underserved communities

Core Competencies
This Continuum: Lifelong Learning in Neurology Cerebrovascular Disease issue covers the
following core competencies:
 Patient Care
 Medical Knowledge
 Practice-Based Learning and Improvement
 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Disclosures
CONTRIBUTORS

Kevin M. Barrett, MD, MSc, Guest Editor

Associate Professor, Vice Chair, Department of Neurology, Mayo Clinic Florida, Jacksonville,
Florida
a
Dr Barrett serves on the editorial board of Neurology, has received research/grant support from the National
Institute of Neurological Disorders and Stroke for serving on the executive committees of the CREST-2 and SHINE
clinical trials, and receives publishing royalties from Wiley Blackwell.
b
Dr Barrett reports no disclosure.

Samir R. Belagaje, MD
Assistant Professor of Neurology and Rehabilitation Medicine, Emory University School of
Medicine; Director of Stroke Rehabilitation, Marcus Stroke and Neuroscience Center, Grady
Memorial Hospital, Atlanta, Georgia
a
Dr Belagaje reports no disclosure.
b
Dr Belagaje discusses the unlabeled/investigational use of fluoxetine for poststroke motor recovery treatment,
cholinesterase inhibitors and memantine for the treatment of aphasia, and dopaminergic agents to aid in the
treatment of poststroke depression.

Cheryl Bushnell, MD, MHS

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

Professor of Neurology, Director, Wake Forest Baptist Comprehensive Stroke Center, Wake
Forest Baptist Health, Winston Salem, North Carolina
a
Dr Bushnell receives research/grant support from the Patient-Centered Outcomes Research Institute (PCS-1403-
14532).
b
Dr Bushnell reports no disclosure.

John W. Cole, MD, MS

Staff Physician, Neurology, Baltimore Veterans Affairs Medical Center; Associate Professor,
Neurology, University of Maryland School of Medicine, Baltimore, Maryland
a
Dr Cole receives research/grant support from the American Heart Association (15GPSPG23770000) and the
National Institutes of Health (1U01NS069208), which partially funded the writing of this article.
b
Dr Cole reports no disclosure.

Shelagh B. Coutts, MD, MSc, FRCPC

Stroke Neurologist; Associate Professor, Departments of Clinical Neuroscience, Radiology,
Community Health Sciences, University of Calgary, Hotchkiss Brain Institute, Calgary, Alberta,
Canada
a
Dr Coutts receives research/grant support from the Canadian Institutes of Health Research, (CRH-112319), the
Heart and Stroke Foundation of Canada (G-16-00012585), and Genome Canada (143TIA-Penn).
b
Dr Coutts reports no disclosure.

Bart M. Demaerschalk, MD, MSc, FAHA, FRCPC

Professor of Neurology, Mayo College of Medicine, Phoenix, Arizona
a
Dr Demaerschalk has received personal compensation as editor-in-chief of The Neurologist and has received
publishing royalties from Springer Publishing Company and John Wiley & Sons, Inc.
b
Dr Demaerschalk reports no disclosure.

Kelly D. Flemming, MD
Consultant in Department of Neurology; Associate Professor of Medicine, Mayo Clinic,
Rochester, Minnesota
a
Dr Flemming reports no disclosure.
b
Dr Flemming discusses the unlabeled/investigational use of statins and fasudil for the treatment of cavernous
malformation.

Amy Guzik, MD
Assistant Professor, Neurology, Wakeforest Baptist Medical Center, Winston Salem, North
Carolina
a,b
Dr Guzik reports no disclosures.

Josephine F. Huang, MD
Instructor of Neurology, Mayo Clinic, Jacksonville, Florida
a
Dr Huang reports no disclosure.
b
Dr Huang discusses the unlabeled/investigational use of tranexamic acid and ε-aminocaproic acid for intracranial
hemorrhage.

David Y. Hwang, MD
Assistant Professor, Division of Neurocritical Care and Emergency Neurology, Yale School of
Medicine; Neurointensivist, Yale-New Haven Hospital, New Haven, Connecticut
a
Dr Hwang has received personal compensation for speaking engagements for the Mayo Clinic and The
Pennsylvania State University and research/grant support from the American Brain Foundation, the Apple Pickers
Foundation, the Neurocritical Care Society, and the National Institute on Aging, via its Loan Repayment Program.
b
Dr Hwang reports no disclosure.

William Jones, MD
Associate Professor of Neurology; Division Chief, Neurohospitalist and Vascular Neurology,
University of Colorado, Anschutz Medical Campus, Department of Neurology, Aurora, Colorado

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

a,b
Dr Jones reports no disclosures.

Pearce J. Korb, MD
Assistant Professor of Neurology, University of Colorado, Anschutz Medical Campus,
Department of Neurology, Aurora, Colorado
a,b
Dr Korb reports no disclosures.

Riten Kumar, MD, MSc

Assistant Professor of Pediatrics, The Ohio State University, Division of Hematology/Oncology,
Nationwide Children's Hospital, Columbus, Ohio
a
Dr Kumar serves on the medical advisory board of Bayer Corporation and receives research/ grant support from
the Hemostasis and Thrombosis Research Society (HTRS Mentored Research Award) and the International Society
on Thrombosis and Haemostasis.
b
Dr Kumar discusses the unlabeled/investigational use of antithrombotic and thrombolytic agents in children with
stroke.

Giuseppe Lanzino, MD
Professor of Neurosurgery, Mayo Clinic, Rochester, Minnesota
a
Dr Lanzino serves as a consultant for Medtronic.
b
Dr Lanzino discusses the unlabeled/investigational use of statins and fasudil for the treatment of cavernous
malformation.

Warren D. Lo, MD
Clinical Professor, Departments of Pediatrics and Neurology, Ohio State University; Pediatric
Neurologist, Nationwide Children’s Hospital, Columbus, Ohio
a
Dr Lo receives research/grant support from the Eunice Kennedy Shriver National Institute of Child Health and
Human Development (5R01HD068345, 1R01HD074574, R01HD083384) and the National Institute of Neurological
Disorders and Stroke (U10NS086484, U54 NS065705) and receives publishing royalties from Springer.
b
Dr Lo discusses the unlabeled/investigational use of antithrombotic and thrombolytic agents in children with
stroke.

Jennifer Juhl Majersik, MD, MS

Associate Professor of Neurology; Director, Stroke Center and Telestroke Services; Chief,
Division of Vascular Surgery, University of Utah, Salt Lake City, Utah
a
Dr Majersik receives research/grant support from the National Institutes of Health (5U10NS086606) and Remedy
Pharmaceuticals, Inc. Dr Majersik has served as an expert witness for FAVROS PLLC.
b
Dr Majersik reports no disclosure.

Cumara B. O’Carroll, MD, MPH

Assistant Professor of Neurology, Mayo Clinic, Phoenix, Arizona
a,b
Dr O’Carroll reports no disclosures.

Alejandro A. Rabinstein, MD, FAAN

Professor of Neurology, Mayo Clinic, Rochester, Minnesota
a
Dr Rabinstein serves as an associate editor for Neurocritical Care; on the editorial boards of Continuum: Lifelong
Learning in Neurology, the Journal of Stroke and Cerebrovascular Diseases, Neurology, and Stroke; and on the
scientific advisory board of Portola Pharmaceuticals, Inc. Dr Rabinstein receives research/grant support from DJO
Global, Inc, and royalties from Elsevier, Oxford University Press, and UpToDate, Inc.
b
Dr Rabinstein reports no disclosure.

Andrew M. Southerland, MD, MSc

Assistant Professor of Neurology and Public Health Sciences, University of Virginia Health
System, Charlottesville, Virginia
a
Dr. Southerland serves as deputy editor of the Neurology podcast and receives research/grant support from the
American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources & Services
Administration (HRSA GO1RH27869-01-00), and the National Institute of Neurological Disorders and Stroke (U01
NS069498).

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

b
Dr Southerland 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.

Adam Kelly, MD
Associate Professor of Neurology, University of Rochester Medical Center; Chief of Neurology,
Highland Hospital, Rochester, New York
a
Dr Kelly has received research support from the Donald W. Reynolds Foundation.
b
Dr Kelly 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.

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 CME and self-assessment offerings, including a self-

assessment pretest, multiple-choice questions with preferred responses, and a patient

management problem. For detailed instructions regarding Continuum CME and self-assessment

activities, visit aan.com/continuum/cme.

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

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 ®

Cerebrovascular Disease
Volume 23 Number 1 February 2017

CONTRIBUTORS
Kevin M. Barrett, MD, MSc, Guest Editor
Associate Professor, Vice Chair, Department of Neurology, Mayo Clinic Florida,
Jacksonville, Florida
aDr Barrett serves on the editorial board of Neurology, has received research/grant support
from the National Institute of Neurological Disorders and Stroke for serving on the executive
committees of the CREST-2 and SHINE clinical trials, and receives publishing royalties from
Wiley Blackwell.
bDr Barrett reports no disclosure.

Samir R. Belagaje, MD
Assistant Professor of Neurology and Rehabilitation Medicine, Emory University
School of Medicine; Director of Stroke Rehabilitation, Marcus Stroke and
Neuroscience Center, Grady Memorial Hospital, Atlanta, Georgia
aDr Belagaje reports no disclosure.
bDr Belagaje discusses the unlabeled/investigational use of fluoxetine for poststroke motor
recovery treatment, cholinesterase inhibitors and memantine for the treatment of aphasia,
and dopaminergic agents to aid in the treatment of poststroke depression.

Cheryl Bushnell, MD, MHS

Professor of Neurology, Director, Wake Forest Baptist Comprehensive Stroke
Center, Wake Forest Baptist Health, Winston Salem, North Carolina
aDr Bushnell receives research/grant support from the Patient-Centered Outcomes Research
Institute (PCS-1403-14532).
bDr Bushnell reports no disclosure.

John W. Cole, MD, MS

Staff Physician, Neurology, Baltimore Veterans Affairs Medical Center;
Associate Professor, Neurology, University of Maryland School of Medicine,
Baltimore, Maryland
aDr Cole receives research/grant support from the American Heart Association
(15GPSPG23770000) and the National Institutes of Health (1U01NS069208),
which partially funded the writing of this article.
bDr Cole reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2017;23(1) ContinuumJournal.com

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Shelagh B. Coutts, MD, MSc, FRCPC
Stroke Neurologist; Associate Professor, Departments of Clinical Neuroscience,
Radiology, Community Health Sciences, University of Calgary, Hotchkiss Brain
Institute, Calgary, Alberta, Canada
aDr Coutts receives research/grant support from the Canadian Institutes of Health Research,
(CRH-112319), the Heart and Stroke Foundation of Canada (G-16-00012585),
and Genome Canada (143TIA-Penn).
bDr Coutts reports no disclosure.

Bart M. Demaerschalk, MD, MSc, FAHA, FRCPC

Professor of Neurology, Mayo College of Medicine, Phoenix, Arizona
aDr Demaerschalk has received personal compensation as editor-in-chief of
The Neurologist and has received publishing royalties from Springer Publishing
Company and John Wiley & Sons, Inc.
bDr Demaerschalk reports no disclosure.

Kelly D. Flemming, MD
Consultant in Department of Neurology; Associate Professor of Medicine,
Mayo Clinic, Rochester, Minnesota
aDr Flemming reports no disclosure.
bDr Flemming discusses the unlabeled/investigational use of statins and fasudil for the
treatment of cavernous malformation.

Amy Guzik, MD
Assistant Professor, Neurology, Wakeforest Baptist Medical Center,
Winston Salem, North Carolina
a,bDr Guzik reports no disclosures.

Josephine F. Huang, MD
Instructor of Neurology, Mayo Clinic, Jacksonville, Florida
aDr Huang reports no disclosure.
bDr Huang discusses the unlabeled/investigational use of tranexamic acid
and ε-aminocaproic acid for intracranial hemorrhage.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

ContinuumJournal.com February 2017

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
David Y. Hwang, MD
Assistant Professor, Division of Neurocritical Care and Emergency Neurology,
Yale School of Medicine; Neurointensivist, Yale-New Haven Hospital,
New Haven, Connecticut
aDr Hwang has received personal compensation for speaking engagements for the Mayo Clinic
and The Pennsylvania State University and research/grant support from the American Brain
Foundation, the Apple Pickers Foundation, the Neurocritical Care Society, and the National
Institute on Aging, via its Loan Repayment Program.
bDr Hwang reports no disclosure.

William Jones, MD
Associate Professor of Neurology; Division Chief, Neurohospitalist and Vascular
Neurology, University of Colorado, Anschutz Medical Campus, Department of
Neurology, Aurora, Colorado
a,bDr Jones reports no disclosures.

Pearce J. Korb, MD
Assistant Professor of Neurology, University of Colorado, Anschutz Medical
Campus, Department of Neurology, Aurora, Colorado
a,bDr Korb reports no disclosures.

Riten Kumar, MD, MSc

Assistant Professor of Pediatrics, The Ohio State University, Division
of Hematology/Oncology, Nationwide Children's Hospital, Columbus, Ohio
aDr Kumar serves on the medical advisory board of Bayer Corporation and receives research/
grant support from the Hemostasis and Thrombosis Research Society (HTRS Mentored
Research Award) and the International Society on Thrombosis and Haemostasis.
bDr Kumar discusses the unlabeled/investigational use of antithrombotic and thrombolytic
agents in children with stroke.

Giuseppe Lanzino, MD
Professor of Neurosurgery, Mayo Clinic, Rochester, Minnesota
aDr Lanzino serves as a consultant for Medtronic.
bDr Lanzino discusses the unlabeled/investigational use of statins and fasudil for the
treatment of cavernous malformation.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2017;23(1) ContinuumJournal.com

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

 LIFELONG LEARNING IN NEUROLOGY ®

CONTRIBUTORS continued
Warren D. Lo, MD
Clinical Professor, Departments of Pediatrics and Neurology,
Ohio State University; Pediatric Neurologist, Nationwide Children’s Hospital,
Columbus, Ohio
aDr Lo receives research/grant support from the Eunice Kennedy Shriver National Institute
of Child Health and Human Development (5R01HD068345, 1R01HD074574, R01HD083384)
and the National Institute of Neurological Disorders and Stroke (U10NS086484,
U54 NS065705) and receives publishing royalties from Springer.
bDr Lo discusses the unlabeled/investigational use of antithrombotic and thrombolytic
agents in children with stroke.

Jennifer Juhl Majersik, MD, MS

Associate Professor of Neurology; Director, Stroke Center and Telestroke Services;
Chief, Division of Vascular Surgery, University of Utah, Salt Lake City, Utah
aDr Majersik receives research/grant support from the National Institutes of Health
(5U10NS086606) and Remedy Pharmaceuticals, Inc. Dr Majersik has served as an expert
witness for FAVROS PLLC.
bDr Majersik reports no disclosure.

Cumara B. O’Carroll, MD, MPH

Assistant Professor of Neurology, Mayo Clinic, Phoenix, Arizona
a,bDr O’Carroll reports no disclosures.

Alejandro A. Rabinstein, MD, FAAN

Professor of Neurology, Mayo Clinic, Rochester, Minnesota
aDr Rabinstein serves as an associate editor for Neurocritical Care; on the editorial boards
of Continuum: Lifelong Learning in Neurology, the Journal of Stroke and Cerebrovascular
Diseases, Neurology, and Stroke; and on the scientific advisory board of Portola
Pharmaceuticals, Inc. Dr Rabinstein receives research/grant support from DJO Global, Inc,
and royalties from Elsevier, Oxford University Press, and UpToDate, Inc.
bDr Rabinstein reports no disclosure.

Andrew M. Southerland, MD, MSc

Assistant Professor of Neurology and Public Health Sciences, University of Virginia
Health System, Charlottesville, Virginia
aDr. Southerland serves as deputy editor of the Neurology podcast and receives research/
grant support from the American Academy of Neurology, American Board of Psychiatry and
Neurology, Health Resources & Services Administration (HRSA GO1RH27869-01-00), and the
National Institute of Neurological Disorders and Stroke (U01 NS069498).
bDr Southerland reports no disclosure.

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

ContinuumJournal.com February 2017

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

 LIFELONG LEARNING IN NEUROLOGY ®

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.

Adam Kelly, MD
Associate Professor of Neurology, University of Rochester Medical Center; Chief
of Neurology, Highland Hospital, Rochester, New York
aDr Kelly has received research support from the Donald W. Reynolds Foundation.
bDr Kelly reports no disclosure

aRelationship Disclosure
bUnlabeled Use of Products/Investigational Use Disclosure

Continuum (Minneap Minn) 2017;23(1) ContinuumJournal.com

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

 Erratum

In the October 2016 issue of Continuum (Neuroimaging, Vol 22, Issue 5), the following error
occurred:

In “Imaging for Adults With Seizures and Epilepsy” by Samuel LaPalme-Remis, MDCM, MA,
FRCPC, and Gregory D. Cascino, MD, FAAN (Continuum: Lifelong Learning in Neurology
2016;22:1467), the text incorrectly states, “These seizures are difficult to fully resect and can
progress to higher-grade tumors, threatening patient survival.” The sentence should read,
“These tumors are difficult to fully resect and can progress to higher-grade tumors, threatening
patient survival.”
Lapalme-Remis S, Cascino GD. Imaging for Adults With Seizures and Epilepsy. Continuum (Minneap Minn)
2016;22(5 Neuroimaging):1451Y1479.

The editors regret this error.

8 ContinuumJournal.com February 2017

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

 Volume 23 n Number 1 n February 2017

LIFELONG LEARNING IN NEUROLOGY ®

ContinuumJournal.com

Cerebrovascular Disease Denotes Online-Only Article

Guest Editor: Kevin M. Barrett, MD, MSc

Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

REVIEW ARTICLES
Stroke Epidemiology and Risk Factor Management . . . . . . . . . . . . . . . . . . . . . . . . . 15
Amy Guzik, MD; Cheryl Bushnell, MD, MHS
Clinical Evaluation of the Patient With Acute Stroke . . . . . . . . . . . . . . . . . . . . . . . 40
Andrew M. Southerland, MD, MSc
Treatment of Acute Ischemic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Alejandro A. Rabinstein, MD, FAAN
Diagnosis and Management of Transient Ischemic Attack . . . . . . . . . . . . . . . . . 82
Shelagh B. Coutts, MD, MSc, FRCPC
Prevention and Management of Poststroke Complications . . . . . . . . . . . . . . . . 93
Josephine F. Huang, MD
Cardioembolic Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Cumara B. O’Carroll, MD, MPH; Kevin M. Barrett, MD, MSc
Large Artery Atherosclerotic Occlusive Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 133
John W. Cole, MD, MS
Arterial Ischemic Stroke in Children and Young Adults . . . . . . . . . . . . . . . . . . . 158
Warren D. Lo, MD; Riten Kumar, MD, MSc
Management of Unruptured Intracranial Aneurysms
and Cerebrovascular Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Kelly D. Flemming, MD; Giuseppe Lanzino, MD
Inherited and Uncommon Causes of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Jennifer Juhl Majersik, MD, MS
Stroke Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Samir R. Belagaje, MD

Volume 23 n Number 1 ContinuumJournal.com 9

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

 LIFELONG LEARNING IN NEUROLOGY ®

ETHICAL AND MEDICOLEGAL ISSUES

Discussing Life-sustaining Therapy With Surrogate Decision Makers . . . . . . 254
David Y. Hwang, MD

PRACTICE ISSUES
Remote Evaluation of the Patient With Acute Stroke . . . . . . . . . . . . . . . . . . . . . 259
Bart M. Demaerschalk, MD, MSc, FAHA, FRCPC
Coding in Stroke and Other Cerebrovascular Diseases . . . . . . . . . . . . . . . . . . . 268
Complete text is available as online-only content in this issue at ContinuumJournal.com
and on the Continuum apps
Pearce J. Korb, MD; William Jones, MD

SELF-ASSESSMENT AND CME

Learning Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Instructions for Completing Postreading Self-Assessment and CME Test
and Tally Sheet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Postreading Self-Assessment and CME Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
Postreading Self-Assessment and CME Test—Preferred Responses . . . . . . . 282
Douglas J. Gelb, MD, PhD, FAAN; Adam G. Kelly, MD
Patient Management Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Patient Management Problem—Preferred Responses . . . . . . . . . . . . . . . . . . . 293
Kevin M. Barrett, MD, MSc

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Back Cover

ERRATUM

Imaging for Adults With Seizures and Epilepsy: Erratum . . . . . . . . . . . . . . . . . . . . 8

10 ContinuumJournal.com February 2017

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

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

s Describe the epidemiology of ischemic stroke and its associated risk factors
and summarize the best evidence for managing stroke risk factors for prevention
of recurrent stroke
Perform key elements in the bedside evaluation of the patient with acute
s

stroke, including the focused stroke history, essential aspects of the bedside
examination, and initial brain imaging, and recognize anatomic stroke
syndromes and common mimics
Discuss the main indications and contraindications of acute reperfusion therapies
s

for ischemic stroke

Diagnose and manage transient ischemic attack and minor stroke and distinguish
s

high-risk transient ischemic attacks from more benign transient events

Discuss common early and late medical complications following acute
s

ischemic stroke
Discuss the comprehensive evaluation of cardioembolic stroke and outline current
s

management options
Evaluate and manage patients with large artery atherosclerotic occlusive disease of the
s

head and neck

Discuss the risk factors, recurrence risk, evaluation, and outcomes of arterial
s

ischemic stroke in children and young adults

Discuss the natural history of and general management and treatment options for
s

unruptured intracranial aneurysms and vascular malformations of the brain

Recognize key historical and clinicoradiographic features of inherited and uncommon
s

causes of stroke
Discuss the natural history of stroke as well as established pharmacologic and
s

nonpharmacologic rehabilitative strategies in the acute, subacute, and chronic

phases of stroke
List recommended steps for practical conflict mediation in situations in which
s

surrogates of patients with severe stroke request life-prolonging treatment that

clinicians believe is potentially inappropriate
Recognize the usefulness of telestroke and its potential to improve acute stroke
s

care in underserved communities

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

Patient Care
s

Medical Knowledge
s

Practice-Based Learning and Improvement

s

Interpersonal and Communication Skills

s

Professionalism
s

Systems-Based Practice
s

Continuum (Minneap Minn) 2017;23(1) ContinuumJournal.com

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

 Editor’s Preface

* 2017 American Academy

Avoiding Infractions of Neurology.

in the Management
of Infarctions
This issue of Continuum emergency treatment of
is devoted to the diag- acute ischemic stroke,
nosis, management, and with particular emphasis
counseling of patients on IV thrombolysis and
with stroke or who are the decision-making pro-
at risk for stroke. To cess with regard to me-
achieve this goal, Guest chanical thrombectomy.
Editor Dr Kevin M. Dr Shelagh B. Coutts next
Barrett, associate pro- discusses the diagnosis
fessor and vice chair of and management of tran-
the department of neu- sient ischemic attacks and
rology at Mayo Clinic the need for, and specifics
Florida, has assembled of, urgent assessment for
an impressive group of etiologic investigation to
This issue of Continuum
experts to update us on inform the optimal pre-
is devoted to the
the cerebrovascular dis- ventive therapy in an in-
diagnosis, management,
eases, including current dividual patient with
and counseling of
information to guide our transient ischemic attack.
patients with stroke
diagnosis and manage- Dr Josephine F. Huang
or who are at risk
ment of patients with provides us with a review
for stroke.
acute ischemic stroke, of the immediate and
for which rapid assess- delayed medical compli-
ment, adherence to protocols, and an cations that can occur after a stroke,
effective multidisciplinary system of emphasizing prevention and manage-
care are essential for optimal outcomes. ment of these complications. Drs Cumara
The issue begins with the article by B. O’Carroll and Kevin M. Barrett next
Drs Amy Guzik and Cheryl Bushnell, discuss cardioembolic stroke, an impor-
who provide an overview of stroke tant potentially preventable cause of
epidemiology and risk factor manage- ischemic stroke, highlight the diverse
ment to inform the preventive manage- underlying mechanisms and their as-
ment of patients at risk for stroke or sessment, and summarize the current
recurrent stroke. Next, Dr Andrew M. options for prevention based on the
Southerland provides an underpinning defined mechanism. Dr John W. Cole
for the rest of the issue with regard to then reviews large artery atherosclerotic
the bedside clinical evaluation of pa- occlusive disease (including asymptom-
tients with acute stroke, advising us to atic and symptomatic extracranial carotid
“Be quick, but don’t hurry,” while also stenosis, intracranial atherosclerosis,
reminding us of relevant neurovascular and extracranial vertebral artery athero-
anatomy and clinical stroke syndromes. sclerotic disease) and the current roles
Dr Alejandro A. Rabinstein then reviews of medical, surgical, and endovascular
the current state of the art in the therapy in each of these scenarios.
Continuum (Minneap Minn) 2017;23(1):13–14 ContinuumJournal.com 13

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

 Editor’s Preface

Drs Warren D. Lo and Riten Kumar Drs Pearce J. Korb and William Jones
review the risk factors, recurrence risk, use an illustrative example of a patient
and evaluation and management of presenting with acute ischemic stroke
arterial ischemic stroke in children and to illustrate the issues involved in
young adults, emphasizing the impor- diagnostic and evaluation and manage-
tance of clinicians recognizing that ment coding of patients with stroke.
patients of these age groups may have As with every issue of Continuum,
particular and potentially remediable several opportunities exist for CME.
impairments in cognition and mood as After reading the issue and taking the
sequelae of their strokes. Drs Kelly D. Postreading Self-Assessment and CME
Flemming and Giuseppe Lanzino next Test written by Drs Douglas J. Gelb
summarize the epidemiology, natural and Adam G. Kelly, you may earn up to
history, and various management strat- 12 AMA PRA Category 1 CreditsTM
egies for unruptured intracranial aneu- toward self-assessment and CME.
rysms, arteriovenous malformations, Readers will note a new format in this
cavernous malformations, developmen- issue’s CME section, where the ques-
tal venous anomalies, and capillary tions are no longer repeated in the
telangiectasias, information that is crit- Preferred Responses section, a move
ical for us to use as we counsel our that will keep our print issues a bit
patients when these lesions are discov- more environmentally friendly. We
ered, often incidentally. welcome readers’ opinions about this
Dr Jennifer Juhl Majersik reviews new format for presenting the answers
many of the inherited monogenic dis- to the multiple-choice questions. The
orders that may cause stroke that clini- Patient Management Problem, written
cians need to be aware of and discusses by Dr Barrett, describes the case of a
the diagnosis and management of other 78-year-old man who presents with an
important but relatively uncommon acute left hemiplegia. By following this
causes of stroke, including moyamoya patient’s case and answering multiple-
disease, cerebral amyloid angiopathy, choice questions corresponding to
and pregnancy-associated stroke. In the diagnostic and management decision
final review article of the issue, Dr Samir points along his course, you will have
R. Belagaje reviews the principles of the opportunity to earn up to 2 AMA
neurorehabilitation that inform the opti- PRA Category 1 CME Credits.
mal poststroke outcomes of our patients. I am indebted to Dr Barrett for his
In this issue’s Ethical and Medicole- insightful leadership and extreme dedi-
gal Issues section, Dr David Y. Hwang cation to this issue throughout the
uses the case example of a patient with process, and I would also like to thank
a devastating posterior circulation infarc- him and each of the expert contributors
tion to discuss the ethical issues involved to this issue for providing us with such
when surrogate decision makers request well-written articles that share their ex-
life-prolonging treatment that members perience and expertise, which we can all
of the care team may believe to be futile. use to inform the timely and accurate
In the Practice Issues article, Dr Bart M. diagnosis and management of our pa-
Demaerschalk provides his state-of-the tients with acute stroke and other cerebro-
art review of the history, principles, and vascular diseases to optimize outcomes.
practice of telestroke for the remote
evaluation of the patient with acute
stroke. In the Coding article (accessible VSteven L. Lewis, MD, FAAN
online and on the Continuum apps), Editor-in-Chief

14 ContinuumJournal.com February 2017

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

 Review Article

Stroke Epidemiology
Address correspondence to
Dr Cheryl Bushnell,
Department of Neurology,
Wake Forest Baptist Health,

and Risk Factor Medical Center Boulevard,

Winston Salem, NC 27157,
[email protected].

Management Relationship Disclosure:

Dr Guzik reports no
disclosure. Dr Bushnell
receives research/grant
Amy Guzik, MD; Cheryl Bushnell, MD, MHS support from the
Patient-Centered Outcomes
Research Institute
(PCS-1403-14532).
ABSTRACT
Unlabeled Use of
Purpose of Review: Death from stroke has decreased over the past decade, with Products/Investigational
stroke now the fifth leading cause of death in the United States. In addition, the Use Disclosure:
Drs Guzik and Bushnell report
incidence of new and recurrent stroke is declining, likely because of the increased no disclosures.
use of specific prevention medications, such as statins and antihypertensives. Despite * 2017 American Academy
these positive trends in incidence and mortality, many strokes remain preventable. The of Neurology.
major modifiable risk factors are hypertension, diabetes mellitus, tobacco smoking,
and hyperlipidemia, as well as lifestyle factors, such as obesity, poor diet/nutrition, and
physical inactivity. This article reviews the current recommendations for the manage-
ment of each of these modifiable risk factors.
Recent Findings: It has been documented that some blood pressure medications
may increase variability of blood pressure and ultimately increase the risk for stroke.
Stroke prevention typically includes antiplatelet therapy (unless an indication for anti-
coagulation exists), so the most recent evidence supporting use of these drugs is
reviewed. In addition, emerging risk factors, such as obstructive sleep apnea, electronic
cigarettes, and elevated lipoprotein (a), are discussed.
Summary: Overall, secondary stroke prevention includes a multifactorial approach.
This article incorporates evidence from guidelines and published studies and uses an
illustrative case study throughout the article to provide examples of secondary prevention
management of stroke risk factors.

Continuum (Minneap Minn) 2017;23(1):15–39.

INTRODUCTION overall prevalence of 2.6% in those

This article describes the incidence, over 20 years of age between 2009 and
prevalence, and mortality associated 2012.2 Approximately 85% of strokes
with ischemic stroke. In addition, the are ischemic, the main focus of this ar-
unresolved health disparities related ticle.2 In addition, 17.8% of those over
to ischemic stroke are described. The 45 years of age have experienced
best evidence for management of each stroke symptoms,3 and silent cerebral
modifiable risk factor is also described, infarction is seen in approximately 6%
with the exception of atrial fibrillation. to 28% of the population, increasing
For more information on atrial fibrilla- with age (Figure1-1).2 The risk of
tion, refer to the article “Cardioembolic recurrent stroke is approximately
Stroke” by Cumara B. O’Carroll, MD, 20% at 5 years.4,5
MPH, and Kevin M. Barrett, MD, MSc,1 Over the past 30 years or more, both
in this issue of Continuum. stroke incidence and mortality have
decreased. The rate of stroke in patients
EPIDEMIOLOGY OF STROKE on Medicare over 65 years of age de-
Stroke is the fifth leading cause of clined 40% from 1988 to 2008,6 and the
death in the United States, with an age-adjusted stroke death rate decreased
Continuum (Minneap Minn) 2017;23(1):15–39 ContinuumJournal.com 15

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

 Epidemiology and Risk Factors

KEY POINT
h Stroke incidence and
mortality have declined
in recent decades,
correlating with
improved risk factor
management.

FIGURE 1-1 Prevalence of stroke by age and sex.

Reprinted with permission from Mozaffarian D, et al, Circulation.2
B 2015 American Heart Association, Inc.

33.7% from 2003 to 2013.2 The rate of versus 58.9% decline).2 Differences in
recurrent stroke is declining as well. stroke risk are seen with race and eth-
In control patients pooled from stroke nicity as well. Overall, the stroke in-
prevention trials, the annual rate of cidence was higher in blacks than in
recurrent stroke fell from 8.71% in the whites in the REasons for Geographic
1960s to 4.98% in the 2000s,7 with the And Racial Differences in Stroke
current annual rate estimated to be (REGARDS) cohort, although this dis-
between 3% and 4%.8 Recurrent stroke parity was more prominent in the
is associated with a larger risk factor young, with a black to white incidence
burden,9 and improvements in stroke rate ratio of 4.02 in those 45 to 54 years
prevention over recent decades corre- of age and 0.86 in those over 85 years
spond to improved risk factor manage- of age.13 While a decline in incidence
ment, including higher rates of statin was seen in whites between 1990 and
(4% to 41.4%) and antihypertensive 2005, stroke incidence remained the
(53% to 73.5%) use between 1992 same in blacks.14 The mean age of
and 2008.6 stroke death is younger in blacks than
Unfortunately, disparities in stroke whites,2 and while death rates declined
risk exist, and the decline has not been by about 50% in all racial groups, rates
universal across all subgroups of the remain higher in blacks (65.7% versus
population. While stroke is more com- 46.9% in whites and 39.6% in Asians).2
mon in men than women when young Mexican Americans are also seen to have
and middle-aged,10 women have a a higher stroke incidence in younger
higher lifetime risk of stroke than men age groups and younger age at stroke
(20% to 21% versus 14% to 17%) with death than non-Hispanic whites.2,15
poorer functional outcomes.11,12 A In the United States, perhaps the
greater decline in age-adjusted death most dramatic are the geographic dis-
rate was seen in men than women be- parities. Mortality is 20% higher in the
tween 1981 and 2013 (61.4% decline stroke belt, identified as North Carolina,

16 ContinuumJournal.com February 2017

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

 KEY POINTS
South Carolina, Georgia, Tennessee, solute number of stroke deaths in- h Disparities in stroke
Mississippi, Alabama, Louisiana, and creased over that time.2,19,20 incidence and mortality
Arkansas. Within the “buckle” of the still exist, particularly
stroke belt, mortality is even higher at RISK FACTOR MANAGEMENT in the stroke belt and
40% (Figure 1-216).17 This has per- Stroke prevention requires manage- among blacks and
sisted through recent decades and is ment of the major risk factors, including Mexican Americans.
particularly evident in black men. While hypertension, hyperlipidemia, diabetes h Hypertension is the
the mortality rate decreased in white mellitus, and tobacco use, as well as most common
women, white men, and black women antithrombotic therapy. A substantial modifiable risk factor
through all geographic regions, minimal portion of strokes can be prevented for stroke.
change was seen in black men in the with this approach.
East and West South Central regions.18
Globally, stroke is the second lead- Hypertension
ing cause of death.2 Between 1990 and Hypertension is the most common
2010, incidence and mortality have modifiable risk factor for stroke, affect-
decreased in high-income countries. ing about one-third of US adults over
However, no significant change has 20 years of age. Unfortunately, although
been seen in the incidence in low- and the majority of US adults with hyper-
middle-income countries, and the ab- tension are aware they have the

FIGURE 1-2 US stroke death rates from 2011 to 2013, adults 35 years of age and older, by county.
Reprinted from Centers for Disease Control and Prevention.16 cdc.gov/dhdsp/maps/national_maps/stroke_all.htm.

Continuum (Minneap Minn) 2017;23(1):15–39 ContinuumJournal.com 17

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 Epidemiology and Risk Factors

KEY POINT
h The recommended condition and are treated, only about 120 mm Hg had significantly reduced
blood pressure targets half have blood pressure that is con- risk of the primary composite end point
are less than trolled.2 Hypertension is particularly (myocardial infarction, acute coronary
140/90 mm Hg in prevalent in blacks, affecting 41% of syndrome, stroke, acute heart failure, or
patients with an men and 44% of women. High blood death from cardiovascular disease
ischemic stroke and pressures occur much earlier in life in events) than those randomly assigned
less than 130/80 mm Hg blacks than whites,2 and the higher sys- to a target less than 140 mm Hg.24 How-
in patients with a small tolic blood pressure explains about 50% ever, patients with prior stroke were ex-
vessel distribution of the excess risk of stroke in this ethnic cluded by design, and no difference was
ischemic stroke. group compared to whites.21 seen in stroke events during follow-up
What is the optimal goal blood pres- between the two treatment groups.24
sure for stroke prevention, and what is The significance of these findings is un-
the threshold for pharmacologic treat- clear for stroke primary prevention.
ment? These questions, which may be Most neurologists will be involved in
most relevant to primary care providers, the care of patients who have already
were addressed in an evidence-based had a stroke, and therefore recommen-
review and guideline recommendations dations from the AHA/American Stroke
from the Eighth Joint National Commit- Association (ASA) Guidelines for the Pre-
tee (JNC 8).22 The panel recommended vention of Stroke in Patients With Stroke
that individuals over 60 years of age or Transient Ischemic Attack8 are the
be treated for blood pressure of most relevant. The recommendations
150/90 mm Hg or more, whereas for are to initiate blood pressure therapy
those under 60 years of age, blood pres- for patients whose blood pressure re-
sure should be treated if greater than mains above 140/90 mm Hg or to re-
140/90 mm Hg (the latter based on ex- sume blood pressureYlowering therapy
pert opinion because of lack of evi- for those with hypertension, both of
dence).22 Those with diabetes mellitus which would be started several days
or chronic kidney disease should have after stroke onset. The specific target is
a goal blood pressure of less than individualized, but a reasonable goal is
140/90 mm Hg. The American Heart less than 140/90 mm Hg and, for those
Association (AHA) published an ad- with lacunar strokes, a target systolic
visory the same year as JNC 8, which blood pressure of less than 130 mm Hg.8
does not distinguish age as a factor in Which blood pressureYlowering strat-
the decision to treat blood pressure, egies are best? Several categories of
rather using the presence of stage 1 blood pressureYlowering medications
hypertension, ie, blood pressure that exist, but those that have been most
is 140 mm Hg to 159 mm Hg systolic extensively tested in the setting of
and 90 mm Hg to 99 mm Hg diastolic.23 secondary prevention of stroke include
What is important from both guidelines angiotensin-converting enzyme inhibi-
is the emphasis on lifestyle change, tors, thiazide diuretics, and calcium
such as exercise and diet, regardless of channel blockers. The AHA/ASA second-
age, diabetes mellitus, chronic kidney ary prevention guideline does not rec-
disease, or stage of hypertension. Of ommend a specific regimen because no
note, the Systolic Blood Pressure Inter- comparative effectiveness trials of these
vention Trial (SPRINT), published after strategies have been conducted. The best
the two guidelines previously de- evidence points toward treatment with
scribed, was stopped early because the diuretics and angiotensin-converting
group randomly assigned to intensive enzyme inhibitors, but consideration
blood pressure treatment to below should also be given to specific patient
18 ContinuumJournal.com February 2017

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 KEY POINT
characteristics, such as extracranial ar- h Avoiding blood
tery disease, renal impairment, cardiac pressureYlowering
disease, and diabetes mellitus.8 medications that
Blood pressureYlowering medica- lead to variability is
tions that increase variability in mea- recommended.
surements between dosing should Treatment with
be avoided. Pooled analyses of the atenolol shows
United Kingdom Transient Ischemic more variability,
Attack (UK-TIA) aspirin trial and the while treatment
Anglo-Scandinavian Cardiac Outcomes with amlodipine is
associated with
TrialYBlood PressureYLowering Arm
less variability.
(ASCOT-BPLA) showed that visit-to-
visit variability in systolic blood pressure
increased the risk of stroke sixfold
(hazard ratio 6.22, 95% confidence
interval 4.16Y9.29, PG.0001), indepen-
dent of mean systolic blood pressure
(Figure 1-325). Similarly, maximum
systolic blood pressure was associated
with a 15-fold increased risk for stroke
(hazard ratio 15.01, 95% confidence
interval 6.56Y34.48, PG.0001).25 In these
trials, they found that amlodipine treat-
ment was associated with reduced
variability over time and that atenolol
increased variability. Atenolol treat-
ment led to the highest standard
deviation systolic blood pressure and
variability independent of the mean
systolic blood pressure, which also
corresponded to the highest hazard
ratio of stroke. By contrast, amlodipine
treatment was associated with lower
variability and a lower hazard ratio for
stroke (Figure 1-4).25 Another analysis
combining the ASCOT-BPLA with
Medical Research Council trials again
showed that atenolol treatment was
associated with increased variability
and higher risk of stroke compared FIGURE 1-3 Hazard ratios for risk of subsequent
stroke by deciles of standard deviation
with diuretics or calcium channel of systolic blood pressure over the
blockers.26 The conclusions of these first seven visits (baseline to 2 years) in the United
Kingdom Transient Ischemic Attack trial. Panel A
studies were that blood pressureY includes all patients in the trial, panel B excludes
lowering strategies should be chosen those with a past history of stroke, and panel C
excludes those with either a past history of stroke
based on the profile of both lowering or infarction on baseline CT brain imaging.
the mean blood pressure and reduc- CI = confidence interval.
ing variability (Case 1-1A).26 Reprinted with permission from Rothwell PM, et al,
Lifestyle modifications for blood Lancet.25 B 2010 Elsevier. thelancet.com/journals/lancet/
article/PIIS0140-6736(10)60308-X/abstract.
pressure lowering are recommended

Continuum (Minneap Minn) 2017;23(1):15–39 ContinuumJournal.com 19

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

 Epidemiology and Risk Factors

FIGURE 1-4 Comparisons of amlodipine and atenolol by outcomes of stroke events.

The first row is mean systolic blood pressure (SBP), the second row is
standard deviation (SD) of SBP, the third row is variation independent of
mean (VIM) SBP, and the fourth row is average successive variability (ASV) of SBP.
Atenolol, but not amlodipine, is consistently in the top decile of SD SBP and VIM SBP,
corresponding to the highest hazard ratio of stroke.
Modified with permission from Rothwell PM, et al, Lancet.25 B 2010 Elsevier. thelancet.com/journals/
lancet/article/PIIS0140-6736(10)60308-X/abstract.

20 ContinuumJournal.com February 2017

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 Case 1-1A
A 59-year-old black woman was seen in stroke clinic 1 month following
a right internal capsule infarct with residual left hemiparesis. She had a
history of hypertension and dyslipidemia. During her hospitalization, her
blood pressure was stable and she was continued on home atenolol 50 mg
2 times a day. She was also started on aspirin 325 mg/d for stroke prevention.
She continued these medications after she was discharged. On physical
examination, her body mass index (BMI) was 27 and her blood pressure was
150/92 mm Hg, but she stated that when she checks it at home, it ranges
from 120/60 mm Hg to, rarely, 160/90 mm Hg. She asked what her goal
blood pressure should be and when to be concerned.
Comment. Typically, a reasonable blood pressure goal is lower than
140/90 mm Hg poststroke, although a systolic goal of less than 130 mm Hg
is recommended for those with lacunar stroke. As the patient’s internal
capsule stroke is likely secondary to small vessel disease, the lower value
should be targeted. In addition, this patient has blood pressure
variability on atenolol, which increases her risk of stroke. Alternative
antihypertensives, such as amlodipine, should be considered. She should
also be counseled on lifestyle modifications.

and should include salt restriction; four groups of individuals deemed likely
weight loss; a diet rich in fruits, to benefit from moderate- or high-
vegetables, and low-fat dairy products potency statins were the following: (1)
(such as the Dietary Approaches to those with clinical atherosclerotic
Stop Hypertension [DASH] diet27 or cardiovascular disease, (2) those with
the Mediterranean diet28); regular aer- LDL-C higher than 190 mg/dL, (3) those
obic physical activity; and limited who are 40 to 75 years of age with dia-
alcohol consumption.8 betes mellitus and LDL-C 70 mg/dL to
189 mg/dL, and (4) those without clini-
Hyperlipidemia cal atherosclerotic cardiovascular dis-
The evaluation and treatment of hy- ease or diabetes mellitus who are 40 to
perlipidemia is such a critical part of 75 years of age with LDL-C 70 mg/dL to
stroke management that it is a quality 189 mg/dL and an estimated 10-year
metric monitored by the Centers for atherosclerotic cardiovascular disease
Medicare & Medicaid Services (CMS) risk of 7.5% or higher. These guide-
as well as The Joint Commission. The lines recommend estimating 10-year
cholesterol management guidelines atherosclerotic cardiovascular disease
published jointly by the American risk using a risk calculator (based on
College of Cardiology and the AHA in pooled cohort equations). The sec-
2013 provided a new perspective on ondary prevention guidelines also rec-
treatment with statins, with a move- ommend intensive statin therapy for
ment away from a specific low-density patients with stroke or transient ische-
lipoprotein cholesterol (LDL-C) target mic attack (TIA) presumed to be of
and toward a focus on treatment with atherosclerotic origin and initiation
statins that are likely to lower choles- of therapy for LDL-C 100 mg/dL or
terol by 50% or more (high-potency higher with or without evidence of
statins) or by 30% to 50% (moderate- clinical atherosclerotic cardiovascu-
potency statins) (Table 1-1).29 The lar disease.8 Secondary prevention

Continuum (Minneap Minn) 2017;23(1):15–39 ContinuumJournal.com 21

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

 Epidemiology and Risk Factors

KEY POINT
h Atherosclerotic causes was of atherosclerotic origin and
of ischemic stroke or the TABLE 1-1 Low-, Moderate-, and whether LDL-C is higher than 100 mg/dL.8
High-Potency Statins In addition to statin therapy, both guide-
finding of a low-density
Recommended
lipoprotein level higher lines encourage a heart-healthy diet for
for Atherosclerotic
than 100 mg/dL should Cardiovascular Diseasea lowering cholesterol, which is described
be treated with a in more detail later in this article.
high-potency statin. In routine practice, many patients
b High-Potency Statin Therapy
(Daily dose lowers LDL-C by are reluctant to start statins because of
approximately Q50% on the high risk of myopathy or general
average) muscle pain, which varies from 7% to
Atorvastatin 40Y80 mg 29% in the literature.30 Statin-associated
myopathy is more likely with female
Rosuvastatin 20 or 40 mg
sex, older age, frailty, surgery, and mul-
b Moderate-Potency Statin tiple medications, among other factors,
Therapy (Daily dose lowers
so it is important to consider these risks
LDL-C by approximately 30%
to G50% on average) when initiating statins.31 Focusing on
women, an analysis of pooled patient
Atorvastatin 10 or 20 mg
level data from six statin trials showed
Rosuvastatin 5 or 10 mg that only one (Incremental Decrease in
Simvastatin 20Y40 mg Endpoints Through Aggressive Lipid
Lowering [IDEAL], atorvastatin 80 mg
Pravastatin 40 or 80 mg
versus simvastatin 20 mg to 40 mg) was
Lovastatin 40 mg associated with a significant interaction
Fluvastatin XL 80 mg between sex and rate of adverse effects.
For women on the high-dose atorvastatin,
Fluvastatin 40 mg
2 times a day 15.1% discontinued atorvastatin versus
4.6% on simvastatin, whereas in men,
Pitavastatin 2Y4 mg
8.3% discontinued atorvastatin versus
b Low-Potency Statin Therapy 4.1% on simvastatin. Multivariable
(Daily dose lowers LDL-C by modeling showed that increasing age,
G30% on average)
higher atorvastatin dose, and number
Simvastatin 10 mg of concomitant medications were pre-
Pravastatin 10Y20 mg dictive of statin discontinuation in both
sexes, and diabetes mellitus was predic-
Lovastatin 20 mg
tive of discontinuation in women, but
Fluvastatin 20Y40 mg not men.32
Pitavastatin 1 mg A helpful algorithm for management
of statin-association muscle symptoms
LDL-C = low-density lipoprotein
cholesterol. was published in 2015 30 in light of the
a
Modified with permission from 2013 cholesterol management guide-
Stone NJ, et al, J Am Coll Cardiol.29
B 2014 The Expert Panel Members. lines and high-potency statins for pre-
sciencedirect.com/science/article/pii/ vention of cardiovascular disease and
S0735109713060282.
stroke. If patients have muscle symp-
toms and a creatine kinase (CK) that is
greater than 4 times the upper limit
guidelines essentially concur with the of normal with or without rhabdomy-
American College of Cardiology/AHA olysis, then the statin should be dis-
recommendations but include consid- continued for 6 weeks and CK repeated.
eration of whether the stroke or TIA If the CK normalizes and symptoms
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 KEY POINT
are improved, a low dose of a second management of side effects. If patients h Intolerance to statins, a
high-potency statin or an alternate day experience severe myalgia that impacts common problem, can
or once or twice weekly dosing regimen their mobility, such as with walking, be addressed by
should be started. If patients have climbing stairs, or exercise, then the stopping the
muscle symptoms and a CK of less than statin should be discontinued to deter- medications, checking
4 times the upper limit of normal, then mine whether the symptoms improve. for muscle enzymes,
patients should discontinue the statin Serum CK should be collected and mea- and reducing the dose
for 2 to 4 weeks. At this point, a second sured to determine whether the statin upon reinitiation.
high-potency statin at the usual start- is causing myopathy. If rechallenge
ing dose is recommended. If symptoms with the statin is still not tolerated, low
reoccur with a second statin, then a or intermittent dosing with a potent or
third high-potency statin at low dose or efficacious statin should be used, and
a high-potency statin with alternate day with nonstatin therapies as adjuncts
or once or twice weekly dosing should as needed to achieve the LDL-C goal
be considered. Patients should be coun- (Case 1-1B). The European Atheroscle-
seled about the risk and successful rosis Society Consensus Panel Statement

Case 1-1B
Review of the records of the patient in Case 1-1A from her stroke hospitalization showed that her
carotid ultrasound showed 50% to 60% internal carotid artery stenosis bilaterally. Her high-density
lipoprotein was 40 mg/dL, and her total cholesterol was 240 mg/dL. A statin was not started at
discharge because she had a history of mild muscle aches on atorvastatin without impairment of
mobility. Her creatine kinase was measured by her primary care provider at the time and was normal.
Comment. With clinical atherosclerotic cerebrovascular disease, as demonstrated by her
extracranial carotid disease and small vessel distribution infarct, a moderate- or high-potency statin
is recommended. In addition, her atherosclerotic cardiovascular disease risk in 10 years was 52.8%
and her lifetime risk was 50% (Figure 1-5). Given the new event and risk that is significantly
higher than someone
her age with optimal
risk factors (2.7%), a
high-potency statin
should be reinitiated,
either atorvastatin or
rosuvastatin,
according to the
guidelines presented
in Table 1-1.
If rechallenge with
the statin leads to
recurrence of muscle
symptoms, then low
or intermittent
dosing with a potent
or efficacious statin
should be considered.
Lifestyle modifications, FIGURE 1-5 Risk calculator results for the patient in Case 1-1B based on age, race, sex, total
cholesterol, high-density lipoprotein cholesterol, treatment for high
such as diet and blood pressure, diabetes mellitus, and smoking.
exercise, should be ASCVD = atherosclerotic cardiovascular disease.
discussed as well.

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 Epidemiology and Risk Factors

KEY POINTS
h Disorders of glucose on Assessment, Aetiology, and Manage- progress toward a goal of less than 7%
metabolism are highly ment also specifically recommends in most adults.34 Although oral hypo-
prevalent in patients against the use of supplements, such as glycemic drugs are not recommended
with stroke. Patients coenzyme Q10 or vitamin D, to alleviate for secondary prevention, some sup-
with new-onset stroke muscle symptoms since no evidence of port exists for their use for patients with
or transient ischemic their benefits exists.30 In most settings, stroke. For example, the Prospective
attack should be neurologists will be conducting this Pioglitazone Clinical Trial in Macro-
screened for diabetes management in collaboration with the vascular Events (PROactive) showed that
mellitus with hemoglobin patient’s primary care provider or a among patients with a history of stroke,
A1c or an oral glucose highly specialized lipid clinic.
tolerance test.
pioglitazone was associated with a nearly
50% reduction in recurrent stroke
h Diabetes mellitus and Diabetes Mellitus and (hazard ratio 0.53; 95% confidence
metabolic syndrome are
Metabolic Syndrome interval 0.34Y0.85).35 The recently con-
key risk factors for
first-ever and recurrent Disorders of glucose metabolism are cluded Insulin Resistance Intervention
ischemic stroke; major risk factors for stroke, including After Stroke (IRIS) trial specifically fo-
therefore, management type 1 and type 2 diabetes mellitus and cused on secondary prevention of
for these conditions prediabetes (defined as hemoglobin A1c stroke in patients with insulin resistance
should include lifestyle of 5.7% to 6.4%). These disorders are and showed a 24% reduction of recur-
and pharmacologic highly prevalent in patients with stroke: rent stroke with pioglitazone (hazard
strategies to reduce the ratio 0.76; 95% confidence interval
28% have prediabetes, and 25% to
hemoglobin A1c to 0.62Y0.93; P=.007).36
45% have diabetes mellitus.8 In addi-
less than 7%.
tion, diabetes mellitus is independently Another important condition that
associated with a 60% risk (hazard ratio often includes impaired glucose me-
1.59; 95% confidence interval 1.07Y2.37) tabolism is metabolic syndrome, a risk
for recurrent stroke in the elderly.33 factor for stroke and cardiovascular
Therefore, the AHA/ASA secondary pre- disease that represents multiple com-
vention guideline recommends that ponents. It is diagnosed when three
patients with new-onset stroke or TIA of the following five risk factors are
should be screened for diabetes mel- present: (1) fasting plasma glucose of
litus with hemoglobin A1c or an oral 100 mg/dL or higher or the patient is
glucose tolerance test.8 Despite the prev- undergoing treatment for increased
alence and the major risk for recurrent glucose; (2) high-density lipoprotein
stroke with diabetes mellitus, the ideal cholesterol (HDL-C) of 40 mg/dL or less
targets for glucose control and the in men or 50 mg/dL or less in women or
treatments needed to reach these goals
the patient is undergoing treatment for
are not fully understood. The American
low HDL-C; (3) triglycerides of 150 mg/dL
Diabetes Association recommends that,
or higher or the patient is undergoing
for most patients with diabetes mellitus,
treatment for high triglycerides; (4)
the target hemoglobin A1c is less than
7%.34 It also recommends participation waist circumference 102 cm (40 in) or
in diabetes mellitus self-management higher in men or 88 cm (34.6 in) or
education and support as well as life- higher in women (may differ by ethnic-
style interventions as the first step to ity); (5) blood pressure 130 mm Hg or
management. Metformin, often initiated higher systolic or 85 mm Hg or higher
at a dose of 500 mg 2 times a day, is the diastolic, or the patient is undergoing
preferred initial pharmacologic agent. drug treatment for hypertension or
Repeat hemoglobin A1c is recommended antihypertensive drug treatment in a
after 3 months of treatment to track patient with a history of hypertension.2

24 ContinuumJournal.com February 2017

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 KEY POINTS
The prevalence of metabolic syndrome tal admissions for stroke were reduced h Cigarette smoking is a
has been difficult to determine because by 14% in Arizona communities after significant risk factor, at
of varying definitions and variation by a public smoking ban, although a simi- least doubling the risk
ethnicity, but it appears to affect about lar decline was not seen in New York of stroke.
22% of the US population. The preva- State.44,45 Patients should be coun- h Nicotine replacement
lence is decreasing, perhaps because of seled on avoidance of environmental therapy, bupropion,
sources of smoke, and smokers in the and, in particular,
a decline in the components of blood
household should be counseled to quit varenicline are effective
pressure and triglyceride levels.2 Meta-
as well. treatments for smoking
bolic syndrome increases the risk of The risk of stroke is not as clear for cessation. While
stroke 1.5 to 23 times in women and other forms of tobacco and nicotine. electronic cigarettes
varies from no significant risk to a six- Few large-scale studies quantifying the may pose less potential
fold risk in men for studies published cerebrovascular or cardiovascular risk stroke risk than
through 2013.37 of smokeless tobacco exist, and risk is traditional cigarettes,
insufficient evidence
often difficult to distinguish from ciga-
exists to counsel
Tobacco Use rette use as much overlap exists. In a
patients to use
Tobacco use is a significant risk factor review of the available literature, the electronic cigarettes
for stroke as well as silent infarction.8 AHA policy statement on the impact as a primary form of
Current smokers have at least a dou- of smokeless tobacco on cardiovascular smoking cessation.
bled risk of stroke, with an apparent disease found that available data sug-
h Environmental exposure
dose-response relationship seen.38,39 gest no impact on hypertension and an to secondhand smoke
This has been seen in multiple unclear association with cardiovascular increases stroke risk by
population-based studies and across outcomes, with differences between as much as 30%
multiple age groups and ethnicities.38 studies likely due in part to the specific among nonsmokers.
In addition, a synergistic effect exists products used by participants.46 The h While the risk of stroke
with high blood pressure,40 and those Atherosclerosis Risk in Communities from smokeless tobacco
with hypertension should be aware (ARIC) registry showed 1.27 times in- products and electronic
of further increased risk. This risk is creased cardiovascular disease incidence cigarettes is less clear
very modifiable, with risk returning to (95% confidence interval 1.06Y1.52) than from cigarette
normal after 10 years of abstinence.38 among smokeless tobacco users, al- smoking, poststroke risk
Smoking cessation counseling should though this was not specific to stroke modification provides
be undertaken to reduce stroke risk, as it included myocardial infarction, an opportune time for
including offering available medica- stroke, cardiac revascularization, and counseling on cessation
cardiovascular/cerebrovascular death.47 from all forms of
tions. In one meta-analysis, all available
tobacco and nicotine.
medications for tobacco dependence Pooled results of studies on use of snus,
(forms of nicotine replacement therapy, the type of smokeless tobacco used in
bupropion, varenicline) were found to Sweden, did not find an increased risk
be superior to placebo in sustained of stroke.48 However, a meta-analysis
smoking cessation, and varenicline showed a relative risk of fatal stroke
was found superior to all treatments.41 in users of smokeless tobacco products
Practical counseling and identification of 1.40 (95% confidence interval
of social support have also been 1.28Y1.54).49 Although the risk of stroke
recommended as especially effective.42 is less clear with smokeless tobacco use
In addition, environmental exposure than in cigarette smoking, poststroke
to secondhand smoke has been iden- risk modification provides an oppor-
tified as a risk factor for stroke, in- tune time for counseling on cessation
creasing risk by as much as 30% among from all forms of tobacco.
nonsmokers.43 Community smoking New forms of nicotine delivery, such
bans have had variable results. Hospi- as electronic cigarettes (e-cigarettes) are

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 Epidemiology and Risk Factors

even less well understood. While more an independent role in stroke risk
than 400 brands of e-cigarettes exist, reduction. As large-scale nutritional
they all commonly contain a liquid studies are difficult to conduct, data
mixture of propylene glycol and nico- come primarily from observational or
tine housed in a cartridge or refillable cohort studies. Findings from the
tank. The device heats and aerosolizes Nurses’ Health Study and Health Pro-
the liquid, triggered by inhalation.50 fessionals Follow-Up Study have pro-
Because this method does not con- vided examples of dietary patterns
tain smoke, tar, or other chemicals, associated with lower risk of stroke.
e-cigarettes are marketed as a safe form Increased fruit and vegetable intake was
of nicotine delivery. Very little informa- associated with reduced stroke risk,
tion is available on the health effects of with the highest protective effect from
e-cigarettes; with less than 15 years on cruciferous and green leafy vegetables
the market, sufficient data do not exist and citrus fruits and juices.52 Each
to determine the risk of long-term additional one serving per day was
toxicity leading to cerebrovascular or associated with a 6% lower risk of
cardiovascular disease. The AHA policy ischemic stroke (relative risk, 0.94;
statement maintains that e-cigarette 95% confidence interval 0.90Y0.99;
regulation and health care screening P=.01).52 A single serving of caffein-
should be similar to other forms of ated or decaffeinated coffee decreased
tobacco.50 However, insufficient evi- stroke risk by approximately 10%.53
dence exists for counseling patients to However, daily servings of soda appear
use e-cigarettes as a primary form of to increase the risk of ischemic stroke,
smoking cessation (Case 1-1C).50 with 13% increase per serving per day
of sugar-sweetened soda and 7% in-
Diet and Nutrition creased risk of ischemic stroke per daily
Diet and nutrition are important to serving of low-calorie soda.53 An addi-
address in stroke prevention counsel- tional meta-analysis indicates lower
ing. Not only have dietary patterns been stroke risk with two to four or more than
associated with risk factor manage- five servings of fish per week compared
ment, but recent studies have indicated to less than one serving per week.54

Case 1-1C
The patient in Case 1-1A was a former smoker who quit 12 years earlier.
Many of her coworkers were smokers, and she joined them on their smoke
breaks to be social. Her husband continued to smoke but was trying to
quit. He asked about the use of electronic cigarettes (e-cigarettes).
Comment. The patient should be commended on smoking cessation and
encouraged to continue abstinence. However, the secondhand smoke she
was exposed to continued to increase her stroke risk. She should be
encouraged to avoid environmental exposure from coworkers, and her
husband should be encouraged to quit smoking or smoke outside the
house. Very little information is available on the long-term health effects of
e-cigarettes. While e-cigarettes may pose less potential stroke risk
compared to traditional cigarettes, insufficient evidence exists to counsel
her husband to use e-cigarettes as a primary form of smoking cessation,
and he should be encouraged to discuss forms of nicotine replacement
therapy, bupropion, or varenicline with his primary care provider.51

26 ContinuumJournal.com February 2017

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 KEY POINT
Perhaps the most compelling evi- women and less than or equal to two h The Mediterranean diet
dence for the influence of nutrition 5-ounce servings for men) with meals, is associated with lower
specific to stroke risk comes from the is optional. The Mediterranean diet risk of stroke. It is
Prevención con Dieta Mediterránea with either olive oil or nut supplemen- characterized by high
(PREDIMED) study comparing the tation was associated with lower risk intake of olive oil, fruits
Mediterranean diet supplemented with of a composite primary end point of and vegetables, nuts,
either extra-virgin olive oil or mixed nuts myocardial infarction, stroke, or car- and whole grains;
compared to a low-fat control diet.28 diovascular death (hazard ratio 0.70, moderate intake of fish
The Mediterranean diet is characterized 95% confidence interval 0.54Y0.92 for and poultry; and low
by high intake of olive oil, fruits and the extra-virgin olive oil group and intake of dairy, red
and processed meats,
vegetables, nuts, and whole grains with hazard ratio 0.72, 95% confidence
and sweets.
moderate intake of fish and poultry and interval 0.54Y0.96 for the nut group).
low intake of dairy, red and processed Secondary end point analysis revealed
meats, and sweets (Table 1-255). Wine, a significant decline in stroke compared
consumed in moderation (less than or to the control diet (hazard ratio 0.61,
equal to one 5-ounce serving for 95% confidence interval 0.44Y0.86,

TABLE 1-2 Composition of the Healthy Mediterranean-Style and Healthy Vegetarian Eating
Patterns at the 2,000-Calorie Level, With Daily or Weekly Amounts From Food
Groups, Subgroups, and Componentsa

Healthy Mediterranean-Style Healthy Vegetarian

Food Group Eating Pattern Eating Pattern
Vegetables 2.5 cups per day 2.5 cups per day
Dark green 1.5 cups per week 1.5 cups per week
Red and orange 5.5 cups per week 5.5 cups per week
Legumes (beans and peas) 1.5 cups per week 3 cups per week
Starchy 5 cups per week 5 cups per week
Other 4 cups per week 4 cups per week
Fruits 2.5 cups per day 2 cups per day
Grains 6 oz per day 6.5 oz per day
Whole grains Q3 oz per day Q3.5 oz per day
Refined grains e3 oz per day e3 oz per day
Dairy 2 cups per day 3 cups per day
Protein foods 6.5 oz per day 3.5 oz per day
Seafood 15 oz per week None
Meats, poultry, eggs 26 oz per week 3 oz per week (eggs)
Nuts, seeds, soy products 5 oz per week 14 oz per week
Oils 27 g per day 27 g per day
Limit on calories for 260 kcal per day (13%) 290 kcal per day (15%)
other uses (% of calories)
a
Reprinted from U.S. Department of Health and Human Services and U.S. Department of Agriculture.55 health.gov/dietaryguidelines/
2015/guidelines/chapter-1/examples-of-other-healthy-eating-patterns/.

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 Epidemiology and Risk Factors

KEY POINTS
h Diet and nutrition can P=.005), but the difference in other sweetened beverages, and red meats.
affect not only risk end points was not significant.28 Lower These recommendations are consis-
factors such as risk of ischemic stroke with adherence tent with the DASH dietary pattern
hypertension and to the Mediterranean diet was confirmed and the AHA Diet.59
hyperlipidemia but also in the REGARDS cohort as well.56 Also of importance in lowering blood
stroke risk specifically. Additional findings show that extra- pressure is reduction of sodium intake.
The Dietary Approaches virgin olive oil in the context of the Lowering of blood pressure was seen
to Stop Hypertension Mediterranean diet may reduce atrial with sodium reduced to 2400 mg/d, with
diet is effective in fibrillation risk,57 and low adherence further improvement with a sodium in-
lowering blood pressure to the Mediterranean diet is associated take of only 1500 mg/d.60 A 1000 mg/d
and low-density
with increased large artery atheroscle- reduction of sodium intake reduces
lipoprotein, with
rotic stroke as well as worse clinical cardiovascular events by approximately
reduction of sodium
intake to 2400 mg/d or
presentation and outcome at dis- 30%, and higher sodium intake is asso-
less recommended for charge (as measured by the modified ciated with a greater risk of fatal and
those with hypertension. Rankin Score).58 nonfatal stroke and cardiovascular
In addition, diet is considered an disease. 59 High salt intake is also
h Obesity is an established
risk factor for ischemic
important strategy for risk factor independently associated with in-
stroke. With every management, in particular for choles- creased risk of stroke (relative risk 1.23,
1-unit increase in body terol and blood pressure lowering. The 95% confidence interval 1.06Y1.43;
mass index (about AHA/American College of Cardiology P=.007) (Case 1-1D).61
7 pounds), the risk for Guideline on Lifestyle Management to
ischemic stroke rises by Reduce Cardiovascular Risk was pub- Obesity
about 5%. lished in 2013. This evidence-based Being overweight or obese is highly
review showed that lowering saturated prevalent in the United States. Overall,
fat or total fat, or replacing saturated data from 2009 to 2012 showed that
fats or trans monounsaturated fats with 69% of US adults were overweight (body
monounsaturated or polyunsaturated mass index [BMI] higher than 25 kg/m2)
fats can successfully lower LDL-C.59 and 35% were obese (BMI of 30 kg/m2
The dietary pattern that is most effec- or higher).2 Obesity is an established
tive for lowering both LDL-C and blood risk factor for ischemic stroke, and epi-
pressure includes intake of vegetables, demiologic studies have shown that
fruits, whole grains, low-fat dairy prod- starting with a BMI of 20 kg/m2, for
ucts, poultry, fish, legumes, nontrop- every 1-unit increase in BMI (about
ical vegetable oils, and nuts while 7 pounds), the risk for ischemic stroke
limiting intake of sweets, sugar- rises by about 5%.62,63

Case 1-1D
The patient in Case 1-1A had been trying to lose weight over the past
5 years, following the Atkins diet. She asked about specific poststroke
dietary restrictions.
Comment. With hypertension, reduction of sodium intake is of
particular importance. To reduce blood pressure, sodium should be
reduced to 2400 mg/d, and the patient should be counseled that further
improvement in blood pressure has been seen with a sodium intake of
only 1500 mg/d. Although the Atkins diet has not been studied extensively
in stroke prevention, the Dietary Approaches to Stop Hypertension
(DASH) diet or Mediterranean diet (Table 1-2) should be encouraged
for risk factor reduction or stroke prevention, respectively.

28 ContinuumJournal.com February 2017

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 The mechanism of cardiovascular dis- Physical Activity
ease and stroke risk with obesity is Exercise is defined as a “subset of phys-
linked to the adipose tissue as a repos- ical activity that is planned, structured,
itory of inflammatory cells, which may and repetitive and has as a final or an
contribute to insulin resistance and hy- intermediate objective the improvement
perglycemia and subsequently promote or maintenance of physical fitness,”
atherosclerosis.64 Some patients with whereas physical activity is “any bodily
obesity may be less likely to have an movement produced by skeletal mus-
adverse metabolic profile, and there- cles that results in energy expendi-
fore the recommendation is that once ture.”68 Physical activity, the focus of
obesity is identified, patients should this section, is defined by four di-
undergo additional testing for meta- mensions (mode or type, frequency,
bolic abnormalities, such as hypergly- duration, and intensity) and four com-
cemia, hypertriglyceridemia, cholesterol mon domains (occupational, domestic,
(especially low HDL), and inflammatory transportation, and leisure time). Al-
markers such as C-reactive protein.64 though physical activity is traditionally
The AHA/ASA secondary prevention reported as leisure time, it is important
guidelines specifically recommend to account for all domains.2 Physical
screening for obesity with determi- inactivity is defined as no sessions of
nation of BMI in all patients with TIA light/moderate or vigorous physical
or stroke. However, no evidence exists activity of more than 10 minutes’ dura-
to support weight loss among patients tion. The prevalence of physical in-
with stroke or TIA for secondary pre- activity is reported to be 28.5% of men
vention, although weight loss is ben- and 31.5% of women and increases with
eficial for improving cardiovascular age (about 50% of those older than
risk factors.8 75 years of age).2 In general, systematic
After stroke, a high prevalence of im- reviews and meta-analyses have shown
paired glucose tolerance and diabetes that engaging in physical activity can
mellitus exists in stroke survivors, which reduce the risk of stroke or mortality
may, in part, be related to physiologic by 25% to 30%.38
changes in muscle in hemiparetic limbs. For those who have survived a
Along with the loss of skeletal muscle stroke, engaging in physical activity
mass and less physical activity, stroke can be challenging because of residual
survivors may have a predisposition to hemiparesis, sensory impairment, ne-
weight gain. In addition, the hemiparetic glect, dyscoordination, spasticity, cog-
muscle may undergo accumulation of nitive dysfunction, or aphasia. As
intramuscular fat and a switch from impairments impact the ability for self-
slow-twitch to fast myosin heavy chain care in up to 40% of stroke survivors
fibers, which rely on anaerobic me- and may impose activity limitations
tabolism.65,66 This type of metabolism and restrictions, it is not surprising that
predisposes to oxidative injury and in- a large proportion of stroke survivors
flammation that leads to glucose intol- ultimately choose a sedentary lifestyle,
erance (insulin resistance). Physical even if they are able to participate in
activity, in addition to being a weight physical activity.69 Unfortunately, no
loss strategy, has important effects on trials of physical activity/exercise pro-
insulin resistance that are nearly imme- grams have been shown to reduce
diate by suppressing fatty acidYinduced the risk of a recurrent stroke, but
insulin resistance and inflammation in studies have shown that exercise has
skeletal muscle.67 a positive effect on risk factors such as

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 Epidemiology and Risk Factors

hypertension, arterial function, and stroke survivors in both the acute and
insulin response.69 rehabilitation phases are outlined
Evidence-based recommendations in Table 1-3,70 including inpatient
for physical activity and exercise for and outpatient exercise therapy. The

TABLE 1-3 Summary of Exercise/Physical Activity Recommendations for Stroke Survivorsa,b

Prescriptive Guidelines:
Setting/Mode of Exercise Goals/Objectives Frequency/Intensity/Time
Hospitalization and early
convalescence (acute phase)
Low-level walking, self-care Prevent deconditioning, hypostatic Approximately 10Y20 beats/min
activities pneumonia, orthostatic increases in resting heart rate (HR);
intolerance, and depression; rate of perceived exertion (RPE)
Intermittent sitting or standing
evaluate cognitive and motor e11 (6Y20 scale); frequency and
Seated activities deficits; stimulate balance duration as tolerated, using an
and coordination interval or work-rest approach
Range-of-motion activities,
motor challenges
Inpatient and outpatient exercise
therapy or rehabilitation
Aerobic Increase walking speed and 40Y70% oxygen uptake (VO2)
efficiency; improve exercise reserve or HR reserve; 55Y80% HR
Large-muscle activities
tolerance (functional capacity); maximum; RPE 11Y14 (6Y20 scale)
(eg, walking, graded
increase independence in
walking, stationary cycle 3Y5 days per week; 20- to
activities of daily living (ADLs);
ergometry, arm ergometry, 60-minute session (or multiple
reduce motor impairment
arm-leg ergometry, functional 10-minute sessions); 5Y10 minutes
and improve cognition; improve
activities with seated of warm-up and cool-down
vascular health and induce
exercises, if appropriate) activities; complement with
other cardioprotective benefits
pedometers to increase lifestyle
(eg, vasomotor reactivity,
physical activity
decrease cardiovascular risk)

Muscular strength/endurance Increase muscle strength and 1Y3 sets of 10Y15 repetitions of
endurance; increase ability to 8Y10 exercises involving the major
Resistance training of upper perform leisure time and muscle groups at 50Y80% of
and lower extremities, occupational activities and 1 repetition maximum; 2Y3 days
trunk using free weights, ADLs; reduce cardiac demands per week; resistance gradually
weight-bearing or partial (ie, rate-pressure product) increased over time as
weight-bearing activities, during lifting or carrying objects tolerance permits
elastic bands, spring by increasing muscular strength,
coils, pulleys thereby decreasing the percentage
Circuit training of maximal voluntary contractions
that a given load now represents
Functional mobility

Flexibility Increase range of motion of Static stretches; hold for

involved segments; prevent 10Y30 seconds
Stretching (trunk, upper
contractures; decrease risk
and lower extremities) 2Y3 days per week (before or
of injury; increase ADLs
after aerobic or strength training)

Continued on page 31

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TABLE 1-3 Summary of Exercise/Physical Activity Recommendations for Stroke Survivorsa,b
Continued from page 30

Prescriptive Guidelines:
Setting/Mode of Exercise Goals/Objectives Frequency/Intensity/Time
Neuromuscular Improve balance, skill reacquisition, Use as a complement to aerobic,
quality of life, and mobility; muscular strength/endurance
Balance and coordination decrease fear of falling; improve training, and stretching activities;
activities
level of safety during ADLs 2Y3 days per week
Tai chi
Yoga
Recreational activities
using paddles/sport balls
to challenge hand-eye
coordination
Active-play video gaming
and interactive
computer games
a
Modified from Gordon NF, et al, Circulation.70 B 2004 American Heart Association, Inc. circ.ahajournals.org/content/109/16/2031.long.
b
Reprinted with permission from Billinger SA, et al, Stroke.69 B 2014 American Heart Association, Inc. stroke.ahajournals.org/content/
45/8/2532.long.

recommendations include aerobic, intensity aerobic exercise per week, KEY POINT
muscular strength/endurance, flexibil- with sessions lasting an average of h Patients with stroke
should engage in three
ity, and neuromuscular activities, as 40 minutes. The guideline also recom-
to four sessions of
well as the frequency, intensity, and mends referral to a comprehensive,
moderate- to
duration of activities that can provide behaviorally oriented program for those vigorous-intensity
multiple benefits for stroke survivors willing and able to initiate physical activ- aerobic exercise per
(Case 1-1E).69 The AHA/ASA second- ity, and, for those with disabilities, week, with sessions
ary prevention guideline recommends supervision by a health care professional lasting an average of
that patients engage in three to four such as a physical therapist or cardiac 40 minutes.
sessions of moderate- to vigorous- rehabilitation expert is reasonable.8

Case 1-1E
On neurologic examination, the patient in Case 1-1A had left facial
asymmetry and 5-/5 strength throughout her left hemibody. Her gait was
slow, but not spastic. She had completed a course of physical therapy
and continued to use a cane for long distances. She asked about activity
restrictions or recommendations.
Comment. This stroke survivor has minimal weakness but some
limitations in mobility after reaching her physical therapy goals. She should
be encouraged to pursue safe mobility by increasing her walking in the
community, starting with 10 minutes at a time and increasing to 20 to
60 minutes at a time, 3 to 5 days per week. This aerobic exercise could also
include stationary cycle ergometry, arm ergometry, arm-leg ergometry, or
functional activities with seated exercises (Table 1-3). Other recommended
neuromuscular exercises include tai chi, yoga, or recreational activities using
paddles/sport balls to challenge hand-eye coordination.69

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 Epidemiology and Risk Factors

To increase physical activity in stroke women, with a higher apnea-hypopnea

survivors, health professionals are en- index threshold (higher than 25) nec-
couraged to incorporate behavioral essary to increase the risk of stroke
counseling on physical activity into visits. in women.74
Although primary care was the target The rate of sleep apnea after stroke
audience for recommendations by is high, although it is unclear if dis-
Berra and colleagues,71 strategies for ordered breathing precedes stroke or
integrating physical activity counseling develops poststroke. One meta-analysis
into clinical practice are important in demonstrated that sleep apnea is seen
stroke prevention clinics as well, espe- in 72% of patients with stroke or TIA if
cially for patients with TIAs. This starts the threshold of an apnea-hypopnea
with making “physical activity a vital index higher than 5 is used; 63% had an
sign at each clinic visit.”71 apnea-hypopnea index higher than 10,
and 38% of patients with stroke or TIA
EMERGING RISK FACTORS have severe sleep apnea with an apnea-
FOR STROKE hypopnea index higher than 20.75 An
Additional risk factors have been iden- apnea-hypopnea index higher than 10
tified in recent years, although their was seen more commonly in men than
contribution to stroke risk is less well women (65% versus 48%, P=.001) and
defined. Treatment of the following was more common in patients with
conditions may further reduce risk of recurrent stroke (74% versus 57%,
stroke, but additional research is re- P=.013). Central apnea was only seen
quired to fully understand best man- in 7%.75 The presence and severity
agement practices in stroke patients. of sleep apnea are independent of
stroke subtype.76
Sleep Apnea OSA has been associated with higher
Sleep apnea is measured by the apnea- poststroke mortality and worse func-
hypopnea index, which identifies the tional outcome.8 However, it is unclear
number of respiratory events per hour, if treatment with continuous positive
including cessations in breathing and airway pressure (CPAP) improves cere-
reductions in air flow. Sleep apnea has brovascular outcomes or reduces re-
been linked to increased risk of incident current stroke.8 Early treatment with
stroke. Although obstructive sleep ap- CPAP in the acute period has not shown
nea (OSA) has been associated with significant benefit.8 When patients were
hypertension across sex and ethnicities, followed for 7 years poststroke, those
some evidence exists of an independent who did not use CPAP had a higher rate
risk of stroke.72 In an observational of recurrent stroke than those who did
cohort study over about 3 years, sleep (32% versus 14%, P=.021).77 In addition,
apnea defined as an apnea-hypopnea well-established stroke risk factors such
index of 5 or higher increased the risk as hypertension and atrial fibrillation re-
of stroke or death from all causes, in- spond favorably to the successful treat-
dependent of other cerebrovascular ment of sleep apnea.78
risk factors (hazard ratio, 1.97; 95% con- With the prevalence of OSA post-
fidence interval 1.12Y3.48; P=.01).73 stroke and the potential for improved
While increased risk of stroke alone outcomes and secondary stroke pre-
was seen in men, with 6% increased vention, the American Academy of
risk with each point in the apnea- Sleep Medicine recommends screening
hypopnea index from 5 to 25, this via polysomnography in patients with
association may not be as strong in stroke and TIA with symptoms of sleep
32 ContinuumJournal.com February 2017

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 KEY POINTS
apnea.79 Unfortunately, identification multiethnic Northern Manhattan Study h Obstructive sleep apnea
of who should receive screening is dif- (NOMAS), elevated lipoprotein (a) has been linked to
ficult as symptoms such as sleepiness levels (both continuous and dichoto- increased risk of
and signs such as BMI and neck cir- mized into higher than 30 mg/dL) were incident stroke, higher
cumference are not adequate predic- associated with incident ischemic poststroke mortality,
tors of OSA in patients with stroke.8 stroke after adjustment for other rele- and worse
Therefore, polysomnography should vant risk factors. When considering functional outcome.
be considered with a high suspicion of gender and race/ethnicity, the strongest Polysomnography
apnea, even without typical signs or association after adjustment for risk should be considered
symptoms, especially in men because factors was in men and in blacks.85 with high suspicion of
apnea, even without
of possible increased correlation With emerging risk factors such as
typical signs
with stroke.8 lipoprotein (a) and a lack of studies
or symptoms.
showing that treatment reduces the risk
Lipoprotein (a) for cardiovascular disease, it is difficult h Lipoprotein (a) is a
lipoprotein that has
Lipoprotein (a) is a lipoprotein that has to know whether to test for lipoprotein
been associated with
been associated with both atheroscle- (a) levels and in whom. It has been
both atherosclerosis and
rosis and thrombogenesis. The mole- shown that lipoprotein (a) levels can be thrombogenesis. While
cule is attached to the LDL receptor decreased with niacin by 30% to 35%, it has been associated
and bears structural similarity to fibrates up to 20%, aspirin 10% to 20%, with increased stroke
plasminogen.80 The levels of this mol- and estrogens 37%, but statins inconsis- risk in children,
ecule appear to vary by gender, race, tently lower lipoprotein (a). Nephrotic association in adults
and genotype of the APOA gene.81 syndrome and end-stage renal disease, is less clear.
While elevated levels of lipoprotein for example, lead to a threefold increase,
(a) appear to be strongly associated likely through increased biosynthesis
with arterial ischemic stroke in chil- and from reduced catabolism, respec-
dren,82 the association in adults is less tively.86 To date, the AHA/ASA second-
certain. A 2007 meta-analysis suggested ary prevention guidelines do not offer
that elevated lipoprotein (a) levels were recommendations for when to test lipo-
associated with stroke events in case- protein (a). In a comprehensive review
control studies (odds ratio 2.39; 1.57Y3.63) of the pathophysiology, impact of ge-
and prospective cohort studies (relative netic and nongenetic factors on lev-
risk 1.22; 1.04Y1.43) but not nested els, and the epidemiologic associations
case-control studies (odds ratio 1.04; of lipoprotein (a) with coronary artery
0.6Y1.8).83 The lack of significance with disease and stroke, Kostner and col-
nested case-control studies could have leagues86 suggest the following:
been because of smaller sample size & Patients with premature
and lack of power. The authors of this cardiovascular disease or stroke
analysis suggest that different methods without evident risk factors should
of measuring lipoprotein (a) may also have lipoprotein (a) levels
contribute to some of the uncertainty.83 measured at least once
Studies that have been conducted since & Patients with intermediate
the meta-analysis have continued to cardiovascular disease risk based
show an association. In the biethnic on risk scores should be tested for
Atherosclerosis Risk in Communities lipoprotein (a), and if the level is
(ARIC) cohort, elevated lipoprotein (a) higher than 50 mg/dL, the patient
levels higher than 300 mcg/mL were would be shifted to a higher
associated with a higher incidence of risk category
ischemic stroke in blacks and white & Patients with recurrent or rapidly
women, but not white men.84 In the progressive vascular disease

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

 Epidemiology and Risk Factors

KEY POINT
h In patients without a and various recognized risk Multiple trials have evaluated the
cardioembolic source, factors should have lipoprotein combination of dipyridamole and aspi-
aspirin monotherapy at (a) levels checked and rin in secondary stroke prevention. The
doses of 50 mg to repeatedly monitored if on European Stroke Prevention Study 2
325 mg is an appropriate drug treatment (ESPS-2) compared the combination of
strategy for secondary & Patients with familial hyper- dipyridamole 200 mg and aspirin 25 mg
stroke prevention. cholesterolemia, genetic 2 times a day to placebo, with a 37% risk
dyslipidemia or low HDL-C, or reduction of subsequent stroke and a
genetic defects of hemostasis or 23% risk reduction when compared
homocysteine metabolism should to aspirin 25 mg 2 times a day.89 While
be tested for lipoprotein (a) bleeding is not significantly increased
& Patients without evident with this combination, headache and
cardiovascular disease but gastrointestinal symptoms have limited
elevated cardiovascular disease its use significantly. However, AHA/ASA
risk, such as a greater than guidelines recommend consideration
10% 10-year risk of fatal or of aspirin alone or combination aspi-
nonfatal coronary heart disease rin and dipyridamole for secondary
as per the risk calculator stroke prevention.8
should also be tested Clopidogrel has been compared to
for lipoprotein (a) aspirin alone in the Clopidogrel Versus
Aspirin in Patients at Risk of Ischaemic
ANTIPLATELET THERAPY Events (CAPRIE) trial, which enrolled
In patients without a cardioembolic over 19,000 patients with stroke, myo-
source, antiplatelet therapy is a main- cardial infarction, or peripheral vascular
stay of stroke prevention, consistently disease.90 The combined outcome of
reducing risk of recurrent stroke across ischemic stroke, myocardial infarction,
studies. The cheapest and most widely and vascular death was significantly lower
available option is aspirin, which has with clopidogrel (5.32% versus 5.83%,
been studied for stroke prevention in relative risk reduction 8.7%, 95% confi-
doses ranging from 50 mg to 1500 mg. dence interval 0.3%Y16.5%, P=.043),
Across placebo-controlled trials of aspi- although the study was not designed
rin for secondary stroke prevention, re- to determine effectiveness in secondary
duction of stroke was approximately stroke prevention. Subgroup analysis of
15% (relative risk, 95% confidence inter- patients entering the trial because of
val 6%Y23%).87 Meta-analysis of head- stroke did not show a significant differ-
to-head trials of aspirin dose found no ence in vascular outcomes. Clopidogrel
significant difference in stroke prevention is a reasonable alternative to aspirin
between low-dose aspirin (lower than or combination aspirin/dipyridamole,
75 mg) and higher doses (75 mg or eg, in patients who are allergic to
higher).88 However, pooled results from aspirin or have other indications for
studies without direct comparison of clopidogrel use.8
doses show a smaller effect with a The combination of aspirin and clo-
dose lower than 75 mg/d. Aspirin mono- pidogrel has been compared to clo-
therapy at doses of 50 mg/d to 325 mg/d pidogrel alone in patients with TIA or
is an appropriate strategy for secondary ischemic stroke in the Management of
stroke prevention and is recommended Atherothrombosis With Clopidogrel
by the AHA/ASA guidelines for the in High-Risk Patients With Recent Tran-
Prevention of Stroke in Patients with sient Ischaemic Attack or Ischaemic
Stroke and TIA.8 Stroke (MATCH) trial,91 and to aspirin
34 ContinuumJournal.com February 2017

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

alone in patients with cardiovascular cumulative relative risk reduction of
disease or risk factors in the Clopidogrel vascular events of 80%.93
for High Atherothrombotic Risk and
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stroke and death. N Engl J Med 2005; Manhattan Stroke Study. Cerebrovasc
353(19):2034Y2041. doi:10.1056/ Dis 2010;30(3):237Y243. doi:10.1159/
NEJMoa043104. 000319065.
74. Redline S, Yenokyan G, Gottlieb DJ, et al. 86. Kostner KM, März W, Kostner GM. When
Obstructive sleep apnea-hypopnea and should we measure lipoprotein(a)? Eur
incident stroke: the sleep heart health study. Heart J 2013;34(42):3268Y3276. doi:10.1093/
Am J Respir Crit Care Med 2010;182(2): eurheartj/eht053.
269Y277. doi:10.1164/rccm.200911-1746OC. 87. Johnson ES, Lanes SF, Wentworth CE 3rd,
75. Johnson KG, Johnson DC. Frequency of sleep et al. A metaregression analysis of the
apnea in stroke and TIA patients: a meta-analysis. dose-response effect of aspirin on stroke.
J Clin Sleep Med 2010;6(2):131Y137. Arch Intern Med 1999;159(11):1248Y1253.
doi:10.1001/archinte.159.11.1248.
76. Brown DL, Mowla A, McDermott M, et al.
Ischemic stroke subtype and presence of 88. Antithrombotic Trialists’ Collaboration.
sleep-disordered breathing: the BASIC sleep Collaborative meta-analysis of randomised
apnea study. J Stroke Cerebrovasc Dis trials of antiplatelet therapy for prevention
2015;24(2):388Y393. doi:10.1016/ of death, myocardial infarction, and stroke
in high risk patients. BMJ 2002;324(7329):
j.jstrokecerebrovasdis.2014.09.007.
71Y86. doi:10.1136/bmj.324.7329.71.
77. Martı́nez-Garcı́a MA, Campos-Rodrı́guez F, 89. Diener H, Cunha L, Forbes C, et al. European
Soler-Cataluña JJ, et al. Increased incidence Stroke Prevention Study. 2. Dypyridamole and
of nonfatal cardiovascular events in stroke acetylsalicylic acid in the secondary prevention
patients with sleep apnoea: effect of CPAP of stroke. J Neurol Sci 1996;143(1-2):1Y13.
treatment. Eur Respir J 2012;39(4):906Y912. doi:10.1016/S0022-510X(96)00308-5.
doi:10.1183/09031936.00011311.
90. CAPRIE Steering Committee. A randomised,
78. Culebras A. Sleep apnea and stroke. Curr blinded, trial of clopidogrel versus aspirin in
Neurol Neurosci Rep 2015;15(1):503. patients at risk of ischaemic events (CAPRIE).
doi:10.1007/s11910-014-0503-3. CAPRIE Steering Committee. Lancet 1996;
348(9038):1329Y1339. doi: 10.1016/
79. Epstein LJ, Kristo D, Strollo PJ Jr, et al. Clinical
S0140-6736(96)09457-3.
guideline for the evaluation, management
and long-term care of obstructive sleep 91. Diener HC, Bogousslavsky J, Brass LM, et al.
apnea in adults. J Clin Sleep Med Aspirin and clopidogrel compared with
2009;5(3):263Y276. clopidogrel alone after recent ischaemic
stroke or transient ischaemic attack in
80. Loscalzo J. Lipoprotein(a). A unique risk high-risk patients (MATCH): randomised,
factor for atherothrombotic disease. double-blind, placebo-controlled trial.
Arteriosclerosis 1990;10(5):672Y679. Lancet 2004;364(9431):331Y337. doi:10.1016/
doi:10.1161/01.ATV.10.5.672. S0140-6736(04)16721-4.
81. Schreiner PJ, Heiss G, Tyroler HA, et al. Race 92. Bhatt DL, Fox KAA, Hacke W, et al.
and gender differences in the association of Clopidogrel and aspirin versus aspirin alone
Lp(a) with carotid artery wall thickness. The for the prevention of atherothrombotic
Atherosclerosis Risk in Communities (ARIC) study. events. N Engl J Med 2006;354(16):
Arterioscler Thromb Vasc Biol 1996;16(3): 1706Y1717. doi:10.1056/NEJMoa060989.
471Y478. doi: 10.1161/01.ATV.16.3.471. 93. Hackam DG, Spence JD. Combining multiple
82. Sultan SM, Schupf N, Dowling MM, et al. approaches for the secondary prevention
Review of lipid and lipoprotein(a) abnormalities of vascular events after stroke. Stroke
in childhood arterial ischemic stroke. Int J 2007;38(6):1881Y1885. doi:10.1161/
Stroke 2014;9(1):79Y87. doi:10.1111/ijs.12136. STROKEAHA.106.475525.

Continuum (Minneap Minn) 2017;23(1):15–39 ContinuumJournal.com 39

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 Review Article

Clinical Evaluation
Address correspondence to
Dr Andrew M. Southerland,
University of Virginia,
Department of Neurology,
Box 800394, McKim Hall,
Room 2113, Charlottesville,
VA 22908, [email protected].
of the Patient With
Relationship Disclosure:
Dr. Southerland serves as
deputy editor of the
Acute Stroke
Neurology podcast and
receives research/grant Andrew M. Southerland, MD, MSc
support from the American
Academy of Neurology,
American Board of Psychiatry
and Neurology, Health
ABSTRACT
Resources & Services Purpose of Review: This article reviews the clinical evaluation of the patient with
Administration (HRSA acute stroke, including key questions in the focused stroke history, important aspects
GO1RH27869-01-00), and
the National Institute of of the National Institutes of Health Stroke Scale and focused neurologic examination,
Neurological Disorders and and the significance of the basic head CT scan in informing a timely treatment decision.
Stroke (U01 NS069498). Recent Findings: Advances in both stroke treatment and enhanced diagnostics
Unlabeled Use of
Products/Investigational
support an evolving paradigm for acute stroke care, ranging from the prehospital set-
Use Disclosure: ting to the rehabilitative setting. An international emphasis on best practice strategies
Dr Southerland reports promotes efficiency and standardization in stroke systems of care.
no disclosure.
Summary: Despite continual changes and augmentations to the field of acute stroke,
* 2017 American Academy
of Neurology. several fundamentals remain. Central among these is in-depth knowledge of neuro-
vascular anatomy, clinical stroke syndromes, and common mimics, which are
foundational to the bedside evaluation of the patient with acute stroke.

Continuum (Minneap Minn) 2017;23(1):40–61.

INTRODUCTION tation of brain imaging, and a thorough

For each of us privileged to care for pa- knowledge of stroke syndromes and
tients with acute stroke, it all begins common mimics.
when the pager goes off. From the All this must happen rapidly, as
earliest days of residency, the acute ‘‘time is brain,’’ in concert with numer-
stroke page sets in motion a sequen- ous members of the emergency team
tial confluence of anxiety and adrena- working toward the same goal. For
line, apprehension and alertness, and, acute ischemic stroke, ultra-early ‘‘door
with proper training and experience, to treatment’’ has become the van-
the application of acumen and alacrity guard.1,2 Toward this goal, initiatives
to whatever stroke scenario we en- such as the American Heart Association
counter. As the great basketball coach (AHA)/American Stroke Association
John Wooden wised, ‘‘Be quick, but (ASA) Get With the Guidelines and Tar-
don’t hurry.’’ get: Stroke programs seek to effect qual-
Navigating the oft-tortuous path of ity standards in stroke care (Table 2-1).3Y6
an acute stroke alert necessitates the Needless to say, acute stroke care is
ability to focus one’s observational at- a dynamic practice and demands a
tention, listen intently for key aspects nonlinear team-based approach to
of the history, and remain aware of arrive rapidly at a well-informed diag-
the team environment in order to faci- nosis and treatment decision. This
litate a swift, efficient, and accurate as- article reviews key aspects along this
sessment. The latter requires a focused continuum in the clinical evaluation of
neurologic examination, rapid interpre- the patient with acute stroke.

40 ContinuumJournal.com February 2017

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TABLE 2-1 American Heart Association/American aStroke Association
Target: Stroke Best Practice Strategies

b Emergency Medical Services Prenotification

Emergency medical services providers should provide early prenotification
to the receiving hospital when stroke is recognized in the field.
b Stroke Tools
A stroke toolkit containing a rapid triage protocol, clinical decision
support, stroke-specific order sets, guidelines, hospital-specific algorithms,
critical pathways, the National Institutes of Health Stroke Scale, and other
stroke tools should be available and used for each patient.
b Rapid Triage Protocol and Stroke Team Notification
Rapid neurologic evaluation should be performed as soon as possible in
the emergency department or on the CT/MRI table.
b Single-Call Activation System
Single-call activation system for the stroke team is defined here as a system in
which the emergency department calls a central page operator, who then
simultaneously pages the entire stroke team, including notification to ensure
rapid availability of the scanner for stroke protocol brain imaging.
b Transfer Directly to CT Scanner
Guided by prespecified protocols, eligible patients with stroke can, if
appropriate, be transported from the emergency department triage area
directly to the CT/MRI scanner for initial neurologic examination and brain
imaging to determine recombinant tissue plasminogen activator (rtPA)
eligibility, bypassing the emergency department bed.
b Rapid Acquisition and Interpretation of Brain Imaging
At the minimum, the CT scan should be performed within 25 minutes of
arrival and interpretation of the CT scan completed within 45 minutes of
arrival to exclude intracranial hemorrhage prior to administration of IV rtPA.
b Rapid Laboratory Tests
When indicated, laboratory tests such as glucose and, for patients in
whom coagulation parameters should be assessed because of suspicion
of coagulopathy or warfarin treatment, international normalized ratio
(prothrombin time)/partial thromboplastin time results should be available
as quickly as possible and no later than 30 minutes after emergency
department arrival.
b Mix rtPA Ahead of Time
A useful strategy is to mix drug and set up the bolus dose and 1-hour
infusion pump as soon as a patient is recognized as a possible rtPA
candidate, even before brain imaging.
b Rapid Access to and Administration of IV rtPA
Once eligibility has been determined and intracranial hemorrhage has
been excluded, IV rtPA should be promptly administered without delay.

Continued on page 42

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 Clinical Evaluation of Acute Stroke

KEY POINT
h Establishing time TABLE 2-1 American Heart Association/American aStroke Association
of stroke onset, or Target: Stroke Best Practice Strategies Continued from page 41
last known well time,
starts the clock on b Team-Based Approach
all further decision
The team-based approach based on standardized stroke pathways and
making for the patient
protocols has proven to be effective in enhancing the number of eligible
with acute stroke.
patients treated and reducing time to treatment in stroke.
Confirming last known
well time with the b Prompt Data Feedback
patient or a reliable Accurately measuring and tracking the hospital’s door-to-needle times, IV
witness, or identifying rtPA treatment rates in eligible patients, other time intervals, and performance
an associated event, is on other stroke performance/quality measures equip the stroke team to
key to informing accurate identify areas for improvement and take appropriate action.
treatment decisions CT = computed tomography; IV = intravenous; MRI = magnetic resonance imaging.
a
going forward. Data from Fonarow GC, et al, Stroke,4 stroke.ahajournals.org/content/42/10/2983.long;
Fonarow GC, et al, JAMA,5 jamanetwork.com/journals/jama/fullarticle/1861802; and Xian Y,
et al, Stroke.6 stroke.ahajournals.org/content/45/5/1387.long.

INITIAL HISTORY is also good practice to establish the last

First and foremost, acute stroke decision known well time as a clock time (eg,
making relies on a brief but accurate 8:00 AM) rather than relaying last
history, the leading question of which known well time as ‘‘45 minutes ago’’
is, ‘‘When was the patient last seen or ‘‘2 hours ago.’’ Using a clock time
normal?’’ This question serves as a sur- ensures that all members of the acute
rogate for time of stroke onset, which stroke evaluation team are operating in
starts the clock on all subsequent time the same time window from stroke onset
windows and management decisions. and reduces the probability of calculation
The question may be modified to, errors when estimating stroke onset.
‘‘When was the patient last seen well?’’ Once the last known well time has
to avoid ambiguity over any prior def- been established, clinical diagnostic
icits, or ‘‘When was the patient last reasoning begins with a history of pre-
known well?’’ in the case that stroke on- senting symptoms. This first descrip-
set is inferred from unwitnessed events. tion informs an initial impression of
Last known well time is often first ‘‘stroke or no stroke’’ and requires a
relayed from a witness or family mem- thorough understanding of clinical
ber to an emergency medical services stroke syndromes (as discussed later
(EMS) provider, then communicated to in this article). Symptom chronology is
the hospital staff through emergency very important to characterizing stroke
dispatch or at the time of arrival, and syndromes. For example, were the
then finally communicated to the neu- symptoms abrupt in onset or more
rologist representing the acute stroke gradual? Stroke tends to be a sudden
team. Circling back with the patient or a and discrete event (maximum deficit
reliable witness, or identifying an asso- at onset) compared to common mim-
ciated event (eg, the patient got up to ickers, such as migraine or enceph-
use the bathroom or made a phone call alopathy, which tend to be more gradual
at a certain time), is important to con- or vague in description.
firm last known well time and often Exceptions to the maximum deficit at
requires a bit of rapid detective work. It onset rule may be a so-called stuttering

42 ContinuumJournal.com February 2017

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 KEY POINTS
transient ischemic attack or a small the time-sensitive assessment and can h Symptom chronology is
vessel stroke, from which symptoms help inform the focused neurologic an important feature to
may fluctuate or crescendo to maxi- examination thereafter. For example, is help distinguish acute
mum deficit over the first 72 hours. the patient awake? Is he or she able to stroke from common
While ‘‘rapid improvement in symp- speak or follow commands? Are the stroke mimics. Stroke
toms’’ is considered a relative contra- eyes open or closed? Is the head or gaze tends to be abrupt and
indication to IV recombinant tissue deviated? How are the limbs positioned maximal at onset, with
plasminogen activator (rtPA), suspi- on the stretcher or bed? Are there the exception of
cion for stroke should remain high purposeful movements? stuttering transient
and treatment should remain an op- Patients with acute stroke with a ischemic attacks or small
vessel strokes that may
tion unless the patient completely re- decreased level of consciousness may
fluctuate in intensity in
turns to a nondisabling baseline. be intubated in the field upon being
the acute period.
Several other key questions are im- ‘‘found down’’ or may require rapid
portant to the acute stroke history. A intubation on ED arrival because of re- h Patients with acute
stroke with decreased
brief review of the patient’s past med- spiratory distress. In the case of ED in-
level of consciousness
ical history, focusing on vascular risk tubation, a focused neurologic inventory
or respiratory distress
factors, informs the likelihood of stroke should be attempted before the patient may require rapid
and possible stroke mechanism. If the is pharmacologically sedated and par- intubation. Prior to
initial stroke syndrome is unclear, alyzed. A quick look for pupillary sedation, rapid
searching for prior nonstroke presenta- function, gaze deviation, blink to threat, assessment of pupillary
tions and common mimics is helpful. motor tone, and purposeful move- function, gaze
Reviewing potential eligibility for IV ments can help formulate an initial im- deviation, blink to
rtPA prompts several additional ques- pression of the neurologic syndrome. threat, motor tone, and
tions. Is the patient taking blood thin- With the initial observation, it is also purposeful movements
ners (ie, anticoagulation)? Has he or she essential to take a quick inventory of can help formulate the
experienced any recent hospitaliza- vital signs. As in any emergency situa- neurologic syndrome.
tions, surgery, trauma, bleeding, or tion, the adage holds true in the patient
other illnesses? Again, it is imperative with acute stroke that airway, breathing,
to verify the brief history with the pa- and circulation (the ABCs) always come
tient or a close family member and first. Vital signs can also provide initial
cross-reference the medical record for clues informing the stroke syndrome.
relevant details as needed. For more Blood pressure, for example, is usually
information about eligibility criteria elevated in acute stroke as the body
for IV rtPA, refer to the article ‘‘Treat- attempts to autoregulate cerebral per-
ment of Acute Ischemic Stroke’’ by fusion pressure.8 In a 2003 nationwide
Alejandro A. Rabinstein, MD, FAAN,7 survey of 563,704 patients presenting
in this issue of Continuum. to the ED with a diagnosis of stroke,
approximately 70% had a systolic blood
INITIAL EXAMINATION pressure of 140 mm Hg or higher, in-
In the clinical evaluation of the patient cluding 77% of patients with ischemic
with acute stroke, the neurologic exam- stroke, 75% of patients with intracere-
ination begins from the first moment bral hemorrhage, and 100% of patients
that eyes are laid upon the patient. For with subarachnoid hemorrhage.9
patients arriving via EMS, this is often as If a patient is potentially eligible for
the patient rolls into the hospital on a IV rtPA but his or her blood pressure is
stretcher or as the patient is stabilized higher than 185/110 mm Hg or if a high
by a team of providers in the emergen- suspicion for hemorrhagic stroke exists
cy department (ED). These initial clin- (eg, sudden onset of severe headache),
ical observations are a critical aspect of preparations should be made for
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 Clinical Evaluation of Acute Stroke

KEY POINTS
h Patients in atrial lowering blood pressure in accordance strokes score approximately 4 points
fibrillation with focal with current treatment guidelines (eg, higher than nondominant (right)
neurologic deficits asking the pharmacist or nurse to hemispheric strokes, reflecting the
should be assumed to prepare IV labetalol or a nicardipine impact of aphasia on the neurologic
have cardioembolic drip to be immediately ready follow- assessment.14 Similarly, for a given
ischemic stroke until ing head CT).10 NIHSS score, the volume of infarction
proven otherwise. In addition to assessing blood pres- is greater for nondominant, right
Inquiring about sure, identifying the cardiac rhythm via hemisphere than dominant left hemi-
anticoagulation and ECG or telemetry informs the acute sphere strokes.15 Additionally, the
medication compliance stroke presentation. Patients present- NIHSS may underestimate posterior
in the acute stroke
ing in atrial fibrillation with focal neuro- circulation stroke deficits compared to
history is essential to
logic deficits should be assumed to be anterior circulation stroke deficits.16
informing an appropriate
treatment decision.
having a cardioembolic stroke until Patients presenting with small brain-
proven otherwise. stem or cerebellar strokes may have a
h The National Institutes low or even 0 NIHSS score, and care-
of Health Stroke Scale The National Institutes of ful vigilance should be employed to
is biased toward left
Health Stroke Scale determine eligibility for acute treatment
hemispheric and
anterior circulation The most important caveat regarding in this population.17
strokes. Therefore, the National Institutes of Health Stroke
careful vigilance should Scale (NIHSS) is to recognize that it is LABORATORY DATA
be employed when not an adequate substitute for a com- In the process of transitioning the
assessing stroke severity prehensive neurologic examination. patient with acute stroke from a
in patients with The NIHSS is, however, a highly reliable focused neurologic examination to an
nondominant, right and valid screening assessment for the initial head CT, the traditional ap-
hemisphere, brainstem, rapid evaluation of a patient with acute proach is to obtain a quick blood draw
or isolated cerebellar stroke.11 The 11-item scale measures for laboratory testing. Importantly,
strokes to guide
consciousness, orientation, visual fields, eligibility criteria for IV rtPA require
treatment.
gaze, language fluency and comprehen- platelet count greater than 100,000/6L,
sion, speech, sensory loss and neglect, prothrombin time less than 15 sec-
motor strength, and limb ataxia. Vali- onds, and partial thromboplastin time
dated for use by neurologists and non- within normal limits. However, the
neurologist providers and nurses, the 2013 AHA/ASA guideline on the early
scale can easily be completed in less management of patients with acute
than 10 minutes and serves as an initial ischemic stroke suggests that only a
measure of stroke severity ranging from finger-stick blood glucose is absolutely
0 (no deficits) to 42 (maximum score). required before initiation of IV rtPA.10
The NIHSS has no minimum score that A prominent exception to this allow-
would exclude eligibility to receive IV ance applies for patients on warfarin
rtPA, and patients with mild but none- or with known hematologic abnormal-
theless disabling symptoms should be ities, for whom pretreatment coagula-
offered therapy.12 Additionally, eligibil- tion profile and complete blood cell
ity for endovascular therapy has re- count is necessary. Other laboratory
cently been established for appropriate tests, such as electrolytes, renal func-
patients with an NIHSS score of 6 or tion, and troponins, are suggested in
higher and the presence of a large the acute stroke evaluation but should
vessel occlusion.13 not delay the transition to head CT or
Of additional note, one should be treatment with IV rtPA. Additionally, ob-
aware of biases within the NIHSS. For taining vascular access for blood draws
instance, dominant (left) hemispheric may delay the transition to head CT;
44 ContinuumJournal.com February 2017

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 KEY POINT
obtaining proper access during emer- In addition to ruling out hemorrhage, h Evidence-based
gency transport and implementing point- important findings include a localizing guidelines suggest the
of-care laboratory testing are potential dense artery sign suggestive of a large only laboratory test
methods to help reduce door-to-CT time. vessel occlusion, early ischemic changes absolutely required prior
suggestive of evolving infarct, or chronic to initiation of IV
INITIAL BRAIN IMAGING infarcts informing a pattern or risk recombinant tissue
The principal goal of initial brain imag- profile for stroke (Case 2-1). plasminogen activator is
ing in the patient with acute stroke is The Alberta Stroke Program Early CT a finger-stick blood
to differentiate hemorrhagic versus Score (ASPECTS) system is a simple and glucose. Other laboratory
ischemic stroke. Of the available mo- reliable 10-point scale for evaluating tests, such as complete
blood cell count and
dalities, noncontrast head CT is es- early ischemic changes in acute stroke20
metabolic panel, should
tablished as a rapidly obtained, highly and is clinically relevant in the evalua-
not delay head CT
sensitive, and widely available tool to tion of eligibility for endovascular ther- or initiation of IV
rule out hemorrhage and inform treat- apy as supported by recent clinical trial recombinant tissue
ment for acute stroke. Rapid brain MRI data and updated guidelines.13,21 For plasminogen activator.
offers the additional advantage of more information on the ASPECTS sys- Exceptions include
being both highly sensitive and specific tem, refer to the article ‘‘Treatment of patients taking
for ischemic stroke, particularly in Acute Ischemic Stroke’’ by Alejandro A. warfarin or with
cases of suspected stroke mimics,18 Rabinstein, MD, FAAN,7 in this issue known hematologic
and can adequately rule out hemor- of Continuum. abnormalities, for whom
rhage on gradient recalled echo (GRE) If CT findings are ambiguous, it rapid coagulation
or susceptibility-weighted imaging is also helpful to search for any prior profiling is warranted.
Obtaining proper vascular
(SWI). While either imaging modality is brain imaging for quick comparison.
access in the emergency
supported in acute stroke guidelines,10 Observational studies suggest good
department may also
the generalizability of rapid brain MRI, interrater reliability between vascular delay door-to-CT time,
particularly for smaller and low-access neurologists and neuroradiologists in so using prehospital
hospitals, remains limited. the interpretation of relevant CT find- access or point-of-care
To the trained eye, the noncontrast ings in the patient with acute stroke.22 testing may
head CT offers additional insights into Nonetheless, after initial treatment de- be beneficial.
the patient with acute stroke beyond cisions are complete, following up with
simply ruling out hemorrhage. Similar neuroradiology for official interpreta-
to the history and examination, per- tion is essential to ensure nothing was
forming an efficient yet accurate as- missed on the acute read.
sessment of the head CT requires a
systematic approach, particularly for STROKE SYNDROMES
the nonradiologist neurologist read- In some ways, defining acute stroke syn-
ing the study at the bedside. For con- dromes is educated pattern recognition
sistency, a top-down or bottom-up influenced by knowledge and experi-
approach to all noncontrast head CTs ence. As a seasoned vascular neurolo-
might be utilized, reviewing each slice gist once put it, ‘‘Does it smell like a
in sequence to gain a three-dimensional stroke or not?’’ In other words, does the
appreciation of the brain. An inside- presentation make neuroanatomic and
out approach begins with reviewing cerebrovascular sense?
brainstem and midline structures, then Inherent in this understanding of
systematically scanning outward to the stroke syndromes is the caveat that
cortex through consecutive slices. stroke is not just one disease. Stroke is
Important components of the acute the downstream effect of a variety of
stroke noncontrast head CT for the neu- different mechanisms, physiologic
rologist to note are listed in Table 2-2.19 properties, and disease states. In this
Continuum (Minneap Minn) 2017;23(1):40–61 ContinuumJournal.com 45

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 Clinical Evaluation of Acute Stroke

TABLE 2-2 Key Aspects of thea Noncontrast Head CT in the Acute

Stroke Evaluation

Finding Appearance Significance

Acute Hyperdensity compared to Absolute contraindication
hemorrhage normal brain parenchyma to IV recombinant tissue
consistent with blood plasminogen activator; requires
products immediate blood pressure
management and often
neurosurgical consultation
Early ischemic Indistinct hypodensity Evidence of evolving infarct;
changes with loss of gray-white not a contraindication to IV
differentiation, often at recombinant tissue plasminogen
the core of infarction (eg, activator; however, extensive
insular ribbon, basal ganglia) early ischemic changes are
associated with poor outcome
and increased risk of
symptomatic hemorrhage
Chronic infarcts Well-defined hypodensity Indicative of stroke risk
or encephalomalacia in and mechanism, which
an arterial territory may inform acute diagnosis
and treatment
Dense artery sign Hyperdensity within an Associated with thrombotic
artery (eg, M1, basilar) large vessel occlusion; M2
compared to a normal dot sign may indicate more
isodense appearance distal branch occlusion
CT = computed tomography; IV = intravenous.

Case 2-1
An independent 73-year-old right-handed man developed the sudden
onset of confusion, slurred speech, and left-sided weakness. His wife called
911, and initial emergency medical services (EMS) assessment revealed
abnormal speech, facial weakness, and left arm drift. He was immediately
transported to the nearest primary stroke center, and the EMS crew
notified the hospital of the last known well time and the estimated time
of arrival. During transport, a point-of-care blood glucose was mildly
elevated, IV access was obtained, and rapid ECG was consistent with
atrial fibrillation (the patient was not on anticoagulation). A prehospital
stroke alert was executed, and upon arrival to the emergency department,
the patient was met by the acute stroke team and triaged directly to
the CT scanner.
His initial blood pressure was 160/80 mm Hg, his heart rate was
90 beats/min (irregularly irregular), and his National Institutes of Health
Stroke Scale score was 13, for disorientation, partial right gaze preference,
left hemianopia, left lower facial weakness, dysarthria, left arm weakness,
left leg drift, sensory loss, and extinction. Noncontrast head CT revealed
a dense artery sign in the distal right M1 trunk and early ischemic changes
in the right insular region. Continued on page 47

46 ContinuumJournal.com February 2017

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 Continued from page 46
After reviewing his eligibility criteria for IV recombinant tissue
plasminogen activator (rtPA), a premixed bolus and infusion were initiated
on the CT table with a door-to-needle time of 19 minutes. The team
immediately prepared for a CT angiogram to evaluate for large vessel
occlusion and eligibility for endovascular therapy.
Comment. This case presents an ideal state for rapid evaluation of the
patient with acute stroke leading to a timely treatment decision. Key
elements included awareness of stroke symptoms prompting a call to 911,
rapid prehospital management and hospital prenotification, early stroke
team notification, premixing of IV rtPA, and direct triage to CT. His stroke
presentation is consistent with likely cardioembolism secondary to atrial
fibrillation not on anticoagulation. The CT findings of early ischemic
changes and a dense artery sign are highly sensitive for a large vessel
occlusion, suggesting potential eligibility for endovascular therapy
following IV rtPA. His acute syndrome localizes to the right middle cerebral
artery territory.

paradigm, stroke is indeed a clinical di- cerebral artery (MCA). Anterior circula-
agnosis, with cerebral infarction repre- tion ischemia accounts for the majority
senting the tissue diagnosis and stroke of all strokes.
subtype informing the mechanism. Internal carotid artery. As the in-
These traditional delineations have ternal carotid artery (ICA) enters the
been reevaluated in the age of ad- cerebral circulation, it branches into
vanced imaging, where stroke can the ACA and MCA. Occlusion of the
be diagnosed by the presence of infarc- ICA most often occurs secondary to
tion on brain MRI (ie, restricted dif- atherosclerotic plaque and critical
fusion) even in the absence of a stenosis at the level of the cervical
persistent stroke syndrome. However, bifurcation or as a thromboembolic
according to a 2013 AHA/ASA state- occlusion of the distal carotid, the so-
ment, the definition of ischemic called carotid T lesion. In the scenario
stroke still invokes ‘‘focal cerebral, spi- of a carotid T lesion, the majority of
nal, or retinal infarction’’ in a ‘‘defined the ipsilateral hemisphere becomes
vascular distribution.’’23 ischemic and will result in ACA/MCA
Therefore, the ability to localize a territory infarction with contralateral
defined vascular distribution in the hemiplegia unless rapid reperfusion
patient with acute stroke remains the can be established.
first tool in the black bag of the neu- Symptomatic ICA stenosis at the
rologist and fundamentally requires cervical bifurcation often manifests as
in-depth understanding of neuroana- minor stroke or transient ischemic at-
tomic stroke syndromes, as discussed tack secondary to artery-to-artery em-
here. Common large vessel stroke syn- bolism into the ipsilateral carotid
dromes are listed in Table 2-3.24 territory. In addition to hemispheric
signs and symptoms, carotid stenosis
Anterior Circulation Syndromes may be heralded by transient central
The anterior circulation encompasses retinal artery occlusion resulting in
the distribution of the internal carotid ipsilateral amaurosis fugax, or transient
artery and its major branches, the an- monocular blindness (the so-called
terior cerebral artery (ACA) and middle ‘‘shade coming down over the eye’’),

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 Clinical Evaluation of Acute Stroke

a,b
TABLE 2-3 Large Vessel Stroke Syndromes (Laterality Assumes Left Hemispheric Dominance)

Vascular Territory Signs and Symptoms

Internal carotid artery Combined anterior cerebral artery/middle cerebral artery syndromes;
ipsilateral monocular visual loss secondary to transient central retinal
artery occlusion (amaurosis fugax); branch retinal artery occlusions may
present as ipsilesional altitudinal field cuts
Left anterior cerebral artery Right leg numbness and weakness, transcortical motor aphasia, possibly
ipsilesional or contralesional ideomotor apraxia
Right anterior cerebral artery Left leg numbness and weakness, motor neglect, possibly ipsilesional or
contralesional ideomotor apraxia
Left middle cerebral artery Right face/arm numbness and weakness more than leg numbness and
weakness, aphasia, left gaze preference
Right middle cerebral artery Left face/arm numbness and weakness more than leg numbness
and weakness, left hemispatial neglect, right gaze preference,
agraphesthesia, astereognosis
Left posterior cerebral artery Complete or partial right homonymous hemianopia, alexia without
agraphia; if midbrain involvement, ipsilateral third nerve palsy
with mydriasis and contralateral hemiparesis (Weber syndrome)
Right posterior cerebral artery Complete or partial left homonymous hemianopia; if midbrain
involvement, ipsilateral third nerve palsy with mydriasis and contralateral
hemiparesis (Weber syndrome)
Superior cerebellar artery Ipsilesional limb and gait ataxia
Anterior inferior cerebellar artery Vertigo and ipsilesional deafness, possibly also ipsilesional facial weakness
and ataxia
Vertebral/posterior inferior Ipsilesional limb and gait ataxia; if lateral medullary involvement,
cerebellar artery may have Wallenberg syndrome (refer to Table 2-5)
Basilar artery Pontine localization with impaired lateral gaze, horizontal diplopia and
dysconjugate gaze, nonlocalized hemiparesis, dysarthria; ‘‘locked-in
syndrome’’ with bilateral pontine infarction (intact vertical eye
movements, anarthria, quadriplegia)
a
Data from Eckerle BJ, Southerland AM, Wiley-Blackwell.24
b
The syndromes listed are reflective of classic neuroanatomy and may vary depending on individual variations in the circle of Willis or
collateral vascular supply.

or more commonly as a nondescript plete occlusion of the MCA trunk, com-

visual disturbance. When encountered, monly referred to as M1, often manifests
this syndrome necessitates immediate with hemispheric signs and symptoms:
imaging of the carotid bifurcation to aphasia (dominant hemisphere), hemi-
rule out symptomatic carotid artery spatial neglect (nondominant hemi-
stenosis for which endarterectomy or sphere), ipsilateral gaze preference
stenting is warranted. (frontal eye fields), contralateral brachio-
Middle cerebral artery. As the pri- facial paralysis (ie, involving the face/
mary source of perfusion to the cere- arm more than the leg), and varying de-
bral hemispheres, the MCA is the most grees of contralateral hemianesthesia.
commonly involved intracranial artery Strokes involving the frontal eye fields
in the patient with acute stroke. A com- create a conjugate deviation of the eyes

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 KEY POINTS
to the ipsilateral ischemic hemisphere, jects, is also an important hallmark of h Strokes involving
ie, ‘‘looking at your stroke.’’ If MCA aphasia. Patients with subtle dysnomia the frontal eye fields
territory ischemia involves the optic ra- may substitute a description of an ob- create a conjugate
diations or extends to the occipital lobe, ject for the actual name, eg, ‘‘that prickly deviation of the eyes to
patients will also have a contralateral thing’’ rather than cactus, or ‘‘that thing the ipsilateral ischemic
hemianopia. The most classic of the you swing in’’ rather than hammock. hemisphere, ie, ‘‘looking
hemispheric stroke syndromes, and per- Receptive aphasia is characterized at your stroke.’’
haps the easiest to recognize, involves as an abnormality with language com- h The classic left middle
the left MCA territory. prehension. Patients with mild recep- cerebral artery syndrome
Dominant (left middle cerebral tive aphasias may do well with simple presents with left gaze
artery). The classic left MCA syndrome commands, such as ‘‘open your eyes’’ preference, right visual
presents with left gaze preference, right or ‘‘close your fist,’’ but struggle with field cut, aphasia, and
visual field cut, aphasia, and right complex or multistep commands, right hemiparesis/
hemiparesis/hemianesthesia. Deter- such as ‘‘point to the ceiling with your hemianesthesia.
mining handedness in patients with thumb.’’ In addition to deficits in h Determining handedness
stroke is key to defining hemispheric language comprehension, neologisms in patients with stroke
dominance and characterizing stroke (made-up words) or nonsensical lan- is key to defining
syndromes. Only a minority of primarily guage without impaired fluency are hemispheric dominance
and characterizing stroke
left-handed individuals are right hemi- hallmarks of receptive aphasia.
syndromes. Only a
sphere dominant for language. As a Aphasia is often difficult to distin-
minority of primarily
majority of the population is left hemi- guish from nonfocal encephalopathy left-handed individuals
sphere dominant for language, the or delirium, particularly for the non- are right hemisphere
hallmark sign of a left MCA stroke is neurologist. A key difference between dominant for language.
aphasia. Aphasia, or dysphasia, is best these two presentations is how atten-
h Listening intently for
defined as any acquired abnormality of tive the patient seems. Patients with phonemic or semantic
language (spoken, written, or signed) aphasia are often aware of their impair- paraphasic errors
and is classically dichotomized as ex- ment and visibly frustrated, attempt- is important to
pressive (motor, nonfluent) or recep- ing to converse and follow commands. recognize subtle
tive (sensory, fluent). Expressive aphasia On the other hand, patients who are aphasia in the patient
ranges from frank mutism to subtle encephalopathic or delirious are often with acute stroke.
word-finding difficulty. The latter can inattentive and unaware of their con- h Diagnosing aphasia
often be difficult to discern, especially dition, in addition to lacking other from other forms of
for the non-neurologist evaluating a focal signs or symptoms. Other fea- encephalopathy may
patient with acute stroke. The NIHSS tures that may further distinguish ap- be distinguished by
aphasia cards are a quick and stan- hasia and assist in localization in the a patient’s level
dardized tool to screen for aphasia at patient with acute stroke are charac- of attentiveness.
the bedside. For example, describing terized in Table 2-4 and Figure 2-1.
the scene in the cookie theft picture Of additional note, mixed aphasia can
gives an overall impression of fluency, result from subcortical strokes, such
cadence, word volume, and accuracy. as so-called thalamic aphasia, which
The patient who is mildly aphasic will has variable features and may result in
often make paraphasic errors, which false localization to the dominant hemi-
are key diagnostic clues in the bedside sphere perisylvian language areas.
evaluation of the patient with acute Nondominant (right middle cere-
stroke. Examples of paraphasic errors bral artery). As aphasia is the hallmark
include phonemic (eg, kite instead of localizing sign of a left MCA or domi-
key) and semantic (eg, substituting nant hemisphere stroke, hemispatial
hand for glove). Defining anomia or neglect suggests injury to the non-
dysnomia, or the inability to name ob- dominant hemisphere. Patients with
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 Clinical Evaluation of Acute Stroke

KEY POINT
h Mild hemispatial a
TABLE 2-4 The Aphasias
neglect from a right
middle cerebral artery Type of Aphasia Fluency Comprehension Repetition
stroke can be
Motor/expressive (Broca) Impaired Normal Impaired
elicited at the bedside
by double simultaneous Sensory/receptive (Wernicke) Normal Impaired Impaired
stimulation, during Conduction Normal Normal Impaired
which the patient
extinguishes the Transcortical motor Impaired Normal Normal
contralateral Transcortical sensory Normal Impaired Normal
sensory stimulus.
Mixed Variable Variable Variable
Global Impaired Impaired Impaired
a 24
Data from Eckerle BJ, Southerland AM, Wiley-Blackwell.

a right MCA stroke can be difficult technique. Identifying tactile neglect is

to diagnose without a directed neuro- most common, but patients with ne-
logic examination, as the neglect syn- glect may exhibit auditory or visual
drome often coexists with anosognosia, extinction with double simultaneous
or unawareness of the deficit. In mild stimulation as well, the latter being
neglect syndromes, testing for extinc- difficult to discern from a frank
tion by double simultaneous stimula- hemianopia. Motor neglect can also con-
tion at the bedside is an essential found true hemiparesis, distinguished

FIGURE 2-1 The graphic aphasia box. Plus symbols indicate intact components of language;
minus symbols indicate impaired components of language.
24
Reprinted with permission from Eckerle BJ, Southerland AM, Wiley-Blackwell. B 2013 John Wiley &
Sons, Ltd.

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by checking tone or eliciting movement nondominant hemisphere stroke be-
of the contralateral limb via noxious cause of their denial of their symptoms
stimulus. Additional cortical sensory secondary to anosognosia (Case 2-2).
signs of a right MCA stroke include Anterior cerebral artery. Isolated
agraphesthesia, astereognosis, and loss ACA territory infarction represents a
of two-point discrimination. Testing minority of stroke presentations, most
for these signs at the bedside can un- often secondary to a thromboembo-
cover a focal nondominant hemi- lus or in situ stenosis. Because of the
spheric stroke secondary to branch cortical representation of the motor
right MCA territory occlusion. It may homunculus, ACA territory strokes
be difficult to gain consent for treat- classically manifest with contralateral
ment from patients presenting with a leg weakness more than arm weakness.

Case 2-2
A 77-year-old right-handed woman was at breakfast when she suddenly
became confused and fell to the ground with convulsive seizure activity
lasting several minutes. Witnesses reported her eyes and head deviated to
the left during the episode. In the emergency department, her National
Institutes of Health Stroke Scale score was 15, and her examination was
notable for mild somnolence, a right gaze preference, decreased blink to
threat on the left, and left hemiplegia of the arm and leg. When her arm
was presented in her right visual field, she did not recognize it as her own.
Head CT demonstrated no acute hemorrhage, with subtle early ischemic
change in the right insula and a dense artery M1 sign on the right (Figure 2-2).

FIGURE 2-2 Head CT of patient in Case 2-2

showing dense right M1
artery sign (arrow).

Continued on page 52

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 Clinical Evaluation of Acute Stroke

Continued from page 51

When discussing her eligibility for IV recombinant tissue plasminogen
activator (rtPA) and endovascular therapy, she was not cognizant of her
stroke and refused treatment. Unfortunately, no family member was
available for assistance with surrogate decision making. However, when
presented with a hypothetical scenario describing her situation if she were
having a stroke, she was able to comprehend and endorsed treatment as
the appropriate course. The acute stroke team proceeded with IV rtPA
followed by CT angiography for eligibility of mechanical thrombectomy.
Comment. Updated American Heart Association/American Stroke
Association stroke guidelines suggest that IV rtPA is ‘‘reasonable in patients
with a seizure at the time of onset of acute stroke if evidence suggests
that residual impairments are secondary to stroke and not a postictal
phenomenon (Class IIa; Level of Evidence C).’’12 In this case, the patient’s
seizure was the initial manifestation of acute ischemic stroke with a
persistent right middle cerebral artery syndrome confirmed by a dense
artery sign and early ischemic changes on head CT. Nondominant
hemisphere strokes manifesting with anosognosia may present a
challenging treatment dilemma in which the patient does not recognize
his or her diagnosis. Worrall and colleagues25,26 suggested that patients
with anosognosia are still able to comprehend despite denying their
diagnosis; therefore, an ‘‘advance directive approach’’ may allow them to
consent as their own surrogate by presenting the treatment decision as
a ‘‘hypothetical’’ discussion. If a patient is deemed to lack capacity and
no surrogate is available, acute stroke treatment may proceed via
emergency exemption.

ACA strokes may also result in abulia tion, equating to approximately 70,000
or apathy (lack of will) from ischemia to 100,000 presentations in the United
to the anterior cingulate gyrus or cau- States each year.27,28 Distinguishing
date head (recurrent artery of Heubner). between anterior and posterior circu-
In addition to ischemic ACA stroke, lation syndromes is essential to defin-
this syndrome may also manifest from ing the likely source and mechanism
a ruptured aneurysm of the ACA or of acute stroke and to guide second-
anterior communicating artery, and, in ary stroke prevention. Moreover, while
the extreme form, may result in latent compromise of the anterior circula-
akinetic mutism. A common anatomic tion can produce larger hemispheric
variant, in which the right and left ACAs strokes, strokes involving the posterior
stem from a common A1 trunk, can circulation can be equally devastating
result in infarction to bilateral ACA when involving vital structures in the
territories and present as bilateral leg brainstem and cerebellum (Table 2-5).
weakness. As noted, infarction of the Brainstem syndromes. Stroke syn-
ACA territory most often results from dromes in the brainstem can be tri-
carotid occlusion and in conjunction chotomized into the three anatomic
with infarction of the MCA territory. levels: midbrain, pons, and medulla. The
midbrain receives circulation from the
Posterior Circulation Syndromes top of the basilar artery and the poste-
According to AHA/ASA stroke statistics, rior cerebral artery (PCA) and is often
approximately 20% of incident strokes infarcted via intrinsic perforator (small
per year involve the posterior circula- vessel) occlusion, intrinsic disease in

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 a
TABLE 2-5 Common Brainstem Stroke Syndromes

Syndrome Signs/Symptoms Localization Vascular Supply

Weber Ipsilesional cranial nerve III Medial midbrain/cerebral Deep penetrating artery
palsy, contralesional peduncle from posterior cerebral
hemiparesis (including the artery (refer to Table 2-3)
lower face)
Benedikt Ipsilesional cranial nerve III Ventral midbrain involving Deep penetrating artery
palsy, contralateral involuntary red nucleus from posterior cerebral
movements (intention tremor, artery or paramedian
hemichorea, or hemiathetosis) penetrating branches of
basilar artery
Nothnagel Ipsilesional cranial nerve III Superior cerebellar peduncle Deep penetrating
palsy, contralesional dysmetria, artery from posterior
and contralesional limb ataxia cerebral artery
Foville Ipsilateral cranial nerves VI Caudal pontine tegmentum Pontine perforator branches
and VII (lateral gaze palsy, involving the facial colliculus off the basilar artery
upper and lower facial
weakness), with or without
contralateral hemiparesis
One-and-a-half Ipsilateral cranial nerve VI Paramedian pons involving Paramedian pontine
(lateral gaze) palsy, bilateral the paramedian pontine perforators off the
internuclear ophthalmoplegia reticular formation and medial basilar artery
longitudinal fasciculi
Wallenberg Ipsilesional facial and Lateral medulla Posterior inferior cerebellar
contralesional body hypalgesia artery (should raise
and thermoanesthesia; concern for disease in
ipsilesional palatal weakness; parent vertebral artery)
dysphagia, dysarthria, nystagmus,
vertigo, nausea/vomiting;
ipsilesional oculosympathetic
defect (Horner syndrome);
skew deviation, singultus
Dejerine Ipsilesional tongue weakness Medial medulla Vertebral artery or anterior
and contralesional hemiparesis spinal artery
with or without contralesional
loss of proprioception and
vibratory sense
a
Data from Eckerle BJ, Southerland AM, Wiley-Blackwell.24

the proximal PCA (large artery), or or death. Bilateral medial thalamic

thromboembolus to the top of the strokes result in a state of depressed
basilar artery. The so-called top of the level of consciousness or coma and
basilar syndrome stroke is the most often occur secondary to occlusion of a
devastating of these events in that it single thalamoperforator trunk off the
can involve infarction of bilateral mid- top of the basilar artery, known as the
brain and thalamic territories and artery of Percheron. Other midbrain
cause subsequent injury to the reticu- stroke syndromes may involve oculo-
lar activating system, resulting in coma motor dysfunction via cranial nerve III

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 Clinical Evaluation of Acute Stroke

KEY POINTS
h Bilateral medial nuclei (third nerve palsy) or the medial Classically, lateral medullary stroke pre-
thalamic strokes result longitudinal fasciculus (internuclear sents with components of dysphagia
in a state of depressed ophthalmoplegia), the corticospinal and dysphonia (nucleus ambiguus,
level of consciousness tracts in the cerebral peduncles (con- vagal and glossopharyngeal nerves),
or coma and often tralateral hemiparesis), cerebellar tracts vertigo and disequilibrium (vestibular
occur secondary to in the superior cerebellar peduncles nuclei), ipsilateral oculosympathetic
occlusion of a single (ipsilateral ataxia), or rubral tracts via Horner syndrome (ptosis/miosis, de-
thalamoperforator trunk the red nuclei (ipsilateral tremor). scending sympathetic tracts), ipsilat-
off the top of the basilar Similarly, pontine strokes are often eral face and contralateral body crossed
artery, known as the the result of small vessel perforator oc- sensory loss of pain and temperature
artery of Percheron.
clusion or intrinsic large artery disease sensation (trigeminal and spinotha-
h When examining or thrombus in the midbasilar artery. lamic tracts), and ipsilateral limb ataxia
patients with stroke Pontine syndromes often include dys- (spinocerebellar tract).
who are tetraplegic or arthria, contralateral hemiparesis via Alternatively, a medial medullary syn-
appear to be comatose,
injury to descending corticospinal tracts drome involves ventral structures in the
the examiner must
in the ventral pons, hemianesthesia via lower brainstem with ipsilateral tongue
always ensure they are
not actually ‘‘locked in’’
ascending sensory tracts, ataxic hemipa- weakness (hypoglossal nucleus) and
from bilateral pontine resis via crossing cortico-pontocerebellar contralateral hemiparesis (pyramidal
infarction and able to tracts, or horizontal gaze palsies via tracts rostral to the decussation). Medial
communicate with involvement of cranial nerve VI nucleus medullary strokes often occur from
vertical eye movements and the paramedian pontine reticu- branch occlusion of the anterior spinal
or other subtle signs. lar formation, the so-called lateral artery, with or without parent vertebral
h Alexia without gaze center. artery disease.
agraphia classically Possibly the most devastating stroke Posterior cerebral artery. Stroke
results from a left syndrome, locked-in syndrome, mani- involving the PCA territories is often
posterior cerebral artery fests from bilateral infarction in the ven- the downstream result of thrombo-
territory stroke causing tral pons, disconnecting the midbrain embolism to the posterior circulation
infarction of the and supratentorial structures from the or intrinsic atherosclerotic disease in
splenium of the corpus rest of the lower nervous system, re- the PCA. The typical circulation of
callosum and left sulting in complete tetraplegia with a the PCA supplies the midbrain, thala-
occipital lobe, leading
preserved level of consciousness. Im- mus, and occipital and dorsomedial
to a disconnection
portantly, with an intact midbrain, temporal lobe. The hallmark local-
of visual and
language integration.
patients with locked-in syndrome can izing sign of a PCA territory stroke is a
still communicate via blinking or ver- contralateral homonymous hemianopia
tical eye movements. Therefore, when secondary to occipital lobe infarction,
examining patients with acute stroke absent of hemiparesis or other hemi-
who are apparently comatose, the ex- spheric signs that would localize to
aminer must always ensure they are the MCA territory. Hemianopias ema-
not actually awake and able to com- nating from PCA stroke are said to be
municate with eye movements or other macular sparing, secondary to redun-
subtle signs (Case 2-3). dancy of macular representation in
Medullary stroke syndromes. The the occipital lobe. Another textbook
medullary stroke syndromes are di- syndrome involving the PCA territory is
vided by the medial and lateral me- alexia without agraphia, which clas-
dulla. The lateral medullary syndrome sically manifests from infarction to
(Wallenberg syndrome) results from the splenium of the corpus callosum
infarction in the posterior inferior cere- and left occipital lobe, resulting in a
bellar artery (PICA) territory, often from disconnection of visual and lan-
occlusion of the parent vertebral artery. guage integration.
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 Case 2-3
A 63-year-old man with multiple vascular risk factors was found down
in his home and unable to communicate, prompting a call from his
family to 911. On arrival of emergency medical services, he was deemed
‘‘comatose’’ and intubated in the field for airway protection. In the
emergency department, his blood pressure was 180/100 mm Hg and his
initial National Institutes of Health Stroke Scale score was 32; his
neurologic examination (off sedation and paralytics) was notable for
horizontal gaze palsy, bifacial paralysis, tetraplegia with bilateral extensor
posturing, and hyperreflexia with bilateral Babinski signs and triple
flexion. On further testing, the patient was consistently able to blink to
command and deviate his gaze vertically. Head CT showed no acute
changes but was significant for a dense basilar artery sign (Figure 2-3).
The acute stroke team rapidly prepared for IV recombinant tissue
plasminogen activator, followed by endovascular therapy.

FIGURE 2-3 Head CT of the patient in Case 2-3

showing dense basilar artery
sign (arrow).

Comment. Locked-in syndrome is a devastating cerebrovascular condition

manifesting from bilateral injury to the ventral pons, often secondary to
basilar artery occlusion. With intact midbrain and supratentorial structures,
patients are able to communicate via blinking or vertical eye movements and
are able to consent for procedures and goals of care. In the acute stroke
setting, locked-in syndrome is a neurovascular emergency and requires rapid
efforts toward reperfusion therapy. Head CT may confirm the clinical suspicion
by presence of a dense basilar sign indicating acute thrombotic occlusion.
Acute stroke guidelines for basilar artery occlusions are limited in the evidence
base. However, the devastating nature of the syndrome likely warrants early
attempts at endovascular therapy and potentially considering treatment
beyond standard stroke treatment time windows.

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 Clinical Evaluation of Acute Stroke

KEY POINTS
h Patients presenting Cerebellar arteries. Of the arteries challenging clinical scenario, even for
with acute-onset supplying the cerebellum, the largest the most seasoned neurologist or
dysequilibrium or gait distribution stems from the PICA. PICA stroke specialist, and can be difficult
ataxia should prompt a territory strokes often involve the lat- to discern from peripheral vestibular
thorough examination eral medulla, as described previously, disorders in the absence of other
of eye movements, or the ipsilateral cerebellar hemisphere. localizing signs, eg, focal limb ataxia
postural stability, Cerebellar hemispheric strokes present or neighborhood signs, such as dysar-
and gait to rule out with ipsilateral limb dysmetria (past- thria, diplopia, dysphagia, or dysphonia.
a paramedian pointing), dyssynergia (incoordination) In these presentations, neuro-
cerebellar stroke. or intention tremor (widened ampli- otologic bedside maneuvers can help
h The HINTS methodology tude at target), impaired check response distinguish central from peripheral
(head impulse test, (rebound with sudden limb decelera- causes of vertigo. One set of methods
pattern of nystagmus, tion), and dysdiadochokinesia (im- is termed HINTS, an acronym for head
and test of skew) paired rapid-alternating movements). impulse test, pattern of nystagmus, and
helps distinguish
Note, cerebellar stroke syndromes in- test for skew. If the head impulse test
central from peripheral
volving the paramedian or flocculono- is normal, the fast phase of nystagmus
vestibulopathy in
patients presenting
dular lobes may be less discrete, apparent changes direction, or a skew devia-
with an acute only as midline signs of titubation (pos- tion is present, it suggests a central
vestibular syndrome. tural instability with sitting upright) or process such as posterior circulation
gait ataxia with ambulating. In this stroke with greater than 90% sensitiv-
scenario, a patient with acute stroke ity.30 In a 2015 study of patients pres-
may actually have an NIHSS score of 0, enting with acute vertigo and either
a reminder that the NIHSS is not a re- nystagmus or imbalance, this testing
placement for a thorough neurologic helped risk stratify patients who went
examination. Patients will often report on to have a confirmed stroke.31 Addi-
listing to the ipsilateral side. tionally, these bedside tests may actu-
While less common than PICA terri- ally have greater sensitivity than brain
tory stroke, occlusion of the anterior MRI for diagnosing small brainstem and
inferior cerebellar artery (AICA) results cerebellar strokes in the hyperacute
in a characteristic syndrome of sudden setting32 and therefore are valuable
vertigo and ipsilateral sensorineural clinical tools to help guide inpatient
hearing loss. This occurs due to ische- versus outpatient management of pa-
mia of the vestibulocochlear nerve and tients presenting with acute dizziness.
inner ear supplied by the labyrinthine Still, these bedside otologic maneuvers
artery. AICA strokes can also include may not capture all central processes
ipsilateral upper and lower facial weak- or causes of stroke in vestibular syn-
ness (cranial nerve VII) due to involve- dromes and should be considered
ment of the pontomedullary junction. supplemental to a dedicated history
The superior cerebellar artery supplies and thorough neurologic examination.
a smaller segment of the rostral cere- Table 2-6 lists red flags that should
bellar hemisphere, and occlusion, from heighten concern for stroke in the dif-
intrinsic arterial disease or thrombo- ferential diagnosis for patients pres-
embolus, also presents with ipsilateral enting with acute vestibular syndrome.
cerebellar signs.
Acute vestibular syndrome. Between Lacunar (Small Vessel) Syndromes
2 million and 4 million emergency de- Distinguishing between large and
partment visits each year are related to small vessel syndromes in acute stroke
dizziness.28,29 Dizziness or vertigo as a has taken on heightened relevance
presenting symptom of stroke is a with the recent evidence in favor of
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TABLE 2-6 Red Flags Concerning for a Central Process in Patients
Presenting With Acute Vestibular Syndrome

b Four Ds: diplopia, dysarthria, dysphagia, dysphonia

b Vertical or direction-changing nystagmus
b Skew deviation
b Normal head-impulse test
b Sudden deafness or tinnitus
b Focal signs (eg, dysmetria, dyssynergia, dysdiadochokinesia)
b Acute neck/occipital pain (ie, rule out vertebral artery dissection)
b The high-risk patient (eg, older age, vascular risk factors, history of stroke
or coronary artery disease)

endovascular therapy for patients with able to the anterior spinal artery can
large vessel occlusion. Small vessel (ie, be isolated to penetrating branch
lacunar syndromes) indicate occlusion occlusions (eg, medial medullary syn-
of perforating arteries in the subcortex, drome) or more completely involve
brainstem, or cerebellum, often associ- the anterior two-thirds of the spinal
ated with chronic hypertension and cord (anterior spinal syndrome), spar-
diabetes mellitus (Table 2-7). Lacunar ing only the sensory tracts of the
infarcts may be clinically silent, as seen dorsal columns.
on head CT, or result in stroke syn- Ischemic vulnerability in the spinal
dromes involving densely packed cord is greatest in the midthoracic sec-
white matter tracts with specific local- tions, where a watershed exists be-
ization patterns. The most commonly tween the anterior spinal artery and
described small vessel syndromes in- more robust radicular arteries supply-
clude pure motor, pure sensory, sen- ing the lumbosacral enlargement (eg,
sorimotor, ataxic hemiparesis, and the the artery of Adamkiewicz). In this sce-
so-called dysarthria-clumsy hand syn- nario, a patient often presents with
drome. The various subcortical locali- sudden neck or back pain, followed by
zations of these syndromes include the paraplegia and a spinal sensory loss of
internal capsule, thalamus, basal ganglia, pain and temperature below the level
pons, cerebellum, and subcortical white of infarction. Spinal shock initially
matter (corona radiata). A less com- appears as flaccidity and hyporeflexia,
mon, but striking, small vessel syn- followed within days by upper motor
drome manifests as hemiballism from neuron signs of spastic paraplegia
infarction in the subthalamic nucleus. and hyperreflexia. In addition to ath-
erosclerosis and aortic dissection as
Spinal Vascular Syndromes common etiologies, anterior cord syn-
Like the brain, the spinal cord has a dromes can also result iatrogenically
robust collateral blood supply. The during aortic surgery.
anterior and posterior spinal arteries
supply the ventral and dorsal cord, STROKE MIMICS
respectively, as branches of the extra- In the clinical evaluation of the patient
dural vertebral artery. Strokes refer- with acute stroke, the ability to rule

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 Clinical Evaluation of Acute Stroke

a
TABLE 2-7 Lacunar Syndromes

Syndrome Signs/Symptoms Localization Vascular Supply

Pure motor Contralesional Posterior limb Lenticulostriate branches of
hemiparesis of internal capsule, the middle cerebral artery or
corona radiata, or perforating arteries from the
basis pontis basilar artery
Pure sensory Contralesional Ventroposterolateral Lenticulostriate branches of
hemisensory loss nucleus of the thalamus the middle cerebral artery or
small thalamoperforators from
the posterior cerebral artery
Sensorimotor Contralesional Thalamus and adjacent Lenticulostriate branches from
weakness and numbness posterior limb of the middle cerebral artery
internal capsule
Dysarthria-clumsy hand Slurred speech and Base of the pons Perforating arteries from
(typically fine motor) between rostral the basilar artery
weakness of one-third and caudal
contralesional hand two-thirds
Ataxic hemiparesis Contralesional Posterior limb of Lenticulostriate branches of
(mild to moderate) internal capsule or the middle cerebral artery or
hemiparesis and limb base of the pons perforating arteries from the
ataxia out of basilar artery
proportion to the
degree of weakness
Hemiballismus/hemichorea Contralesional limb Subthalamic nucleus Perforating lenticulostriate
flailing or dyskinesia arteries
a
Data from Eckerle BJ, Southerland AM, Wiley-Blackwell.24

out stroke holds equal importance common conundrums when discern-

to the ability to rule it in. Many stroke ing stroke from stroke mimics include
mimics, or chameleons, exist that multiple localizations (eg, embolic
challenge clinical diagnostic reason- stroke), encephalopathy versus apha-
ing.33 Table 2-8 lists some common sia, postictal syndromes, peripheral
stroke mimics. With this challenge, one neuromuscular disorders or myelopa-
must rely on a targeted history, neuro- thy with lateralized weakness, compli-
logic examination, and fundamental cated migraine aura, and sophisticated
understanding of cerebrovascular local- somatization disorders. Nonetheless,
ization to effectively limit the excessive the risk of treating patients with stroke
treatment of false positives or neglected mimics is very low, and absolute cer-
treatment of false negatives. Further, tainty cannot be the threshold to make
the time-sensitive nature of treatment a vital treatment decision in a time-
for acute ischemic stroke does not sensitive setting.34
always allow for a final diagnosis prior
to making a treatment decision. CONCLUSION
Mimics often present with vague The clinical evaluation of the patient
symptoms and neurologic syndromes with acute stroke is clearly a dynamic
lacking in defined localization. Some process, requiring mastery in the

58 ContinuumJournal.com February 2017

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 a
TABLE 2-8 Common Stroke Mimics

Mimic Clinical Aspects Differentiating From Stroke

Seizures Witnessed seizure activity,b postictal period (eg, Todd
paresis), direction of gaze preference (eyes gaze
away from seizure during ictus), history of seizures
Metabolic Hypoglycemia, electrolyte abnormalities (eg,
encephalopathyc hypernatremia), hepatic or renal encephalopathy
Toxic Alcohol or illicit drug exposure, neuro-active or
encephalopathyc sedating medications
Infectious Urinary tract infection, sepsis, meningitis/encephalitis,
encephalopathyc brain abscess
Brain tumor Gradual onset of symptoms, systemic malaise, may
present with seizure at onset
Neuromuscular Focal weakness or numbness localizing to a spinal level,
root, plexus, or peripheral nerve; may be associated with
exacerbating trauma or limb compression
Migraine with aura Gradual onset, preceding aura, throbbing headache with
migrainous features, history of stereotypical episodes
Psychogenic Lack of objective signs, inconsistent examination,
neurologic symptoms in a nonvascular distribution,
history of similar events
a
Data from Eckerle BJ, Southerland AM, Wiley-Blackwell.24
b
Embolic cerebral infarcts may manifest with seizure activity as a presenting symptom and should
be considered in the differential of new seizure presentation, particularly in patients who are older.
c
Encephalopathy is often differentiated from stroke by a more gradual and less discrete onset of
symptoms. Note that patients with a history of stroke may present with a reactivation syndrome
mimicking prior stroke symptoms in the setting of toxic/metabolic/infectious encephalopathy.

focused stroke history, neurologic USEFUL WEBSITES

examination, and diagnostic assess- National Institutes of Health Stroke
ment, all while working through a Scale
time-sensitive and team-based envi-
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warrants proficiency with acute stroke Public_Domain.pdf
protocol but also requires knowledge National Institutes of Health Stroke
of neurovascular anatomy, clinical Scale Certification Training
stroke syndromes, and common mim-
ics (ie, does the case make neuroana- nihstrokescale.org
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 Review Article

Treatment of Acute
Address correspondence to
Dr Alejandro Rabinstein, Mayo
Clinic, Department of
Neurology, W8B, 200 First St
SW, Rochester, MN 55905,
[email protected].
Relationship Disclosure:
Ischemic Stroke
Dr Rabinstein serves as an Alejandro A. Rabinstein, MD, FAAN
associate editor for
Neurocritical Care; on the
editorial boards of Continuum:
Lifelong Learning in Neurology, ABSTRACT
the Journal of Stroke and
Cerebrovascular Diseases, Purpose of Review: This article provides an update on the state of the art of the
Neurology, and Stroke; and on emergency treatment of acute ischemic stroke with particular emphasis on the
the scientific advisory board of alternatives for reperfusion therapy.
Portola Pharmaceuticals, Inc.
Dr Rabinstein receives research/ Recent Findings: The results of several randomized controlled trials consistently
grant support from DJO Global, and conclusively demonstrating that previously functional patients with disabling
Inc, and royalties from Elsevier, strokes from a proximal intracranial artery occlusion benefit from prompt recanaliza-
Oxford University Press, and
UpToDate, Inc. tion with mechanical thrombectomy using a retrievable stent have changed the
Unlabeled Use of landscape of acute stroke therapy. Mechanical thrombectomy within 6 hours of
Products/Investigational symptom onset should now be considered the preferred treatment for these patients
Use Disclosure:
Dr Rabinstein reports
along with IV thrombolysis with recombinant tissue plasminogen activator (rtPA) within
no disclosure. the first 4.5 hours for all patients who do not have contraindications for systemic
* 2017 American Academy thrombolysis. Patients who are ineligible for IV rtPA can also benefit from mechanical
of Neurology. thrombectomy. Collateral status and time to reperfusion are the main determinants
of outcome.
Summary: Timely successful reperfusion is the most effective treatment for patients
with acute ischemic stroke. Systems of care should be optimized to maximize the
number of patients with acute ischemic stroke able to receive reperfusion therapy.

Continuum (Minneap Minn) 2017;23(1):62–81.

INTRODUCTION treatments are the most effective in-

Over the past 2 decades, the thera- terventions for acute ischemic stroke.
peutic approach to acute ischemic However, the treatment of acute
stroke has been deeply transformed. stroke also includes adequate hemo-
Long gone is the nihilism of former dynamic management, monitoring
times, now replaced by the excite- and management of ischemic brain
ment of proven treatment options that edema, and early recognition of and
can reverse ischemia and bring back therapy for systemic complications
function to patients who were otherwise (such as infections, cardiac arrhyth-
destined to death or severe disabil- mias, heart failure, and venous throm-
ity. The wide adoption of IV thrombol- boembolism) in a stroke unit staffed
ysis that began 20 years ago has recently by specially trained personnel. The
been followed with clear evidence management of acute ischemic stroke
that the addition of endovascular treat- starts with the prompt recognition of
ment with mechanical thrombectomy the diagnosis in the field, and atten-
can further improve outcomes in pa- tion is currently aimed at optimizing
tients with severe neurologic defi- the time to reperfusion in the emer-
cits from a proximal intracranial vessel gency department and the angio-
occlusion. graphic suite. However, what happens
This article primarily focuses on in the stroke unit or intensive care
reperfusion strategies because these unit after hospitalization is also very

62 ContinuumJournal.com February 2017

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 KEY POINTS
important to maximize the chances of of presentation and why neurologic h Prompt reperfusion
good recovery. Comprehensive guide- function can improve after reperfu- is the most effective
lines offer useful advice in these addi- sion. This collateral flow, however, is treatment for
tional areas.1 often tenuous and can sustain viability patients with acute
only for a limited period of time. Thus, ischemic stroke.
PRINCIPLES OF ACUTE without recanalization, the ischemic h The three principles of
STROKE CARE penumbra is destined to progress to acute stroke therapy are
The three main principles of acute infarction. Collateral flow can be pro- to achieve recanalization
stroke care are: (1) achieve timely tected by avoiding blood pressure drops of the occluded vessel
recanalization of the occluded artery and supported by the administration (and reperfusion of the
and reperfusion of the ischemic tis- of IV fluids. The value of keeping the ischemic tissue), to
sue, (2) optimize collateral flow, and head of the bed flat for patients with optimize collateral flow,
(3) avoid secondary brain injury. acute ischemic stroke is being investi- and to avoid secondary
Recanalization and reperfusion are gated in the ongoing Head Position in brain injury.
the mainstay of acute stroke treatment Stroke Trial (HeadPoST) and should be h The ischemic penumbra
and can reduce infarct size and re- weighed against the risk of aspiration.3 is the region of
verse neurologic deficits. Recanaliza- Hemodynamic augmentation with va- hypoperfused brain that
tion is defined by the degree of sopressors may be beneficial in well- can still be viable with
prompt recanalization
reopening of the occluded artery. selected cases (such as patients with
of the occluded artery.
Reperfusion is measured by the de- cervical internal carotid artery occlusion
gree of flow reaching the previously without tandem intracranial occlusion), h Collateral flow is
hypoperfused brain region. Opening but the safety and efficacy of this strat- responsible for
the temporary
the occluded artery works because, in egy is otherwise unknown. Invasive in-
preservation of the
most cases, when the occlusion oc- terventions to improve collateral flow
ischemic penumbra.
curs, an area of brain tissue becomes remain investigational.
hypoperfused but is initially not in- Despite promising results in basic h No neuroprotective
agent has been proven
farcted. This tissue represents the and translational experiments, numer-
to be beneficial for
ischemic penumbra that can be sal- ous neuroprotective agents have failed
acute ischemic stroke in
vaged if adequate blood flow is to improve outcomes in clinical trials. clinical trials.
promptly reestablished. Advanced Yet, avoidance of secondary insults is a
brain imaging with CT perfusion or form of neuroprotection. Hypoglyce-
magnetic resonance (MR) diffusion/ mia can exacerbate energy failure and
perfusion can visualize this tissue at should be strictly averted. Hyperglyce-
risk (penumbra imaging).2 Chemical mia might also be deleterious; so far,
thrombolysis with recombinant tissue we know that it correlates with worse
plasminogen activator (rtPA), also outcomes after an ischemic stroke but
known as alteplase, and mechanical do not have proof that its correction
embolectomy with a retrievable stent improves outcomes.4 The Stroke Hy-
are the two evidence-based strategies perglycemia Insulin Network Effort
to achieve reperfusion. (SHINE) trial is a randomized controlled
Collateral flow is responsible for trial comparing tight glycemic control
keeping the ischemic penumbra via- with IV insulin to maintain a glucose
ble. It provides enough flow to pre- level between 80 mg/dL and 130 mg/dL
vent critical ischemia and infarction versus standard glycemic control using
but not sufficient flow to maintain subcutaneous insulin dosed according
normal cellular function. This explains to a sliding scale to keep the glucose
why the acute neurologic deficits level lower than 180 mg/dL in patients
exceed what would be expected for with acute ischemic stroke within
the established infarct core at the time 12 hours of symptom onset.5 It is
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 Acute Ischemic Stroke

KEY POINTS
h IV thrombolysis with hoped that this trial will answer the stroke onset, but regulatory agencies
rtPA and endovascular question whether tight glycemic control in most other countries (including
thrombectomy with is safe and beneficial after an acute is- those in the European Union) have
a retrievable stent chemic stroke. Fever is associated with approved its administration within
are both solidly worse clinical results; thus, treating fever 4.5 hours of stroke onset.
established treatments may be beneficial.6 The value of hypo- The initial evaluation of a patient
for appropriate thermia continues to be investigated. with a possible acute stroke in the
candidates with acute Preventing infections (which notably emergency department should focus
ischemic stroke. includes dysphagia assessment before on establishing whether the patient is
h Time to reperfusion is a any oral intake) and early recurrent eligible for reperfusion therapy. Nec-
major determinant of strokes are additional priorities in the essary information includes the time
outcome in acute care of the patient with acute stroke. the patient was last known to be well,
ischemic stroke. medical conditions or recent surgery
h Randomized ACUTE REPERFUSION that could contraindicate thrombolysis,
placebo-controlled trials TREATMENTS neurologic examination to calculate the
have demonstrated that There is incontrovertible evidence National Institutes of Health Stroke
IV thrombolysis with that IV thrombolysis with rtPA and Scale (NIHSS) score, a capillary glucose
rtPA is beneficial for endovascular thrombectomy with a level, blood pressure, and brain imaging
patients with acute
retrievable stent improve neurologic (CT scan with or without a CT angio-
ischemic stroke up to
outcomes in patients with acute ische- gram depending on whether endovas-
4.5 hours from
symptom onset.
mic stroke. Both treatments should cular therapy is being considered).
be administered as quickly as possi- Recently, the indications and contra-
h Some previously cited ble after stroke onset, can be com- indications for IV rtPA have been re-
contraindications for IV
bined, and are safe in appropriately visited in a scientific statement of the
thrombolysis have been
revisited, thus expanding
selected candidates. American Heart Association (AHA)12
the pool of patients IV thrombolysis and mechanical and modified by the FDA in the pack-
who can be considered thrombectomy can produce reperfu- age insert for the drug (Table 3-113).
good candidates for sion injury after recanalization. Re- As a result, more patients can be con-
this treatment. perfusion injury can manifest with sidered for IV thrombolysis in clinical
hemorrhage and edema. It is more practice. IV thrombolysis should not be
severe when the area of established withheld because of advanced age, and
infarction is larger. Good patient se- mild but disabling deficits justify treat-
lection (ie, absence of a large ischemic ment. Individualized clinical judgment
core) and prompt treatment are cru- is necessary when deciding whether to
cial to avoid this complication. recommend thrombolysis to patients
with weaker indications (such as non-
Intravenous Thrombolysis disabling deficits) or relative contrain-
IV thrombolysis with rtPA is proven to dications. The safety and efficacy of
be effective in improving functional IV thrombolysis in pediatric patients
outcomes after an ischemic stroke up (younger than 18 years of age) is not
to 4.5 hours after symptom onset.1,7Y9 well established.
Randomized controlled trials8,9 fol- IV rtPA infused within 3 hours of
lowed by large observational studies symptom onset increases the chances
confirming the rates of recovery noted of functional independence at 3 months
in these trials10 and meta-analyses7 by one-third.7,8 The benefit is time de-
support this therapeutic indication pendent and much stronger when the
(Figure 3-111). The US Food and Drug drug is administered within the first
Administration (FDA) has only ap- 90 minutes after symptom onset (esti-
proved rtPA for use within 3 hours of mated number necessary to treat to help
64 ContinuumJournal.com February 2017

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 KEY POINT
h Benefit from IV
thrombolysis is much
greater in the first
90 minutes from
symptom onset.

FIGURE 3-1 Results of meta-analysis of individual data from major randomized trials of IV
recombinant tissue plasminogen activator (rtPA) (alteplase) for acute ischemic
stroke showing that thrombolysis increases the chances of achieving a modified
Rankin Scale score of 0 to 1 (no symptoms or mild symptoms with no disability) at 90 days.
Notice that the benefit is time dependent and no longer significant when the drug is
administered more than 4.5 hours after symptom onset. Treatment is beneficial in patients older
than 80 years, and the benefit is fairly consistent across all degrees of initial stroke severity.
CI = confidence interval; NIHSS = National Institutes of Health Stroke Scale.
Reprinted with permission from Emberson J, et al, Lancet Neurol.11 B 2014 Emberson et al. thelancet.com/journals/
lancet/article/PIIS0140-6736(14)60584-5/fulltext.

one more patient achieve functional receive either 0.9 mg/kg or 0.6 mg/kg
independence is 3.6 within the first of IV rtPA within 4.5 hours of stroke
90 minutes and 4.3 between 91 and onset.16 The reduced dose was inferior
180 minutes) 14 (Case 3-1). Older to the standard dose for the end point
patients and those with a very severe of death or any degree of disability at
stroke at presentation have worse 90 days, although it was associated with
prognosis15 but can still benefit from a lower risk of symptomatic intracere-
IV rtPA. The benefit is less robust bral hemorrhage (which was low in
for patients treated between 3 and both treatment groups).
4.5 hours, but rtPA is still beneficial in No other thrombolytic agent has
this extended window (number neces- been approved for use in ischemic
sary to treat 5.9).9,14 stroke. In emergency departments of
The standard dose of IV rtPA for medical centers with more limited
acute ischemic stroke is 0.9 mg/kg, capabilities, patients can receive the
with 10% administered as a bolus and bolus of rtPA and then be transferred
the remainder infused over 1 hour. to a primary stroke center or compre-
The total dose should not exceed hensive stroke center while the rest of
90 mg. The phase 3 Enhanced Control the dose of the drug is being infused
of Hypertension and Thrombolysis (the drip-and-ship strategy).
Stroke Study (ENCHANTED) enrolled Hemorrhage is the most dangerous
3310 predominantly Asian patients to complication after thrombolysis. The

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 Acute Ischemic Stroke

TABLE 3-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen Activator

American Heart Association American Heart Association US Food and Drug Administration
Guideline 20131 Scientific Statement 201512 (FDA) Package Insert 201513
Indications
Diagnosis of ischemic stroke with Same Same
measurable neurologic deficit
Symptom onseta within 4.5 hours Same Within 3 hours
Age Q18 years Same Warning for age 977 years with risk
factors for intracranial hemorrhage
Contraindications
Severe head trauma within Same Contraindicated
3 months
Ischemic stroke within 3 months Risk increased, but degree is unclear Removedb
Arterial puncture at Risk uncertain Not listed
noncompressible site within
7 days
Previous intracranial Same Warning for recent intracranial
hemorrhage hemorrhage (contraindicated if
active intracranial hemorrhage)
Suspected subarachnoid Same Contraindicated
hemorrhage
Intracranial neoplasm, Probably recommended if Contraindicated
arteriovenous malformation extraaxial neoplasm is present; not
(AVM), or aneurysm recommended if intraaxial neoplasm
is present; risk unclear for AVM;
probably recommended if unruptured
unsecured aneurysm G10 mm is
present, but risk unclear if greater size
Recent intracranial or Same Contraindicated
intraspinal surgery
(within 3 months)
Active internal bleeding Same Contraindicated
Systolic blood pressure (BP) Same, but treatment recommended Contraindicated for severe uncontrolled
9185 mm Hg or diastolic BP if BP can be lowered safely hypertension (BP values removedb);
9110 mm Hg warning for BP 9175/110 mm Hg
Bleeding diathesis Consider case by case in patients Contraindicated for bleeding
with history of bleeding diathesis; diathesis (laboratory
International normalized
not recommended if INR 91.7, values removedb)
ratio (INR) 91.7
low-molecular-weight heparinoid
Heparin within 48 hours with within 24 hours, direct thrombin
abnormal activated partial inhibitor or factor Xa inhibitor
thromboplastin time within 48 hours (unless coagulation
3 testsc are normal)
Platelets G100,000/mm
Current use of direct thrombin
inhibitor or factor Xa inhibitor
c
with abnormal coagulation tests Continued on page 67

66 ContinuumJournal.com February 2017

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 American Heart Association American Heart Association US Food and Drug Administration
Guideline 20131 Scientific Statement 201512 (FDA) Package Insert 201513
Contraindications (continued)
Blood glucose G50 mg/dL Consider recombinant tissue Removedb
plasminogen activator (rtPA) if deficits
still present after glucose normalization
CT showing hypodensity 91/3 Same Removedb
of the cerebral hemisphere
Relative contraindications
Minor stroke (typically rtPA should be administered to patients Removedb
National Institutes of Health with mild but disabling symptoms
Stroke Scale [NIHSS] score G5) within 3 hours of onset; possible risk and
benefit should be weighed in patients
with nondisabling symptoms
Rapidly improving symptoms rtPA should be administered if Not listed
symptoms are still disabling
Pregnancy rtPA may be considered in moderate Warning (Category C)
to severe stroke when anticipated
benefit outweighs the anticipated
risk of uterine bleeding
Seizure at onset with rtPA administration is reasonable Removedb
postictal residual deficits if residual deficits are thought
to be caused by a stroke
Major extracranial trauma rtPA can be considered Warning for recent trauma
within 14 days
Major surgery within 14 days rtPA can be considered in carefully Warning for recent surgery
selected cases
Gastrointestinal or genitourinary Consider rtPA if no structural Warning
surgery within 21 days bleeding lesions
Acute myocardial infarction Administer rtPA (stroke dose) if concurrent Not listed
within 3 months stroke and acute myocardial infarction
(MI); it is also reasonable to give rtPA
after recent MI unless it was a STEMI
involving the left anterior myocardium
Additional contraindications for
3- to 4.5-hour window
Age 980 years rtPA recommended
Warfarin use (regardless rtPA probably recommended if INR G1.7 FDA has not approved rtPA for
of INR) use after 3 hours
NIHSS 925 Risk and benefit uncertain
Previous strokeor diabetes mellitus rtPA probably recommended

CT = computed tomography; STEMI = ST-segment elevation myocardial infarction.

a
Last known well.
b
The term removed is used to denote a change compared with the previous version of the package insert (2009).
c
Activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, factor Xa activity assays.

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 Acute Ischemic Stroke

KEY POINT
h Most cases of
symptomatic intracerebral
Case 3-1
A 54-year-old woman presented with the sudden onset of left-sided
hemorrhage are caused
weakness and dysarthria. Her husband promptly called 911, and the
by reperfusion injury
patient arrived by ambulance to the emergency department 15 minutes
causing hemorrhagic
after symptom onset. Her National Institutes of Health Stroke Scale (NIHSS)
transformation of an
score was 6. Noncontrast CT scan showed no hemorrhage, acute ischemic
already severe stroke.
changes, or hyperdense vessel sign. She had no contraindications for
thrombolysis. IV rtPA was started 32 minutes after symptom onset. Within
the following 2 hours, the patient improved remarkably, and the following
day she had no residual symptoms.
Comment. The benefit from IV thrombolysis for patients with acute
ischemic stroke is highly dependent on time to administration.
Administration of the bolus within 60 to 90 minutes affords maximal
chances of improvement. In order to treat patients within this short time
window, it is essential to optimize the efficiency of early evaluation, CT
scanning, and drug delivery. In the United States, stroke centers are
expected to be able to consistently administer IV rtPA within 60 minutes of
patient arrival to the emergency department.

reported rates of symptomatic intrace- consists of control of hypertension (sys-

rebral hemorrhage (sICH) have varied tolic target 140 mm Hg to 160 mm Hg)
(between 1.9% and 6.4%), depending and reversal of the fibrinolytic effect
on its definition and the design of the with cryoprecipitate (10 units) or an
study.17 However, most cases of sICH antifibrinolytic agent (tranexamic acid
are caused by reperfusion injury and 10 mg/kg to 15 mg/kg IV over 20 minutes
worsen strokes that were already or (-aminocaproic acid 5 g IV followed
severe and destined to be disabling. by an infusion of 1 g/h if necessary).
Hemorrhagic transformation of a large Additional cryoprecipitate may be given
infarction can increase the risk of if the serum fibrinogen level remains
death, but sICH rarely negates what below 150 mg/dL.21
would have otherwise been a good Orolingual angioedema is a rare but
recovery. In fact, the number needed potentially serious complication of
to harm for IV rtPA has been estimated rtPA administration. The risk is higher
to be 126 for the combined end point in patients previously taking angiotensin-
of disability or death.18 The risk of converting enzyme inhibitors. It is typ-
sICH is increased with old age, diabe- ically asymmetric and tends to involve
tes mellitus, severe hyperglycemia, the hemiparetic side. The most severe
uncontrolled hypertension, and larger cases can compromise airway patency;
hypodensity on baseline CT scan.19 thus careful monitoring is indispens-
The risk of sICH might also be higher able. Treatment consists of a combina-
in patients with cerebral microbleeds, tion of diphenhydramine (50 mg IV),
although this association is not entirely ranitidine (50 mg IV), and dexametha-
certain.20 sone (10 mg IV).
When sudden neurologic decline While IV thrombolysis is the stan-
occurs during rtPA infusion, the infu- dard of care for eligible patients with
sion should be immediately stopped acute ischemic stroke, this treatment
and a CT scan should be obtained has limitations. In addition to its short
emergently. Whenever postthrom- time window and contraindication in
bolysis sICH is diagnosed, treatment patients with increased bleeding risk,

68 ContinuumJournal.com February 2017

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 KEY POINTS
IV rtPA often fails to recanalize proxi- both arms were treated with IV rtPA. h Six recent randomized
mal artery occlusions caused by large The results were unequivocal: patients controlled trials have
clots. These are the most disabling treated with mechanical thrombectomy conclusively proven that
strokes, and strong evidence now had high rates of reperfusion and endovascular therapy
exists that these patients should be much better functional outcomes at with mechanical
considered for endovascular therapy. 90 days. thrombectomy improves
When taken in combination, these functional outcomes in
Mechanical Thrombectomy trials demonstrated that between three patients with acute
Although endovascular recanalization and seven patients must be treated to stroke from a proximal
treatment for selected patients with help one additional patient regain func- intracranial artery
occlusion (internal
severe acute ischemic stroke has been tional independence,33 which is par-
carotid artery, M1 or M2
practiced in many centers for decades, ticularly remarkable considering the
segments) when the
the publication of several recent pos- severity of the symptoms upon pre- intervention is performed
itive trials has catapulted this therapy sentation (Case 3-2). Furthermore, within 6 hours of
to the status of evidence-based treat- since the benefit conferred by mechan- symptom onset.
ment for patients with large intracra- ical thrombectomy spanned through
h Candidates for
nial artery occlusion. Previous trials the entire range of functional outcome, endovascular stroke
had failed to show a benefit from the number necessary to treat to therapy are patients
endovascular therapy because of reduce disability by one level on the with severe neurologic
suboptimal inclusion criteria (by not modified Rankin Scale was only 2.6. symptoms, no major
requiring proof of a proximal intracra- This benefit was confirmed across ischemic changes
nial artery occlusion before randomi- multiple subgroups (including patients on the baseline CT scan,
zation), longer time to intervention, older than 80 years and those with very good prestroke
and use of less effective reperfusion severe strokes as indicated by a base- functional status, and
devices.22Y24 Instead, the six positive line NIHSS score higher than 20).33 early presentation.
trials25Y30 shared the requirement of Mechanical thrombectomy was also h Mechanical
CT angiogram for patient screen- proven to be quite safe, with a pooled thrombectomy can be
ing (only patients with documented rate of sICH of 4.4% across all patients attempted when IV
internal carotid artery or proximal treated in the intervention arms of thrombolysis does not
middle cerebral artery occlusions could the five trials.33 Few emergency treat- result in rapid clinical
improvement and also
be entered into the studies), empha- ments in medicine have shown this
in patients who are
sized the importance of prompt inter- degree of success.
ineligible for IV rtPA.
vention, and almost exclusively used The dramatic benefit observed in
retrievable stents to achieve reper- these trials relied on very high reper-
fusion, devices that have been solidly fusion rates using retrievable stents.
proven to be more effective than These devices are deployed at the
their predecessors.31,32 level of the occlusive clot, capture
The main characteristics of the ran- the clot in their mesh, and are then
domized controlled trials establishing retrieved along with the clot. Inter-
the benefit of mechanical throm- ventions in these trials were prompt
bectomy are summarized in Table 3-2. and typically performed by experi-
All of them enrolled patients with enced specialists. Delays to treatment
severe neurologic deficits and good were minimized, and consequently
prestroke functional status who pres- the times to reperfusion were rela-
ented mostly within 6 hours of symp- tively short. In fact, those trials with
tom onset (Table 3-3). Major early shorter average time to reperfusion
ischemic changes on the baseline showed the greatest clinical benefit.34
CT scan were a reason for exclusion. Some unanswered questions still
The great majority of patients in exist regarding the best application of
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 Acute Ischemic Stroke

TABLE 3-2 Summary of the Main Trials Evaluating Mechanical Thrombectomy With
Retrievable Stents for Acute Ischemic Stroke

Study MR CLEAN25 ESCAPE26 EXTEND-IA27

Size (intervention 500 (233 versus 267) 315 (165 versus 150) 70 (35 versus 35)
versus control)
Age, median (years) 65.8 versus 65.7 71 versus 70 68.6 versus 70.2
a
Time to randomization 6 hours 12 hours 6 hours
Image to puncture
G60 minutes
Clinical selection Any age Any age Any age
NIHSS Q2 Any NIHSS (disabling Any NIHSS
symptoms)
Barthel Index990 Premorbid mRS G2
b
Imaging selection CTA (+/- CTP) CT ASPECTS 6Y10 with good CTA/CTP (core G70 mL)
collaterals 950% of MCA
Any ASPECTS

NIHSS, median 17 versus 18 16 versus 17 17 versus 13

ASPECTS, median 9 9 versus 9 Not reported
IV rtPA, % 87.1 versus 90.6 72.7 versus 78.7 100 versus 100
Onset to groin puncture, 260 185 210
median (minutes)
Onset to reperfusion, Not reported 241 248
median (minutes)
M1 occlusion, % 66.1 versus 62 68.1 versus 71.4 57 versus 51
TICI 2bY3, % 58.7 72.4 86
mRS -0Y2 at 90 days, % 32.6 versus 19.1 53 versus 29.3 71 versus 40
OR 1.7 OR 1.8 OR 4.2
(95% CI 1.2Y2.3) (95% CI 1.4Y2.4) (95% CI 1.4Y12)
mRS 0Y2 at 90 days, NNT 7.1 4.2 3.2
sICH, % 6 versus 5.2 3.6 versus 2.7 0 versus 6
+/- = with or without; ASPECTS = Alberta Stroke Program Early CT Score; CI = confidence interval; CT = computed tomography;
CTA = computed tomography angiography; CTP = computed tomography perfusion; ESCAPE = Endovascular Treatment for Small
Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times; EXTEND-IA = Extending the
Time for Thrombolysis in Emergency Neurological DeficitsVIntra-Arterial; ICA = internal carotid artery; IV= intravenous; MCA = middle cerebral
artery; MR CLEAN = Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands;
MRA = magnetic resonance angiography; mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale; NNT = number
needed to treat; OR = odds ratio; REVASCAT = Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy
in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within 8 Hours of Symptom Onset;
rtPA = recombinant tissue plasminogen activator; sICH = symptomatic intracerebral hemorrhage; SWIFT PRIME = Solitaire With the Intention
for Thrombectomy as Primary Endovascular Treatment; THRACE = The Contribution of Intra-arterial Thrombectomy in Acute Ischemic
Stroke in Patients Treated With Intravenous Thrombolysis; TICI = thrombolysis in cerebral infarction.
a
84% within 6 hours.
b
67% of MR CLEAN subjects and 81% of SWIFT PRIME subjects had CT perfusion.

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 SWIFT PRIME28 REVASCAT29 THRACE30
196 (98 versus 98) 206 (103 versus 103) 414 (204 versus 208)

65 versus 66.3 65.7 versus 67.2 66 versus 68

6 hours 3.7 hours 4.5 hours
Image to puncture Onset to groin puncture
G90 minutes 5 hours
Age 18Y80 years Age 18Y80 years Age 18Y80 years
NIHSS Q8 NIHSS Q6 NIHSS 10Y25

Premorbid mRS G2 Premorbid mRS G2

CTA (+/- CTP)b CTA CTA or MRA

ASPECTS 6Y10 ASPECTS 7Y10 Any ASPECTS

No cervical ICA occlusion
17 versus 17 17 versus 17 18 versus 17
9 versus 9 7 versus 8 Median not reported
100 versus 100 68.0 versus 77.7 100 versus 100
224 269 250

250 355 303

67 versus 77 64.7 versus 64.4 86 versus 79

88 65.7 69
60.2 versus 35.5 43.7 versus 28.2 53 versus 42
OR 1.7 OR 2.1 OR 1.55
(95% CI 1.2Y2.3) (95% CI 1.1Y4.0) (95% CI 1.05Y2.30)
4.0 6.3 9.1
1 versus 3 1.9 versus 1.9 2 versus 2

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 Acute Ischemic Stroke

KEY POINTS
h Careful assessment of pedient method to quantify the extent
brain imaging is TABLE 3-3 Candidates for of early ischemic damage (Figure 3-335).36
Acute Endovascular However, the noncontrast CT scan is
necessary to exclude Stroke Therapy
a large established not sensitive for the visualization of
infarction (core). early ischemia. One of the trials used
b Age Q18 years
h The optimal radiologic multiphase CT angiography to evaluate
method to select
b NIHSS score Q6 collateral vessels,26 and another re-
candidates for b Time from symptom onset quired a CT perfusion showing a
endovascular therapy is to groin puncture G6 hours limited infarct core and evidence of
not yet established, but b Good prestroke functional penumbra before randomization.27
the Alberta Stroke status Furthermore, many patients in trials
Programs Early CT that did not require CT perfusion by
Score, evaluation of b ASPECTS score Q6 on baseline
CT scan protocol had this imaging before in-
collaterals on CT clusion in the study because that was
angiography, and CT b Presence of proximal
the prevailing practice in the enrolling
perfusion or MRI intracranial artery occlusion
center.25,28 CT perfusion can provide
diffusion/perfusion are ASPECTS = Alberta Stroke Program Early
all available options. CT Score; CT = computed tomography; more reliable assessment of the is-
NIHSS = National Institutes of Health chemic region, but its acquisition re-
Stroke Scale.
quires additional time. MRI diffusion/
perfusion is broadly considered the
most accurate method to determine
mechanical thrombectomy for pa- the ischemic core and the extent of the
tients with acute ischemic stroke. In penumbra, but this technique is less
particular, the best imaging modal- available. New software packages
ity to select patients for the inter- promise to accelerate the time re-
vention remains to be determined. quired to obtain perfusion imaging.
All trials excluded patients with an Yet, at this time, it is unclear if the
Alberta Stroke Program Early CT Score additional time needed to obtain these
(ASPECTS) lower than 6 on baseline images is justified.37 Figure 3-438 illus-
CT scan. The ASPECTS provides an ex- trates the current work flow in the

Case 3-2
A 62-year-old man without past medical history collapsed in his bathroom. The noise alerted his son,
who found his father on the ground, unable to move the right side of his body and mute. He
immediately called an ambulance. Paramedics in the field noted a blood pressure of 180/100 mm Hg
and an irregularly irregular pulse. In the emergency department, the patient had a fluctuating level of
alertness, forced left gaze deviation, a right visual field deficit, global aphasia with mutism, right
hemiplegia, and severe right hypoesthesia. His National Institutes of Health Stroke Scale (NIHSS) score
was 22. Noncontrast head CT scan showed a hyperdense left middle cerebral artery sign, but his
Alberta Stroke Program Early CT Score (ASPECTS) was 10 (Figure 3-2A). CT angiogram showed a flow
gap in the left middle cerebral artery with good collateral flow distal to it (Figure 3-2B). IV
thrombolysis was started 55 minutes after symptom onset, and the patient was taken to the angiographic
suite for endovascular therapy. Groin puncture took place 67 minutes after symptom onset. Initial
injection of contrast into the left internal carotid artery showed that this vessel was occluded at the top of
its supraclinoid segment (Figure 3-2C). Complete recanalization with full reperfusion was rapidly
achieved with mechanical thrombectomy using a retrievable stent (Figure 3-2D). The patient began
improving on the angiographic table and continued to improve overnight. By the next morning, his
NIHSS score was 3. Repeat CT scan showed a small infarction in the left lenticular nucleus (Figure 3-2E).
At 3 months, the patient had full function and no residual symptoms.
Continued on page 74

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 Continued from page 73

FIGURE 3-2 Imaging of the patient in Case 3-2. A, CT scan of the brain showing hyperdensity in the left middle cerebral
artery consistent with acute thrombus (arrow). B, CT angiogram showing a focal area of left middle cerebral
artery occlusion (arrow) with good collateral flow in the vessels distal to the occlusion. C, Digital subtraction
angiogram demonstrating occlusion of the distal segment of the left internal carotid artery as well as intact collaterals
supplying the peripheral middle cerebral artery branches. D, Full recanalization and reperfusion after mechanical
thrombectomy. E, Repeat CT scan showing a small residual infarction in the left basal ganglia (arrow).

Comment. Thanks to technologic advances, endovascular therapy with mechanical thrombectomy is

highly effective in achieving reperfusion in patients with proximal intracranial artery occlusions. It is
usually combined with IV thrombolysis. However, endovascular recanalization is also beneficial in
patients with contraindications for IV rtPA. Adequate patient selection (in this case, the patient had
no evidence of ischemic changes on CT scan and good collaterals on CT angiogram) and prompt
intervention are crucial to optimize the chances of therapeutic success.

evaluation and treatment of acute is- Randomized Clinical Trial of Endovas- KEY POINT
chemic stroke. cular Treatment for Acute Ischemic h Endovascular
A growing body of evidence sug- Stroke in the Netherlands (MR CLEAN) interventions for acute
stroke should be
gests that interventions performed trial.40 It is becoming increasingly clear
performed under
under conscious sedation have better that most interventions can be safely
conscious sedation
outcomes than those performed un- completed using conscious sedation. whenever possible.
der general anesthesia. This finding An appropriately powered large ran-
was first reported in retrospective domized trial will be necessary to
studies39 and subsequently confirmed conclusively determine if conscious
in a subanalysis of the Multicenter sedation should be preferred over

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 Acute Ischemic Stroke

FIGURE 3-3 The Alberta Stroke Program Early CT Score

(ASPECTS) is designed to quantify the severity
of brain parenchymal changes in acute stroke.
The 10 areas are depicted on this illustration. A normal CT scan
is represented by an ASPECTS of 10. One point is subtracted for
each of the 10 regions when any evidence of early ischemic
change exists. Thus, the lower the ASPECTS, the larger the
extent of the ischemic damage.
Reprinted from Puetz V, et al, Int J Stroke.35 B 2009 World Stroke Organization.
wso.sagepub.com/content/4/5/354.abstract.

FIGURE 3-4 Graphic illustrating the sequence of steps in contemporary acute stroke therapy. IV thrombolysis should be given to
all patients without contraindications within 60 minutes of their arrival to the emergency department. The use of
perfusion imaging is considered optional at this time. Ideally, the time from the qualifying scan to the groin
puncture in candidates for endovascular therapy should be shorter than 60 minutes.
CT = computed tomography; DSA = digital subtraction angiography; IV = intravenous; rtPA = recombinant tissue plasminogen activator.
Reprinted with permission from Rabinstein AA, Nat Rev Neurol.38 B 2016 Alejandro A. Rabinstein. nature.com/nrneurol/journal/v12/n2/full/nrneurol.2015.241.html.

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 KEY POINTS
general anesthesia during endovascular Triage of Wake-Up and Late Presenting h Patients with wake-up
stroke therapy. Strokes Undergoing Neurointervention strokes and those with
Perhaps the main question is (DAWN),43 PerfusiOn Imaging Selec- stroke of unknown time
whether the outcomes observed in tion of Ischemic STroke Patients for of onset might benefit
the randomized trials can be repli- EndoVascular ThErapy (POSITIVE),44 from acute reperfusion
cated in daily practice. To achieve this Diffusion and Perfusion Imaging Eval- if a large infarct core can
goal, triaging mechanisms must be uation for Understanding Stroke Evo- be reliably excluded.
refined and expertise must become lution 3 (DEFUSE 3),45 and A Phase IIa h It is prudent not to
more readily available. Organization Safety Study of Intravenous Thrombol- administer IV thrombolysis
and implementation of stroke net- ysis With Alteplase in MRI-Selected in patients taking the
works around comprehensive stroke Patients (MR WITNESS)46 trials. novel oral anticoagulants
centers with 24/7 neurointerventional (dabigatran, rivaroxaban,
capability must become a priority. In Intravenous Thrombolysis apixaban, edoxaban)
turn, neurointerventional centers will in Patients Taking because readily available
tests in the emergency
have to prove compliance with strict Newer Anticoagulants
department cannot
metrics of efficiency and safety. IV rtPA can be administered within quantify the degree of
3 hours of symptom onset to patients active anticoagulation.
SPECIAL SITUATIONS taking warfarin whose international
Special clinical situations remain for normalized ratio (INR) is 1.7 or less.
which the evidence is insufficient to However, no adequate safety data
determine the best course of action. with the newer anticoagulants (the
Until more definite data become avail- direct thrombin inhibitor dabigatran
able, these cases should be approached and the factor Xa inhibitors riva-
considering individual factors and what roxaban, apixaban, and edoxaban)
is known from collective experience. exist. Readily available laboratory stud-
ies cannot quantify the degree of anti-
Wake-up Strokes coagulation. Thus, it is most prudent
Patients whose neurologic deficits are to withhold thrombolysis in patients
first noticed upon their awakening taking these agents.12 However, patients
represent a particular challenge to with proximal intracranial artery occlu-
the clinician. The same applies to sion may benefit from mechanical
those with unclear time of onset (such thrombectomy.
as when the patient is aphasic and the
onset of symptoms was not witnessed). Minor and Rapidly
These situations constitute formal con- Improving Deficits
traindications for IV rtPA, but it is widely Although thrombolysis is often with-
agreed that some of these patients may held because the symptoms are
benefit from reperfusion therapy. When considered mild or patients appear
the baseline CT scan shows no evidence to be rapidly improving, several ob-
of a large established infarction, it is servational studies have shown that
likely that advanced imaging with CT up to one-third of patients who are
perfusion or MR diffusion/perfusion otherwise eligible for thrombolysis
may identify those patients who can be but do not receive it for these reasons
safely treated and can improve after are disabled at 3 months.47 Thus, one
successful recanalization (Case 3-3). must be very careful when assess-
Observational studies support this ap- ing these patients. IV rtPA might be
proach,41,42 which is currently being justified when the NIHSS score is low
tested in the DWI or CTP Assess- but the symptoms are nonetheless dis-
ment With Clinical Mismatch in the abling for the patient (eg, hemianopia

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 Acute Ischemic Stroke

Case 3-3
A 74-year-old woman with a history of atrial fibrillation on aspirin woke up with speech difficulties
and right-sided weakness. She was feeling well when she had gone to bed the night before. Her
husband called an ambulance, and upon arrival to the emergency department, she had a National
Institutes of Health Stroke Scale (NIHSS) score of 15. CT scan of the brain was unremarkable, but CT
angiogram showed occlusion of the left middle cerebral artery with good collateral flow (Figure 3-5A).
CT perfusion demonstrated a large mismatch between the cerebral blood flow (Figure 3-5B) and
the cerebral blood volume (Figure 3-5C) throughout the entire left middle cerebral artery territory.
Consequently, the patient was taken to the angiographic suite and underwent successful recanalization
of the left middle cerebral artery by means of a retrievable stent (Figures 3-5D and 3-5E). She experienced
great clinical improvement over the subsequent 3 days. Follow-up CT scan is shown in Figure 3-5F. At
3 months, she had regained full function.

FIGURE 3-5 Imaging of the patient in Case 3-3. A, CT angiogram showing occlusion of the left middle cerebral artery (arrow);
collateral flow distal to the occlusion was satisfactory. B, Cerebral blood flow image of the CT perfusion
disclosing hypoperfusion throughout the left middle cerebral artery distribution. C, Cerebral blood volume
image of the CT perfusion showing no definite areas of established infarction. D, Digital subtraction angiogram confirming
the presence of an occlusive/subocclusive clot in the proximal left middle cerebral artery. E, Angiographic run after full
reperfusion following treatment with a retrievable stent. F, On follow-up CT scan 24 hours later, a relatively small infarction in
comparison with the initial region of hypoperfusion in the left basal ganglia and internal capsule is seen (arrow).

Comment. Wake-up strokes and strokes of unclear time of onset are particularly problematic because
these cases were not included in the trials supporting IV thrombolysis or mechanical thrombectomy.
Yet, patients with small infarct core and large penumbra can be good candidates for acute reperfusion
therapy. This is one of the situations in which the use of penumbral imaging (CT perfusion or MR
diffusion/perfusion) can be invaluable to identify good candidates for treatment. Ongoing trials should
be able to establish the best strategy for treatment of stroke with uncertain time of onset.

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 KEY POINTS
in a professional driver). Improving pontine or cerebellar infarction to be h Patients with mild or
deficits that are still disabling at the time reasonable. rapidly improving
of the neurologic evaluation may simi- strokes who present
larly warrant thrombolysis. The value of FUTURE DIRECTIONS within the time window
IV rtPA within 3 hours of symptom Current efforts are focused on increas- for IV thrombolysis and
onset in patients with mild (NIHSS ing the efficiency of systems of care and still have disabling
score of 5 or less) or rapidly improving investigating new strategies for acute symptoms at the time of
deficits is being investigated in the stroke therapy. The common objective the evaluation should
Phase IIIB, Double-Blind, Multicenter is to increase the number of patients probably be offered
Study to Evaluate the Efficacy and Safety with acute ischemic stroke who can treatment with rtPA.
of Alteplase in Patients With Mild Stroke: regain perfusion of the ischemic tissue h Although patients with
Rapidly Improving Symptoms and Neu- before infarction is established. basilar artery occlusion
rologic Deficits (PRISMS) trial.48 Mobile stroke units are rapidly were not included in the
gaining acceptance. These are special randomized controlled
Posterior Circulation Strokes ambulances equipped with a portable trials of IV thrombolysis
or mechanical
Randomized trials of IV thrombolysis CT scanner and digital technology to
thrombectomy, these
and mechanical thrombectomy (ex- enable telecommunication with a
patients should be
cept for very few patients enrolled stroke specialist. They have been shown treated with acute
in The Contribution of Intra-arterial to allow safe initiation of IV throm- reperfusion therapies
Thrombectomy in Acute Ischemic bolysis while en route to the stroke because of their dismal
Stroke in Patients Treated With Intra- center.53 This option, although expen- prognosis if recanalization
venous Thrombolysis [THRACE] trial)30 sive, can be a very welcome solution cannot be achieved.
have been restricted to patients for some heavily populated urban com- h Mobile stroke units have
with anterior circulation strokes. Yet, munities. Dispatchers and paramedics been shown to provide
clinical experience with treating pos- must receive specific stroke education a safe way to start
terior circulation infarctions with these to optimize the efficiency and safety of thrombolysis in the
therapies exists. Basilar artery occlu- these mobile units. prehospital setting.
sions can be devastating unless recan- Ways to extend the therapeutic win-
alization is achieved. Registry data dow (beyond 4.5 hours for IV therapy
indicate that IV rtPA49 and mechanical and 6 hours for mechanical thrombec-
thrombectomy50 can result in func- tomy) are being actively investigated.
tional independence at 3 months in Using more fibrin-specific fibrinolytic
30% to 40% of cases; these rates of agents has been considered a promis-
favorable outcome are clearly greater ing option for years. Trials using
than those reported without reper- desmoteplase showed no benefit,54
fusion therapy.51 The value of endo- but tenecteplase is still being studied.55
vascular therapy for acute basilar Radiologic identification of patients
occlusion is currently being investi- with better collateral flow resulting
gated in the Basilar Artery International in persistently salvageable tissue is
Cooperation Study (BASICS).52 Even broadly considered a reasonable,
among patients who are treated with albeit still unproven, approach. Se-
reperfusion strategies, mortality re- lection of candidates using perfusion
mains high (30% to 35%).49,50 There- imaging modalities is being tested in
fore, many consider extending the ongoing trials (DAWN, DEFUSE 3, and
therapeutic window for IV thromboly- MR WITNESS).43,45,46
sis beyond 4.5 hours and for mechan- Collateral flow augmentation is an-
ical thrombectomy far beyond 6 hours other proposed strategy. In current
in patients with basilar artery occlusion practice, this is sometimes attempted
who do not have a large established with vasopressors. Evidence is restricted

Continuum (Minneap Minn) 2017;23(1):62–81 ContinuumJournal.com 77

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

 Acute Ischemic Stroke

to small case series and one pilot should be given unless a solid contra-
feasibility study.56 Yet, hemodynamic indication exists.
augmentation with vasopressors can At this juncture, efforts should be
occasionally work, in particular in pa- concentrated on refining systems of
tients with proximal vessel occlusions care to allow more patients to have
who are not deemed candidates for access to reperfusion treatment. Ex-
endovascular recanalization or in panding the number of candidates for
whom the recanalization attempt was intervention will require continuous
unsuccessful. Mechanical techniques education of the community to recog-
for collateral recruitment (such as ex- nize signs of stroke, improving the
ternal counterpulsation and intraaortic initial triage of patients with stroke,
inflation devices) have been shown and speeding evaluation and treat-
feasible and safe, but their efficacy ment in the hospital. Ongoing trials
remains to be proven.57 are also evaluating the possibility of
The evolution of emergency treat- extending the therapeutic window by
ment for acute ST-segment elevation using advanced imaging modalities to
myocardial infarction can inform the identify patients in whom good collat-
future of acute stroke therapy from a erals have preserved tissue viability for
proximal artery occlusion. Fibrinolysis a longer time. Collateral augmentation
followed by endovascular therapy was strategies and ultra-early administra-
initially a common practice but was tion of neuroprotective agents may
later abandoned after randomized tri- provide additional treatment venues
als demonstrated that proceeding di- in the future.
rectly to the endovascular intervention
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 Review Article

Diagnosis and
Address correspondence to
Dr Shelagh Coutts, Foothills
Medical Centre, 1403 29th St
NW, C1242, Calgary, AB,
Canada T2N 2T9,
[email protected].
Relationship Disclosure:
Management
Dr Coutts receives
research/grant support from
the Canadian Institutes
of Transient
of Health Research
(CRH-112319), the Heart
and Stroke Foundation of
Canada (G-16-00012585),
Ischemic Attack
and Genome Canada Shelagh B. Coutts, MD, MSc, FRCPC
(143TIA-Penn).
Unlabeled Use of
Products/Investigational
Use Disclosure: ABSTRACT
Dr Coutts reports no disclosure. Purpose of Review: This article reviews the diagnosis, investigation, and recom-
* 2017 American Academy mended management after a transient ischemic attack (TIA) and discusses how to
of Neurology.
make an accurate diagnosis, including the diagnosis of mimics of TIAs.
Recent Findings: Up to a 10% risk of recurrent stroke exists after a TIA, and up to
80% of this risk is preventable with urgent assessment and treatment. Imaging of
the brain and intracranial and extracranial blood vessels using CT, CT angiography,
carotid Doppler ultrasound, and MRI is an important part of the diagnostic assess-
ment. Treatment options include anticoagulation for atrial fibrillation, carotid revas-
cularization for symptomatic carotid artery stenosis, antiplatelet therapy, and vascular
risk factor reduction strategies.
Summary: TIA offers the greatest opportunity to prevent stroke that physicians
encounter. A TIA should be treated as a medical emergency, as up to 80% of strokes
after TIA are preventable.

Continuum (Minneap Minn) 2017;23(1):82–92.

INTRODUCTION rologic signs or symptoms referable

Transient ischemic attack (TIA) and to known cerebral arterial distributions
minor ischemic stroke are associated without direct measurement of blood
with brain dysfunction in a circum- flow or cerebral infarction. It is impor-
scribed area caused by a regional re- tant to note that TIA and stroke repre-
duction in blood flow (ie, ischemia), sent different ends of an ischemic
resulting in either transient or minor continuum from the physiologic per-
observable clinical symptoms. Identi- spective, but clinical management is
fication of ischemia is important as similar. The historical time-based defi-
20% of patients with ischemic stroke nition of TIA was based on full resolu-
present with a TIA in the hours to days tion of all symptoms within 24 hours
preceding the stroke.1,2 Up to 80% of of onset. The time-based definition has
strokes after TIA are preventable; thus, been debated in light of diffusion-
early diagnosis and treatment are key. weighted MRI demonstrating relevant
ischemic lesions in 30% to 50% of
DEFINITION AND CLINICAL patients fulfilling the time-based defi-
DIAGNOSIS nition of TIA (Case 4-1).3,4 It is also
The clinical definitions of TIA and is- relevant that the diagnoses of TIA
chemic stroke are based on focal neu- and minor stroke are commonly used

82 ContinuumJournal.com February 2017

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 KEY POINT

Case 4-1 h Minor ischemic stroke

and transient ischemic
A 57-year-old man presented with
attack should be
a 2-minute episode of left hand
managed similarly.
weakness. During the episode, his
left hand became unusable and he
could not pick anything up; he was
able to lift his arm, although it felt
weak. He was able to walk and talk
normally throughout the episode.
On presentation to the emergency
department, he was completely
back to normal. Head CT and CT
angiogram were normal. However,
the diffusion-weighted MRI
showed a small lesion in the right
hemisphere consistent with his
symptoms (Figure 4-1).
Comment. This case illustrates
that transient neurologic symptoms FIGURE 4-1 Diffusion-weighted MRI
can be associated with evidence of showing restricted
diffusion in the
ischemia on diffusion-weighted right hemisphere.
brain MRI sequences. As many
as 50% of patients clinically
diagnosed with a transient ischemic attack using a time-based definition
have evidence of restricted diffusion on an acute MRI scan.

interchangeably and recorded as such nitions of stroke and TIA is that they
in medical records. Although this article rely on the presumed cause of the symp-
focuses primarily on TIA, a significant toms: ischemia. Symptoms are attrib-
difference in the outcome of TIA com- uted to ischemia based mainly on the
pared to minor ischemic stroke has not time course of the deficits (an acute
been demonstrated by compelling evi- deficit is more consistent with ische-
dence. Treatment to prevent ischemic mia), the distribution of the deficits,
stroke following TIA and treatment to and background risk factors for ische-
prevent recurrent stroke following mia in the patient. Because patients
minor ischemic stroke are also similar. vary in reliability in reporting the events
Very early assessment of these patients they have experienced, even an astute
also makes the distinction between TIA physician may find it challenging to
and minor ischemic stroke difficult. make a certain diagnosis based on the
The diagnosis of TIA depends on history and physical examination alone.
the quality and quantity of information Even experts do not agree about which
available and the time of assessment. clinical events are in fact TIAs.5Y7
The main criteria used are the clinical One of the problems with assessment
history or objective findings on neuro- is that half of all patients presenting to
logic examination consistent with focal emergency departments and physicians’
neurologic dysfunction at some point offices in North America with transient
of the evaluation and imaging of the or mild neurologic deficits have symp-
brain. A limitation of the clinical defi- toms with an uncertain diagnosis or

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 Transient Ischemic Attack

KEY POINT
h Making the correct prognosis. Some have, indeed, had an Although the proportion of patients
diagnosis of transient ischemic event, but others have had with true ischemia is lower in those
ischemic attack is key, symptoms related to a stroke or TIA without motor or speech symptoms,
as 50% of patients mimic, such as migraine, epilepsy, multi- it is important not to miss patients
assessed for possible ple sclerosis, or peripheral nerve en- with true TIAs and minor ischemic
transient ischemic trapment (Case 4-2). The prevalence strokes.10,11
attack will have an of these mimics is higher among clin-
alternative diagnosis ical presentations without motor and TAKING A HISTORY FROM A
(ie, are a mimic). speech symptoms. Motor and speech PATIENT WITH A POSSIBLE
symptoms may have a higher likeli- TRANSIENT ISCHEMIC ATTACK
hood of brain ischemia as the cause The diagnosis of TIA remains largely
of the symptoms because the differ- clinical and is based on taking an
ential diagnosis for such clinical pre- accurate history. This contributes to
sentations is much narrower, and the variability in the diagnosis of TIA,
patients who present with motor or with high rates of disagreement seen
speech symptoms are known to be at even between neurologists.5 As many
high risk for recurrent stroke.8 However, as 60% of patients referred to a TIA
patients who present with symptoms clinic will not have a final diagnosis
other than motor and speech symp- of TIA.12,13 Identification of possible
toms (eg, sensory symptoms or dizzi- TIA mimics is an important stage in
ness) have a more uncertain etiology.9 the assessment of patients with tran-
This is likely related to the higher sient neurologic symptoms. An accu-
probability of a nonischemic cause of rate diagnosis of a stroke mimic impacts
symptoms in these patients. Posterior treatment decisions and provides reas-
circulation ischemia can pose an ad- surance when the diagnosis is some-
ditional diagnostic challenge as symp- thing more benign than TIA.
toms are more variable than those that The clinical history is most accurate
occur with hemispheric ischemia.10 when taken close to the resolution of

Case 4-2
A 75-year-old man presented to the emergency department after
experiencing a 10-minute episode of right hand weakness 2 hours earlier,
after which he completely returned to normal. He had no significant
past medical history and was on no medications. Neurologic examination
was normal. Urgent brain CT showed a left-sided chronic subdural
hematoma. He was referred for neurosurgical assessment.
Comment. Many different mimics of transient ischemic attack exist, as in
this case. Hemorrhage is a rare, but important, cause of transient neurologic
symptoms. This case highlights the recommendation that all patients with
transient neurologic symptoms should have brain imaging not only to look
for ischemia but also to look for other causes of transient neurologic
symptoms. It also emphasizes the fact that clinically one cannot reliably
diagnose brain hemorrhage; brain imaging is necessary to differentiate
between ischemia and hemorrhage. Subdural hematomas are common in
the elderly and may occur spontaneously without a history of trauma. The
mechanism behind why subdural hematomas can present with transient
neurologic symptoms is not entirely clear, but theories include mechanical
compression of vessels, partial seizures, or spreading cortical depression.

84 ContinuumJournal.com February 2017

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 KEY POINT
the event. Accuracy is also best when the exception of symptomatic large h Atrial fibrillation is a
the patient first reports symptoms com- vessel occlusive disease, recurrent ste- common cause of
pared to the history obtained after the reotyped events raise the possibility of transient ischemic attack
patient has provided multiple itera- an alternative diagnosis (eg, seizure). and ischemic stroke.
tions to medical personnel.
A TIA is a clinical syndrome charac- INVESTIGATIONS
terized by the sudden onset of a focal A full neurologic and cardiac exami-
neurologic deficit presumed to be on nation should be completed on all
a vascular basis. As the definition patients with suspected TIA. Blood
implies, key points of the history need pressure, pulse rate, and oxygen satu-
to be elicited from the patient. Imaging ration should be obtained, and an ECG
can support the diagnosis, but TIA is should be performed to evaluate for
primarily a clinical diagnosis. Descrip- atrial fibrillation. Many patients will also
tors such as ‘‘numb,’’ ‘‘dead,’’ ‘‘heavy,’’ require an echocardiogram and some
or ‘‘weak’’ may have different mean- form of extended cardiac monitoring
ings for different patients and require if no definitive cause is found for the
clarification, similar to the different TIA. For more information about as-
meanings patients may have for ‘‘dizzy.’’ sessment for a cardiac source of emboli,
The most important clinical determina- refer to the article ‘‘Cardioembolic
tion is whether the neurologic symp- Stroke’’ by Cumara B. O’Carroll, MD,
toms are focal or nonfocal. Regional MPH, and Kevin M. Barrett, MD, MSc,14
cerebral ischemia causes focal symp- in this issue of Continuum.
toms. Focal neurologic symptoms usu- Routine blood work should also be
ally affect one side of the body (eg, completed on all patients, including:
weakness or sensory abnormality on & Complete blood count to measure
the right or left side). Nonfocal neuro- total hemoglobin and screen for
logic symptoms include generalized anemia or erythrocytosis as a cause
weakness, light-headedness, fainting, of TIA. Platelet count is relevant
blackouts, and bladder or bowel symp- as thrombocytosis is a potential
toms. Although patients with the cause of TIA.
nonfocal symptoms of syncope or & Coagulation screen (partial
presyncope are sometimes referred thromboplastin time, international
for assessment of possible TIA, loss of normalized ratio [INR]) as, rarely,
consciousness is only very rarely a disorders of coagulation can
symptom of stroke or TIA. present as a TIA. In specific clinical
After clarifying the patient’s symp- circumstances, more detailed
toms, the circumstances of the event screening bloodwork, including
should be determined. What was the a thrombophilia screen, may
patient doing at the time? Have the be advised.
symptoms occurred before? Was & Blood glucose, as hypoglycemia
the onset sudden or gradual? A vascu- and hyperglycemia are important
lar event usually has a sudden onset, potential mimics of a TIA.
with the deficit being maximal at the Hypoglycemia, in particular, needs
time of onset. A slow gradual migra- to be recognized and treated quickly.
tion of symptoms from one body part Fasting lipids and glucose need to
to another is frequently a symptom of be assessed as well, but these are often
a migrainous event. Whether or not obtained after the first visit. Although
the symptoms have happened before most patients will have a single diag-
is an important consideration. With nosis, diagnostic tests such as ECG and

Continuum (Minneap Minn) 2017;23(1):82–92 ContinuumJournal.com 85

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

 Transient Ischemic Attack

KEY POINT
h All patients with possible oxygen saturation can be useful to iden- rospectively recorded clinical features
transient ischemic attack tify the occasional patient who has of TIA associated with a higher risk of
require structural two concurrent diagnoses, such as TIA stroke are motor or speech symptoms
imaging of the brain to and pulmonary embolus or a myocar- and long duration. The total ABCD2
rule out mimics. dial infarction. score ranges from 0 to 7, with points
After basic investigations are com- given for five clinical factors: (1) age
pleted, brain imaging is key. In many 60 or older (1 point); (2) blood pres-
parts of the world, the first point of sure 140/90 mm Hg or higher (1 point);
assessment for patients with possible (3) clinical features of unilateral weak-
TIA is the emergency department; in ness (2 points) or speech impairment
this setting, a noncontrast CT scan of without weakness (1 point); (4) dura-
the brain is usually the first imaging tion of symptoms 60 minutes or more
study obtained. This is a key investi- (2 points) or 10 to 59 minutes (1 point);
gation as it rules out structural causes and (5) presence of diabetes mellitus
for the symptoms, such as subdural (1 point). The ABCD2 score was well
hematoma (Case 4-2), intracranial hem- validated on independent cohorts
orrhage, or brain tumor. with areas under the curve of 0.62 to
0.83 (0I5 = chance prediction and
PROGNOSIS 1I0 = perfect prediction). More im-
About 10% of patients presenting with portant, this score allowed stratifica-
TIAs or minor strokes will have a stroke tion of patients into high risk (score 6
within the next 90 days,8,15,16 with or 7, 8.1% 2-day risk of stroke), mod-
the highest risk period being the first erate risk (score 4 or 5, 4.1% 2-day risk
24 hours.17 Wide consensus exists that of stroke), and low risk (score 0 to 3, 1%
TIA and minor ischemic stroke are 2-day risk of stroke).
medical emergencies that necessitate The ABCD2 score has emphasized
immediate management.18 that taking a detailed history is impor-
tant, and it has raised awareness
Clinical/Event Features within the general medical community
and Scores that recognizing TIA is an important
Certain clinical features have been as- way of preventing stroke. However,
sociated with recurrent stroke after TIA. the problem with the ABCD2 score is
These include diabetes mellitus,8 hy- that patients in the low-risk category
pertension,19,20 symptom duration, and still have recurrent strokes.22 Also, in
weakness or speech disturbance.8,20 terms of absolute numbers, the majority
Using a combination of factors, clinical of recurrent strokes are in the moderate
risk stratification tools have been de- category. Some patients who are classi-
veloped to help identify patients at fied as having low risk on the ABCD2
high risk of recurrent events, includ- score may have important potentially
ing the California,8 ABCD (age, blood treatable TIA etiologies, such as symp-
pressure, clinical features, duration),20 tomatic carotid artery stenosis or atrial
and ABCD2 (which adds the presence fibrillation, that require urgent treat-
of diabetes mellitus to the factors mea- ment.23 These limitations have pre-
sured in ABCD)21 scores,with the aim vented widespread adoption of the
of determining the need for urgent ABCD2 score to triage patients with TIA.24
hospitalization and investigation. These The Rotterdam Study25 followed
scores were mostly developed with ret- patients with transient neurologic at-
rospective data. From these studies,8,20 tacks for 10 years and found an
it was determined that the major ret- increased risk of stroke not only in
86 ContinuumJournal.com February 2017

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

 KEY POINT
patients with focal symptoms (ie, pos- normal imaging being assessed as out- h Urgent imaging using
sible TIAs) but also in patients who had patients.29 Other modalities for imaging CT/CT angiography can
transient episodes of nonspecific cervicocephalic vessels, such as mag- identify patients at high
symptoms. It is likely that these pa- netic resonance angiography (MRA), risk for recurrent stroke.
tients represent a heterogeneous are also acceptable. Carotid duplex
group with variable risk of recurrent ultrasound is an additional noninva-
stroke. It is therefore timely for the sive modality commonly used to eval-
neurologic community to progress be- uate for hemodynamically significant
yond the ABCD2 score to improve our carotid occlusive disease at the bifur-
ability to define the clinical outcome of cation. Identification of high-grade
patients on an individual basis. Poste- stenosis in the carotid artery ipsilateral
rior circulation events, in particular, to retinal or hemispheric symptoms
can cause nonspecific symptoms.26 may be indicative of stroke mecha-
nism and near-term stroke risk. Carotid
Imaging and Prognosis ultrasound does not adequately evalu-
Evidence of an acute infarct on a ate the carotid circulation beyond the
noncontrast CT alone has been shown bifurcation (ie, distal cervical and in-
to be predictive of recurrent stroke in tracranial segments), and additional
patients with TIA (ie, patients whose vascular imaging modalities may be
symptoms had resolved), although the necessary when the index of clinical
proportion of patients with evidence suspicion is high for vertebrobasilar or
of acute infarcts was small (4%).27 Pa- intracranial occlusive disease.
tients with minor ischemic stroke and Brain imaging using MRI is a very
TIA who are at the highest risk of re- sensitive way of assessing for brain is-
current events and disability can be chemia. Diffusion-weighted imaging
identified using noninvasive CT angi- (DWI), which shows the abnormal dif-
ography (CTA).28 CTA is a quick and fusion of water in the setting of focal
easy addition to the noncontrast CT brain ischemia, is the most helpful se-
that is completed on most patients and quence. Up to 50% of patients clinically
provides much more information than diagnosed with a TIA using a time-
a noncontrast CT alone, with imaging of based definition have evidence of re-
the intracranial and extracranial vessels. stricted diffusion on an acute MRI scan.
The addition of better imaging tech- Most studies of recurrent stroke after
niques, such as multiphase CTA and TIA have shown an increased risk of
CT perfusion, provides the ability to short-term recurrent stroke in the pres-
identify more distal occlusions than ence of a lesion seen on DWI. How-
previously. Evidence of 50% or greater ever, the exact magnitude of the risk
stenosis or occlusion in a symptom- depends on the population studied.
relevant vessel in the intracranial or Whether the presence or absence of a
extracranial circulation puts a patient lesion on DWI changes the longer-term
at high risk of a recurrent stroke.28 (1- to 5-year) risk of stroke is less clear.
Understanding the pathophysiology of The lesion pattern on an MRI can
a TIA or minor ischemic stroke is par- change the vascular localization in up
amount to preventing recurrent stroke. to one-third of patients. Infarct topog-
Using CT/CTA to assess patients in the raphy can also be useful to inform
emergency department has allowed stroke mechanism (eg, involvement of
many patients to be safely triaged, with more than one vascular territory being
patients with abnormal CT/CTA admit- suspicious for a proximal embolic
ted for observation and those with source such as atrial fibrillation).
Continuum (Minneap Minn) 2017;23(1):82–92 ContinuumJournal.com 87

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

 Transient Ischemic Attack

KEY POINTS
h Although the presence Many stroke neurologists find MRI tients get the appropriate early assess-
of a lesion seen on particularly helpful in cases in which ment and treatment (Table 4-130).
diffusion-weighted the diagnosis is not 100% clear based
imaging can be helpful on the history. MRI results must TREATMENT
by proving that ischemia always be taken in the appropriate Recognition and management of TIA
occurred, the absence clinical context. Most stroke neurolo- offers the greatest opportunity to pre-
of a lesion does not rule gists would agree that patients who vent disabling stroke. Studies have
out ischemia. have a negative DWI but have truly shown up to an 80% reduction in the
h Finding out why a had TIAs clearly exist, and thus they risk of stroke after TIA with the early
transient ischemic will treat patients for TIA even with a implementation of secondary stroke
attack occurred is the negative DWI. There has been some prevention strategies,11,12 including
key to preventing a discussion over the past few years revascularization of patients with
recurrent stroke. about calling transient symptoms a symptomatic carotid artery stenosis,
h Recognition and clinical TIA, but calling symptoms in anticoagulation of patients with atrial
management of combination with a lesion seen on fibrillation, treatment with anti-
transient ischemic attack DWI a stroke. From a practical per- platelet agent(s), treatment with
offers the greatest spective, it does not matter what it is statins for most patients, manage-
opportunity to prevent called; what is important is that pa- ment of hypertension, and lifestyle
disabling stroke.

TABLE 4-1 Clinical and Imaging Features That Increase the Risk
of a Recurrent Stroke or Symptom Progression After
Transient Ischemic Attack or Minor Strokea

High Risk Low Risk

Feature
Timing Hours ago Weeks ago
Age (years) 960 G45
Blood pressure at presentation (mm Hg) 9140/90 G140/90
Diabetes mellitus Yes No
Symptoms Speech, weakness Dizziness,
numbness
Duration (minutes) 960 G10
Frequency of events One or few Many
Degree of clinical improvement Vanishing severe Improving
deficit mild deficit
Intracranial stenosis Severe None
Extracranial stenosis Present Absent
Intracranial occlusion Present Absent
Diffusion-weighted imaging lesion Multiple greater None
than single
Transcranial Doppler emboli detection 950 None
(microembolic signals/hour)
a
Modified with permission from Couillard P, et al, Expert Rev Cardiovasc Ther.30 B 2009 Taylor & Francis.
tandfonline.com/doi/full/10.1586/erc.09.105.

88 ContinuumJournal.com February 2017

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interventions, such as smoking ces- All patients with TIAs should be
sation or weight loss. on an antiplatelet agent, except for
Early carotid revascularization for pa- those who are being anticoagulated
tients with 50% or greater symptomatic for atrial fibrillation. For most pa-
carotid artery stenosis is an effective tients, it will be a single antiplatelet
form of stroke prevention when per- agent, usually aspirin monotherapy
formed within the first 2 weeks after (81 mg/d to 325 mg/d). Other op-
an event. If a patient is stable, surgery tions include 75 mg/d clopidogrel or
should be performed as soon as pos- a combination of 25 mg aspirin and
sible (Case 4-3). It is important to iden- 200 mg extended-release dipyridamole
tify carotid stenosis because, although 2 times a day.29
it causes only 10% of all TIAs, it causes Two randomized clinical trials have
50% of early recurrences. It is a treatable provided evidence for the short-term
condition, and it is tragic when a re- use of dual antiplatelet therapy after
current stroke occurs in someone wait- TIA and minor ischemic stroke. The Fast
ing for a carotid endarterectomy. Assessment of Stroke and Transient

Case 4-3
A 50-year-old man presented to the emergency department with an episode
of left hemiplegia that lasted 5 minutes. He smoked cigarettes but otherwise
had no significant past medical history. His examination was normal, with
blood pressure of 125/75 mm Hg and an ABCD2 (age, blood pressure, clinical
features, duration,
presence of diabetes
mellitus) score of 2.
Head CT was normal,
but CT angiography
showed a high-grade
stenosis of the right
internal carotid artery
(Figure 4-2). He was
started on 81 mg aspirin
and 40 mg of simvastatin
daily. The patient
underwent right carotid
endarterectomy the
next day without
complication.
Comment. This
patient had a transient
ischemic attack and was
at high risk of early FIGURE 4-2 CT angiogram demonstrating
recurrent stroke, although high-grade right internal carotid artery
stenosis (red arrow).
it was not identified as
such by the ABCD2 score.
Carotid artery stenosis is an important cause of a transient ischemic attack
with a high risk of recurrence. Early vascular imaging is required to
identify this treatable cause of stroke. Carotid revascularization should be
performed as soon as reasonably possible if the patient is medically stable.

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 Transient Ischemic Attack

Ischemic Attack to Prevent Early Re- medical management alone. The study
currence (FASTER) trial compared the results showed aggressive medical man-
effectiveness of 3 months of treat- agement alone was superior to stent-
ment with 81 mg aspirin and 75 mg ing in the prevention of recurrent
clopidogrel commenced within 24 hours stroke. Medical management included
of onset versus aspirin alone in pa- 325 mg aspirin and 75 mg clopidogrel
tients with minor strokes/TIAs.31 This for 90 days, together with intensive
trial was small and ended early because medical management of modifiable
of slow recruitment; however, there was vascular risk factors. Medical manage-
a suggestion that the combination ther- ment was superior to stenting because
apy may reduce recurrent stroke events of a combination of higher than ex-
with a low risk of complications. The pected periprocedural risk and a lower
Clopidogrel in High-risk Patients With recurrence rate in the medical man-
Acute Non-disabling Cerebrovascular agement arm. Both arms received dual
Events (CHANCE) trial32 was performed antiplatelet therapy, so it is not known
in China and randomly assigned 5170 if the combination of aspirin and clo-
high-risk patients with TIA (defined pidogrel reduced the recurrent stroke
as an ABCD2 score of 4 or higher at risk; however, the National Institutes
assignment) and minor stroke to treat- of Health (NIH)-sponsored Platelet-
ment within 24 hours of onset with Oriented Inhibition in New TIA and
either combination therapy with clo- Minor Ischemic Stroke (POINT) trial34
pidogrel and aspirin (clopidogrel is examining this question and is cur-
at an initial dose of 300 mg, followed rently enrolling patients. It is hoped
by 75 mg/d for 90 days, plus aspirin at that this study will provide a definitive
a dose of 75 mg/d for the first 21 days) answer. For now, North American sec-
or placebo plus aspirin (75 mg/d for ondary stroke prevention guidelines
90 days). Recurrent stroke was seen do not recommend dual antiplatelet
in 8.2% of patients in the clopidogrel- agent therapy.29
aspirin group, as compared with 11.7%
of those in the aspirin-only group Outpatient Versus Inpatient
(hazard ratio, 0.68; 95% confidence Assessment
interval, 0.57Y0.81; PG.001). The risk For stroke prevention, the location of
of hemorrhage was not different in treatment matters less than the speed
the two groups. The CHANCE trial has of the assessment. However, in most
issues with generalizability, including parts of the world, assessing patients
the fact that it was a Chinese-only pop- and completing urgent (on the same
ulation, a high proportion of males were day, within a few hours) imaging is most
included, and the proportion of pa- easily done in the emergency depart-
tients treated with antihypertensive and ment given the easy access to imaging.
lipid-lowering medications was less In clinical settings that do not have
than typically seen in North American access to timely outpatient neuroimag-
populations. In the Stenting vs. Aggres- ing, patients are often admitted to the
sive Medical Management for Preven- hospital to complete TIA evaluation and
ting Recurrent Stroke in Intracranial expedite initiation of secondary pre-
Stenosis (SAMMPRIS) study,33 patients vention strategies. Some advantages
with recently symptomatic severe intra- of admitting the patient to the hospital
cranial stenosis were randomly assigned include close neurologic monitoring
to intracranial stenting plus aggressive and early completion of investigations
medical management or aggressive and appropriate treatment.
90 ContinuumJournal.com February 2017

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CONCLUSION attack fairly low among stroke-trained
neurologists. Stroke; 41(7):1367Y1370.
The assessment of TIA is all about doi:10.1161/STROKEAHA.109.577650.
making the correct diagnosis, and tak- 8. Johnston SC, Gress DR, Browner WS,
ing a good history is key. Once a TIA Sidney S. Short-term prognosis after
diagnosis has been made, cardiac and emergency department diagnosis of TIA.
JAMA 2000;284(22):2901Y2906. doi:10.1001/
neurovascular imaging can help inform jama.284.22.2901.
the potential etiology and guide initia-
9. Johnston SC, Sidney S, Bernstein AL, Gress DR.
tion of evidence-based secondary stroke A comparison of risk factors for recurrent TIA
preventative strategies. Ideally, obtain- and stroke in patients diagnosed with TIA.
ing the history, imaging, and identifying Neurology 2003;60(2):280Y285. doi:10.1212/
01.WNL.0000042780.64786.EF.
the etiology occur on the same day as
presentation to reduce the risk of re- 10. Rothwell PM, Giles MF, Chandratheva A,
et al. Effect of urgent treatment of transient
current cerebral ischemia. ischaemic attack and minor stroke on early
recurrent stroke (EXPRESS study): a prospective
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 Review Article

Prevention and
Address correspondence to
Dr Josephine F. Huang,
4500 San Pablo Rd,
Department of Neurology,

Management of Jacksonville, FL 32224,

[email protected].
Relationship Disclosure:

Poststroke Complications Dr Huang reports no disclosure.

Unlabeled Use of
Products/Investigational
Use Disclosure:
Josephine F. Huang, MD Dr Huang discusses the
unlabeled/investigational use
of tranexamic acid and
ABSTRACT *-aminocaproic acid for
intracranial hemorrhage.
Purpose of Review: This article provides a synopsis of the immediate and delayed * 2017 American Academy
medical complications of stroke, with an emphasis on prevention and management of Neurology.
of these complications.
Recent Findings: Meta-analysis of the trials for endovascular treatment of acute
stroke shows no significant increase in hemorrhagic events. Rehabilitation guidelines
published by the American Heart Association and American Stroke Association in 2016
aid in providing the best clinical practice for patients with stroke, from the time of their
initial hospitalization to their return to the community.
Summary: Medical complications from stroke are common and are associated with
poor clinical outcomes, increased length of hospital stays and higher rates of read-
mission, increased cost of care, delayed time to rehabilitation, and increased mortality.
Being cognizant of the common complications encountered, taking appropriate mea-
sures to prevent them, and knowing how to manage them when they do occur are
essential to the continued care of patients with stroke.

Continuum (Minneap Minn) 2017;23(1):93–110.

INTRODUCTION following the event are frequently

Medical complications following acute encountered in the hospital setting.
ischemic stroke are common and are These issues can influence the clini-
associated with poor clinical outcomes, cian’s decision for level of care on ad-
increased length of hospital stay and mission, duration of hospital stay, and
higher rates of readmission, increased hospital disposition.
cost of care, delayed time to rehabili-
tation, and increased mortality.1 While Acute Reperfusion Therapy
the majority of deaths that occur in Orolingual angioedema from IV recom-
the first week after stroke are at- binant tissue plasminogen activator
tributed to the direct effects of the (rtPA) is uncommon, occurring in 1%
ischemic stroke, mortality beyond the to 8% of patients, and is often mild and
first week is largely attributed to med- transient. The risk is increased in pa-
ical complications.2,3 This article dis- tients concurrently taking angiotensin-
cusses measures that should be used converting enzyme inhibitors and in
to reduce the risk and rate of these those with CT findings of ischemia
complications following acute stroke. in the frontal or insular cortices.4
Orolingual angioedema is usually uni-
EARLY COMPLICATIONS lateral and affects the tongue and lips
Sequelae from acute ischemic stroke contralateral to the ischemic hemi-
occurring in the initial days to weeks sphere. Angioedema and anaphylaxis

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 Poststroke Complications

KEY POINT
h Angioedema resulting have been reported up to 2 hours 2, with more confluent but still hetero-
from use of recombinant following IV rtPA infusion, and swell- geneous petechiae within the infarct;
tissue plasminogen ing can develop gradually over several (3) parenchymal hematoma 1, with a
activator often involves hours. In cases of life-threatening an- homogeneous hematoma involving
the unilateral tongue and gioedema, laryngospasm, and hypo- less than 30% of the infarct volume
lips contralateral to the tension, the infusion should be and with mild space-occupying effect;
side of the infarct. It is stopped immediately and the patient and (4) parenchymal hematoma 2, with
often mild and transient, treated with antihistamines, IV corti- a dense hematoma involving more
but in severe cases, costeroids, epinephrine, and endotra- than 30% of the infarct volume with
IV recombinant tissue cheal intubation for airway protection significant space-occupying effect
plasminogen activator
as clinically indicated. Favored treat- (Table 5-1). Hemorrhagic infarction 1,
should be stopped
ment is 50 mg IV diphenhydramine, hemorrhagic infarction 2, and paren-
immediately and
anaphylaxis
50 mg IV ranitidine, and 10 mg IV chymal hematoma 1 within the first
appropriately treated. dexamethasone. In severe cases or as 36 hours of stroke onset were not
clinically indicated, 0.3 mg IM epi- associated with a higher risk of neu-
nephrine can be added.5 Short-term rologic decline when compared to
maintenance doses of corticosteroids patients without hemorrhagic trans-
and antihistamines can be considered formation. Parenchymal hematoma 2
in cases of severe edema that fail to is associated with a significantly in-
promptly respond to the first doses creased risk of early deterioration and
of medications. 3-month mortality.
In the National Institute of Neuro- Most symptomatic intracranial hem-
logical Disorders and Strokes (NINDS) orrhages occur within the first 24 hours
trial, symptomatic intracranial hemor- following treatment. When intracranial
rhage was defined as hemorrhage seen hemorrhage is suspected, the adminis-
on CT within 36 hours of treatment, tration of thrombolytics should be
and deemed to be temporally related stopped until intracranial hemorrhage
to neurologic decline.6 Symptomatic is excluded. Once intracranial hemor-
intracranial hemorrhage occurred in rhage is confirmed on imaging, an
6.4% of patients treated with IV rtPA. initial dose of 10 units of cryopre-
The European Cooperative Acute cipitate should be transfused.9,10 If
Stroke Study (ECASS) III trial defined cryoprecipitate is contraindicated or
symptomatic intracranial hemorrhage unavailable in a timely fashion, consid-
as evidence of hemorrhage seen on CT eration can be made to use an anti-
or MRI that was felt to be associated fibrinolytic agent, such as IV tranexamic
with an increase in the National In- acid 10 mg/kg to 15 mg/kg over
stitutes of Health Stroke Scale (NIHSS) 20 minutes or IV *-aminocaproic acid
score of 4 or more points.7 Symptom- 5 g.10 Fibrinogen levels can be checked
atic intracranial hemorrhage occurred after administering reversal agents; if
in 2.4% of patients treated with IV rtPA the level is less than 150 mg/dL, addi-
in the extended treatment time window tional cryoprecipitate can be given.
of 3 to 4.5 hours. The benefit of using other agents, such
Figure 5-1 demonstrates the sub- as prothrombin complex concen-
types of hemorrhagic transformation trate, fibrinogen, platelets, or fresh
defined by the ECASS I investigators.8 frozen plasma, is unknown, and further
The four subtypes are: (1) hemorrhagic studies are warranted. Surgical inter-
infarction 1, with scattered heteroge- vention can be considered in select
neous petechiae along the margins of patients when the rtPA has been ade-
the infarct; (2) hemorrhagic infarction quately reversed. Case 5-1 provides an

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 FIGURE 5-1 Subtypes of hemorrhagic transformation. A, Hemorrhagic infarction 1, B,
hemorrhagic infarction 2, C, parenchymal hematoma 1, and D, parenchymal
hematoma 2.
Reprinted with permission from Berger C, et al, Stroke.8 B 2001 American Heart Association,
Inc. stroke.ahajournals.org/content/32/6/1330.full.

example of the evaluation and treatment use, thrombocytopenia, leukoaraiosis

of suspected symptomatic intracranial (cerebral white matter disease), and
hemorrhage. persistent arterial occlusion after IV
The risk of hemorrhage following rtPA infusion.11 However, given the
administration of IV rtPA is increased low rate of hemorrhage and higher
in patients with higher stroke severity potential for improved outcomes with
and older age. Other factors associated thrombolytic therapy, these factors do
with an increased risk of symptomatic not preclude the patient from receiv-
hemorrhage include heart failure, is- ing treatment. Care must be taken to
chemic heart disease, atrial fibrillation, follow posttreatment protocols to min-
hyperglycemia, diabetes mellitus, renal imize the risk of hemorrhage.
impairment, hypertension in the first The Highly Effective Reperfusion
24 hours, preceding antithrombotic Evaluated in Multiple Endovascular
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 Poststroke Complications

TABLE 5-1 Hemorrhagic Transformation Subtypes

Subtype CT Findings
Hemorrhagic 1 Heterogeneous petechiae along the infarct margins
infarction 2 More confluent heterogeneous petechiae within
the infarct
Parenchymal 1 Homogeneous hematoma involving G30% of the infarct
hematoma volume; mild space-occupying effect
2 Homogeneous hematoma involving 930% of the infarct
volume; significant space-occupying effect
CT = computed tomography.

Case 5-1
A 77-year-old man with hypertension, type 2 diabetes mellitus, and obesity
presented to the emergency department at 10:38 AM with acute onset
of left-sided weakness that occurred at 9:45 AM. Examination revealed
a mild left hemiparesis with severe left-sided sensory loss and neglect, with
a National Institutes of Health Stroke Scale (NIHSS) score of 9. His wife
reported he was taking a daily aspirin 81 mg and had no history of
anticoagulant use. Head CT showed no evidence of intracranial hemorrhage
or early ischemic changes. His presenting blood pressure was 210/98 mm Hg,
which was controlled and maintained below 180/105 mm Hg with a nicardipine
infusion. IV recombinant tissue plasminogen activator (rtPA) was administered
at 11:17 AM. CT angiogram showed occlusion of a distal left M2 branch of
the middle cerebral artery and thrombi in several distal M3 branches, but no
proximal large vessel occlusion was identified that would be amenable to
thrombectomy. After returning from the CT angiogram, the patient began
grimacing and held his head with his right hand. At 11:42 AM , his nurse then
noted that his left facial droop had worsened and the patient seemed more
confused and lethargic. Upon reexamination, he was noted to have a dense
left hemiplegia with right gaze deviation. He was no longer arousable to vocal
stimulus, and his repeat NIHSS score was 20. The IV rtPA infusion was
stopped and a repeat head CT was performed, which demonstrated a 32 mL
intraparenchymal hematoma in the right frontoparietal lobe with mass
effect and midline shift. A complete blood cell count, prothrombin time,
international normalized ratio (INR), activated partial thromboplastin
time, fibrinogen, D-dimer, and type and screen were drawn. The
patient was intubated, cryoprecipitate was started, and neurosurgery
was called.
Comment. In this case, the patient had neurologic deterioration
secondary to suspected intracranial hemorrhage, and the IV rtPA was
stopped immediately. Airway, breathing, and circulation must be continuously
addressed as a patient’s clinical decline can be rapid. Cryoprecipitate is
recommended to restore decreased fibrinogen levels, but no study has been
conducted to establish the optimal way to treat post-rtPA hemorrhage;
further studies are warranted.

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Stroke (HERMES) meta-analysis of Patients at the highest risk for devel-
pooled data of 1287 patients from five oping malignant cerebral edema are
randomized trials of endovascular those who have an identified large
thrombectomy of large vessel occlu- vessel occlusion of the terminal inter-
sions showed no significant difference nal carotid artery or proximal middle
in rates of symptomatic intracranial cerebral artery with a large infarct
hemorrhage between those who un- volume (Case 5-2).19Y21 Head CT with
derwent thrombectomy and patients frank hypodensity within 6 hours of
who received standard care.12 stroke onset, infarct in one-third or
A single-center retrospective study more of the middle cerebral artery
of patients with acute ischemic stroke territory, or midline shift of 5 mm or
who underwent thrombectomy with more in the first 2 days are predictive
stent retriever between 2010 and 2012 of malignant edema and poor out-
demonstrated that a low baseline comes.22Y25 Diffusion-weighted MRI
Alberta Stroke Program Early CT Score volume of 80 mL or more within
(ASPECTS) independently predicted 6 hours of stroke onset is predictive
symptomatic intracranial hemorrhage of a rapid fulminant course toward
at 24 hours (5.0 versus 6.9).13 It also malignant edema.20,26
found that the independent factors of An NIHSS score greater than 20
atrial fibrillation on admission and in dominant hemispheric strokes or
hemodynamic instability during the greater than 15 in nondominant hemi-
procedure were associated with intra- spheric strokes has been associated
cranial hemorrhage at 24 hours. with malignant infarction, but the
scores alone have low specificity in
Malignant Cerebral Edema predicting the development of a ma-
An estimated 5% to 10% of patients lignant syndrome.22 Other clinical fac-
with ischemic stroke may develop tors associated with edema are early
malignant cerebral edema.14 Neuro- nausea and vomiting, female sex,
logic deterioration is often observed congestive heart failure, and leukocy-
within 72 to 96 hours from onset of tosis22,23 at presentation.
the stroke.15 It is important to iden- Medical management of patients
tify patients who are at high risk of who are at high risk for progression
developing this complication to en- to malignant cerebral edema includes
sure that they are placed under close frequent neurologic examinations to
surveillance at a center with neuro- monitor for neurologic deterioration,
logic critical care and neurosurgery maintenance of normothermia, avoid-
services.16 Frequent neurologic exami- ance of hypercarbia, maintenance of
nations are necessary to monitor for euvolemia while avoiding hypotonic
a decreased level of arousal, which solutions, control of glucose to be-
may be the earliest clinical change in- tween 140 mg/dL and 180 mg/dL, and
dicating symptomatic cerebral edema correction of hyponatremia.16
and thus necessitating medical and Initiation of osmotic therapy is
possible surgical treatment.17 The in- indicated in patients with clinical
creased somnolence can precede pu- and radiographic evidence of swell-
pillary changes and worsened motor ing. Choosing the appropriate os-
function and is attributed to tissue motic therapy may depend on
swelling and shift of the thalamus and individual patient characteristics. Man-
brainstem rather than due to a signifi- nitol can be given at 0.5 g/kg to 1 g/kg
cant increase in intracranial pressure.18 IV every 4 to 6 hours.16 Continued
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 Poststroke Complications

Case 5-2
A 62-year-old man with no known medical history was teaching a class when he suddenly became dizzy
and collapsed without loss of consciousness. On arrival to the emergency department, his neurologic
examination revealed right hemiplegia, left gaze deviation, and mutism. His National Institutes
of Health Stroke Scale (NIHSS) score was 26. Head CT within 40 minutes of symptom onset showed
a hyperdense left middle cerebral artery sign and early ischemic changes in the left hemisphere. He was
given IV recombinant tissue plasminogen activator and transferred to a certified stroke center for
potential thrombectomy. Due to local weather conditions, his transfer was delayed, and a repeat head
CT 4 hours after symptom onset demonstrated early ischemic changes in a larger area of the left
hemisphere. Angiography revealed a distal left M1 occlusion. Postthrombectomy, the M1 was recanalized,
but there were multiple M2 branch occlusions. Repeat head CT the following day showed continued
evolution of the infarct without significant midline shift (Figure 5-2A). His wife was updated with the
results, and the possibility of decompressive craniectomy was discussed in detail. The following
morning, the patient was difficult to arouse, and the repeat head CT demonstrated 7 mm of midline
shift with increasing vasogenic edema (Figure 5-2B). He was taken for emergent decompressive
craniectomy. The postoperative head CT showed improvement of the midline shift (Figure 5-2C).

FIGURE 5-2 Imaging of the patient in Case 5-2. A, Head CT 1 day after stroke shows continued evolution of the infarct
without significant midline shift. B, Repeat head CT the following day shows 7 mm of midline shift with increasing
vasogenic edema. C, Head CT following decompressive craniectomy shows improvement of midline shift.

Comment. In this case, the patient had a proximal large vessel occlusion, large infarct volume
greater than one-third of the left middle cerebral artery territory, and an NIHSS score greater than
20. The presence of these factors indicated the possibility of progression toward malignant edema,
and early discussions with his wife helped to define the goals of care before the patient decompensated
the following day.

treatment can be guided by goal se- result in hypotension and hypo-

rum osmolarity between 310 mOsm/L volemia. Hypertonic saline can be
and 320 mOsm/L or by goal osmolar given in different concentrations, with
gap of less than 10. Potential exists for goal serum sodium of 150 mEq/L to
mannitol toxicity to the renal tubular 155 mEq/L. Use of hypertonic saline
cells, so renal impairment is a rela- can cause volume overload, so it
tive contraindication. Because of its should be used with caution in pa-
diuretic effects, mannitol therapy can tients with heart failure.

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 KEY POINTS
Early discussions should take place Venous Thromboembolism h The peak incidence of
with the neurosurgical team and the The estimated incidence of pulmonary deep venous thrombosis
patient’s medical decision maker re- embolism in the first few months formation is in the first
garding the potential for a decom- following a stroke is between 1% and week after stroke, while
pressive hemicraniectomy.16 A pooled 3%,29 but up to 13% to 25% of early pulmonary embolism is
analysis of three randomized controlled deaths after stroke are due to pulmo- most commonly seen
trials (Decompressive Craniectomy in nary embolism.30 Fatal pulmonary em- in weeks 2 to 4.
Malignant Middle Cerebral Artery In- Prevention of deep
bolism is uncommon in the first week
farcts [DECIMAL], Decompressive Sur- venous thrombosis and
following an acute stroke and most pulmonary embolism
gery for the Treatment of Malignant commonly encountered in weeks 2 to 4. starts with early
Infarction of the Middle Cerebral Artery The development of a deep venous initiation of venous
[DESTINY], and Hemicraniectomy After thrombosis (DVT) may take place as thromboembolism
Middle Cerebral Artery Infarction With early as day 2 after stroke onset, with a prophylaxis.
Life-threatening Edema Trial [HAMLET]) peak incidence between days 2 and 7.30
of patients younger than 60 years of h Patients with stroke
The incidence of DVT in immobile who are at high risk
age demonstrated that the number patients with stroke was between 11% of developing deep
needed to treat for survival with a modi- and 15% of patients within the first venous thrombosis and
fied Rankin Scale (mRS) score of 4 or month of stroke in the Clots in Legs or pulmonary embolism
less was 2 and for survival with an mRS Stockings After Stroke (CLOTS) obser- include those who are
score of 3 or less was 4.27 The results immobilized, dehydrated,
vational study.31 Risk factors for the
demonstrated decreased death and dis- or elderly and those
development of DVT include severity
ability, but no patients had complete who have a history of
of impaired mobility, dehydration, ad-
freedom from disability. DESTINY II malignancy, previous
vanced age, malignancy, prior history deep venous thrombosis,
evaluated decompressive hemicraniec-
of DVT, and clotting disorders.32 Early or clotting disorders.
tomy in patients older than 60 years
mobilization is encouraged in patients
of age,28 demonstrating a significant
who can tolerate activity to decrease the
increase in survival, but most survi-
risk of venous thromboembolism.
vors had significant disability. It is
In patients with stroke with re-
notable that no patients had an mRS
stricted mobility, chemical DVT prophy-
score of 2 or less, and outcomes were
less favorable when compared to laxis should be initiated at the time of
their younger counterparts from the presentation if they do not receive
prior studies. The discussion with thrombolytic therapy. Either subcuta-
family and medical decision makers neous low-molecular-weight heparin
should include realistic expectations or subcutaneous unfractionated hepa-
for level of disability following sur- rin should be started immediately in
gery. Patients younger than 60 years patients without significant risk for
of age who deteriorate within 48 hours bleeding. A systematic review of ran-
due to malignant cerebral edema domized controlled trials comparing
despite medical management should administration of either low-molecular-
be considered for decompressive hemi- weight heparin or unfractionated hep-
craniectomy. Outcomes from decom- arin with controls suggested that
pression at a later time are not known, low-dose low-molecular-weight hep-
but the procedure should be consid- arin provided the best benefit to risk
ered.16 In patients older than 60 years ratio for venous thromboembolism
of age, careful selection of those with prophylaxis, reducing the risk of DVT
excellent prior baseline function and and pulmonary embolism with no sig-
few or no major comorbidities can nificant increase in risk of major hem-
be considered. orrhagic events.33 The PREvention of
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 Poststroke Complications

KEY POINT
h Contraindications to VTE [venous thromboembolism] After leg edema. Aspirin is also reasonable for
unfractionated heparin Acute Ischemic Stroke With LMWH DVT prophylaxis in patients who cannot
or low-molecular-weight [low-molecular-weight heparin] receive heparin or intermittent pneu-
heparin for deep venous Enoxaparin (PREVAIL) study demon- matic compression.9
thrombosis prophylaxis strated a significantly lower rate of Therapeutic anticoagulation is
or therapy for venous thromboembolism without a recommended for patients who are
symptomatic deep significant increase in major hemor- found to have a symptomatic proximal
venous thrombosis or DVT, since pulmonary embolism can
rhagic events in patients treated with
pulmonary embolism occur in 50% of patients if untreated.
include intracranial
40 mg/d enoxaparin versus 5000 IU
unfractionated heparin 2 times a day.34 Untreated acute pulmonary embolism
hemorrhage, recent
A meta-analysis of three randomized has a 30% mortality rate, with most
thrombolytic therapy,
and active extracranial trials demonstrated that low-molecular- deaths occurring within the first few
hemorrhage. Alternatives weight heparin was superior to hours after the initial event due to
include intermittent unfractionated heparin for venous recurrent pulmonary embolism. Risks
pneumatic compression thromboembolism prevention without associated with anticoagulation in-
or aspirin for prophylaxis
a significant difference for rates of in- clude hemorrhagic transformation of
and inferior vena cava ischemic stroke, hematoma expan-
tracranial hemorrhage, overall hemor-
filter or surgical sion or recurrent bleeding in patients
embolectomy for
rhage, or mortality.35
with intracranial hemorrhage, or
symptomatic deep In patients receiving IV rtPA, the
extracranial hemorrhage. These risks
venous thrombosis or initiation of heparin prophylaxis should
must be carefully weighed against
pulmonary embolism. be delayed until 24 hours after throm-
the benefits when considering ther-
bolytic therapy, and the therapy is rec-
apeutic anticoagulation.
ommended to be continued during the In patients who are not suitable
hospitalization or until the patient re- candidates for anticoagulation, inferior
gains mobility.9 vena cava filter placement is an option.
For patients presenting with an in- For large or severe acute pulmonary
tracerebral hemorrhage, intermittent embolism in patients unable to receive
pneumatic compression devices should anticoagulation, catheter or surgical
be used on the day of admission. Once embolectomy is also a treatment op-
the cessation of bleeding is confirmed, tion. For symptomatic distal DVTs,
a low dose of low-molecular-weight anticoagulation can be considered in
heparin or unfractionated heparin can patients who are felt to be at high risk
be considered for patients with re- for proximal extension of the thrombus.
stricted mobility after 1 to 4 days fol- If anticoagulation is not pursued, serial
lowing the event.36 Table 5-2 provides noninvasive vascular imaging can be
examples of DVT prophylaxis in differ- performed to assess for proximal ex-
ent clinical scenarios. tension of the DVT in the first 2 weeks.
For patients with contraindications
for heparin use, intermittent pneumatic Dysphagia and Nutritional
compression devices can be used. The Considerations
use of intermittent pneumatic com- Many patients cannot receive fluids or
pression has been demonstrated to nutrition orally because of dysphagia
be effective in DVT prevention in or impaired mental status. Dysphagia
immobilized patients with stroke. 31 is commonly encountered following
Contraindications to intermittent pneu- stroke, and the risk is increased in
matic compression include peripheral patients who are male; are older than
vascular disease causing leg ischemia, 70 years of age; have had severe
leg ulcerations, dermatitis, and severe stroke; or have impaired pharyngeal

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 KEY POINTS

TABLE 5-2 Deep Venous Thrombosis Prophylaxis in Patients h Aspiration may be

With Stroke prevented with early
dysphagia screening.
Clinical Scenario Timing of Initiation Therapy h Provide adequate
Stroke without On admission Unfractionated heparin 5000 hydration and early
thrombolysis IU every 8Y12 hours OR nutrition in patients
low-molecular-weight heparin who are unable to take
Enoxaparin 40 mg/d SC anything by mouth.
Dehydration carries an
Dalteparin 5000 units/d SC increased risk of deep
Fondaparinux 2.5 mg/d SC venous thrombosis,
while early nutrition
Mechanical prophylaxis with

f
through a nasogastric
intermittent pneumatic
tube is associated with
compression devices on
Stroke with IV 1 day after admission until chemical improved survival.
recombinant tissue thrombolytic therapy prophylaxis can be started, then:
plasminogen activator
Unfractionated heparin
5000 IU every 8Y12 hours
OR low-molecular-weight
heparin
Intracranial 1 to 4 days after
hemorrhage bleeding cessation Enoxaparin 40 mg/d SC
is demonstrated
Dalteparin 5000 units/d SC
Fondaparinux 2.5 mg/d SC
Contraindication On admission Mechanical prophylaxis with
to anticoagulation intermittent pneumatic
compression devices and
chemical prophylaxis with
aspirin 325 mg/d orally
IV = intravenous; SC = subcutaneous.

response, incomplete oral clearance, patients at high risk, a videofluoro-

or palatal weakness or asymmetry.37 scopic evaluation of swallow or a fiber-
Prevention of aspiration pneumo- optic endoscopic evaluation of swallow
nia begins with proper identification may be performed.
of patients with dysphagia, and every In patients who are unable to take
patient with stroke should have a anything by mouth, adequate hydra-
swallow evaluation before initiating a tion with isotonic fluids should be
diet or oral medication intake in the maintained to prevent DVT. Early place-
hospital. A prospective multicenter ment of a nasogastric or nasoduodenal
study demonstrated that the use of a tube can facilitate administration of
formal screening protocol for dyspha- nutrition and medications in patients
gia with a water swallow test signifi- at high risk for aspiration. Patients who
cantly decreased the risk of aspiration receive early nasogastric tube feeding
pneumonia in patients admitted with have a significantly reduced risk for
acute stroke.38 A wet voice or sponta- death. If long-term tube feeding is
neous cough after swallowing are anticipated, a percutaneous endoscopic
predictors of high aspiration risk. For gastrostomy tube should be placed.

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 Poststroke Complications

KEY POINTS
h Up to 70% of patients Infection become more apparent following the
with stroke will have a Fever after a stroke should prompt acute hospitalization.
fall, thus all patients evaluation for common sources, in-
with stroke should have cluding pneumonia and urinary tract Falls
a formal fall prevention infection. Prophylactic antibiotic use is All patients with stroke should be
program. not recommended. The most common provided with a formal fall prevention
h Fractures in patients cause of fever in the first 48 hours program during hospitalization.40 A
who are poststroke after acute stroke is pneumonia, which fall prevention program includes iden-
often occur on the is attributed to aspiration in 60% of tifying the patient at high risk for falls,
paretic side and are cases.3 In addition to aspiration, im- counseling the patient and family
secondary to mobility and atelectasis can lead to about the risk, encouraging the pa-
accidental falls. development of pneumonia. Early tient and family to seek assistance if
mobilization and good pulmonary needed, preventing delirium, minimiz-
care should be encouraged in the ing the use of mechanical restraints,
hospital to prevent pneumonia. For using bed and chair alarms, using
patients who are intubated, preven- ceiling lifts to facilitate transfers, and
tive measures include ventilation in effectively communicating the pa-
a semirecumbent position, appro- tient’s care plan with the team with
priate airway positioning, suctioning shift changes. Patients at high risk for
of secretions, and daily assessments falls include those with cognitive im-
for potential extubation. Nausea pairment, neglect, anosognosia, and
should be addressed and treated to polypharmacy. In the acute setting,
prevent vomiting. most falls are observed during the day
Urinary tract infections occur in in the patient’s room or restroom, often
11% to 15% of patients with stroke, associated with transfers or attempts
and are often seen during the first at activities without supervision. Once
5 days of the hospitalization, but they the patient returns to the community,
can occur up to 3 months poststroke. the rate of falls associated with trans-
Urinary tract infection is an indepen- fers decreases, and subsequent falls
dent predictor of worse outcomes and are most commonly associated with
prolonged hospitalizations. 1,39 In- ambulation.41 A retrospective study
dwelling catheters should be avoided showed that 5% of patients with stroke
to reduce the risk of catheter-associated fell during their acute hospitalization,
urinary tract infection. However, they and these falls were associated with
may be required in certain circum- greater stroke severity and history of
stances, such as in cases of acute uri- anxiety.42 In the first 6 months after
nary retention or obstruction or when hospitalization, up to 70% of patients
strict monitoring of urinary output is with stroke will have a fall.43
needed in patients who are critically Most fractures in patients who are
ill. The catheter should be removed as poststroke occur on the paretic side
soon as possible, and intermittent and are secondary to accidental falls.
catheterization can be implemented Of all poststroke fractures, hip frac-
to decrease infection risk. tures represent 45% and are 2 to
4 times more common in the stroke
LATE COMPLICATIONS community when compared with the
Many late complications of stroke age-matched population.44 Patients
can be seen in the acute setting, but who ambulate early after stroke ap-
issues such as falls, seizures, sleep- pear to lose bone mineral density on
disordered breathing, and depression the paretic side only, as opposed to
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 KEY POINTS
those who are not ambulatory, who seizures occurred in 8.9% of patients h Decreased mobility
lose bone mineral density on both after hemispheric ischemic or hemor- is associated with
sides.44,45 Bone mineral density can rhagic stroke. Of those patients, 43% decreased bone
decrease by more than 10% in the had their seizure within 24 hours of the mineral density.
paretic leg in patients who are non- stroke. Early-onset seizures are postu- h Balance training can
ambulatory within the first year af- lated to be due to ion shifts and release help to reduce falls.
ter stroke, as opposed to a reduction of excitotoxic neurotransmitters in the
h Patients with stroke in
of 3% in patients who are ambula- ischemic cascade.52
long-term care facilities
tory.46,47 Ambulating at 2 months Late-onset seizures occur at least should be assessed for
is associated with less decrease of 2 weeks after a stroke and are calcium and vitamin D
bone mineral density compared to commonly encountered 6 months to supplementation.
patients who are wheelchair depen- 2 years after stroke but can occur
h Seizures after stroke are
dent.47 A cross-sectional study showed several years later.53 The development often focal in onset and
that poststroke hip fractures were prev- of chronic epilepsy is higher in pa- can have secondary
alent in the first 2.4 years after stroke in tients with late-onset seizures. Late- generalization. They
women with dementia, a history of onset seizures are believed to be due may have early or late
transient ischemic attack, hypertension, to the permanent lesion causing an onset; late-onset seizures
coronary artery disease, low vitamin D alteration in neuronal excitability. A are associated with a
levels, secondary hyperparathyroidism, population-based study demonstrated higher rate of developing
high bone resorption, higher serum an incidence of poststroke epilepsy in chronic epilepsy.
vitamin B12, or increased disability.48 1.5%, 3.5%, 9.0%, and 12.4% of pa- h Prophylactic antiepileptic
Because of the high incidence of tients at 3 months, 1 year, 5 years, drugs are not
poststroke falls and because of the and 10 years, respectively.54 recommended
high morbidity associated with hip No studies have shown a benefit to after stroke.
fractures, it is recommended that starting prophylactic antiepileptic
patients with stroke participate in drugs after acute stroke, and routine
exercise programs with balance train- seizure prophylaxis is not recom-
ing to reduce falls when discharged mended.40 Characteristics such as
from the hospital. It is also reasonable stroke severity, hemorrhagic lesion,
to assess a patient’s fall risk on an and cortical location are associated
annual basis and to provide patients with an increased risk of developing
and their caregivers with information seizures.54 Future trials are needed
to reduce falls at home. Additionally, to stratify patients who may benefit
it is recommended that patients with from prophylactic antiepileptic drug
stroke residing in long-term care use. Until then, the management of
facilities be evaluated for calcium seizures after stroke should be similar
and vitamin D supplementation.40 to the management of seizures that can
complicate other neurologic illnesses.40
Seizures
Stroke is the most common cause of Sleep-disordered Breathing
seizures in adults older than 35 years The prevalence of obstructive and cen-
of age.49 Most seizures are focal at onset tral sleep apnea/hypopnea is increased
and may have secondary generalization. in patients with stroke, occurring in up
Less than 10% of patients with ischemic to 70% of patients when defined as an
stroke develop seizures.50,51 The inci- apnea-hypopnea index of five or more
dence of seizures appears to be higher events per hour.55 Patients commonly
in those patients who have had hem- have preexisting obstructive sleep ap-
orrhagic transformation of the stroke. nea or central sleep apnea, which is
In a large prospective study, poststroke often undiagnosed at the time of the
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 Poststroke Complications

stroke. These breathing patterns can

worsen following a stroke, especially TABLE 5-3 Clinical Features
when the level of consciousness is im- Associated With
paired. Some sleep-disordered breath- Increased Risk of Sleep-
Disordered Breathing
ing is a consequence of brain injury
from the stroke. Patients with stroke
b History
to the medullary respiratory centers
High stroke severity
can have obstructive sleep apnea,
central sleep apnea, or a combination Early neurologic deterioration
of the two. Bihemispheric strokes can Stroke occurring at night
result in Cheyne-Stokes respiration. Stroke associated with
Early complications encountered diabetes mellitus
as the result of sleep apnea include Stroke due to
early neurologic deterioration in the macroangiopathy
acute setting. The reversed Robin Hemorrhagic stroke
Hood syndrome has been described History of prior stroke
as a possible mechanism for early
Cor pulmonale
neurologic deterioration, in particular
in patients with proximal large vessel Obesity
occlusions and sleep apnea.56 In this b Sleep Review of Systems
syndrome, compensatory vasodilata- Loud snoring
tion during hypercapnia increases
Daytime sleepiness
blood flow velocity in the unaffected
Gasping or choking
intracranial vessels. This creates a steal
phenomenon that decreases the Nonrestorative sleep
blood flow velocity in the vessels sup- Witnessed apnea during
plying the ischemic territory, thus sleep
causing a decline in neurologic status. Frequent nighttime
Late complications as a result of awakenings
sleep apnea include those seen in the Morning headache
general population in addition to Nocturia
increased hospital length of stay, func- Irritability
tional impairment, and mortality.57,58
Cognitive impairment
The risk of stroke has a strong inde-
pendent association with sleep apnea b Physical Examination and
Clinical Findings
in the general population. Additionally,
a prospective cohort study demon- Systolic hypertension
strated an increased risk for recurrent Nocturnal desaturation
stroke in patients with stroke with Hypercapnia
moderate to severe obstructive sleep Cardiac arrhythmias
apnea who could not tolerate contin-
Pulmonary hypertension
uous positive airway pressure (CPAP)
when followed over 7 years.59 Increased body mass index
Because of the increased preva- Crowded airway
lence of sleep-disordered breathing Increased neck circumference
in patients with stroke, a high index Dysphagia or dysphonia
of suspicion and a low threshold to
Floppy eyelid syndrome
pursue formal sleep testing should be
upheld. Table 5-3 provides clinical
104 ContinuumJournal.com February 2017

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features that are associated with an outcomes. In a prospective study,
increased risk for sleep-disordered patients who were depressed at
breathing. In the acute hospital setting, 3 months were found to have poorer
if patients have nocturnal desaturations, functional outcomes at 1 year.68 It is
they can be treated with supplemental notable that patients who were de-
oxygen, CPAP, or bilevel positive airway pressed had more neurologic impair-
pressure. Emerging evidence suggests ments; thus, it is unclear whether the
that auto-titrating CPAP has diagnostic depression was due to the patient
validity and may be feasible in patients being significantly disabled or if the
with nonsevere stroke or transient depression had an impact on stroke
ischemic attack.60Y62 Polysomnography recovery. Another study of patients
can be arranged as an outpatient with poststroke depression showed
evaluation and should be considered that patients with improved mood at
as a necessary part of the management follow-up had significantly greater re-
of secondary stroke prevention.63 covery in their activities of daily living
than patients whose mood did not im-
Depression prove.69 Again, it is notable that these
Poststroke depression affects up to results were observational, and causal-
one-third of stroke survivors at any ity cannot be inferred. The Fluoxetine
given time after stroke, with the for Motor Recovery After Acute Ischaemic
highest frequency in the first year and Stroke (FLAME) trial showed significant
a cumulative incidence of 55%.64Y66 It improvement in motor function as well
is associated with increased mortality as lower rates of poststroke depression
and poor functional outcomes. Risk fac- in patients given fluoxetine compared
tors include stroke severity, severe dis- to placebo.70 Further studies are need-
ability, cognitive impairment, prestroke ed to assess antidepressant treatments
depression, previous stroke, family his- in poststroke depression.
tory of psychiatric disorder, and female While no clear evidence indicates
sex.40 Studies have not demonstrated that improvement of poststroke depres-
a relationship between depression and sion is independently associated with
stroke size or location.67 The cause of functional improvement, untreated
poststroke depression is poorly un- depression can negatively impact the
derstood but is likely a combination patient’s ability to participate in reha-
of psychological and biological factors. bilitation (Case 5-3).71,72 In addition,
Evidence is lacking with regard fatigue can be significantly disabling.
to treatment of depression and stroke Poststroke fatigue can occur in the

Case 5-3
A 74-year-old woman presented to clinic for follow-up 1 month after a left
middle cerebral artery territory stroke. She had a residual moderate mixed
aphasia and right hemiparesis but was able to ambulate with a walker. During
her hospitalization, she was identified to be at risk for obstructive sleep
apnea; this was confirmed on polysomnography in the sleep clinic. Continuous
positive airway pressure therapy had been initiated, and she noticed
significantly improved sleep and a moderate improvement of her daytime
sleepiness. However, she continued to have difficulty getting out of bed in
the mornings and struggled with persistent daytime fatigue since her
Continued on page 106

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 Poststroke Complications

Continued from page 105

hospitalization. Upon further questioning, her husband endorsed that she
appeared withdrawn and had been avoiding social contact with family and
friends. She no longer enjoyed her prior activities of watching films,
picking fruit from her mango trees, or playing with her great-grandson.
She missed multiple outpatient therapy appointments because of lack of
motivation and significant fatigue. She denied suicidal or homicidal
ideation but reported a history of a suicide attempt in her teenage years.
Comment. This patient’s untreated depression is preventing her from
optimizing her stroke recovery through therapy and is associated with poor
functional outcome. She would likely benefit from starting antidepressant
therapy. With adequate treatment of her depression, she may also experience
improvement of her daytime fatigue.

absence of depression and can be dif- pression after stroke. Until then, pa-
ficult to treat. However, fatigue asso- tients should be screened for sleep
ciated with depression can potentially apnea and depression in both the hos-
be alleviated when the depression is pital and outpatient settings, as these
treated73; thus, a standard approach to can have implications for their func-
treating depression with nonpharma- tional outcomes. Patients should also
cologic and pharmacologic treatment be regularly assessed for fall risk
options should be offered to patients beginning with their initial hospitaliza-
with poststroke depression. Screening tion and continuing in the clinic set-
tools such as the Center of Epidemio- ting during follow-up visits.
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 Review Article

Cardioembolic Stroke
Address correspondence to
Dr Cumara B. O’Carroll, Mayo
Clinic Arizona, 13400 E Shea
Blvd, Scottsdale, AZ 85259,
Cumara B. O’Carroll, MD, MPH; Kevin M. Barrett, MD, MSc [email protected].
Relationship Disclosure:
Dr O’Carroll reports no
disclosure. Dr Barrett serves
ABSTRACT on the editorial board of
Purpose of Review: Cardioembolic stroke is common and disproportionately more Neurology, has received
research/grant support from
disabling than nonembolic mechanisms of stroke. Its incidence is expected to rise the National Institute of
because of the age-related incidence of atrial fibrillation and an aging population. Neurological Disorders and
This article summarizes the different causes of cardioembolism and outlines current Stroke for serving on the
executive committees of
management guidelines. the CREST-2 and SHINE
Recent Findings: Since cardioembolic stroke is not a single disease entity, its diagnosis clinical trials, and receives
requires initial clinical suspicion and a comprehensive evaluation, including ECG, publishing royalties from
Wiley Blackwell.
echocardiography, brain imaging, and cardiac monitoring. Atrial fibrillation is the most Unlabeled Use of
common cause of cardioembolic stroke, and anticoagulation is usually recommended. Products/Investigational
This article reviews risk stratification models to assist in the decision-making process Use Disclosure:
Drs O’Carroll and Barrett
and highlights the increased use of novel oral anticoagulants for stroke prevention in report no disclosure.
atrial fibrillation. New data support the importance of prolonged cardiac monitoring * 2017 American Academy
for diagnosing occult atrial fibrillation. Current data on other mechanisms of of Neurology.
cardioembolic stroke, such as prosthetic heart valves and aortic arch atherosclerosis,
are also presented, and the available evidence regarding patent foramen ovale closure
in cryptogenic stroke is summarized.
Summary: Cardioembolism is an important cause of ischemic stroke, with diverse
underlying mechanisms requiring a tailored approach to diagnosis, management,
and prevention.

Continuum (Minneap Minn) 2017;23(1):111–132.

INTRODUCTION different vascular distributions, whether

Cardioembolic stroke accounts for ap- concurrent or sequential, should raise
proximately 20% to 30% of all ischemic suspicion for a proximal source of
strokes but is usually more disabling embolus. Posterior circulation strokes
than nonembolic mechanisms of stroke also commonly occur as a result of car-
given the propensity for large intracra- dioembolism.7 Additionally, cardioem-
nial vessel occlusion resulting in larger bolic strokes are more likely to result
in seizures when compared to lacunar
areas of ischemic brain.1Y3 Cardioem-
strokes given the distal cortical ischemia
bolic stroke is not a single disease entity
that occurs.2 While no pathognomonic
or etiology, as it can result from atrial
imaging patterns exist in cardioembolic
fibrillation (AF), ventricular thrombus,
stroke, a distal cortical wedge-shaped
structural heart defects, aortic arch infarct involving a large artery territory
atheroma, acute myocardial infarction, on CT or MRI is a common finding.
or valvular heart disease. As with other Imaging may also show a classic scat-
types of stroke, the clinical presenta- tered pattern of ischemia, suggesting a
tion is typically sudden, with maximal shower of emboli or the distal migra-
deficits at onset and, at times, a swift tion of an embolus after it fragments.
recovery because of the instability of Embolism is also highly probable when
embolic material with further migra- hemorrhagic transformation of an is-
tion downstream and reestablishment chemic infarct has occurred, suggesting
of flow.4Y6 Multiple cortical infarcts in reperfusion injury after recanalization.2,4
Continuum (Minneap Minn) 2017;23(1):111–132 ContinuumJournal.com 111

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 Cardioembolic Stroke

KEY POINTS
h Cardioembolism DIAGNOSTIC APPROACH TO risk factors. Transthoracic echocardi-
accounts for 20% to 30% CARDIOEMBOLIC STROKE ography (TTE) is essential to cardio-
of all ischemic strokes. The initial clinical evaluation for po- embolic stroke evaluation as it is a
tential cardioembolic stroke should noninvasive way to assess heart struc-
h Multiple cortical infarcts
in different vascular be systematic and thorough, given all ture and function, and, when used in
distributions in an the possible underlying mechanisms combination with an injection of agi-
individual patient and evidence-based recommendations tated saline (bubble study), it allows
should raise suspicion dependent on these mechanisms. Per- for detection of right-to-left shunting
for a proximal source forming a detailed history and physical (eg, patent foramen ovale or atrial septal
of embolus. examination is crucial, as is obtaining defect). While transesophageal echo-
h Transesophageal neuroimaging, ECG, laboratory stud- cardiography (TEE) involves greater
echocardiography is ies, and echocardiography (Table 6-1). procedural risk than TTE, it has been
superior to transthoracic When neuroimaging is performed in shown to be superior for evaluating the
echocardiography in the acute setting, it is usually a noncon- aortic arch, the left atrial appendage, the
assessing the anatomy trast head CT as this is widely available aortic valve, and the atrial septum.11Y13
of the ascending and fast, excludes intracerebral hemor- If TTE does not identify a cardiac source
aorta/aortic arch; rhage (ICH), and assists in determining of embolism and the index of suspi-
evaluating for the
eligibility for thrombolysis.8 MRI can be cion for a proximal source of embo-
presence of thrombus
useful in establishing the presence of lism remains high, then TEE should
in the left atrium; and
both clinically evident and subclinical be performed.14,15
detecting and measuring
an atrial septal defect, strokes, delineating their vascular dis-
tributions, as well as chronic infarcts. It ATRIAL FIBRILLATION
atrial septal aneurysm, or
patent foramen ovale. is more sensitive in detecting smaller AF is the most common significant car-
areas of ischemia, especially in the diac arrhythmia and is a major risk
h Atrial fibrillation is
associated with left posterior fossa, when compared to CT. factor for ischemic stroke, associated
atrial enlargement, The patterns of cardioembolic stroke with a fivefold increase in risk.16 Its
resulting in stasis of seen on neuroimaging are typically incidence increases with age, and it is
blood and increased cortical or cortical-subcortical wedge- estimated to affect between 2.7 and
propensity for clot shaped areas of ischemia, with involve- 6.1 million Americans, with an esti-
formation, with ment of multiple vascular territories, or mated 16 million people affected by
subsequent embolization scattered infarcts.2 Vessel imaging (ca- the year 2050.17Y20 Given the aging
to the brain. rotid ultrasound, CT angiography, or US population, this will have a sub-
MR angiography [MRA]) may serve to stantial impact not only on individuals
discover an alternate mechanism of but on society as a whole as strokes
stroke, such as artery-to-artery embo- from AF tend to be more severe, re-
lism. A baseline ECG should be ob- sulting in greater disability and mor-
tained in patients with new stroke, as tality. Preventing stroke in patients with
well as telemetry when hospitalized, but AF has significant implications on
many patients will require prolonged lowering health care costs attributed
monitoring in the form of Holter or to cardioembolism.
event monitoring to detect occult AF.9,10 AF leads to ineffective contraction
Basic laboratory studies include com- of the atria and is associated with left
plete blood cell count, prothrombin atrial enlargement. This results in stasis
time, activated thromboplastin time, of blood and increased propensity for
thyroid function tests, and troponin clot formation within the left atrium
level.8 Young patients should undergo and atrial appendage, with subsequent
a hypercoagulable workup, especially if embolization to the brain. Both valvu-
they have a family history suggestive lar and nonvalvular AF exist. Valvular
of thrombophilia or have no vascular AF occurs in the setting of a prosthetic
112 ContinuumJournal.com February 2017

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TABLE 6-1 Diagnostic Approach to Suspected Cardioembolic Stroke

b Physical Examination
Vital signs
Neurologic examination
Cardiac examination
Murmurs, arrhythmias, cardiac enlargement
Lung auscultation
Neck examination
Bruits
Peripheral vascular examination
Bruits, peripheral edema, decreased or absent pulses, assessment of
jugular venous pressure
Ophthalmologic examination
Retinal changes (hypertensive, cholesterol crystals, venous-stasis retinopathy);
inflammatory, infectious, and genetic diseases; retinocerebral arteriopathies
Skin examination
Ischemic skin changes, petechiae, angiokeratomas (Fabry disease)
b Imaging Studies
CT/MRI brain
CT: Widely available, fast, excludes intracerebral hemorrhage, assists in
determining eligibility for thrombolysis.
MRI: Useful for clinically evident and subclinical strokes, vascular distributions,
chronic infarcts; more sensitive for detecting ischemia in the posterior fossa.
Vascular imaging
Doppler ultrasound, CTA, MRA
Chest x-ray
b Cardiac Evaluation
Serial ECG
Cardiac telemetry
Extended cardiac monitoring
Many patients require Holter or event monitoring to detect occult atrial fibrillation
Transthoracic echocardiography (TTE)
Noninvasive, evaluates heart structure and function, good for left
ventricular thrombus
Transesophageal echocardiography (TEE)
Superior for evaluating the aortic arch, the left atrial appendage, the
aortic valve, and the atrial septum, but more invasive than TTE
Continued on page 114

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 Cardioembolic Stroke

KEY POINTS
h Paroxysmal atrial TABLE 6-1 Diagnostic Approach to Suspected Cardioembolic Stroke
fibrillation seems to Continued from page 113
present a similar
risk of stroke as b Laboratory Studies
persistent or permanent
Complete blood cell count
atrial fibrillation.
h For both the CHADS2 Blood cultures
and CHA2DS2VASc Infective endocarditis
scores, a previous
Erythrocyte sedimentation rate, C-reactive protein
history of stroke or
transient ischemic Elevated in infection, vasculitis, malignancy
attack usually confers Prothrombin time, partial thromboplastin time, international normalized ratio
a high enough
annual risk to Detect coagulopathies
warrant anticoagulation. Thyroid function tests
Lipid profile
Hypercoagulable panel
Young patients with family history suggestive of thrombophilia and no
vascular risk factors
CT = computed tomography; CTA = computed tomography angiography; ECG = electrocardiogram;
MRA = magnetic resonance angiography; MRI = magnetic resonance imaging.

valve or rheumatic mitral valve steno- cation tools have been developed to
sis, and nonvalvular AF occurs without estimate whether the embolic risk in
an underlying structural valve defect. an individual patient exceeds the risk
Similarly, different types of AF exist of major bleeding, as illustrated in
(paroxysmal, persistent, permanent),21 Case 6-1. One of the most commonly
but even transient episodes of AF re- used tools is the CHADS2 (congestive
sult in thrombus formation; thus, the heart failure, hypertension, age 75 years
approach to anticoagulation should be or older, diabetes mellitus, and pre-
similar in patients with paroxysmal AF vious stroke/transient ischemic at-
and those with persistent/permanent AF. tack [TIA]) 22,23 risk stratification
scheme (Table 6-224), although in
Risk Stratification in recent years it has been expanded to
Atrial Fibrillation the CHA2DS2VASc (congestive heart
The annual risk of stroke in patients failure, hypertension, age 75 years or
with AF not on thromboprophylaxis is older, diabetes mellitus, stroke, vascular
approximately 5%.18 This risk is highly disease, age 65 to 74 years, sex category
dependent on the other risk factors a [female sex]) score (Table 6-3).23,25
specific patient may have and increases These risk stratification scores incorpo-
as the number of risk factors increases. rate individual clinical factors and
One of the most important decisions provide clinicians with an estimate of
that must be made for patients with annual stroke risk. For both of these
AF is whether or not anticoagulation scoring systems, a previous history of
is indicated to prevent stroke. Since stroke or TIA usually confers a high
anticoagulation itself is associated enough annual risk to warrant anti-
with the risk of bleeding, risk stratifi- coagulation. The CHA2DS2VASc score

114 ContinuumJournal.com February 2017

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 Case 6-1
An 82-year-old woman with a history of hypertension presented to the
emergency department with expressive aphasia and right-sided weakness.
CT head was negative for acute ischemic changes or intracerebral
hemorrhage. She received IV thrombolysis within the 3-hour window,
with good recovery. The next day, a brain MRI confirmed a small acute
infarction in the left middle cerebral artery territory. Atrial fibrillation was
captured on telemetry on hospital day 2, even though it was not present
on the initial ECG. Transthoracic echocardiography showed severe left
atrial enlargement.
Prior to discharge, a family discussion took place with the patient and
her children regarding the initiation of anticoagulation for her newly
diagnosed atrial fibrillation. Her daughter was concerned about the
bleeding risk associated with anticoagulation, as a family friend had
experienced a gastrointestinal bleed while on a novel oral anticoagulant.
Her son was worried about her fall risk. After much discussion (weighing
risks and benefits), it was decided that she would start anticoagulation
with warfarin, with plans for an aspirin bridge until her international
normalized ratio (INR) was therapeutic.
Comment. This case outlines the patient’s high risk for recurrent stroke.
The stroke team calculated her CHA2DS2VASc (congestive heart failure,
hypertension, age 75 years or older, diabetes mellitus, stroke, vascular
disease, age 65 to 74 years, sex category [female sex]) score as 6, placing
her yearly stroke risk at 9.8%. Her HAS-BLED (hypertension, abnormal liver
or renal function, history of stroke or bleeding, labile INRs, elderly, use of
drugs that promote bleeding or alcohol use) score was a 3, which justified
caution (3.74 bleeds per 100 patient-years). Ultimately, the benefits of
anticoagulation outweighed the risk of bleeding. Additionally, emphasizing
tight blood pressure control potentially modifies a bleeding risk factor.

has a broader score range and includes serve as a guide for clinical decision
more risk factors than CHADS2 and making and not as the sole reason to
thus is thought to more accurately withhold anticoagulation. A HAS-BLED
estimate stroke risk. score of 3 or higher suggests that a
While several scales are available patient is at high risk for bleeding and
to estimate annual bleeding risk in caution is warranted, with close mon-
patients who are anticoagulated, the itoring for adverse events, tight INR
HAS-BLED (hypertension, abnormal control, and possibly a lower dose
liver or renal function, history of of anticoagulant. 23
stroke or bleeding, labile international
normalized ratios [INRs], elderly, use Antithrombotic Therapy
of drugs that promote bleeding or for Stroke Prevention in
alcohol use) score is the most widely Atrial Fibrillation
used (Table 6-426,27).23,26,28 This score The choice of antithrombotic ther-
assists with quantifying risk of hem- apy for stroke prevention in patients
orrhage and highlights modifiable risk with AF should be individualized. Anti-
factors (ie, alcohol intake, concomitant thrombotic therapy as a category in-
use of antiplatelet drugs or nonsteroidal cludes both antiplatelet agents and
anti-inflammatory drugs), but it should anticoagulants.

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 Cardioembolic Stroke

KEY POINT
h Warfarin is superior TABLE 6-2 CHADS2 Score to Estimate Stroke Risk in Patients With
to aspirin in preventing Atrial Fibrillationa,b,c
stroke for high-risk
patients with atrial Adjusted Stroke Rate
fibrillation, and thus CHADS2 Score (% per Year) Recommendation
anticoagulation is 0 1.9 No antithrombotic
preferred over
antiplatelet agents 1 2.8 Antiplatelet or anticoagulation
for secondary stroke 2 4.0 Anticoagulation
prevention in
3 5.9 Anticoagulation
these patients.
4 8.5 Anticoagulation
5 12.5 Anticoagulation
6 18.2 Anticoagulation
a
Data from Gage BF, et al, JAMA,22 jamanetwork.com/journals/jama/article-abstract/193912 and
January CT, et al, J Am Coll Cardiol.23 content.onlinejacc.org/article.aspx?articleid=1854231.
b
Modified with permission from Kim A, Continuum (Minneap Minn).24 B 2014 American Academy
of Neurology. journals.lww.com/continuum/Fulltext/2014/04000/Evaluation_and_Prevention_
of_Cardioembolic_Stroke.10.aspx.
c
CHADS2
Congestive heart failure 1 point
Hypertension 1 point
Age Q 75 years 1 point
Diabetes mellitus 1 point
Stroke/transient ischemic attack/thromboembolism 2 points
Maximum score 6 points

Antiplatelet versus warfarin therapy. in preventing stroke for high-risk pa-

Antithrombotic medications diminish tients with AF, with a relative risk
the formation of platelet-rich and reduction of 36%. In general, concom-
thrombotic clots in the left atrium, thus itant use of warfarin (or one of the
preventing strokes and systemic embo- newer agents) and aspirin is not recom-
lization in patients with underlying AF. mended because of increased bleeding
Since the 1950s, oral anticoagulation risk without clear additional benefit,
with warfarin (goal INR of 2 to 3) has with the possible exception of an acute
been the foundation of stroke preven- coronary syndrome or stent place-
tion in patients with AF. Based on the ment.30 For patients who have a con-
results of a meta-analysis (six trials, traindication to oral anticoagulation,
2900 participants), warfarin reduces the aspirin monotherapy is usually the
relative risk of stroke by 62% (95% con- treatment of choice. The addition of
fidence interval 48% to 72%) compared clopidogrel to aspirin may provide
to placebo, with 2.7% absolute risk added benefit in stroke prevention,
reduction per year for primary preven- but it is also associated with an in-
tion and 8.4% for secondary preven- creased risk of hemorrhage. In the
tion.29 In contrast, aspirin compared to Atrial Fibrillation Clopidogrel Trial With
placebo (six trials, 3119 participants) Irbesartan for Prevention of Vascular
is less effective, reducing the incidence Events (ACTIVE A), the rate of ischemic
of stroke by 22% (confidence interval stroke among patients with AF was
2% to 38%). Several large prospective significantly lower in the clopidogrel/
trials and meta-analyses have also aspirin group compared to the aspirin-
shown warfarin to be superior to aspirin only group (1.9% per year versus 2.8%

116 ContinuumJournal.com February 2017

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 KEY POINT

TABLE 6-3 CHA2DS2VASc Score to a,b,c

Estimate Stroke Risk in Patients h Patients with atrial
With Atrial Fibrillation fibrillation may
require medications
Adjusted Stroke for control of rate and
CHA2DS2VASc Score Rate (% per Year) Recommendation rhythm, but this does
0 0 No antithrombotic not preclude the need
for antithrombotic therapy
1 1.3 Antiplatelet or anticoagulation for stroke prevention.
2 2.2 Anticoagulation
3 3.2 Anticoagulation
4 4.0 Anticoagulation
5 6.7 Anticoagulation
6 9.8 Anticoagulation
7 9.6 Anticoagulation
8 6.7 Anticoagulation
9 15.2 Anticoagulation
a
Data from January CT, et al, J Am Coll Cardiol,23 content.onlinejacc.org/article.aspx?articleid=1854231 and
Olesen JB, et al, BMJ.25 bmj.com/content/342/bmj.d124.
b
Reprinted with permission from Kim A, Continuum (Minneap Minn).24 B 2014 American
Academy of Neurology. journals.lww.com/continuum/Fulltext/2014/04000/Evaluation_and_Prevention_
of_Cardioembolic_Stroke.10.aspx.
c
CHA2DS2VASc
Congestive heart failure 1 point
Hypertension 1 point
Age Q 75 years 2 points
Diabetes mellitus 1 point
Stroke/transient ischemic attack/thromboembolism 2 points
Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) 1 point
Age 65Y74 years 1 point
Sex category (female) 1 point
Maximum score 10 points

per year, PG.001), but this was neutral- Even with its proven efficacy in
ized by a higher rate of major bleeding stroke prevention, limitations are asso-
(2.0% versus 1.3% annual risk; relative ciated with warfarin therapy (Table 6-5).
risk 1.57; PG.001). Additionally, a non- In addition to an increased risk of bleed-
significant increase in the rate of ing, warfarin has a narrow therapeutic
hemorrhagic stroke was seen in the window (INR 2 to 3), requiring fre-
clopidogrel/aspirin group.31 The American quent blood monitoring (weekly ini-
Heart Association/American Stroke As- tially, then monthly).32 As the INR
sociation guidelines state that it “might drops below 2, the risk of stroke rises
be reasonable” to consider adding rapidly. In clinical practice as well as
clopidogrel to aspirin therapy in patients in the most reputable trials, time in
with AF and previous stroke who are the therapeutic range for patients on
unable to take oral anticoagulants.30 Many warfarin is estimated at 55% to 66%.23
patients with AF require medications for Warfarin interacts with other medica-
both rate and rhythm control, but this tions and is affected by fluctuations in
does not preclude the need for antithrom- diet, which poses a challenge for both
botic therapy for stroke prevention. clinicians and patients.

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 Cardioembolic Stroke

KEY POINTS
h All of the novel oral factor Xa inhibitors (rivaroxaban, api-
anticoagulants were TABLE 6-4 HAS-BLED Score to xaban, and edoxaban)33Y37 and one di-
Estimate the Risk of rect thrombin inhibitor (dabigatran)38,39
found to be noninferior Hemorrhagea,b
to warfarin, with dabi- have been approved by the US Food
gatran (high dose) and and Drug Administration (FDA) for pre-
HAS-BLED Bleeds per
apixaban meeting Score 100 Patient-yearsc vention of stroke in nonvalvular AF
superiority end points. (Table 6-6). The first to be approved
Apixaban also resulted 0 1.13
was dabigatran (Randomized Evaluation
in lower mortality and 1 1.02 of Long-Term Anticoagulant Therapy
less major bleeding. With Dabigatran Etexilate [RE-LY]38),
2 1.88
h Potential benefits of followed by rivaroxaban (Rivaroxaban
3 3.74
the novel oral Once-daily Oral Direct Factor Xa Inhi-
anticoagulants over 4 8.70 bition Compared With Vitamin K Antag-
warfarin include fixed onism for Prevention of Stroke and
Q5 Insufficient data
dosing, rapid onset of a
Data from Pisters R, et al, Chest,26 Embolism Trial in Atrial Fibrillation
action, fewer drug journal.publications.chestnet.org/article. [ROCKET-AF]33), apixaban (Apixaban
interactions, no dietary aspx?articleid=1045174&issueno=5
restrictions, lack of &rss=1&ssource=mfr and Lip GY, Am J Med.27 for the Prevention of Stroke in Subjects
laboratory monitoring,
amjmed.com/article/S0002-9343(10)00452-3/ With Atrial Fibrillation [ARISTOTLE]35),
abstract.
and lower rates of b
HAS-BLED and, most recently, edoxaban (A Phase 3,
intracerebral hemorrhage. Hypertension 1 point Randomized, Double-Blind, Double-
Systolic blood pressure
9160 mm Hg Dummy, Parallel Group, Multi-Center,
Abnormal renal and/or 1 or 2 points Multi-National Study for Evaluation
liver function
Renal: Chronic dialysis or renal transplant
of Efficacy and Safety of Edoxaban
or serum creatinine Q200 2mol/L [DU-176b] Versus Warfarin In Subjects
Liver: Chronic hepatic disease or With Atrial Fibrillation - Effective Anti-
evidence of significant hepatic
derangement (bilirubin 92 upper coagulation With Factor Xa Next Gen-
limit of normal, in association with eration in Atrial Fibrillation [ENGAGE-AF
aspartate transaminase/alanine
transaminase/alanine transaminase TIMI-48]37). All of these novel oral anti-
93 upper limit of normal) coagulants (NOACs) were found to be
Stroke history 1 point
Bleeding history 1 point noninferior to warfarin, with dabigatran
Previous bleed, predisposition to (150 mg) and apixaban meeting superi-
bleeding, anemia
Labile international 1 point ority end points. All NOACs also had
normalized ratio lower rates of ICH when compared to
Time spent in therapeutic range G60% warfarin. However, there was more gas-
Elderly 1 point
Age 965 years trointestinal bleeding with dabigatran,
Drugs or alcohol 1 or 2 points rivaroxaban, and edoxaban. Not only
Drugs: Concomitant use of antiplatelet
agents and nonsteroidal was apixaban superior to warfarin in
anti-inflammatory drugs preventing stroke, it also resulted in
Excess alcohol: Q8 alcoholic units/wk
Maximum score 9 points lower mortality and less bleeding.
c
Based on initial validation cohort The NOACs can be considered as an
published by Pisters R, et al,26 with
insufficient events at HAS-BLED scores Q5.
alternative to warfarin in some patients,
as illustrated in Case 6-2. They have the
benefit of fixed dosing, rapid onset of
Novel oral anticoagulants. In recent action, fewer drug interactions, no
years, considerable effort has been dietary restrictions, and lack of labora-
made in evaluating new oral anticoagu- tory monitoring (Table 6-5). The lower
lant therapies as an alternative to war- rates of ICH are thought to outweigh
farin for preventing stroke in patients the higher rates of gastrointestinal
with AF. As of December 2016, three bleeding. NOACs may not be the best
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TABLE 6-5 Advantages and Disadvantages of Warfarin and Novel Oral Anticoagulants

b Advantages
Warfarin
Once-daily dosing
Prothrombin time/international normalized ratio used for monitoring and widely available
Reversal agents widely available: vitamin K, fresh frozen plasma, prothrombin complex concentrate,
recombinant activated factor VIIa
Inexpensive
Longer half-life; better protection in patients who are noncompliant
Safer than novel oral anticoagulants in patients with significant renal dysfunction
Novel Oral Anticoagulants
No dietary restrictions
Can be used in fixed doses; with adjustments for age and renal function
No need for routine blood monitoring
Wide therapeutic window with low interindividual and intraindividual variability
Idarucizumab reverses dabigatran; hemodialysis and activated charcoal can also be used to reverse
this agent
Less risk of intracerebral hemorrhage than warfarin
Rapid onset of action
b Disadvantages
Warfarin
Dietary restrictions; need relatively constant vitamin K intake
Requires frequent blood monitoring, especially with initiation
Time in therapeutic range is approximately 55Y66%
Many drug interactions
Novel Oral Anticoagulants
May require more frequent dosing
Expensive
Renal function affects pharmacokinetics
Factor Xa inhibitors interact with cytochrome P450-3A4 and P-glycoprotein inhibitors; dabigatran
may be affected by P-glycoprotein inducers and/or inhibitors
Noncompliance less apparent since routine blood monitoring not required
No specific reversal agent for factor Xa inhibitors, although prothrombin complex concentrate or plasma
exchange may be used for life-threatening bleeds
Thrombin time, ecarin clotting time, and antifactor Xa assay are not as readily available in the acute setting
Because of short half-lives, strict compliance is crucial; missing even one dose results in diminished protection

Continuum (Minneap Minn) 2017;23(1):111–132 ContinuumJournal.com 119

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 Cardioembolic Stroke

a
TABLE 6-6 Summary of Oral Anticoagulant Therapies

Warfarin Dabigatran Rivaroxaban Apixaban Edoxaban

Mechanism Vitamin K Direct Factor Factor Xa inhibitor Factor Xa
antagonist thrombin Xa inhibitor inhibitor
inhibitor
Dose for Atrial Variable 150 mg 2 times 20 mg/d 5 mg 2 times a day 60 mg/d
Fibrillation a day
Renal dosing: Renal 2.5 mg 2 times Renal
75 mg dosing: a day if two of dosing:
2 times a day 15 mg/d the following: 30 mg/d
creatinine Q1.5,
age Q80 years,
weight G60 kg (132 lb)
Half-life 20Y60 hours 12Y17 hours; 5Y9 hours; 12 hours 10Y14 hours
longer in renal
impairment
Time to Peak 24Y72 hours 1Y2 hours 11Y13 hours 3Y4 hours 1Y2 hours
Concentration in elderly
2Y4 hours
Reversal Agent Yes; vitamin K, Yes; idarucizumab, No No No
fresh frozen hemodialysis,
plasma, activated
prothrombin charcoal
complex
concentrate,
recombinant
activated
factor VIIa.
a
Modified with permission from Kim A, Continuum (Minneap Minn).24 B 2014 American Academy of Neurology. journals.lww.com/
continuum/Fulltext/2014/04000/Evaluation_and_Prevention_of_Cardioembolic_Stroke.10.aspx.

KEY POINTS option in patients with a history of non- zumab is now available to reverse
h The selection of compliance, given twice-daily dosing, dabigatran.40 No validated method ex-
an appropriate method short half-lives resulting in a rapid sub- ists for reversing the factor Xa inhibi-
of anticoagulation therapeutic effect, and lack of routine tors. National guidelines suggest that
should be based on the laboratory testing to monitor compli- patients who have taken NOACs with-
individual’s risk factors,
ance. Dosing adjustments must be in the past 48 hours are ineligible for
cost, tolerability,
made in patients with renal dysfunc- thrombolytic therapy in the setting of
potential for drug
interactions, and
tion, and sometimes NOACs should be acute stroke, unless they have normal
patient preference. avoided altogether if renal impairment direct factor Xa activity assays, ecarin
is severe. Dosing adjustments have not clotting time, and thrombin time.41
h Idarucizumab is the
been established for obese individuals. These laboratory tests are not widely
newly approved reversal
agent for dabigatran.
The higher cost of the NOACs and the available in most acute settings.
ability to pay for long-term treatment Anticoagulation in the elderly. AF
must also be taken into account. Until prevalence increases with age, and
recently, no reversal agents were approximately 35% of patients with AF
approved for the NOACs, but idaruci- are over 80 years of age. In general, oral

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 KEY POINTS

Case 6-2 h A patient with

atrial fibrillation on
A 76-year-old woman with a history of gastroesophageal reflux, atrial
oral anticoagulation
fibrillation, and previous stroke had been well managed on warfarin therapy
would have to fall
for 2 years. She had good medication compliance with regular appointments
approximately 295
at the anticoagulation clinic and maintained her international normalized
times a year for the
ratio (INR) between 2 and 3 consistently. She asked about switching to a novel
risk of a traumatic
oral anticoagulant as she was planning an extended trip around the world
subdural hematoma to
and would not be able to reliably monitor her INR. She weighed 55 kg (121 lb)
outweigh the benefit of
and had normal renal function.
stroke prevention.
Comment. If a patient is well managed on warfarin therapy, it is reasonable
to continue that treatment. However, because of a change in circumstances, h For most patients with
it would not be possible for this patient to monitor her INR regularly; thus acute ischemic stroke
switching to a novel oral anticoagulant may be a reasonable option. Apixaban and underlying atrial
5 mg 2 times a day was chosen for this patient, since apixaban was superior fibrillation, it is
to warfarin in preventing stroke or systemic embolism in the Apixaban reasonable to initiate
for the Prevention of Stroke in Subjects With Atrial Fibrillation (ARISTOTLE) oral anticoagulation
study and resulted in lower mortality and less major bleeding. She felt within 14 days of
she could comply with twice-daily dosing, and authorization was symptom onset, but
obtained from her insurance company. It is important to be mindful the exact timing is
that once this patient is 80 years of age or older, or should she ever unclear and often varies
develop renal dysfunction with a creatinine of 1.5 or higher, she will in clinical practice.
require the lower dose of 2.5 mg 2 times a day. Either of these factors
would necessitate a lower dose of apixaban as her weight is less than
60 kg (132 lb).

anticoagulation is underused among hematoma to outweigh the benefit of

patients with AF and high risk of stroke, preventing stroke.45 When prescrib-
but more so in elderly patients.42 The ing anticoagulation to elderly patients,
most common deterrent for clinicians clinicians should instruct them on
is the bleeding risk associated with limiting fall risks by participating in
advanced age and frequent falls. Elderly regular exercise programs, wearing
patients with AF on anticoagulation good shoes, reducing polypharmacy,
who are prone to falling are at higher and using assistive devices if appropri-
risk of traumatic ICH, but anticoagula- ate. Ultimately, before initiating anti-
tion is still warranted if their CHADS2 coagulation, extensive discussions
score is 2 or higher.43 A meta-analysis of with patients should take place, weigh-
12 trials (8932 patients, 17,685 years of ing pros and cons and taking their
observation) found that the absolute preferences into account.
benefit of oral anticoagulation in- Anticoagulation after acute stroke.
creases as patients get older, because After an acute ischemic stroke, particu-
stroke risk also increases.44 The rela- larly a large hemispheric infarction, the
tive efficacy of antiplatelet agents for risks (ie, hemorrhagic transformation)
stroke prevention in AF decreases outweigh the benefits (ie, prevention
with age but does not change for oral of recurrent thromboembolism) of ur-
anticoagulants. Interestingly, it has gent initiation of anticoagulation. For
been reported that a patient with AF most patients with acute stroke and un-
on oral anticoagulation would have derlying AF, it is reasonable to initiate
to fall approximately 295 times a year oral anticoagulation within 14 days
for the risk of a traumatic subdural of symptom onset, but the exact timing

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 Cardioembolic Stroke

KEY POINT
h Patients with is unclear and often varies in clinical diagnosed AF during their hospitali-
cryptogenic stroke practice. In higher-risk patients, such zation.23 The higher diagnostic yield
or transient ischemic as those with large territory infarcts, of longer periods of continuous car-
attack should have initial hemorrhagic transformation, diac monitoring posthospitalization has
prolonged cardiac uncontrolled hypertension, and bleed- been shown in the 30-Day Cardiac Event
monitoring within ing tendencies, the initiation of Monitor Belt for Recording Atrial Fibril-
6 months of the initial anticoagulation can be delayed beyond lation After a Cerebral Ischemic Event
vascular event. 2 weeks to closer to 4 weeks.23,30,46 (EMBRACE)47 and Study of Continuous
Large infarcts are usually defined as Cardiac Monitoring to Assess Atrial
more than one-third of the middle Fibrillation After Cryptogenic Stroke
cerebral artery territory or more than (CRYSTAL AF)48 trials and is illustrated
one-half of the posterior cerebral ar- in Case 6-3. In EMBRACE, 572 patients
tery territory. In the meantime, daily with cryptogenic stroke/TIA and no AF
aspirin should be administered. In the captured on 24-hour cardiac monitor-
setting of IV thrombolysis for acute ing were assigned to either 30 days
ischemic stroke, aspirin, as well as of an external loop recorder (inter-
other antiplatelet agents and anticoag- vention) or a 24-hour Holter monitor
ulants should be held for 24 hours. (control). Significantly higher rates
Notably, our knowledge of safety pro- of AF were detected in the external
files of the NOACs in the acute stroke loop recorder group compared with the
setting is limited, as patients with acute Holter group (16.1% versus 3.2%,
stroke 7 to 30 days prior were excluded PG.001), resulting in nearly double the
from the original trials.33,35,37,38 rate of anticoagulant initiation in the
intervention group at 90 days. CRYSTAL
Monitoring for Occult AF looked at a similar patient popu-
Atrial Fibrillation lation (441 patients) but instead ran-
Capturing paroxysmal AF can be chal- domly assigned patients to long-term
lenging as it is frequently asymptomatic monitoring with an insertable cardiac
and often first detected when patients monitor versus conventional follow-up.
present with an acute embolic stroke. The investigators concluded that insert-
A normal ECG in the setting of acute able cardiac monitoring was superior
stroke does not exclude the possibility to conventional follow-up for detect-
of paroxysmal AF preceding the event. ing occult AF in patients with crypto-
Paroxysmal AF may also go undetected genic stroke. At 6 months, AF had
on continuous hospital telemetry and been detected in 8.9% of the interven-
24- to 48-hour Holter monitors. National tion group versus 1.4% of the control
guidelines suggest that all patients with group (PG.001).
cryptogenic stroke or TIA have pro-
longed rhythm monitoring (approxi- VALVULAR DISEASE
mately 30 days) within 6 months of the The risk of cardioembolism in patients
initial vascular event,30 even though with valvular heart disease is depen-
the optimal method of monitoring is dent on many factors, including the lo-
uncertain. Several options exist for ex- cation of the diseased valve, severity of
tended cardiac monitoring, including the disease, and underlying pathology
ambulatory ECG (Holter) monitors, (eg, bacteria, malignancy, inflamma-
event (loop) monitors, and implantable tion). Some high-risk patients may be
loop recorders. candidates for antithrombotic therapy
An estimated 10% of patients with (antiplatelet agents, anticoagulants, or
acute stroke or TIA will have newly both), but the risk of adverse events
122 ContinuumJournal.com February 2017

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 Case 6-3
A 55-year-old man with a history of treated obstructive sleep apnea
developed sudden vision loss while watching a movie one night. He
described not being able to see the left half of the screen and thinking
that something was in his eye or that his allergies were acting up. When
the symptoms persisted the next day, he presented to the nearest hospital,
where an MRI of his brain showed an acute infarction in the right occipital
lobe in the posterior cerebral artery distribution. An extensive stroke workup
was completed in the hospital, including a hypercoagulable panel, all of
which was negative. A transesophageal echocardiogram revealed a large
patent foramen ovale, atrial septal aneurysm, and a left ventricular ejection
fraction of 62%, but no mass or thrombus in the atrium and no aortic arch
plaque. Since telemetry was also unremarkable, he was started on daily
aspirin therapy and discharged home with a 24-hour Holter monitor. During
follow-up in the stroke clinic 1 month later, it was determined that this
patient would be a good candidate for an implantable loop recorder given
his young age and cryptogenic stroke, and he was referred to cardiology.
Two months into continuous cardiac monitoring, the cardiologist and
neurologist were notified that a 3-minute episode of atrial fibrillation (AF)
had been captured.
Comment. This case emphasizes the value of long-term cardiac
monitoring for occult AF. This patient had been on telemetry while in the
hospital as well as a 24-hour Holter monitor, but neither showed
paroxysmal AF. It would have been tempting to attribute his stroke to the
large patent foramen ovale associated with the atrial septal aneurysm, but
further investigation revealed paroxysmal AF. This discovery influenced
management of the patient as he was switched from aspirin to daily
anticoagulation with rivaroxaban.

must be weighed against the risk of (odds ratio 0.21; 95% confidence inter-
thromboembolism. val 0.16 to 0.27).49 The risk of throm-
boembolism is higher for a prosthetic
Prosthetic Mechanical Valves and mechanical valve in the mitral position
Bioprosthetic Valves compared to the aortic position, and
Patients with prosthetic mechanical thus a higher goal INR is recom-
valves are at high risk for thromboem- mended. In patients with a mechanical
bolization and should be treated with aortic valve (current-generation single
lifelong anticoagulation. Not only does tilting disc or bileaflet) and no other
the prosthetic material itself cause risk factors for thromboembolism, the
thrombogenicity, but the mechanical recommended goal INR is 2.5. A goal
valve promotes abnormal flow condi- INR of 3.0 is recommended in patients
tions with areas of low flow and areas with a mechanical mitral valve replace-
of high shear stress causing platelet ac- ment, patients with a mechanical aortic
tivation, which results in possible valve valve replacement who have other risk
thrombosis and subsequent emboliza- factors for thromboembolism (eg,
tion. Anticoagulation with warfarin is hypercoagulable state, AF, history of
protective against valve thrombosis (odds thromboembolism), or patients with an
ratio 0.11; 95% confidence interval 0.07 older-generation mechanical aortic
to 0.2) and thromboembolic events valve replacement (ball-in-cage).49 All

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 Cardioembolic Stroke

KEY POINTS
h All patients with patients with mechanical valve prosthe- year) when compared to prosthetic
mechanical valve ses should be on daily aspirin therapy mechanical valves, and thus daily aspi-
prostheses should (75 mg to 100 mg) in addition to anti- rin (75 mg to 100 mg) is recommended,
be on daily aspirin coagulation, as it decreases the inci- rather than warfarin therapy, to prevent
therapy in addition to dence of major embolism or death thromboembolism. Among biopros-
anticoagulation as this (1.9% versus 8.5% per year; PG.001) thetic valves, mitral prostheses also have
lowers the risk of stroke. and the risk of stroke (1.3% versus a higher risk of thromboembolism
h Novel oral 4.2% per year; PG.027). Therapy with compared to aortic prostheses, thus
anticoagulants are not low-dose aspirin and warfarin does in- warfarin is recommended for the first
indicated in patients crease the risk of minor bleeding 3 months after bioprosthetic mitral
with mechanical heart (bruising, epistaxis, hematuria) but valve replacement or repair, with a goal
valves, and warfarin not the risk of major bleeding.49 The INR of 2.5 (Table 6-7).49
remains the NOACs should not be used in patients
preferred treatment. with mechanical valve prostheses be- Infective Endocarditis
cause of lack of data on their safety Infective endocarditis is an infection
and effectiveness. involving the endocardial surface of
The risk of thromboembolism is the heart. It will often present with
lower in bioprosthetic valves (0.7% per stroke and has a high mortality rate,

TABLE 6-7 Antithrombotic Therapy ina,b

Patients With Mechanical and
Bioprosthetic Heart Valves

b Class I (Benefit >>> Risk; treatment should be administered)

Anticoagulation with a vitamin K antagonist and international
normalized ratio (INR) monitoring is recommended in patients with a
mechanical prosthetic valve. (Level A)
Anticoagulation with a vitamin K antagonist to achieve an INR of 2.5 is
recommended in patients with a mechanical aortic valve replacement
(AVR) (bileaflet or current-generation single tilting disc) and no risk
factors for thromboembolism. (Level B)
Anticoagulation with a vitamin K antagonist is indicated to achieve an
INR of 3.0 in patients with a mechanical AVR and additional risk factors for
thromboembolic events (atrial fibrillation, previous thromboembolism, left
ventricular dysfunction, or hypercoagulable conditions) or an
older-generation mechanical AVR (such as ball-in-cage). (Level B)
Anticoagulation with a vitamin K antagonist is indicated to achieve an INR
of 3.0 in patients with a mechanical mitral valve replacement. (Level B)
Aspirin 75Y100 mg/d is recommended in addition to anticoagulation with a
vitamin K antagonist in patients with mechanical valve prostheses. (Level A)
b Class IIa (Benefit >> Risk; it is reasonable to administer treatment,
but additional studies needed)
Aspirin 75Y100 mg/d is reasonable in all patients with a bioprosthetic
aortic or mitral valve. (Level B)
Anticoagulation with a vitamin K antagonist is reasonable for the first
3 months after bioprosthetic mitral valve replacement or repair to
achieve an INR of 2.5. (Level C)
Continued on page 125

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 KEY POINTS

TABLE 6-7 Antithrombotic Therapy ina,b

Patients With Mechanical and h Staphylococcus aureus,
Bioprosthetic Heart Valves Continued from page 124 Streptococcus viridans,
and Enterococcus are
b Class IIb (Benefit >
_ Risk; treatment may be considered, additional studies the most common
with broad objectives needed) organisms in infective
endocarditis.
Anticoagulation with a vitamin K antagonist to achieve an INR of 2.5 may
be reasonable for the first 3 months after bioprosthetic AVR. (Level B) h Transthoracic
echocardiography will
Clopidogrel 75 mg/d may be reasonable for the first 6 months after
not definitely exclude
transcatheter aortic valve replacement in addition to lifelong aspirin
75Y100 mg/d. (Level C) vegetations or abscesses
in infective endocarditis,
b Class III (Harm) and transesophageal
Anticoagulant therapy with oral direct thrombin inhibitors or anti-Xa agents echocardiography is
should not be used in patients with mechanical valve prostheses. (Level B) considered superior for
a
Data from Nishimura R, et al, J Am Coll Cardiol.49 sciencedirect.com/science/article/pii/
making the diagnosis.
S0735109714012790.
b
Levels of Evidence
Level A: Multiple populations evaluated; data derived from multiple randomized clinical trials
or meta-analyses.
Level B: Limited populations evaluated; data derived from a single randomized trial or
nonrandomized studies.
Level C: Very limited populations evaluated; only consensus opinion of experts, case studies,
or standard of care.

even with aggressive antibiotic therapy monly affects the mitral valve. Multiple
and surgical intervention. It is esti- microorganisms can cause infective en-
mated that the in-hospital mortality docarditis, but the most common are
approaches 20%, while the 1-year Staphylococcus aureus, Streptococcus
mortality is closer to 40%.49 Patients viridans, and Enterococcus.50
with infective endocarditis may pre- All patients with suspected infective
sent with fever, weight loss, new cardi- endocarditis should have at least two
ac murmur, septic pulmonary infarcts, sets of blood cultures, complete blood
conjunctival hemorrhages, embolic cell count, TTE, serial ECGs, and TEE.
strokes, ICH, cerebral abscesses, renal TTE can sometimes detect valvular
infarcts, glomerulonephritis, or osteo- vegetations in infective endocarditis,
myelitis. Commonly associated risk but it will not definitely exclude vegeta-
factors include IV drug use, dental tions or abscesses. TTE can be useful in
infection, chronic hemodialysis, hu- characterizing the hemodynamic sever-
man immunodeficiency virus (HIV) ity of valvular dysfunction, evaluating
infection, prosthetic heart valves, intra- ventricular size and systolic function,
cardiac devices, structural heart dis- and measuring pulmonary pressures.
ease such as valvular disease (eg, However, TEE is superior to TTE in
rheumatic heart disease, mitral valve visualization of vegetations and de-
prolapse, aortic valve disease), and con- tecting perivalvular complications
genital heart lesions (eg, aortic stenosis, (eg, valve perforation, abscesses, peri-
bicuspid aortic valve). In developing cardial effusion, valve regurgitation,
countries, infective endocarditis is intracardiac thrombi) and is a mini-
most often associated with rheumatic mally invasive test for reliably diagnos-
heart disease (a complication of group ing infective endocarditis.49 Patients
A streptococcal infection), which com- should also have a brain MRI when

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 Cardioembolic Stroke

KEY POINTS
h Patients with infective possible as it is better than a head CT vegetations to embolize and cause ex-
endocarditis often have for showing multifocal infarcts of dif- tensive systemic infarcts. It is impor-
multifocal infarcts of fering ages with superimposed micro- tant to have a high index of suspicion
differing ages with hemorrhages, all characteristics classic to diagnose nonbacterial thrombotic
superimposed for infective endocarditis. endocarditis as many patients are ini-
microhemorrhages Antibiotic therapy is the foundation tially asymptomatic. The diagnosis is
on brain MRI. of treating patients with infective en- made when echocardiography dem-
h Antithrombotic therapy docarditis. The specific antibiotic and onstrates the presence of vegetations
(antiplatelet or duration of treatment depends on the in the absence of systemic infection. In
anticoagulant agents) underlying organism and should be contrast to infective endocarditis, pa-
in patients with infective guided by blood cultures and suscep- tients with nonbacterial thrombotic
endocarditis does not tibility profiles. Antithrombotic therapy endocarditis are routinely anticoagu-
reduce the risk of (antiplatelet or anticoagulant agents)
embolization and is
lated. Full-dose unfractionated heparin
does not reduce the risk of emboliza- or low-molecular-weight heparin is re-
instead associated
tion and is instead associated with a commended over warfarin, and this is
with a higher risk
higher risk of ICH. Patients with infec- usually continued indefinitely, assuming
of intracerebral
hemorrhage.
tive endocarditis classically have septic no serious complications develop.51
emboli, resulting in ischemic strokes While head-to-head trials comparing
h Full-dose with superimposed hemorrhagic trans-
unfractionated heparin heparin to warfarin in patients with
formation. Additionally, they develop nonbacterial thrombotic endocarditis
or low-molecular-weight
heparin is recommended
mycotic aneurysms and septic erosion have not been conducted, some older
over warfarin in patients of arteritic vessels, thus accentuating
studies (especially in cancer patients)
with nonbacterial the bleeding risk if antithrombotics are
have suggested that warfarin is less ef-
thrombotic endocarditis on board. It may be necessary to hold all
fective than heparin in preventing re-
to reduce embolization. antithrombotic therapy, including war-
farin therapy, in patients with AF and current thromboembolism, and this
mechanical valves because of the high has influenced clinical practice.
risk of bleeding in the acute setting.49
PATENT FORAMEN
This is a complex decision and should
OVALE CLOSURE FOR
be evaluated on an individual basis,
CRYPTOGENIC STROKE
weighing the risk of recurrent embo-
lization or valve dysfunction with that A patent foramen ovale (PFO) is an em-
of ICH. bryonic defect (hole) in the interatrial
septum that persists into adulthood in
Nonbacterial Thrombotic approximately 25% of the population.30
Endocarditis PFO is associated with cryptogenic stroke
Nonbacterial thrombotic endocarditis, and is considered a possible source in
or marantic endocarditis, is a some, as it potentially allows for a par-
noninfectious form of endocarditis adoxical embolus originating in the
that involves the deposition of sterile venous circulation to cross over into the
thrombi on heart valves (mostly mitral arterial circulation and reach the brain.
and aortic) and is primarily associated In recent years, percutaneous closure
with advanced malignancy. It is less of PFOs in patients with cryptogenic
commonly associated with inflamma- stroke has received considerable in-
tory conditions such as systemic lupus terest as a way to reduce the risk of
erythematosus and antiphospholipid recurrent stroke. Meta-analysis of three
antibody syndrome. Compared to pa- randomized controlled trials includ-
tients with infective endocarditis, a ing patients 60 years of age or younger
greater tendency exists for the fragile with cryptogenic stroke (A Prospective,

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 KEY POINTS
Multicenter, Randomized Controlled in the CLOSURE I and RESPECT trials, h Available data do
Trial to Evaluate the Safety and Effica- potentially not allowing the demonstra- not support patent
cy of the STARFlex Septal Closure tion of benefit. Because of these limita- foramen ovale closure
System Versus Best Medical Therapy tions, it has not been possible to draw for patients with
in Patients With a Stroke and/or Tran- definitive conclusions from these trials. cryptogenic stroke
sient Ischemic Attack Due to Presumed Several more randomized controlled or transient
Paradoxical Embolism Through a Patent trials to evaluate whether device PFO ischemic attack.
Foramen Ovale [CLOSURE I], Ran- closure improves outcomes compared h Anticoagulation is
domized Clinical Trial Comparing the with medical therapy are under way.56Y58 recommended for at
Efficacy of Percutaneous Closure of National guidelines reaffirm that avail- least 3 months in
Patent Foramen Ovale [PFO] With able data do not support PFO closure patients with
myocardial infarction
Medical Treatment in Patients With for patients with cryptogenic stroke or
and left ventricular
Cryptogenic Embolism [PC-Trial], TIA. They recommend antiplatelet ther- thrombus because
and Randomized Evaluation of Recur- apy for patients with PFO who have an of high risk
rent Stroke Comparing PFO Closure to ischemic stroke or TIA, and anticoagu- of embolization.
Established Current Standard of Care lation if the patient is found to have both
Treatment [RESPECT]) found that de- a PFO and venous source of embolism.
vice closure of a PFO did not offer a They state that PFO closure “might be
significant benefit over medical thera- considered” in the setting of PFO and
py for the prevention of recurrent deep vein thrombosis, depending on the
ischemic stroke.52Y55 The CLOSURE I risk of recurrent deep vein thrombosis.30
trial randomly assigned 909 adult
patients to PFO closure with the ACUTE MYOCARDIAL
STARFlex device versus medical ther- INFARCTION AND LEFT
apy and followed them for 2 years.52 VENTRICULAR THROMBUS
PC-Trial (414 patients) and RESPECT Acute myocardial infarction, especially
(980 patients) both studied device anteriorly, is associated with regional
closure with the AMPLATZER PFO wall-motion abnormalities and dimin-
Occluder versus medical therapy, fol- ished ejection fraction, predisposing
lowing patients for an average of 4 patients to the formation of a left ven-
and 2 years, respectively. 53,54 All tricular thrombus. Left ventricular dys-
three trials had point estimates sug- function allows relative stasis of blood
gesting that PFO closure was more within the ventricle and, coupled with
effective than medical therapy for re- endocardial injury and inflammation,
ducing event rates, but they failed to results in a higher risk of clot formation
show statistical significance for their and subsequent embolization. Without
primary end point in an intention-to- anticoagulation, the risk of emboliza-
treat analysis. Subgroup analysis of the tion in the first 3 months after a myo-
RESPECT trial suggested that PFO cardial infarction complicated by a left
closure may provide greater benefit for ventricular thrombus is 10% to 20%.30
patients with substantial right-to-left If a left ventricular thrombus is identified
shunts and atrial septal aneurysms, but on echocardiography or another imag-
this was not supported by the other ing modality in a patient with recent
studies. All three trials had significant myocardial infarction, then warfarin
limitations, including low numbers of therapy is recommended for at least
primary events, uneven dropout rates 3 months, with follow-up TTE ultimately
among the different arms, slow enroll- determining the duration of therapy. Anti-
ment, and short duration of follow-up coagulation may also be beneficial in

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 Cardioembolic Stroke

KEY POINTS
h The effectiveness patients without a left ventricular throm- heart failure and sinus rhythm on either
of anticoagulation bus but with anterior apical akinesis or anticoagulation or antiplatelet therapy
compared to dyskinesis. If patients are intolerant to should be individualized.
antiplatelet therapy warfarin therapy, dabigatran, rivaroxaban,
for secondary stroke or apixaban may be an alternative.30 AORTIC ARCH ATHEROSCLEROSIS
prevention in patients Aortic arch atheroma is an important
with heart failure HEART FAILURE risk factor for both cerebral and sys-
and sinus rhythm Patients with heart failure are at in- temic embolism, especially when
is uncertain. creased risk of stroke because of the plaque thickness measures 4 mm or
h Until further relative stasis of blood within the di- more, has mobile components, and is
randomized data are lated heart chambers (predisposing to noncalcified.61,62 Plaque ulceration is
obtained, guidelines thrombus formation) and high risk of thought to promote thrombogenicity,
suggest the use of superimposed AF. Several randomized and mobility suggests an unstable
antiplatelet and statin controlled trials have evaluated anti- plaque with superimposed thrombus.
therapy for patients
thrombotic therapies for use in patients TEE is better than TTE for evaluating
with ischemic stroke or
with heart failure and sinus rhythm, the aortic arch. Aortic arch athero-
transient ischemic
attack and aortic arch
with the largest and most recent being sclerosis shares many of the same risk
atheroma, since the the Warfarin Versus Aspirin in Reduced factors as ischemic stroke (eg, cigarette
effectiveness of Cardiac Ejection Fraction (WARCEF) smoking, hypertension, hyperlipid-
warfarin compared trial.59 WARCEF randomly assigned emia, diabetes mellitus), and most pa-
to antiplatelet therapy 2305 patients with sinus rhythm and tients benefit from aggressive risk
is uncertain. an ejection fraction of 35% or less to factor modification and statin and
receive either aspirin or warfarin and antiplatelet therapy. Since the risk of
followed them for a mean of 3.5 years. recurrent stroke is high (especially if
The rates of the primary outcome (time the atheroma is more than 4 mm in
to the first event in a composite end thickness or mobile), the best anti-
point of ischemic stroke, ICH, or death thrombotic therapy for secondary
from any cause) were 7.47 events per stroke prevention has been the subject
100 patient-years in the warfarin group of debate for many years. The Aortic
and 7.93 per 100 patient-years in the Arch Related Cerebral Hazard Trial
aspirin group, with no statistically sig- (ARCH) randomly assigned patients
nificant difference between the two with recent vascular events and aortic
groups. Warfarin, as compared to aspi- arch plaque measuring 4 mm or more
rin, was associated with a statistically or plaque measuring less than 4 mm but
significant reduction in the rate of is- with mobile elements to receive either
chemic stroke, 0.72 per 100 patient- aspirin plus clopidogrel or warfarin for
years versus 1.36 per 100 patient-years secondary prevention. The trial was
(hazard ratio 0.52; P=.005), with no terminated early for futility after enroll-
difference in the rates of ICH or death ment of 349 patients and was, thus, in-
between groups. The rate of major he- conclusive because of lack of power. A
morrhage (especially gastrointestinal) nonsignificant 24% reduction in rate of
was significantly higher with warfarin. recurrent stroke, myocardial infarction,
The WARCEF findings were confirmed peripheral embolism, and vascular
by a meta-analysis of four trials that death was seen in the aspirin plus
showed that warfarin was associated clopidogrel group, and these results
with a 41% reduction in the risk of may be the catalyst for further hypoth-
stroke and nearly twice the risk of major esis formation. Until further random-
hemorrhage.60 Because of these results, ized data are obtained, guidelines
the decision to place a patient with suggest the use of antiplatelet and statin
128 ContinuumJournal.com February 2017

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therapy for patients with ischemic 8. Jauch EC, Saver JL, Adams HP Jr, et al.
Guidelines for the early management of
stroke or TIA and aortic arch atheroma, patients with acute ischemic stroke: a
since the effectiveness of warfarin com- guideline for healthcare professionals
pared to antiplatelet therapy is uncer- from the American Heart Association/
American Stroke Association. Stroke
tain.30 Surgical resection of aortic arch 2013;44(3):870Y947. doi:10.1161/
plaque is not recommended for sec- STR.0b013e318284056a.
ondary stroke prevention. 9. Alhadramy O, Jeerakathil TJ, Majumdar SR,
et al. Prevalence and predictors of paroxysmal
atrial fibrillation on Holter monitor in
CONCLUSION patients with stroke or transient ischemic
Cardioembolism is an important cause attack. Stroke 2010;41(11):2596Y2600.
doi:10.1161/STROKEAHA.109.570382.
of stroke and is associated with a sig-
10. Stahrenberg R, Weber-Krüger M, Seegers J,
nificant amount of disability and high et al. Enhanced detection of paroxysmal
rate of recurrence. Cardioembolic stroke atrial fibrillation by early and prolonged
has multiple etiologies, thus the evalua- continuous Holter monitoring in patients
with cerebral ischemia presenting in sinus
tion should be systematic and compre- rhythm. Stroke 2010;41(12):2884Y2888.
hensive. AF remains the most common doi:10.1161/STROKEAHA.110.591958.
cause of cardioembolism, especially with 11. Pearson AC, Labovitz AJ, Tatineni S, Gomez CR.
an aging population, but various other Superiority of transesophageal
mechanisms exist, all of which require a echocardiography in detecting cardiac
source of embolism in patients with
tailored therapeutic approach supported cerebral ischemia of uncertain etiology.
by the latest clinical evidence. J Am Coll Cardiol 1991;17(1):66Y72.
doi:10.1016/0735-1097(91)90705-E.
12. American College of Cardiology Foundation
REFERENCES Appropriate Use Criteria Task Force;
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 Review Article

Large Artery
Address correspondence
to Dr John Cole, Maryland
Stroke Center, University of
Maryland School of Medicine,

Atherosclerotic 655 W Baltimore St, Room

12Y006, Baltimore, MD 21201,
[email protected].

Occlusive Disease Relationship Disclosure:

Dr Cole receives
research/grant support from
the American Heart
John W. Cole, MD, MS Association (15GPSPG23770000)
and the National Institutes of
Health (1U01NS069208),
which partially funded the
ABSTRACT writing of this article.
Purpose of Review: Extracranial or intracranial large artery atherosclerosis is often Unlabeled Use of
identified as a potential etiologic cause for ischemic stroke and transient ischemic Products/Investigational
Use Disclosure:
attack. Given the high prevalence of large artery atherosclerosis in the general pop- Dr Cole reports no disclosure.
ulation, determining whether an identified atherosclerotic lesion is truly the cause of a * 2017 American Academy
patient’s symptomatology can be difficult. In all cases, optimally treating each patient of Neurology.
to minimize future stroke risk is paramount. Extracranial or intracranial large artery
atherosclerosis can be broadly compartmentalized into four distinct clinical scenarios
based upon the individual patient’s history, examination, and anatomic imaging findings:
asymptomatic and symptomatic extracranial carotid stenosis, intracranial atheroscle-
rosis, and extracranial vertebral artery atherosclerotic disease. This review provides a
framework for clinicians evaluating and treating such patients.
Recent Findings: Intensive medical therapy achieves low rates of stroke and death in
asymptomatic carotid stenosis. Evidence indicates that patients with severe symptomatic
carotid stenosis should undergo carotid revascularization sooner rather than later and
that the risk of stroke or death is lower using carotid endarterectomy than with carotid
stenting. Specific to stenting, the risk of stroke or death is greatest among older
patients and women. Continuous vascular risk factor optimization via sustained
behavioral modifications and intensive medical therapy is the mainstay for stroke
prevention in the setting of intracranial and vertebral artery origin atherosclerosis.
Summary: Lifelong vascular risk factor optimization via sustained behavioral
modifications and intensive medical therapy are the key elements to reduce future
stroke risk in the setting of large artery atherosclerosis. When considering a revascu-
larization procedure for carotid stenosis, patient demographics, comorbidities, and the
periprocedural risks of stroke and death should be carefully considered.

Continuum (Minneap Minn) 2017;23(1):133–157.

INTRODUCTION findings: asymptomatic and symptom-

Large artery atherosclerosis of the head atic extracranial carotid stenosis, intra-
and neck is responsible for approxi- cranial atherosclerotic disease, and
mately 15% of all ischemic strokes. The extracranial vertebral artery atheroscle-
identification and appropriate treatment rotic disease. While the anatomic le-
of such atherosclerotic lesions is an es- sion locations differ for each of these,
sential skill for all physicians diagnosing it is important to note they all share
and treating patients with stroke. Large the same risk factor profiles and some-
artery atherosclerotic lesions can be what overlapping treatment options. In
broadly classified into four distinct clin- short, continuous vascular risk factor
ical scenarios as based upon the indi- optimization via sustained behavioral
vidual patient’s anatomic and clinical modifications and intensive medical

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 Atherosclerotic Occlusive Disease

KEY POINTS
h Continuous vascular therapy is critical to prevent stroke in lesion is proximal to a vascular territory
risk factor optimization the setting of large artery atheroscle- that corresponds to the patient’s stroke
via sustained behavioral rosis. In fact, specific to the settings of on imaging or symptoms in the setting
modifications and intracranial and vertebrobasilar ath- of a transient ischemic attack (TIA). To
intensive medical erosclerosis as well as asymptomatic optimize anatomic localization (ante-
therapy is critical to carotid atherosclerosis, risk factor rior versus posterior circulation) in the
prevent stroke in the modification is the primary treatment setting of both stroke and TIA, clini-
setting of large cians must take a detailed history, ask-
option. In patients with symptomatic
artery atherosclerosis. ing about symptoms (eg, weakness,
extracranial carotid atherosclerosis,
h It is important to treatment options also include revas- sensory changes, vision changes, bal-
determine if the ance problems) and whether these oc-
cularization procedures such as carotid
identified large artery curred recently in isolation or multiple
endarterectomy (CEA) and carotid ar-
atherosclerotic lesion times in the past, over both the near
is proximal to a tery stenting, but, again, optimal med-
ical therapy is a critical treatment and long term. All patients with
vascular territory that
modality. Appropriate patient selection stroke and suspected TIA warrant an
corresponds to the
expedited evaluation that can be sim-
patient’s stroke on and timing of such revascularization
imaging or symptoms
ply defined as from heart to head. In
procedures must also be considered.
in the setting of a other words, the heart, proximal aorta,
Across each of these four clinical sce-
transient ischemic attack. and vasculature of the head and neck
narios, the results of numerous ran-
should be evaluated, and clinical and
domized and nonrandomized clinical
laboratory testing related to vascular
trials lead to periodically updated meta-
risk factors should be performed on an
analyses and consensus guidelines that inpatient basis. While it is beyond the
provide evidence-based recommenda- scope of this review to provide detailed
tions for practicing clinicians. While testing recommendations, at a mini-
each of these four clinical scenarios mum, a transthoracic echocardiogram,
could easily be (and often is) the sub- brain imaging via an emergent CT and
ject of independent reviews, this article then MRI, and vessel imaging of the
aims to provide a concise framework head and neck by CT angiography
for clinicians evaluating and treating (CTA) or magnetic resonance angiogra-
patients across all four scenarios, em- phy (MRA) should be performed in all
phasizing key clinical considerations, clin- patients with stroke and TIA. If large
ical trial evidence, and the most recent artery atherosclerotic disease is iden-
professional and societal guidelines. tified, other techniques, such as carotid
Doppler studies, contrast-enhanced
CONSIDERATIONS ACROSS MRA, and even judicious use of cere-
ALL CASES OF LARGE bral angiogram, can be used to better
ARTERY ATHEROSCLEROSIS define stenosis severity. To identify
While the clinical manifestations of patients at the greatest risk for stroke,
large artery atherosclerosis of the head large artery atherosclerotic plaque
and neck differ based upon the lesion stability and emboli potential can be
location, it is important to note that accessed via transcranial Doppler
they all share the same risk factor pro- (TCD) microembolus detection and
files, similar workups, and somewhat other, more research-oriented, tech-
overlapping treatment options. niques, such as plaque echolucency
measurements, that have yet to be
Clinical Presentation and Workup formally defined.1
First, it is important to determine if the Positive imaging demonstrating a
identified large artery atherosclerotic clearly defined infarction can make
134 ContinuumJournal.com February 2017

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 KEY POINT
the large artery atherosclerosis etio- lines and position statements is a critical h Population-wide
logic diagnosis easier, assuming the tool for physicians and other health improved control of
infarct is located in a vascular territory professionals working to reduce stroke hypertension,
distal to a highly stenosed vessel or an risk. In 2014, the American Heart Associ- dyslipidemia, and
irregularly calcified plaque. Large artery ation (AHA) and the American Stroke diabetes mellitus,
atherosclerosis leads to ischemic symp- Association (ASA) released updated coupled with a
tomatology via two mechanisms: em- Guidelines for the Primary Prevention reduction in tobacco
bolic phenomena and regional brain of Stroke3 and updated Guidelines for use, has resulted in a
hypoperfusion. Clearly embolic phe- the Prevention of Stroke in Patients decline in stroke
nomena should be considered as With Stroke and Transient Ischemic mortality from the third
to the fifth leading
symptomatic, necessitating clinicians Attack.4 These guidelines emphasize
cause of death in the
to consider potential revascularization an individualized approach to life-
United States.
procedures as possible to the specific style modification, including physical
case. Stroke in the setting of hypoper- activity, diet and nutrition, smoking ces-
fusional states from large artery ath- sation, and management of obesity and
erosclerosis, while symptomatic, offers dyslipidemia. Taken in aggregate, these
additional choices such as intensive med- guidelines offer up-to-date comprehen-
ical therapy in combination with per- sive evidence-based recommendations
missive hypertension, thereby allowing for the primary and secondary preven-
the individual patient time to develop tion of stroke, including those related
improved collateral circulatory path- to large artery atherosclerosis. While it
ways and potentially reducing the need is beyond the scope of this review to
for a revascularization procedure. cover all the latest recommendations
regarding vascular risk factor control, a
Vascular Risk Factors few specifics as related to large artery
Across all locations of large artery ath- atherosclerosis are warranted.
erosclerosis discussed in this article, Vascular risk factor control via in-
continuous lifelong vascular risk factor tensive medical therapy. Based upon
optimization via sustained behavioral the results of numerous recent clinical
(lifestyle) modifications and intensive trials, and as incorporated into the afore-
medical therapy is critical for stroke pre- mentioned guidelines, intensive (or
vention. This point cannot be empha- best) medical therapy is emphasized
sized enough. Over the past 10 years, for all patients with large artery ath-
our understanding of the importance erosclerosis. While the precise defini-
of medical management in the setting tion of intensive medical therapy can
of atherosclerosis has markedly in- be debated, Table 7-1 summarizes the
creased. Population-wide improved key elements.5 Intensive medical ther-
control of hypertension, dyslipidemia, apy includes smoking cessation, diet,
and diabetes mellitus, coupled with a exercise, control of blood pressure
reduction in tobacco use, has resulted (including diagnosis of the physiologic
in a decline in stroke mortality from drivers of resistant hypertension by mea-
the third to the fifth leading cause of suring plasma renin and aldosterone),6
death in the United States.2 Clinicians antiplatelet therapy (mono versus dual),
should take pride in these facts, as and intensive lipid-lowering therapy, not
these improvements are based upon just achieving a target level of fasting
their efforts in implementing profes- low-density lipoprotein cholesterol
sional society position statements and (LDL-C). Overall, the goals of these ther-
guidelines. As such, maintaining a work- apies are first to stop and then reverse
ing knowledge of these evolving guide- large artery atherosclerotic plaque
Continuum (Minneap Minn) 2017;23(1):133–157 ContinuumJournal.com 135

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 Atherosclerotic Occlusive Disease

TABLE 7-1 Key Elements of Intensive Medical Therapy in the Setting of Large Artery
Atherosclerotic Diseasea

Measure Intervention and Comments

Lifestyle modification
For all patients Show patients images of their plaques, compare the patient’s plaque burden
with that of healthy persons of the same age and sex, describe the risks associated
with that degree of plaque burden and progression and the possibility of
plaque regression.
Smoking cessation Counseling, liberal nicotine replacement therapy, varenicline or bupropion
(depending on history of depression or contraindications).
Mediterranean diet Counseling, provision of a booklet summarizing advice and providing recipes and
links to Internet sites; repeated at follow-up visits as necessary.
Obesity Counseling on caloric restriction, referral to dietitian, bariatric surgery in refractory
patients with severe obesity and diabetes mellitus or insulin resistance.
Exercise Recommendations for moderate exercise at least 30 minutes per day, with advice
tailored to the patient’s disabilities, if any.
Blood pressure Advice on how to reduce salt intake, limit alcohol intake, avoid licorice
and decongestants.
Medical therapy
Blood pressure control Physiologically individualized therapy for resistant hypertension based on renin/
aldosterone profile; switch nonsteroidal anti-inflammatory drugs to sulindac.
Lipid lowering Statins dosed according to plaque progression to the highest dose tolerated, then
addition of ezetimibe and, as needed for low high-density lipoprotein/high
triglycerides, the addition of fibrates or niacin. Additional considerations: (1) In the
setting of combined statin and ezetimibe therapy, alanine aminotransferase (ALT)
should be monitored; (2) gemfibrozil should not be initiated in patients on statin
therapy due to an increased risk of rhabdomyolysis; (3) fenofibrate may be
considered concomitantly with a low- or moderate-intensity statin only if the
benefits from atherosclerotic cardiovascular disease risk reduction or triglyceride
lowering when triglycerides are Q500 mg/dL are judged to outweigh the potential
risk for adverse effects.
Antiplatelet agents Low-dose aspirin, with addition of clopidogrel for 3 months while optimizing other
vascular risk factors, in patients with severe stenosis or other indicators of high risk.
Anticoagulation In patients with atrial fibrillation or other potential cardiac source of emboli.
Insulin resistance Pioglitazone, reinforcement of lifestyle issues.
Diabetes mellitus Reinforcement of lifestyle changes, referral to diabetes mellitus clinic.
Other considerations
Obstructive sleep apnea Causes nighttime high blood pressure; referral for sleep study and faithful
continuous positive airway pressure use.
Poor dentition Induces systemic inflammation that can destabilize atherosclerotic plaques;
dental evaluation.
Gout Induces systemic inflammation that can destabilize atherosclerotic plaques;
diagnose and treat.
a
Data from Spence JD, Curr Neurol Neurosci Rep.5 link.springer.com/article/10.1007%2Fs11910-015-0605-6.

136 ContinuumJournal.com February 2017

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progression. Such regimens clearly are PG.001) with no increase in major
effective. One study demonstrated that hemorrhage by the short-term use of
by implementing a regimen similar to the combination of clopidogrel and
that outlined in Table 7-1, the risk of aspirin, showing it to be more effective
stroke and myocardial infarction (MI) than aspirin alone.12 More recently, the
was reduced by more than 80% among CHANCE investigators demonstrated
patients with asymptomatic carotid ste- that the early benefit of clopidogrel-
nosis.7 Similarly, the Stenting vs. Aggres- aspirin treatment in reducing the risk
sive Medical Management for Preventing of subsequent stroke persisted after
Recurrent Stroke in Intracranial Steno- 1 year of follow-up.13 Again, no differ-
sis (SAMMPRIS) trial demonstrated that ence in moderate or severe hemorrhage
“aggressive” (intensive) medical therapy was demonstrated in the combined
resulted in better outcomes than stenting treatment group versus the aspirin-
among patients with intracranial stenosis.8 alone group (0.3% versus 0.4%, re-
Antiplatelet agents. Antiplatelet spectively; P=.44). Dual antiplatelet
agents, including aspirin and clopidogrel, therapy with aspirin and clopidogrel
are routinely used for primary and was also used in the SAMMPRIS trial
secondary stroke prevention in the of intracranial arterial stenosis, which
setting of large artery atherosclerosis. In demonstrated that aggressive medical
individuals whose 10-year risk of stroke management was superior to percuta-
is greater than 10% and whose risk of neous transluminal angioplasty and
stroke outweighs the risks associated stenting.8 Of note, the CHANCE study
with aspirin therapy, the latest guide- was performed in China; while the
lines for the primary prevention of results might be generalizable to
stroke recommend the daily use of Western populations, this hypothesis
aspirin.3 A cardiovascular risk calculator is currently being evaluated in the on-
can assist in estimating 10-year risk (my. going Platelet-Oriented Inhibition in
americanheart.org/cvriskcalculator).9 New TIA and Minor Ischemic Stroke
Aspirin is not recommended for pri- (POINT) trial.14
mary stroke prevention in individuals Several recent studies using TCD
with lower risk or in those with diabetes evaluations to assess for microemboli
mellitus who do not have other risk found that dual antiplatelet therapy is
factors. In those for whom aspirin more efficacious than aspirin alone in
therapy is deemed appropriate, faith- reduction of microemboli for both in-
ful daily use of low-dose aspirin is con- tracranial15 and extracranial16 arterial
sidered sufficient. Since coated aspirin stenosis. While dual antiplatelet therapy
is less efficacious than uncoated aspirin is commonly used for risk reduction in
in about 40% of individuals, uncoated the setting of coronary disease, particu-
aspirin is recommended. Clopidogrel larly in the setting of cardiac stenting, it
alone reduces stroke by only 1.7% is not widely used in carotid disease
more than aspirin10 and is thus only based on the results of one study in
marginally better, whereas combined which an excess of bleeding was seen
aspirin-dipyridamole is no better than in the dual therapy group.17 To reduce
clopidogrel.11 The Clopidogrel in High- the risk of intracranial hemorrhage in
risk Patients With Acute Non-disabling the setting of dual antiplatelet therapy,
Cerebrovascular Events (CHANCE) effective blood pressure control is crit-
study indicated that secondary stroke ical, as evidenced by the North American
may be reduced by 32% (hazard ratio Symptomatic Carotid Endarterectomy
0.68; 95% confidence interval 0.57Y0.81; Trial (NASCET), in which effective
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 Atherosclerotic Occlusive Disease

KEY POINT
h Hypertension and blood pressure control reduced intra- 2015 Systolic Blood Pressure Interven-
diabetes mellitus cranial hemorrhage to 0.4% of strokes.18 tion Trial (SPRINT) comparing a systolic
remain undertreated, Gastrointestinal hemorrhages could blood pressure target of less than
and personalized theoretically be reduced by the identi- 120 mm Hg (intensive treatment) to a
approaches to fication and treatment of Helicobacter target of less than 140 mm Hg (standard
lifestyle changes and pylori infections prior to the initiation treatment) was stopped early as related
medical therapy are of dual therapy. to a significantly lower rate of vascular
critical for successful In summary, dual antiplatelet therapy events in the intensive-treatment group
stroke prevention. can be considered across most settings than in the standard-treatment group
of large artery atherosclerosis, particu- (1.65% per year versus 2.19% per year;
larly in symptomatic carotid stenosis hazard ratio with intensive treatment,
or if the patient was already on mono- 0.75; 95% confidence interval 0.64Y0.89;
therapy at the time of his or her event. PG.001).20 While lowering blood pres-
The optimal duration of therapy will sure is strongly associated with reduc-
remain a topic of debate until further tion of stroke risk, the reduction of
informed by randomized clinical trials blood pressure to lower targets may
and their subgroup analyses. In the not be beneficial in all groups of
meantime, as consistent with SAMMPRIS, individuals, such as in patients with
3 months of dual antiplatelet therapy is flow-limiting large artery atherosclero-
reasonable while working to optimize sis or diabetes mellitus or the very
vascular risk factors, including healthy elderly. Diabetes mellitus is another
lifestyle decision making. well-established risk factor for stroke
Treatment of vascular risk factors. and large artery atherosclerosis. Opti-
Treatment of vascular risk factors, in- mal glucose control is achieved by
cluding dyslipidemia, hypertension, and reinforcing lifestyle changes (eg, dietary
diabetes mellitus, over both the near changes, regular exercise, weight loss)
and long term is of critical importance and through the faithful use of medica-
in the prevention and treatment of tions. Hypertension and diabetes
atherosclerotic disease. Recent changes mellitus remain undertreated, and per-
to lipid guidelines dramatically alter the sonalized approaches to lifestyle
prior emphasis focusing on specific changes and medical therapy are critical
LDL-C targets.19 Instead, the guide- for successful stroke prevention.
lines now emphasize the 10-year risk for
the development and progression of Other Emerging Risk Factors
atherosclerotic cardiovascular disease. Other emerging risk factors for large
As based on an individual’s estimated artery atherosclerosis have been iden-
risk, a statin at low, moderate, or high tified, including elevated homocyste-
potency is now prescribed. Although ine, fibrinogen, lipoprotein (a), and
these new guidelines shift the emphasis C-reactive protein levels. Other lesser-
away from specific lipid targets, total known risk factors implicated include
cholesterol and high-density lipopro- obstructive sleep apnea,21 gout,22 and
tein values are components of the cardio- poor dentition.23 Future studies should
vascular risk calculator previously work to verify the results of these pre-
mentioned.9 Hypertension also con- liminary reports while considering im-
tinues to be a major well-documented plications for preventive strategies.
and modifiable risk factor for stroke, From a genetic standpoint, a recently
with the treatment of hypertension being published study by the National Insti-
the most effective strategy for stroke tutes of Health (NIH)/National Institute
prevention across all populations. The of Neurological Disorders and Stroke
138 ContinuumJournal.com February 2017

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 KEY POINT
(NINDS) Stroke Genetics Network (SiGN) results at the level of the individual h Physicians should
details the largest and most comprehen- can be confusing, particularly if an in- consider each patient on
sive genome-wide association study dividual does not fulfill the clinical trial an individual basis,
of stroke and its subtypes ever per- inclusion criteria driving the recom- working to optimize
formed.24 This study verified several pre- mendations. As such, physicians should their risk factor profile
vious genetic associations with ischemic consider each patient on an individual over the long term while
stroke and identified a new risk locus on basis, working to optimize their risk inferring upon the most
chromosome 1p13. Of the replicated factor profile over the long term while recent professional
loci, it is notable that this study confirmed inferring from the most recent guide- society statement
the association between the HDAC9 lines. While the described multifaceted recommendations.
locus and large artery atherosclerotic approach of intensive medical therapy
ischemic stroke. Interestingly, this same reduces stroke risk in all patients with
locus (and the same specific variant) has large artery atherosclerosis, broadly
also been reproducibly associated with classifying patients with large artery
coronary artery disease, suggesting a atherosclerosis into one of four clinical
shared underlying causal gene and scenarios as based upon the individual
mechanism. The novel locus identified patient’s history, examination, and
by the SiGN investigators was detected anatomic imaging findings is a use-
near TSPAN2 and was also found to be ful way to help clarify treatment op-
associated with large artery atherosclero- tions. These four scenarios include
sis. TSPAN2 is a scaffolding protein asymptomatic and symptomatic extra-
expressed in large arteries. This locus cranial carotid stenosis, intracranial
has not been reproducibly associated atherosclerosis, and atherosclerotic
with coronary artery disease in genome- vertebrobasilar disease.
wide association studies. This suggests
that TSPAN2 is potentially specific to EXTRACRANIAL CAROTID
ischemic stroke and therefore may pro- ATHEROSCLEROSIS
vide insight into the pathophysiology of Carotid atherosclerosis accounts for
large artery atherosclerotic ischemic approximately 10% of cases of ische-
stroke rather than just generic athero- mic stroke. Although carotid artery
sclerosis. Studies regarding the mecha- stenosis is a risk factor for stroke, not
nistic links between both HDAC9 and every carotid stenosis carries the same
TSPAN2 with large artery atherosclerotic risk for future stroke. Assuming a
stroke are ongoing. Given the rapid relevant stenosis is identified, key
evolution of genomic medicine, it is factors to consider include the degree
anticipated that in the near future dis- of stenosis and the stability of the
ease susceptibility within individuals, plaque in the setting of the individual
families, and populations will be able patient. Clinicians should work toward
to be genetically evaluated, thereby answering two questions: (1) Which
allowing preventive stroke therapies patients should opt for revasculariza-
as based on individualized genotype. tion procedures (versus intensive med-
In summary, the most recent guide- ical therapy alone)? and (2) Which is
lines emphasize intensive medical ther- the appropriate revascularization pro-
apy with a focus on optimal vascular risk cedure, CEA or carotid artery stenting?
factor control but now implementing a
more patient-centered approach than Assessment of Carotid Stenosis
in the past. Given that the results from Hemodynamically significant carotid ste-
multiple clinical trials drive these recom- nosis corresponds to a 60% diameter-
mendations, the applicability of these reducing stenosis and produces a pressure
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 Atherosclerotic Occlusive Disease

drop across the lesion or a flow reduc- arterial segment distal to the stenosis
tion distal to the lesion. Using the where the arterial walls first become
North American measurement method parallel.3 In contrast, the European
(Figure 7-1), the minimal residual lumen method (Figure 7-1) directly estimates
at the level of the stenotic lesion is the stenosis at the internal carotid bulb
compared to the diameter of the more using the formula: stenosis = (1jA/C) 
distal internal carotid artery (ICA) 100%, where C is the estimated diameter
where the walls of the artery first be- of the disease-free carotid bulb. Catheter
come parallel using the formula: steno- angiography is considered the gold
sis = (1jA/B)  100%, where A is the standard for assessing stenosis but
diameter at the point of maximum carries a small risk of causing a stroke.
stenosis and B is the diameter of the Duplex ultrasound is the most
commonly used method to screen the
extracranial carotid artery for athero-
sclerotic stenosis and carries the lowest
risks and costs. Of note, duplex ultra-
sound may not accurately differen-
tiate between high-grade stenosis and
complete occlusion, with additional
testing required in such situations.
MRA noninvasively provides images of
both the cervical and intracranial vas-
culature. Notably, time-of-flight MRA
without contrast may overestimate the
degree of stenosis; thus, a gadolinium-
enhanced MRA may be useful, partic-
ularly when working to differentiate
high-grade stenosis from total occlu-
sion. Clinicians should be mindful
that nephrogenic systemic fibrosis is a
rare complication among patients with
poor renal function in the setting of
gadolinium use.
CTA is yet another method that can
be used to evaluate both the extra-
cranial and intracranial carotid cir-
culation. CTA disadvantages include
radiation exposure and the need for IV
injection of contrast material, with a
creatinine higher than 1.7 or a glomer-
ular filtration rate less than 45 mL/min/
1.73 m2 being common limiting fac-
Schematic contrasting tors. Additionally, atherosclerotic calci-
FIGURE 7-1
internal carotid artery fications with similar density to the
stenosis measurement
methods. The North American contrast material may confound accu-
measurement method: % stenosis = rate measurements of the stenosis. On
(1jA/B)  100%. The European physical examination, a carotid bruit
method: % stenosis = (1jA/C) 
100%. can reflect an underlying carotid steno-
sis; however, sensitivity can be limited.
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Asymptomatic Extracranial outcome of any stroke or death occur-
Carotid Stenosis ring in the perioperative period and
All patients with carotid stenosis have ipsilateral cerebral infarction thereafter
atherosclerosis that warrants the imple- was evaluated. A clear benefit was seen
mentation of intensive medical ther- in those undergoing CEA, leading the
apy as soon as possible. While several study to be stopped early. Patients were
methods exist to identify those patients randomly assigned to surgery as based
with carotid stenosis who are at greater on contrast angiography that demon-
risk for future events, probably the best strated diameter-reducing lesions of
validated methodology is TCD embolus 60% or greater using the North American
detection. In one study evaluating measurement method. Both treatment
319 patients with asymptomatic carotid groups received what was considered the
stenosis, it was found that the 10% of best medical management at the time.
patients with two or more microemboli The aggregate risk over 5 years for any
in 1 hour of monitoring had a 15.6% perioperative stroke, ipsilateral stroke,
1-year risk of stroke, while patients and death was 5.1% among the surgical
without microemboli had only a 1% patients and 11% among the medical
1-year risk of stroke.25 Similar find- patients (relative risk reduction 53%;
ings were demonstrated in follow-up 95% confidence interval 22% to 72%).
studies of 468 patients7 and in the The Asymptomatic Carotid Surgery
Asymptomatic Carotid Emboli Study Trial (ACST) included 3120 patients with
(ACES) among 467 patients (3.62% asymptomatic carotid stenoses of 60%
annual ipsilateral stroke risk with em- or greater, as measured by duplex ultra-
bolic signals versus 0.70% without em- sonography.29 Subjects were randomly
bolic signals).26 As a general guideline, assigned to immediate CEA versus in-
population screening for asymptomat- definite deferral of the operation. The
ic carotid artery stenosis is not recom- trial end points were perioperative mor-
mended by the US Preventive Services tality and morbidity (stroke and MI) and
Task Force, which found “no direct the incidence of non-perioperative
evidence that screening adults with du- stroke. Excluding perioperative events
plex ultrasonography for asymptomatic and nonstroke mortality, stroke risks
stenosis reduces stroke.”27 In general, (immediate versus deferred CEA) were
since about 2005, the risk of ipsilateral 4.1% versus 10.0% at 5 years (gain 5.9%;
stroke with intensive medical therapy 95% confidence interval 4.0% to 7.8%)
has been much lower than the risk of and 10.8% versus 16.9% at 10 years
CEA or carotid artery stenting, even in (gain 6.1%; 95% confidence interval
the carefully controlled clinical trials 2.7% to 9.4%). Subgroup analysis dem-
discussed in this article. The studies of onstrated the benefits of CEA were
risk stratification using TCD suggest confined to patients younger than
this may be a useful tool to identify 75 years of age.
those patients with the highest near- Some caveats regarding these trials
term risk of ipsilateral stroke. should be considered. First, it should
Endarterectomy for asymptomatic be noted that both ACAS and ACST
carotid stenosis. The Asymptomatic were conducted at a time when best
Carotid Atherosclerosis Study (ACAS), medical management was far less
which included 1662 patients, was the than the intensive medical therapy
first large-scale study comparing CEA implemented today. Second, careful
plus best medical therapy to medical screening of surgeons participating in
therapy alone.28 A composite primary these clinical trials potentially led to
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 Atherosclerotic Occlusive Disease

KEY POINT
h Current surgical results that cannot be generalized to the 10.2% with CEA (P=.20) and 5.4% with
best practice restricts community. This is particularly evi- carotid artery stenting at 30 days and
carotid endarterectomy dent when the complications from 21.5% among patients who received
for asymptomatic angiography are removed from the CEA and 9.9% among patients who
carotid stenosis to surgical groups; when this is done, received carotid artery stenting (P=.02)
patients with 70% or the 30-day rate of stroke and death at 1 year. Of note, 3-year outcomes
greater carotid stenosis for CEA in ACAS drops to 1.52%.30 among patients receiving carotid artery
if the surgery can be Study complication rates are often stenting demonstrated a significantly
performed with a 3% lower than what is seen in standard higher death rate (20.0%) than stroke
or less risk of perioperative practice. In general, current surgical rate (10.1%).34 Further, there was no
complications.
best practice restricts CEA for asymp- medically treated control group in
tomatic carotid stenosis to patients with SAPPHIRE. The high complication rates
70% or greater carotid stenosis if the in both treatment groups raised con-
surgery can be performed with a 3% or cerns about the benefit of either inter-
less risk of perioperative complications. vention over medical therapy alone.
Of note, one recent review suggested The Carotid Revascularization Endar-
that for patients who are medically terectomy Versus Stenting Trial (CREST)
stable and have a life expectancy of at enrolled patients with both symptom-
least 5 years and a high-grade (80% or atic and asymptomatic carotid stenosis
greater) asymptomatic carotid stenosis who were eligible for either CEA or
at baseline or have progression to 80% carotid artery stenting.35 Patients with
or greater stenosis despite intensive asymptomatic carotid stenosis could be
medical therapy while under observa- included in the study if their stenosis
tion, CEA is reasonable, provided the was 60% or greater on angiography,
combined perioperative risk of stroke 70% or greater on ultrasound, or 80% or
and death is less than 3%.31 Further greater on CTA or MRA if the stenosis
research regarding this topic is ongo- on ultrasound was 50% to 69%.3,35
ing, with the NINDS-sponsored Carotid Patients were randomly assigned based
Revascularization and Medical Manage- upon symptom status. The primary
ment for Asymptomatic Carotid Stenosis end point was a composite of stroke,
Study (CREST-2) comparing centrally MI, or death resulting from any cause
managed intensive medical therapy during the periprocedural period or
alone to intensive medical therapy with any ipsilateral stroke within 4 years
CEA or carotid artery stenting.32 after randomization.3,35 No statistically
Endovascular treatment for asymp- significant difference was shown in
tomatic carotid stenosis. Carotid an- the 4-year occurrence rates of the
gioplasty and stenting was initially composite primary end point between
evaluated in patients thought to be at carotid artery stenting (7.2%) and CEA
high risk for CEA in the Stenting and (6.8%; hazard ratio, 1.11; 95% confi-
Angioplasty With Protection in Pa- dence interval 0.81Y1.51; P=.51),
tients at High Risk for Endarterectomy without any significant heterogeneity
(SAPPHIRE) trial.33 Using a composite based on symptom status. Notably,
outcome of stroke, MI, or death within the primary end point in CREST
30 days or death resulting from neuro- demonstrated an interaction with
logic cause or ipsilateral stroke between age, with age older than 70 years
31 and 365 days, it was demonstrated showing a significant benefit for CEA
that carotid artery stenting was not in- over carotid artery stenting. There-
ferior (within 3%; P=.004) to CEA. fore, it is important to consider
Rates of stroke, MI, or death were patient age when considering the
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two procedures in any specific pa- of these results. The ongoing CREST-2
tient. Periprocedural stroke occurred trial will compare centrally managed
more often in patients undergoing intensive medical therapy with or with-
carotid artery stenting than CEA (4.1% out carotid artery stenting or CEA
versus 2.3%; P=.01), with peripro- (Case 7-1).
cedural MI occurring less frequently In practice, carotid artery stenting
in those undergoing carotid artery should be reserved for patients who
stenting than CEA (1.1% versus 2.3%; are at high risk of stroke and have
P=.03). Unfortunately, as consistent anatomic features that would make CEA
with several of these trials, the lack of difficult. Such considerations include
medically treated control groups in severe comorbidities (eg, congestive
CREST complicates the interpretation heart failure, angina, coronary artery

Case 7-1
A 77-year-old woman presented for a neurologic evaluation after ‘‘some blockage’’ was detected in her
‘‘right neck artery’’ during ultrasound screening at a local mall. She had a history of dyslipidemia and
hypertension and was a former heavy smoker, and her mother had a stroke in her late fifties. She denied
prior stroke or transient ischemic attack symptoms. She was on aspirin 325 mg/d, atorvastatin 20 mg/d,
amlodipine 10 mg/d, and a diuretic. Her blood pressure was 130/80 mm Hg, and her heart rate was
70 beats/min and regular. Neurologic examination was normal, except for the presence of a right carotid
bruit. Carotid duplex ultrasonography was ordered and revealed bilateral plaques, with 70% or greater
stenosis (peak systolic velocity = 242 cm/s) on the right and less than 50% (peak systolic velocity = 72 cm/s)
on the left (Figure 7-2). CT angiography (CTA) was performed and interpreted as showing approximately
70% stenosis on the right and approximately 30% stenosis on the left. Low-density lipoprotein was
77 mg/dL. The patient was counseled regarding the uncertain benefit of revascularization in her age group.

FIGURE 7-2 Carotid duplex ultrasonography of the patient in Case 7-1. A, Right internal carotid artery: greater than
70% stenosis (peak systolic velocity = 242 cm/s). B, Left internal carotid artery: less than 50% stenosis
(peak systolic velocity = 72 cm/s).

Comment. This patient should be placed on intensive medical therapy, including her current agents
and increasing her moderate-intensity statin therapy of atorvastatin to 40 mg/d as based upon her age
and low-density lipoprotein level. This type of patient could be considered for enrollment in a clinical trial
such as the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Study
(CREST-2), which is comparing outcomes with intensive medical therapy alone versus intensive medical
therapy plus carotid endarterectomy or carotid artery stenting.

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 Atherosclerotic Occlusive Disease

KEY POINT
h As consistent with disease, ejection fraction 30% or less, Affairs Cooperative Study Program
recent guidelines, recent MI, severe lung or renal dis- (CSP).37 Patients with symptomatic
patients with ease) and anatomic factors (eg, prior carotid stenosis included those who
asymptomatic carotid neck operation or irradiation, post- had both greater than 70% ipsilateral
stenosis should be CEA restenosis, surgically inaccessible carotid stenosis and TIAs, transient
prescribed a daily aspirin lesions above C2 or below the clavicle, monocular blindness, or nondisabling
and statin and screened contralateral carotid occlusion, contra- strokes. A pooled analysis of these three
for other treatable risk lateral vocal cord palsy, or the presence randomized trials included more than
factors with appropriate of a tracheostomy).4 As consistent 3000 patients with symptomatic carotid
medical therapies with recent guidelines, patients with stenosis and demonstrated a 30-day
and lifestyle changes
asymptomatic carotid stenosis should stroke and death rate of 7.1% in patients
instituted.
be prescribed a daily aspirin and statin who were surgically treated.38 In pa-
and screened for other treatable risk tients with 70% to 99% (severe) steno-
factors with appropriate medical thera- sis, NASCET criteria found that for every
pies and lifestyle changes instituted. It six patients treated, one major stroke
is reasonable to consider performing would be prevented at 2 years (ie, a
CEA in patients who are asymptomatic number needed to treat of 6). Addition-
and have greater than 70% stenosis of ally, all three trials demonstrated that
the ICA if the risk of perioperative for patients with less than 50% (mild)
stroke, MI, and death is low (less than stenoses, surgical intervention did not
3%). In patients with greater than 50% reduce stroke risk. The role of CEA was
stenosis, it is reasonable to perform an- less clear among patients with symp-
nual duplex ultrasonography; however, tomatic stenosis in the 50% to 69%
screening low-risk populations for (moderate) range. Among the 858
asymptomatic carotid artery stenosis is patients who were symptomatic with
not recommended.3,4 50% to 69% stenosis in NASCET, the
5-year rate of any ipsilateral stroke
Symptomatic Extracranial was 15.7% in those surgically treated
Carotid Stenosis versus 22.2% in those medically treated
Over the past half century, numerous (P=.045).18 Therefore, 15 patients
clinical trials have compared CEA plus would have to undergo CEA to prevent
medical therapy to medical therapy one ipsilateral stroke during the 5-year
alone in the setting of symptomatic follow-up period. As such, CEA is only
carotid stenosis. Many of these studies justifiable when the risk-benefit ratio
predate the intensive medical therapy favors the patient when evaluating sur-
now recommended. Further, CEA tech- gical and anesthetic risks. Given that
niques have evolved and carotid artery medical management has improved
stenting has emerged as an alternative since NASCET, current guidelines ad-
preventive treatment. vise proceeding with CEA in the setting
Endarterectomy for symptomatic of symptomatic stenosis only if the
carotid stenosis. Three important surgeon’s rate for perioperative stroke
randomized clinical trials established or death is less than 6%.
the superiority of CEA plus medical In summary, for patients with a
therapy over medical therapy alone in TIA or ischemic stroke within the past
the setting of symptomatic high-grade 6 months and ipsilateral severe (70%
(greater than 70% angiographic steno- to 99%) carotid artery stenosis, CEA
sis) carotid stenosis: the European Ca- is recommended; for those with mod-
rotid Surgery Trial (ECST),36 NASCET,18 erate (50% to 69%) carotid stenosis,
and the US Department of Veterans CEA is recommended depending on
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 KEY POINTS
patient-specific factors, such as age, sex, intracerebral hemorrhage risk may be h For patients with a
and comorbidities; and for those with a increased in patients with large cere- transient ischemic attack
degree of stenosis of less than 50%, bral infarctions undergoing early sur- or ischemic stroke within
CEA and carotid artery stenting are gery via a hyperperfusion or reperfusion the past 6 months and
not recommended.3,4 syndrome because of the sudden in- ipsilateral severe (70%
Patient-selection criteria influencing crease in perfusion of the vasculature to 99%) carotid artery
surgical risk should include sex and age. distal to stenosis. Optimal control of stenosis, carotid
Subgroup analyses of the NASCET trial blood pressure before, during, and after endarterectomy is
raised concerns regarding the benefit of the procedure is emphasized. As a gen- recommended; for those
CEA in women with symptomatic eral rule, before elective CEA, a systolic with moderate (50% to
69%) carotid stenosis,
carotid stenosis, suggesting that women pressure of 160 mm Hg or less should
carotid endarterectomy is
are more likely to have less favorable be targeted, with therapy continuing
recommended depending
outcomes, including surgical mortality, up to the morning of surgery, with the on patient-specific factors,
neurologic morbidity, and recurrent possible exceptions of angiotensin- such as age, sex, and
carotid stenosis (14% in women versus converting enzyme inhibitors and comorbidities; and for
3.9% in men; P=.008).39 Notably, CREST angiotensin II receptor antagonists, those with a degree of
was designed with preplanned subgroup with normal therapy restarting as soon stenosis of less than 50%,
analysis intended to evaluate the effects as possible after surgery with a goal carotid endarterectomy
of sex and age on the primary outcome systolic pressure of 140 mm Hg or less. and carotid artery stenting
end point and found no significant However, it is important to emphasize are not recommended.
interaction in the primary end point by that therapy should be tailored to the h The optimal
sex. However, CREST did identify a sig- individual patient. timing of carotid
nificant interaction in relation to age, Endovascular treatment for symp- revascularization via
with superior results for CEA in patients tomatic carotid stenosis. The theo- carotid endarterectomy
older than 70 years of age.35,40 retical advantages of carotid artery after a completed
The optimal timing of carotid revas- stenting being a less invasive procedure nondisabling stroke has
been defined to be
cularization via CEA after a completed resulting in decreased patient discom-
within 2 weeks if no
nondisabling stroke has been defined fort and a shorter recovery period were
contraindications exist.
to be within 2 weeks if no contraindica- indeed demonstrated in CREST, with
tions exist. This time period is driven by an improved health-related quality of
data from the three major randomized life in the perioperative period, although
clinical trials mentioned previously, this difference was not sustained at
among others. In these trials, the 1 year. 41 As mentioned previously, in
median time from randomization to the past carotid artery stenting was typi-
surgery was 2 to 14 days, with approx- cally reserved for patients who were
imately one-third of the perioperative considered high risk for CEA. The
strokes occurring within this time in- majority of the published trials evaluat-
terval. Among the patients who were ing carotid artery stenting have been
medically treated, the risk of stroke was industry sponsored, focusing on the
also greatest in the first 2 weeks. After efficacy of a single stent/neuroprotection
2 to 3 years, the annual rate of stroke system. The previously described
among the patients who were medically SAPPHIRE trial had the primary objec-
treated approached that of patients tive of comparing the safety and effi-
with asymptomatic carotid stenosis. cacy of carotid artery stenting with an
Also of note, these three trials included embolic protection device to CEA in
only patients with TIA or nondisabling 334 high-risk patients with symptom-
strokes, further reporting low intra- atic and asymptomatic carotid steno-
cerebral hemorrhage rates as associ- sis.33 In the periprocedural period (up
ated with CEA (0.2%). Perioperative to 30 days), the cumulative incidence of
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 Atherosclerotic Occlusive Disease

KEY POINT
h Carotid artery stenting stroke, MI, or death was 4.8% among 2502 asymptomatic and symptomatic
can be considered as an patients assigned to receive a stent and participants with carotid stenosis (greater
alternative to carotid 9.8% among those assigned to undergo than 50% by angiography or greater
endarterectomy for endarterectomy. One-year rates of the than 70% by ultrasonography).35 No sig-
patients who are primary end point (death, stroke, or nificant difference was demonstrated in
symptomatic with MI at 30 days plus ipsilateral stroke or the composite primary outcome (30-day
greater than 70% death of neurologic causes within rate of stroke, death, and MI and 4-year
stenosis if the 31 days to 1 year) were 12.2% for carotid ipsilateral stroke) among those treated
anticipated rate of artery stenting versus 20.1% for CEA with carotid artery stenting versus CEA
periprocedural stroke or (P=.05) and were primarily driven by (7.2% versus 6.8%; P=.51). Among
death is less than 6%;
differences in the periprocedural MI patients with asymptomatic carotid
age should be
rates. Overall, the primary conclusion stenosis, the 4-year primary outcome
considered when
choosing between
from this trial was that carotid artery rate was 5.6% with carotid artery stent-
carotid endarterectomy stenting was noninferior to CEA in this ing versus 4.9% with CEA (P=.56),
and carotid high-risk cohort. However, outcome and among patients with symptomatic
artery stenting. analyses raised concerns that neither carotid stenosis, the rates were 8.6%
procedure was beneficial as compared with carotid artery stenting versus 8.4%
with medical management in patients with CEA (P=.69). When analyzing all
with asymptomatic carotid stenosis. patients, an interaction between age
Several other randomized controlled and treatment efficacy was shown
trials have compared CEA and carotid (P=.02), demonstrating increased risk
artery stenting for patients with symp- of carotid artery stenting in patients who
tomatic carotid stenosis, including the were older. The risk of MI did not
Carotid and Vertebral Artery Translu- increase with age in either treatment
minal Angioplasty Study (CAVATAS),42 group. The effects of age were primarily
Endarterectomy Versus Angioplasty in driven by stroke risk, which showed
Patients with Symptomatic Severe Carotid greater increase with age in the carotid
Stenosis (EVA-3S), Stent-Supported Per- artery stenting group than in the CEA
cutaneous Angioplasty of the Carotid group. The age at which the hazard
Artery Versus Endarterectomy (SPACE), ratio was 1.0 was approximately 70 years
and the International Carotid Stenting for the primary outcomes and 64 years
Study (ICSS). These trials have been for stroke. No difference in periproce-
analyzed in isolation and the latter three dural events was shown between carotid
in aggregate,43,44 with a preplanned meta- artery stenting and CEA among men, but
analysis demonstrating the rate of stroke a nonstatistically significant trend to-
and death at 120 days after randomiza- ward fewer events was demonstrated
tion to be 8.9% for carotid artery stent- with women and CEA. Periprocedural
ing and 5.8% for CEA (P=.0006). complications were lower in CREST
Notably, in subgroup analyses, among compared with older trials. An analysis
patients 70 years of age or older, the for the type of periprocedural compli-
rate of stroke or death at 120 days was cation identified important distinctions.
12.0% with carotid artery stenting com- Patients who had carotid artery stenting
pared with 5.9% with CEA (P=.0053). had lower rates of MI than patients who
In patients younger than 70 years of had CEA (1.1% versus 2.3%; 95% con-
age, no significant difference in out- fidence interval 0.26Y0.94) but higher
come was shown between carotid rates of stroke (4.1% versus 2.3%; 95%
artery stenting and CEA.44 confidence interval 1.14Y2.82).35
CREST compared the efficacy of ca- In summary and as consistent with
rotid artery stenting versus CEA among published guidelines, carotid artery
146 ContinuumJournal.com February 2017

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 KEY POINTS
stenting can be considered as an alter- for repeat or surveillance ultrasonog- h For patients who are
native to CEA for patients with symp- raphy after carotid revascularization older (70 years of
tomatic carotid stenosis with greater is not well established. age or older), carotid
than 70% stenosis if the anticipated Extracranial-intracranial bypass. endarterectomy may be
rate of periprocedural stroke or death The International Cooperative Study of associated with
is less than 6%; age should be consid- Extracranial-Intracranial (EC-IC) Bypass improved outcome
ered when choosing between CEA and Study was the first major trial of EC-IC compared with carotid
carotid artery stenting. For older pa- bypass surgery, randomly assigning artery stenting, in
tients (70 years of age or older), CEA 1377 participants within 3 months of particular when arterial
may be associated with improved out- a TIA or minor ischemic stroke to sur- anatomy is unfavorable
gery or best medical management.46 for endovascular
come compared with carotid artery
intervention. For
stenting, in particular when arterial Eligible patients had severe stenosis of
patients who are
anatomy is unfavorable for endovas- the (surgically inaccessible) ipsilateral
younger, carotid artery
cular intervention (Case 7-2). For distal ICA, occlusion of the ipsilateral stenting is equivalent to
younger patients, carotid artery stent- midcervical ICA, or severe narrowing or carotid endarterectomy
ing is equivalent to CEA in terms of risk occlusion of the ipsilateral middle in terms of risk
for periprocedural complications (eg, cerebral artery (MCA). After approxi- for periprocedural
stroke, MI, or death) and long-term mately 5 years of follow-up, the primary complications (eg,
risk for ipsilateral stroke.3 outcome (fatal or nonfatal stroke) oc- stroke, myocardial
Follow-up imaging and restenosis curred more often in the surgical infarction, or death) and
after carotid endarterectomy or carotid patients. EC-IC bypass was more re- long-term risk for
artery stenting. In ACAS, the risk for cently evaluated for ipsilateral stroke ipsilateral stroke.
restenosis after CEA, defined as 60% or prevention in 195 patients with evi- h Extracranial-intracranial
greater narrowing of the lumen, was dence of hemodynamic cerebral ische- bypass surgery is not
greatest in the first 18 months follow- mia distal to a symptomatic ipsilateral recommended for
ing surgery (7.6%), with a low incidence carotid occlusion using positron emis- patients with a recent
sion tomography (PET).47 The trial was transient ischemic
of 1.9% over the next 42 months. Of
attack or ischemic
note, these 18-month estimates are stopped early because of futility. The
stroke ipsilateral to a
similar to the findings from the CEA 30-day rate of ipsilateral stroke was
stenosis or occlusion
arm of the CREST trial, which demon- 14.4% in the surgical arm and 2.0% in of the middle cerebral
strated a 6.3% risk of restenosis greater the nonsurgical arm. However, the or carotid artery
than 70% after 24 months of observa- 2-year rate for the primary outcome and is considered
tion. In a 2012 review representing the (30-day stroke or death or subsequent investigational for those
most reliable data on this topic, 2191 ipsilateral stroke) was similar (P=.78), with progressive
CREST patients were evaluated using 21.0% in the surgical group and 22.7% symptoms despite optimal
standardized ultrasonography to exam- in the nonsurgical group. As such, medical management.
ine the incidence of restenosis.45 At EC-IC bypass surgery is not recom-
2 years, no difference in the incidence mended for patients with a recent
of restenosis was shown between the TIA or ischemic stroke ipsilateral to
two groups, 6% among patients who a stenosis or occlusion of the middle
received carotid artery stenting and cerebral or carotid artery and is con-
6.3% among patients who received CEA sidered investigational for those with
(P=.58). Diabetes mellitus, hyperten- progressive symptoms despite optimal
sion, and female sex were indepen- medical management.
dent predictors of restenosis. Smoking
was an independent predictor for re- INTRACRANIAL
stenosis with CEA but not with carotid ATHEROSCLEROSIS
artery stenting. Therefore, unless a pa- Intracranial atherosclerosis is a common
tient has recurrent symptoms, the need cause of stroke carrying a high risk for

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 Atherosclerotic Occlusive Disease

Case 7-2
A 78-year-old man with a history of diabetes mellitus and current smoking presented to the
emergency department because of several episodes of transient speech difficulty and right hand
weakness occurring over the previous 2 days. He also reported flulike symptoms, including a productive
and persistent cough that had worsened recently. He stated he would not have come in, but
‘‘he couldn’t hold his cigarettes.’’ He was on aspirin 81 mg/d and metformin but was not on a statin. His
blood pressure was 135/75 mm Hg. Examination was notable for coarse breath sounds bilaterally and
decreased fine finger strength in the right hand rated at 3/5, but was otherwise normal. His initial head
CT was read as normal, with a subsequent brain MRI demonstrating a small cortical infarct in the left
frontal lobe on the diffusion sequence. Magnetic resonance angiography (MRA) demonstrated severe left
internal carotid artery (ICA) stenosis just distal to the bulb (Figures 7-3A and 7-3B). Carotid duplex
ultrasonography demonstrated severe left ICA stenosis (80% to 99%) and less than 40% stenosis on the
right side. Catheter-based angiography confirmed a focal high-grade ICA stenosis (Figure 7-3C). Given
the clinical transient ischemic attacks, the small infarct consistent with the proximal large artery
atherosclerosis lesion, and the large amount of brain at risk, he was scheduled for an urgent carotid
endarterectomy (CEA) to occur the following day.

FIGURE 7-3 Imaging of the patient in Case 7-2 with severe atherosclerotic high-grade stenosis
in the left internal carotid artery just distal to the bifurcation as shown on magnetic
resonance angiography (MRA) sequences (A, time-of flight; B, noncontrast arterial
spin labeling); trickle flow seen on conventional catheter angiogram (C).

Comment. Because of this patient’s age and symptoms, urgent carotid revascularization was
recommended, with CEA preferred. Because of the higher complication rate with carotid artery stenting
in patients 70 years of age or older, CEA is preferred over carotid artery stenting. His blood pressure
was normal, lowering his risks associated with reperfusion. He should be counseled to stop smoking
and provided with aggressive medical therapy and close outpatient follow-up.

148 ContinuumJournal.com February 2017

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 KEY POINT
recurrence. To date, only a few large lead to reduced cerebral blood flow, h Current guidelines
multicenter randomized trials evaluat- thereby causing an increased stroke recommend that
ing stroke preventive therapies for this risk in patients with large vessel ste- patients with a stroke or
disease have been conducted; the two nosis, follow-up analysis demonstrated transient ischemic
primary trials are the Warfarin-Aspirin that patients with a mean systolic attack caused by 50%
Symptomatic Intracranial Disease blood pressure less than 140 mm Hg to 99% stenosis of a
(WASID) study48 and the previously had a significantly reduced risk of re- major intracranial artery
mentioned SAMMPRIS study.8 Notably, current stroke compared with patients be treated with aspirin
the results of these studies infer on the with a mean systolic blood pressure 325 mg/d in preference
management of both symptomatic and of 140 mm Hg or higher (P=.01).50 to warfarin.
asymptomatic intracranial atheroscle- Patients with a mean LDL-C less than
rotic disease. 100 mg/dL had a significantly reduced
In the WASID study, 569 patients risk of recurrent stroke as compared
were randomly assigned to aspirin with patients with a mean LDL-C of
1300 mg or warfarin (target interna- 100 mg/dL or higher (P=.03).
tional normalized ratio [INR] 2 to 3) The SAMMPRIS trial compared
following a TIA or stroke that was at- endovascular therapy versus medical
tributable to 50% to 99% intracranial therapy for the prevention of recurrent
stenoses of the MCA, intracranial ICA, stroke among patients with symptom-
intracranial vertebral artery, or basilar atic intracranial arterial stenosis.8 In
artery. The trial was stopped early SAMMPRIS, patients with TIA or stroke
because of higher rates of death and within the past 30 days related to 70%
major hemorrhage in the warfarin arm. to 99% stenosis of a major intracranial
Over a mean follow-up of 1.8 years, the artery were randomly assigned to ag-
primary end point (ischemic stroke, gressive medical management alone
brain hemorrhage, or nonstroke vascu- or aggressive medical management
lar death) occurred in 22% of patients in plus percutaneous transluminal angio-
both treatment arms. The 1- and 2-year plasty and stenting (PTAS) using a self-
rates of stroke in the territory of the expanding stent. Intensive medical
stenotic artery were 11% and 13% in therapy in both arms was the same
the warfarin arm and 12% and 15% in and consisted of aspirin 325 mg/d and
the aspirin arm, respectively. In a clopidogrel 75 mg/d for 90 days after
combined analysis of both arms, the enrollment, intensive risk factor man-
rates of stroke in the territory of the agement that primarily targeted systolic
stenotic artery at 1 year were approx- blood pressure lower than 140 mm Hg
imately 7% in patients with 50% to (lower than 130 mm Hg in patients with
69% stenosis and 18% in patients with diabetes mellitus) and LDL-C lower
70% or greater stenosis.49 Follow-up than 70 mg/dL, and a lifestyle mod-
analyses did not identify any sub- ification program. 8 Enrollment in
group that benefited from warfarin, SAMMPRIS was stopped early after
including patients who had their quali- 451 patients had been assigned because
fying event while taking aspirin. As the 30-day rate of stroke and death
such, current guidelines recommend (primary end point) was significantly
that patients with a stroke or TIA higher in the PTAS arm. Within 30 days
caused by 50% to 99% stenosis of a of enrollment, a statistically significant
major intracranial artery be treated with difference in stroke or death was seen
aspirin 325 mg/d in preference to war- between the two arms, occurring in
farin. Further, while concern existed 13 patients (5.8%) in the medical arm
that blood pressure lowering could and in 33 patients (14.7%) in the PTAS
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 Atherosclerotic Occlusive Disease

KEY POINTS
h Current guidelines arm (P=.002). Also, at 1 year, the primary while already being treated with anti-
recommend that in end point rate was significantly higher thrombotic therapy. As such, current
patients with a recent in the PTAS arm (20.0%) versus the guidelines recommend that in patients
stroke or transient medical arm (12.2%; P=.009), primar- with a recent stroke or TIA (within
ischemic attack (within ily driven by the increased 30-day 30 days) attributable to severe stenosis
30 days) attributable to events in the PTAS arm. A subsequent (70% to 99%) of a major intracranial
severe stenosis (70% to analysis of the 30-day events in the artery, it is reasonable to add clopid-
99%) of a major SAMMPRIS PTAS arm revealed that a ogrel 75 mg/d to aspirin for 90 days,
intracranial artery, it is large number of the ischemic strokes along with the initiation of high-
reasonable to add occurred from occlusion of perforators potency statin therapy and a goal sys-
clopidogrel to aspirin for
(basilar perforators to the pons or tolic blood pressure below 140 mm Hg
90 days, along with
lenticulostriate perforators from the (Case 7-3).3 For patients with a stroke
the initiation of
high-potency statin
MCA) with the PTAS occluding the or TIA attributable to stenosis (greater
therapy and a goal perforator takeoffs (ie, ostium). Of than 50%) of a major intracranial artery,
systolic blood pressure the strokes that occurred within 30 days, angioplasty or stenting is not recom-
below 140 mm Hg. 10 of 33 (30.3%) in the PTAS arm and mended given the low rate of stroke
h For patients with a none of 12 (0%) in the medical arm with medical management and the
stroke or transient were symptomatic brain hemorrhages inherent periprocedural risk of endo-
ischemic attack (P=.04). The results of the medical vascular treatment, even among those
attributable to stenosis arm demonstrated better than ex- already taking an antithrombotic agent
(greater than 50%) pected 1-year event rates as compared at the time of the stroke or TIA.3 No-
of a major intracranial with WASID (12.2% observed versus tably, the current guidelines emphasiz-
artery, angioplasty 25% expected) and were thought to be ing maximal medical therapy after a
or stenting is not associated with the intensive medical stroke or TIA also apply to asymptom-
recommended given therapy used in the trial. A key distinc- atic intracranial atherosclerotic disease.
the low rate of tion is that patients in the WASID study One other notable study in the set-
stroke with medical
were treated with aspirin 1300 mg/d, while ting of intracranial stenosis is the previ-
management and the
the SAMMPRIS medical arm used aspi- ously described EC-IC Bypass Study.46
inherent periprocedural
risk of endovascular
rin 325 mg/d (in combination with While the focus of this study was pa-
treatment, even clopidogrel 75 mg/d) while achieving tients who were symptomatic with
among those favorable rates of stroke as compared extracranial carotid occlusion, it also in-
already taking with the intervention arm. Lower doses cluded patients with MCA stenosis and
an antithrombotic of aspirin have also been effective in patients with ICA stenosis above the
agent at the time of other large trials of secondary preven- second cervical vertebra (C2). Specifi-
the stroke or transient tion, many of which enrolled patients cally, 109 patients with 70% or greater
ischemic attack. with more heterogeneous stroke sub- MCA stenosis and 149 patients with 70%
types. Notably, of the 451 patients en- or greater ICA stenosis were randomly
rolled in SAMMPRIS, 284 (63%) had assigned to bypass surgery or medical
their qualifying event while undergoing treatment with aspirin 1300 mg/d and
antithrombotic therapy. In this large followed for a mean of about 4.5 years.
subgroup of the SAMMPRIS cohort, A statistically significant difference was
the rates of the primary end point were demonstrated in the rates of stroke
16.0% and 4.3% at 30 days and 20.9% during follow-up in patients with 70%
and 12.9% at 1 year in the stenting and or greater MCA stenosis, favoring the
medical arms, respectively (P=.03).51 medical arm (23.7%; 14 of 59) as com-
Overall, these results indicate that pared to the bypass arm (44%; 22 of
stenting (with the tested system) is not 50). Among patients with 70% or greater
a safe or effective rescue treatment for ICA stenosis above C2, the stroke rates
patients who experience a TIA or stroke during follow-up were 36.1% (26 of
150 ContinuumJournal.com February 2017

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 Case 7-3
A 69-year-old man presented with multiple episodes of transient dizziness,
feeling off balance, and double vision occurring over the previous 2 weeks.
His double vision persisted, prompting him to come to the emergency
department. He rarely saw doctors and appeared to have a history of
uncontrolled hypertension, dyslipidemia, and diabetes mellitus. He
reported remote cigarette smoking and continued to smoke one cigar per
day. His initial head CT was negative for acute ischemia; however, the
accompanying head and neck CT angiogram demonstrated severe but
nonYflow-limiting stenosis in the distal third of the basilar artery. Brain
MRI demonstrated a small region of ischemia in the superior right pons in
the distribution of a perforator originating from the region of the
stenosed distal basilar artery. The patient was placed on aspirin 81 mg/d,
clopidogrel 75 mg/d, and rosuvastatin 40 mg/d, with blood pressure and
diabetes mellitus medications instituted. After 3 months of dual
antiplatelet therapy, clopidogrel was discontinued, and he continued on
the aspirin and his other medications.
Comment. This patient was appropriately placed on a Stenting vs.
Aggressive Medical Management for Preventing Recurrent Stroke in
Intracranial Stenosis (SAMMPRIS)-style regimen. At present, no proven role
exists for endovascular intervention in this type of patient. The importance
of medication compliance and lifestyle modifications over the long term
should be emphasized and periodically reinforced through close
outpatient monitoring.

72) in the medical arm and 37.7% (29 intensive medical therapy, endovas-
of 77) in the bypass arm. Given these cular stenting, and, in rare cases, open
results, EC-IC bypass has largely been surgical revascularization; while maxi-
discontinued as a treatment for intra- mal medical therapy is the mainstay of
cranial stenosis. treatment in asymptomatic extracranial
vertebral artery atherosclerotic dis-
EXTRACRANIAL VERTEBRAL ease. Unfortunately, scant randomized
ARTERY ATHEROSCLEROTIC trial results exist specific to this set-
DISEASE ting, although analyses of some par-
Extracranial vertebral artery atheroscle- ticipants in the previously mentioned
rotic disease is a well-established cause CAVATAS trial42 as well as the Oxford
of posterior circulation stroke. Proximal Vascular Study (OXVASC)54 indicate that
vertebral (V1 segment) lesions account treatment should focus on vascular risk
for approximately 9% of all posterior factor reduction. The most relevant
circulation strokes,52 while vertebral study performed on this topic, the
artery ostial lesions may account for 2015 phase 2 Vertebral Artery Stenting
another one-third.53 Consistent with the Trial (VAST), was conducted in the
anterior circulation, the two primary Netherlands and identified patients
stroke mechanisms include plaque with a recent TIA or minor stroke asso-
rupture with subsequent artery-to- ciated with an extracranial (or intracra-
artery thromboembolism and hemody- nial) vertebral artery stenosis of at least
namic insufficiency. Treatment options 50%.55 Patients were randomly as-
for symptomatic extracranial vertebral signed to stenting plus best medical
artery atherosclerotic disease include treatment or best medical treatment

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 Atherosclerotic Occlusive Disease

KEY POINT
h Routine preventive alone. All patients received best medical similar condition of recently symptom-
therapy with an treatment at the discretion of the atic large vessel intracranial stenosis, that
emphasis on treating neurologist, including anti- an aggressive medical therapy strategy,
antithrombotic therapy, thrombotic agents, a statin, and rigorous including dual antiplatelet therapy for
lipid lowering, blood control of other vascular risk factors. 3 months, statin therapy, blood pres-
pressure control, and The primary outcome was the compos- sure and glycemic control, and risk
lifestyle optimization ite of vascular death, MI, or any stroke factor modification, is highly effective
is recommended for within 30 days after the start of treat- for secondary prevention of stroke. It
all patients with ment. The trial was stopped after the remains unclear if aggressive medical
recently symptomatic inclusion of 115 patients because of therapy is as effective for patients with
extracranial vertebral
altered regulatory requirements, with symptoms caused by hemodynamic
artery stenosis.
57 patients assigned to stenting and compromise from extracranial vertebral
58 to medical treatment alone. Three artery atherosclerotic disease.
patients in the stenting group experi- In summary and as per current guide-
enced the primary outcome (5%, 95% lines, routine preventive therapy with
confidence interval 0% to 11%) versus an emphasis on antithrombotic therapy,
one patient in the medical treatment lipid lowering, blood pressure control,
group (2%, 95% confidence interval 0% and lifestyle optimization is recom-
to 5%). During the planned 4 years of mended for all patients with asymptom-
follow-up, 60 serious adverse events atic or recently symptomatic extracranial
(eight strokes) occurred in the stenting vertebral artery stenosis (Case 7-4).3
group and 56 serious adverse events Numerous retrospective nonrandom-
(seven strokes) in the medical treat- ized case series specific to stenting in
ment group. The investigators concluded the setting of extracranial vertebral ar-
that stenting of symptomatic vertebral tery atherosclerotic disease have been
artery stenosis was associated with a published. One review including 980
major periprocedural vascular compli- patients from 27 studies demonstrated
cation in about 1 in 20 patients and the a technical success rate of 99%, with a
risk of recurrent vertebrobasilar stroke periprocedural risk of 1.2% for stroke
under best medical treatment alone and 0.9% for TIA.57 In this study, parti-
was low. Based upon these results, a cipants were followed for an average
phase 3 study was deemed unwar- of 21 months perioperatively, with
ranted. Another study that completed vertebrobasilar territory stroke occur-
enrollment in February 2015 is the ring in 1.3% and TIA occurring in 6.5%.
Vertebral Artery Ischaemia Stenting Trial In a different prospectively maintained
(VIST).56 This is a UK multiple-center database of 114 patients undergoing
randomized controlled trial comparing stenting for 127 vertebral ostial lesions,
vertebral artery stenting/angioplasty of which 88% were considered to be
versus the best medical therapy alone either “highly likely” or “probably” the
in patients with symptomatic vertebral cause of the patient’s posterior circula-
artery stenosis greater than 50%. Re- tion symptoms, recurrence of symptoms
cruitment was stopped early at 182 at 1 year was just 2% after stenting.53
patients because of a cessation of In another review of 300 endovascular
funding as related to low recruitment. interventions in symptomatic vertebral
The primary end points are perioper- artery origin stenosis, periprocedural
ative risk and long-term efficacy, not neurologic complications occurred in
further specified; the final results are 5.5%, and the restenosis rate was 26%.58
pending. One can also infer from Based upon these results, current
SAMMPRIS, 8 which evaluated the guidelines3,4 indicate that endovascular
152 ContinuumJournal.com February 2017

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 KEY POINT

Case 7-4 h Current guidelines

indicate that
A 69-year-old woman presented to the emergency department with acute
endovascular stenting of
dizziness and difficulty walking. She reported a history of hypertension,
patients with extracranial
dyslipidemia, and former smoking. She was obese and also reported
vertebral stenosis may
chronic fatigue and poor sleep. Further, she stated she had been
be considered when
noncompliant with her medications as she had run out of them a few
patients are having
weeks previously. At presentation, her blood pressure was 167/88 mm Hg
symptoms despite optimal
and she was in normal sinus rhythm. Pertinent findings on examination
medical treatment.
included mild dysmetria in the left arm and leg and gait instability. Initial
head CT demonstrated diffuse periventricular white matter changes but
no areas of obvious ischemia. MRI demonstrated a small acute left
cerebellar ischemic stroke, and magnetic resonance angiography (MRA) of
the head and neck demonstrated diffuse nonYflow-limiting atherosclerosis
throughout the anterior and posterior head and neck vasculature.
Notably, the left vertebral artery takeoff was poorly visualized. A
subsequent CT angiogram (CTA) of the neck demonstrated stenosis at the
origin of both vertebral arteries, left greater than right as associated with
calcific plaques. The patient was placed on daily aspirin, clopidogrel, and
40 mg rosuvastatin, and her blood pressure medication was reinstituted with
good control. After discharge, an outpatient sleep study demonstrated
obstructive sleep apnea, and she was placed on nighttime continuous
positive airway pressure. After 3 months of dual antiplatelet therapy, the
clopidogrel was discontinued while she continued on daily aspirin and a
statin as well as her other medications.
Comment. Similar to the patient in Case 7-3, this patient was placed on
a Stenting vs. Aggressive Medical Management for Preventing Recurrent
Stroke in Intracranial Stenosis (SAMMPRIS)-style regimen. At present,
endovascular intervention has no proven role in symptomatic extracranial
vertebral artery disease. The importance of medication compliance and
lifestyle modifications over the long term should be reinforced. Stenting
and open surgical procedures can be considered if she experiences further
ischemia despite optimal medical therapy.

stenting of patients with extracranial rate in the bare metal stent group
vertebral stenosis may be considered (33.57%) as compared to the drug-
when patients are having symptoms eluting stent group (15.49%) was
despite optimal medical treatment. identified (P=.001). When compared
Symptomatic restenosis rates in the with the drug-eluting stent group,
setting of extracranial vertebral artery the bare metal stent group also had a
atherosclerotic disease stenting remain significantly higher rate of recurrent
uncertain and are a topic of study. A symptoms (2.76% versus 11.26%; odds
2016 pooled analysis59 of five studies ratio = 3.32, P=.01).
comparing drug-eluting versus bare- Open surgical procedures for re-
metal stents found no significant dif- vascularization of extracranial verte-
ference in the technical success (odds bral artery atherosclerotic disease
ratio = 1.53, P=.62), clinical success include vertebral artery transposition
(odds ratio = 1.92, P=.27), and peri- and vertebral artery endarterectomy.
procedural complications (odds ratio = While such procedures are performed
0.74, P=.61) between the two stent rarely, they can be considered in pa-
types. A significantly higher restenosis tients with persistent symptoms despite

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 Atherosclerotic Occlusive Disease

KEY POINT
h While vertebral intensive medical therapy. In one modifications and intensive medical
artery transposition older series of 27 patients, no periop- therapy.
and vertebral artery erative stroke or death was seen and
endarterectomy are two permanent neurologic complica- ACKNOWLEDGMENTS
performed rarely, they tions occurred (one case of Horner This work was supported by grants
can be considered in syndrome and one case of hoarseness); from the American Heart Association
patients with in addition, two patients developed (Cardiovascular Genome Phenome
persistent symptoms posterior circulation neurologic symp-
despite intensive Study ID number 15GPSPG237700000),
toms after the perioperative period.60
medical therapy. the National Institutes of Health
Larger randomized trials are required
(1U01NS069208), and the US Depart-
to better define evidence-based rec-
ment of Veterans Affairs.
ommendations for patients with extra-
cranial vertebral artery atherosclerotic
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2. CDC 2013. Detailed Tables for the National

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 Review Article

Arterial Ischemic Stroke

Address correspondence to
Dr Warren D. Lo, Nationwide
Children’s Hospital, 700
Children’s Dr, EDU 582,
Columbus, OH 43205,
warren.lo@
nationwidechildrens.org.
in Children and
Relationship Disclosure:
Dr Lo receives research/grant
support from the Eunice
Young Adults
Kennedy Shriver National
Institute of Child Health and Warren D. Lo, MD; Riten Kumar, MD, MSc
Human Development
(5R01HD068345,
1R01HD074574,
R01HD083384) and the
ABSTRACT
National Institute of Purpose of Review: This article reviews risk factors, recurrence risk, evaluation, man-
Neurological Disorders and agement, and outcomes of arterial ischemic stroke in children and young adults.
Stroke (U10NS086484,
U54 NS065705) and receives Recent Findings: The risk for recurrence and mortality appear to be low for neonatal
publishing royalties from and childhood stroke. Most children have relatively mild deficits, but those who have
Springer. Dr Kumar serves on greater neurologic deficits, poststroke epilepsy, or strokes early in life are at risk for
the medical advisory board
of Bayer Corporation and lower overall cognitive function. Stroke recurrence and long-term mortality after stroke
receives research/grant support in young adults are greater than originally thought. Cognitive impairments, depres-
from the Hemostasis and sion, and anxiety are associated with higher levels of poststroke unemployment and
Thrombosis Research Society
(HTRS Mentored Research represent targets for improved poststroke care. Poststroke care in young adults involves
Award) and the International more than medical management. Self-reported memory and executive function im-
Society on Thrombosis pairments may be more severe than what is detected by objective measures. As-
and Haemostasis.
Unlabeled Use of
sessment of possible cognitive impairments and appropriate management of
Products/Investigational psychological comorbidities are key to maximizing the long-term functional outcome
Use Disclosure: of stroke survivors.
Drs Lo and Kumar discuss the
unlabeled/investigational use
Summary: Childhood and young adult stroke survivors survive for many more years
of antithrombotic and than older patients with stroke. To ensure that these survivors maximize the pro-
thrombolytic agents in ductivity of their lives, neurologists must not only optimize medical management but
children with stroke.
also recognize that impairments in cognition and mood may be remediable barriers
* 2017 American Academy
of Neurology. to long-term functional independence.

Continuum (Minneap Minn) 2017;23(1):158–180.

INTRODUCTION cords with brain imaging reports deter-

This article reviews risk factors, recur- mined an incidence of 2 per 100,000 to
rence risk, evaluation, management, and 4 per 100,000 in children 1 month to
outcomes of arterial ischemic stroke in 18 years of age.1 The group with the
children and young adults. In particular, highest incidence of ischemic stroke is
recent insights in risk factors and recur- neonates, where the estimated incidence
rence risks in children, the implications ranges from 1 in 4400 to 1 in 7700 live
for secondary prevention of stroke in births.2,3 Strokes also occur in utero.
children, and a detailed emphasis on While the incidence is unknown, the US
poststroke outcomes are highlighted. prevalence of cerebral palsy is 3.1 per
1000 children eight years of age.4 Uni-
EPIDEMIOLOGY lateral spasticity accounts for 19% to
Ischemic stroke is uncommon in chil- 35% of the total, and many of these
dren beyond the neonatal period. One cases are due to in utero stroke.
population-based estimate in California Ischemic stroke in young adults is
that combined a search of medical re- estimated to account for 15% of all cases.5

158 ContinuumJournal.com February 2017

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 KEY POINTS
Whether the incidence is changing is treatment with IV thrombolysis or me- h In children, the group
unclear. Evidence from epidemiologic chanical thrombectomy. A major con- with the highest
studies in the United States suggests tributor to delayed diagnosis in children incidence of ischemic
that the prevalence may be rising, while is the wide range of stroke mimics that stroke is neonates,
a study in Sweden found no evidence have to be considered in the differential where the estimated
for a changing incidence. A study of a diagnosis.14 In a study of children pre- incidence ranges from
US national hospital discharge database senting to an emergency department 1 in 4400 to 1 in 7700
found that from the years 1995/1996 to with the sudden onset of brain dysfunc- live births.
2007/2008, the prevalence of individ- tion,15 migraine, seizures, and Bell’s h Strokes also occur in
uals 15 to 34 years of age discharged palsy were the most commonly iden- utero. While the
with ischemic stroke increased by 30%, tified diagnoses (Table 8-1). Stroke was incidence is unknown,
and the prevalence of individuals 35 to the fourth most common diagnosis but the US prevalence of
44 years of age discharged with ischemic only accounted for 7% of cases.15 In cerebral palsy is 3.1
stroke increased by 37%.6 Consistent contrast, in one study of adults with per 1000 children at
eight years of age.
with this finding was a population-based acute focal neurologic dysfunction,
Unilateral spasticity
study in the greater Cincinnati-Northern stroke accounted for 69% of attacks,
accounts for 19% to
Kentucky region that found the propor- 35% of the total, and
tion of all types of strokes occurring in many of these cases are
adults 20 to 50 years of age significantly TABLE 8-1 Stroke Mimics in due to in utero stroke.
increased from 13% to 19% from 1993/ Children by
Frequencya h The relative rarity of
1994 to 2005.7 In contrast, a population- ischemic stroke in
based study from Gothenburg, Sweden, children and young
found no change in the incidence of b Migraine
adults contributes to
ischemic stroke from 1987 to 2006 for b Seizures/epilepsy delays in diagnosis.
adults 20 to 54 years of age.8 b Bell’s palsy
An in-depth discussion of the global
aspects of stroke is beyond the scope b Conversion disorder
of this review; however, it is important b Miscellaneous neurologic
to note that 89% of strokes in children disorders
and 78% of strokes in young and middle- b Miscellaneous non-neurologic
aged adults occur in low- and middle- disorders
income nations.9 Furthermore, 63% of b Syncope
first-time ischemic strokes and 80% of
b Headache not otherwise
first-time hemorrhagic strokes occur
specified
in low- and middle-income countries.10
The high frequency of stroke in low- b Encephalopathy
and middle-income countries is a sig- b Cerebellitis
nificant social burden. b Central nervous system (CNS)
demyelination
DELAYS IN DIAGNOSIS
b Peripheral nerve disorder
The relative rarity of ischemic stroke in
children and young adults contributes b CNS infection
to delays in diagnosis.11,12 A 2014 study b Drug intoxication
from the United Kingdom documented
b CNS tumors
the delays for children that occur at
every step, with a median total delay of b Cord demyelination
a
24 hours between symptom onset and Data from Mackay MT, et al, Neurology.15
neurology.org/content/82/16/1434.short.
diagnosis.13 This delay in diagnosis far
exceeds the therapeutic window for
Continuum (Minneap Minn) 2017;23(1):158–180 ContinuumJournal.com 159

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 Stroke in Children and Young Adults

KEY POINT
h The striking difference while seizures, sepsis, and toxic/metabolic were misdiagnosed and seven were ini-
between stroke in conditions accounted for much of the tially released from emergency evalua-
children and young remainder.16 Therefore, when an acute tion before stroke was diagnosed. What
adults is the pattern of brain attack is assessed in a child, many can delay stroke diagnosis further is a
identified risk factors more alternative diagnoses must be con- nonlocalizing presentation or if the symp-
and associated diseases. sidered than in an adult. Ideally, some toms are atypical or nonspecific, such as
type of recognition tool would help isolated acute vestibular symptoms.18
distinguish strokes from stroke mimics
in children.15 To date, no such tool has RISK FACTORS AND
been developed. The authors found that RECURRENCE RISK
an adult stroke tool did not distinguish The striking difference between stroke
children who had acute stroke from those in children and young adults is the
who had acute facial or limb weakness pattern of identified risk factors and
due to other causes.17 associated diseases (Table 8-2).19Y21
Young adults who present with strokes In the Vascular Effects of Infection in
may encounter similar delays in diag- Pediatric Stroke (VIPS) study of 355
nosis when stroke is not considered children who had arterial ischemic
because of their age. In one prospective stroke after the neonatal period, 30%
series, 57 individuals 16 to 50 years of had congenital or acquired cardiac dis-
age had acute stroke. Of these, eight ease, 36% had definite vascular disease

TABLE 8-2 Risk Factors and Comorbidities for Stroke in Children and
Young Adultsa

Pediatricb Young Adultc

Definite Arteriopathy 36% Well-Documented Risk Factors
Arterial dissection 7% Tobacco smoking 56%
Transient cerebral arteriopathy 7% Physical inactivity 48%
Moyamoya (primary or secondary) 10% Hypertension 47%
Genetic or syndromic arteriopathy 2% Dyslipidemia 35%
Secondary vasculitis 4% High LDL cholesterol 42%
Fibromuscular dysplasia 1% Low HDL cholesterol 28%
Not further classified 5% Obesity 22%
Cardiac Diseases 30% Diabetes mellitus 10%
Congenital heart disease 18% Cardiovascular disease 9%
Acquired heart disease 6% Coronary heart disease 4%
Isolated patient foramen ovale 6% Congestive heart failure 1%
Stroke at cardiac surgery G72 hours 3% Myocardial infarction 3%
Other cardiac disease 12% Peripheral arterial disease 2%
Valvular disease 2%
Atrial fibrillation 2%

Continued on page 161

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TABLE 8-2 Risk Factors and Comorbidities for Stroke in Children and
Young Adultsa Continued from page 160

Pediatricb Young Adultc

Other Chronic Disorders Potentially Modifiable Risk Factors
Sickle cell anemia 4% High-risk alcohol 33%
consumption
Down syndrome 3%
Migraine, lifetime history 27%
Other genetic syndrome 5%
Sleep e6 hours per night 18%
Migraine 3%
Obstructive sleep apnea 3%
Prothrombotic state 3%
Oral contraceptives (girls) 6%
Indwelling catheter 3%
Iron deficiency anemia 2%
Brain tumor 1%
Aneurysm 1%
PHACES syndrome/hemangioma 1%
Hematologic malignancy 1%
L-Asparaginase therapy 1%
Connective tissue disease 1%
Acute systemic illness
Fever lasting 948 hours 12%
Systemic sepsis or bacteremia 6%
Dehydration 5%
Shock 9%
Viral gastroenteritis 1%
HDL = high-density lipoprotein; LDL = low-density lipoprotein; PHACES = posterior fossa malformations,
hemangioma, arterial anomalies, cardiac defects, eye anomalies, and sternal defects.
a
Subcategories are not mutually exclusive.
b
Pediatric data from Wintermark M, et al, Stroke.19 stroke.ahajournals.org/content/45/12/3597.long.
c
Adult data from von Sarnowski B, et al, Stroke.21 stroke.ahajournals.org/content/44/1/119.long.

(arteriopathy), 10% had suspected tion, 12% had small vessel occlusion, 9%
arteriopathy, and 18% had acute fever had large-artery atherosclerosis, and
or systemic sepsis.19 The risk factors 9% had other identified causes (not dis-
seen in older adults (hypertension, hy- section), followed by thrombophilias, an-
perlipidemia, smoking, and diabetes tiphospholipid antibody syndrome,
mellitus) were not commonly found in systemic vasculitis, migraine with aura,
this age range. In comparison, in a large and others.22 Young adults have a sub-
European cross-sectional study of 3331 stantial number of potentially modifiable
young adults with first-time ischemic risk factors20,21 that are similar to those
stroke, 17% had cardioembolic dis- common in older adults (Table 8-2).
ease, 13% had cervical artery dissec- The presence of these modifiable risk

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 Stroke in Children and Young Adults

factors offers opportunities for second- ciated with an increasing odds ratio for
ary prevention in young adults, while stroke in the infant. Circulating antico-
the opportunities for secondary pre- agulant proteins are normally low in the
vention in children are far more limited. fetus and do not rise to adult levels
The difference in presumed risk fac- until 1 year of age.25 This combination
tors is even more pronounced in neo- of temporary procoagulant states has
nates. The identification of stroke risk been proposed to contribute to neona-
factors in neonates has been limited, tal arterial ischemic stroke (Case 8-1).26
but pregnancy, particularly in the months The risk factor profiles influence the
just before delivery, is a relatively hy- type of stroke mechanistic evaluation
percoagulable state.23 This may con- for different age ranges and the strate-
tribute to clotting in the placenta, which, gies used for secondary prevention. A
in turn, might serve as a source of key question is the rate of stroke recur-
embolus to the fetus/newborn. A 2016 rence for children and young adults. In
case-control study of infants with neo- the VIPS study mentioned previously,
natal arterial ischemic stroke found 278 subjects were followed for at least
that their mothers had experienced 1 year after the incident stroke. Of these
more intrapartum complications when subjects, 40 (14%) had a recurrent stroke
compared with controls.24 Prolonged that occurred at a median of 23 days
rupture of membranes (21% versus 2%), after the incident stroke. The risk factors
fever (14% versus 3%), thick meconium associated with the highest 1-year risk
(25% versus 7%), prolonged second of recurrence were definite arteriopathy
stage (31% versus 13%), and tight nuchal (N = 127), with recurrence risk of 21%;
cord (15% versus 6%) occurred more possible arteriopathy (N = 34), with
frequently in the mothers whose infants recurrence risk of 12%; cardioembolic
had stroke. The presence of more than stroke (N = 65), with a recurrence risk
one intrapartum complication was asso- of 8.1%; and idiopathic stroke (N = 90),

Case 8-1
A 7-year-old girl had 1 week of upper respiratory tract symptoms, then 5 days of high fever. She was
treated with an antibiotic for pharyngitis, but became increasingly sleepy and confused. Reevaluation
determined meningismus and an altered mental state. A blood culture from her initial evaluation
grew Streptococcus pneumoniae. She was given fluids and antibiotics and transferred to the authors’
institution for treatment of sepsis.
On arrival, she was hypotensive and obtunded; she was intubated and given fluids, vasopressors,
and broad-spectrum antibiotics. An echocardiogram identified a large vegetation on the mitral valve.
A lumbar puncture showed bacterial meningitis. Her neurologic examination while sedated and
intubated was remarkable for meningismus, limited arousal to painful stimulation, equal movements
of all limbs, and hyperactive symmetric tendon reflexes.
A brain MRI was obtained on the third hospital day for the mitral valve vegetation, showing
abnormal diffusion in the territory of the left middle cerebral artery (MCA) but no occlusion of the
major cerebral arteries (Figure 8-1). Repeat neurologic examination noted limited pain arousal, no right
arm movement, decreased right face and leg movement, and hyperactive tendon reflexes on her
right. The risk for acute recurrent embolic stroke necessitated emergency replacement of the mitral
valve. She received no anticoagulation until the third postoperative day when warfarin was started.
A follow-up CT scan showed cerebral edema with mild midline shift to the right. The patient’s sepsis
improved so she could be extubated, off sedation, and followed clinically.
Continued on page 163

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 Continued from page 162
Over several weeks, movement improved in the right leg but not in the right arm or hand. She denied
any abnormal or diminished sensation on her right. Her mother reported her saying yes once and
laughing with her brothers, but otherwise she had no language production. Her mother felt the child
was more emotional than she was prestroke.
She had ongoing problems following discharge, including receptive and expressive language
deficits, slow processing, easy frustration, increased impulsivity, and difficulty persisting on cognitive
tasks. She could walk under supervision up to 150 feet but needed a wheelchair for long distances.
She could grasp with her right hand for a short time and pick up small blocks and puzzle pieces. She
required assistance to zip or snap her jacket and pants and tie her shoes.

FIGURE 8-1 Imaging of the patient in Case 8-1. A, Diffusion restriction on brain MRI in the
distribution of the left middle cerebral artery consistent with extensive acute
infarction. B, Intracranial magnetic resonance angiography (MRA) shows
patent proximal segment of the left middle cerebral artery without evidence of large
vessel occlusion.

Comment. Detection of acute stroke may be difficult in patients who are sedated because of severe
acute systemic illness. Although acute revascularization strategies have been proposed in children,
applications may be constrained by clinical events. Acute stroke in children presents with similar issues
as in young adults; large MCA infarcts require close observation for malignant MCA syndrome. From a
rehabilitation perspective, multiple challenges exist in children as they have a much longer lifespan
than an adult who is elderly. How the potential for neural plasticity can best be harnessed in a child,
how long rehabilitation should be pursued for children poststroke, and whether long-term
interventions offer sustained benefits are questions yet to be answered.

with a recurrence risk of 4.5%.27 For with underlying nonatherosclerotic cere- KEY POINT
those children with definite arteriopathy, brovascular disease. In neonatal stroke, h In neonatal stroke, the
those with moyamoya had a 1-year the immediate recurrence risk appears to immediate recurrence
risk appears to be very
recurrence risk of 32% (N = 34), those be very low, unless a congenital heart
low, unless a congenital
with transient cerebral arteriopathy had a lesion associated with cardiogenic embo-
heart lesion associated
25% recurrence risk (N = 25), those with lism or a hypercoagulable disorder asso- with cardiogenic
arterial dissection had a 19% recurrence ciated with systemic thrombosis exists.28 embolism or a
risk (N = 26), and those with vasculitis In young adults, the problems of re- hypercoagulable disorder
secondary to acute infections had a 6.7% currence are very different, for increased associated with systemic
recurrence risk (N = 15). In children, the risk exists not only for recurrent cere- thrombosis exists.
risk of recurrence is most strongly linked bral ischemia but also for myocardial
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 Stroke in Children and Young Adults

KEY POINT
h Brain imaging is essential ischemia and death. In a Finnish study stenosis are not routinely ordered. Atrial
in children to confirm the of 807 patients, the 5-year cumulative fibrillation is distinctly uncommon in
presence of an ischemic recurrence rate for ischemic stroke or children, so extended cardiac rhythm
stroke and to rule out myocardial infarction (nonfatal and fatal) monitoring is not routinely performed
a hemorrhagic stroke, was 11.5%.29 Predictors of recurrence in children with cryptogenic stroke.
but each modality were type 1 diabetes mellitus, large ar- Brain imaging is essential to confirm
has benefits and tery atherosclerosis, heart failure, pre- the presence of an ischemic stroke and
disadvantages to vious transient ischemic attack (TIA), to rule out a hemorrhagic stroke, but
consider. and increasing age. Similarly, in a Dutch each modality has benefits and disad-
study of 446 patients with ischemic vantages to consider (Table 8-3).31 CT
stroke, the 20-year risk of recurrent is fast and readily available and is sen-
ischemic stroke was 19.4%.30 Patients sitive for hemorrhage but has low sen-
who had atherothrombotic, cardioem- sitivity for acute ischemia within the
bolic, or lacunar stroke had increased first 6 hours of symptom onset. MRI is
risk for recurring stroke. These findings sensitive to acute ischemia but is less
were similar to an Italian study of 1867 readily available, and younger chil-
young adults with first ischemic stroke. dren may not be able to lie still for a
The 10-year cumulative risk for a com- complete study without general anes-
posite end point of ischemic stroke, TIA, thesia. Some pediatric centers have
or myocardial infarction was 14.7%. Fac- developed minimum-sequence MRI pro-
tors that increased the risk of these tocols to reduce the scanning time
events included migraine with aura, fam- when looking for an acute stroke. Such
ily history of stroke, discontinuation of a protocol would include diffusion-
antiplatelet or antihypertensive medica- weighted imaging, a fluid-attenuated
tion, or antiphospholipid antibodies. inversion recovery (FLAIR) sequence,
a gradient recalled echo (GRE) or
EVALUATION susceptibility-weighted imaging (SWI)
The risk factor and recurrence profiles sequence, and time-of-flight MRA of
suggest that the evaluation for a child the head and neck.33 If the patient
should be somewhat different from that does not have a stroke, however, such a
for an adult. In a child, the diagnostic limited protocol may be insufficient to
approach should focus on identification characterize other pathology. Magnetic
of possible factors that might lead to resonance vascular imaging avoids
short-term recurrence, such as a car- radiation exposure, but the resolution
diac source for embolism.31,32 A vascul- limits the ability to look at medium
opathy may lead to further strokes from and small cerebral vessels. CT angiog-
progressive stenosis or thromboembo- raphy can be performed quickly, and
lism, so vascular imaging of the brain the resolution approaches that of
and neck is important to identify intra- catheter angiography, but the amount
cranial and extracranial pathology. ECG of radiation has generated a debate
and echocardiogram (transesophageal about its use in young children, par-
when appropriate) also should be per- ticularly if longitudinal follow-up is
formed when a child has a first-time needed. Catheter angiography is the
arterial ischemic stroke. In contrast, ath- gold standard and is sensitive to small
erosclerosis is not known to play a sig- vessel disease, such as is found in vas-
nificant role in pediatric arterial ischemic culitis, but involves the risks of an in-
stroke, although lipid profiles are not sys- vasive procedure and is less feasible
tematically pursued in children. Doppler for longitudinal follow-up. For children
evaluations looking for carotid artery who have a pattern of venous infarcts,
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TABLE 8-3 Benefits and Disadvantages of Neuroimaging Techniques in Children With
Suspected Strokea

Stroke Imaging Advantages for Infants and Limitations for Infants and
Modalities Young Children Young Children
CT brain Fast; sufficient for hemorrhage; readily Radiation exposure; insensitive to acute
available at all hours ischemic change
MRI brain Sensitive to early ischemic change; higher Not readily available at some hospitals
resolution than CT scan during nights, weekends, holidays;
complete MRI study frequently requires
sedation/anesthesia in younger children;
some hospitals have protocols with limited
sequences specific for stroke; implanted
hardware/devices pose potential restrictions
and safety concerns handled case by case
CT angiography Fast; approaches catheter angiography in Significant radiation burden; requires
resolution postprocessing
CT venography Fast; can localize and grade diseased Significant radiation burden; requires
venous segments postprocessing
CT perfusion Can provide absolute and relative Significant radiation burden; requires
measures of perfusion in local regions postprocessing; negligible pediatric
of hemisphere experience at present
MR angiography Can localize and grade diseased vascular Same limitations as MRI; resolution not as
segments; no radiation exposure so sensitive as CT angiography or catheter
can be used serially angiography; requires postprocessing
MR venography Can localize and grade diseased venous Same limitations as MRI; requires
segments; no radiation exposure so postprocessing; very susceptible to
can be used serially technical artifact; hypoplastic sinuses
may mimic thrombotic occlusion
MR perfusion Can provide measures of perfusion to Same limitations as MRI; requires
identify regions at hemodynamic risk; no postprocessing; emerging experience
radiation exposure so can be used serially in children
SPECT perfusion Acetazolamide challenge can demonstrate Requires radionuclide exposure; younger
areas where perfusion varies with children require sedation/anesthesia;
challenge; can be used to anticipate requires postprocessing; limited
regions at risk for infarction availability at pediatric centers
Catheter angiography Gold standard Invasive; typically requires sedation; does
not provide perfusion data
CT = computed tomography; MR = magnetic resonance; MRI = magnetic resonance imaging; SPECT = single-photon emission computed
tomography.
a
Data from Moharir M, Deveber G, Continuum (Minneap Minn).31 journals.lww.com/continuum/Fulltext/2014/04000/Pediatric_Arterial_
Ischemic_Stroke.14.aspx.

SWI is a powerful tool to identify large THROMBOPHILIA EVALUATION

venous or sinus thromboses. Magnetic AND CONTROVERSIES
resonance venous imaging can identify Thrombophilia is the association be-
regions of diminished flow, but then tween laboratory markers of congeni-
hypoplastic vessels must be distin- tal or acquired abnormalities in the
guished from occluded vessels. coagulation system and an increased

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 Stroke in Children and Young Adults

risk of arterial and venous thrombo- in children with arterial ischemic stroke
embolic events. Deficiencies in the end- is estimated to range from 20% to 50%.35
ogenous anticoagulants were described However, given that most pediatric
in the 1960s (antithrombin) and the arterial ischemic strokes occur in the
1980s (protein C and protein S). More setting of multiple risk factors, the
recently, point mutations in the factor exact significance of identifying a
V gene (F5) R506Q and factor II gene, thrombophilia on the eventual neuro-
(F2) G20210A were identified and found logic outcome, treatment selection, and
to be more prevalent than the previ- duration of therapy remains unclear.
ously described deficiencies in natural The association between thrombo-
anticoagulants.34 Other defects, includ- philia and perinatal arterial ischemic
ing dysfibrinogenemia, elevated factor stroke is difficult to estimate given the
VIII activity (FVIII:C), elevated lipoprotein physiologically low levels of endoge-
(a), and hyperhomocysteinemia, have nous anticoagulants in neonates.36 A
since been associated with arterial is- 2010 meta-analysis of six studies esti-
chemic stroke (Table 8-4). The preva- mated a 3.56-fold (95% confidence
lence of an identifiable thrombophilia interval 1.02Y3.99) increased risk of
heterozygosity for F5 R506Q, and a
2.02-fold (95% confidence interval
TABLE 8-4 Common 1.02Y3.99) increased risk of heterozy-
Thrombophilias
Detected During gosity for F2 G20210A in perinatal ar-
Laboratory Testing terial ischemic stroke/cerebral sinus
venous thrombosis.37 The association
b Congenital between thrombophilia and risk of re-
current stroke following perinatal arte-
Deficiency of natural
anticoagulants rial ischemic stroke is unknown.
Two systematic reviews assessed the
Antithrombin deficiency
relationship between thrombophilia and
Protein C deficiency childhood-onset stroke (Table 8-5).37Y39
Protein S deficiency Interestingly, these reviews arrived at
contradictory conclusions. Haywood and
Blocking anticoagulant
effect
colleagues reviewed 18 case-control stud-
ies published between 1996 and 2002
Factor V Leiden (F5) R506Q investigating the association between
mutation
thrombophilia and childhood-onset
Elevated levels of procoagulant stroke (1 month to 18 years of age).
proteins Only protein C deficiency was statisti-
Prothrombin (F2) G20210A cally associated with childhood-onset
mutation stroke (odds ratio 6.5; 95% confidence
Elevated factor FVIII level interval 3Y14.3).38 Kenet and colleagues
performed a more recent meta-analysis
Others
of 22 studies (published between 1970
Hyperhomocysteinemia and 2009) and concluded that all throm-
Elevated lipoprotein (a) bophilias, except for antithrombin and
b Acquired
protein S deficiencies, were statisti-
cally associated with pediatric stroke.37
Antiphospholipid antibody Different inclusion criteria for the two
syndrome
analyses likely explain the different re-
sults. However, these results should be
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TABLE 8-5 Associations Between Thrombophilia and Childhood-onset Arterial Ischemic
Stroke From Selected Meta-analyses and Cohort Studiesa

Incident Childhood Arterial Recurrent Childhood Arterial

Ischemic Stroke Odds Ratio Ischemic Stroke Odds Ratio
Thrombophilia Prevalence (95% Confidence Interval) (95% Confidence Interval)
b
Factor V R506Q È1:20 3.7 (2.8Y4.9)37 0.3 (0.4Y2.3)39
1.2 (0.8Y1.9)38
Prothrombin G20210Ab È1:50 2.6 (1.7Y4.1)37 1.8 (0.2Y15.0)39
1.1 (0.5Y2.3)38
Antithrombin deficiencyb È1:2000Y5000 3.3 (0.7Y15.5)37 NA
38
1 (0.3Y3.7)
Protein C deficiencyb È1:500 11.0 (5.1Y23.6)37 10.7 (2.5Y45.8)39
6.5 (3Y14.3)38
Protein S deficiencyb È1:500 1.5 (0.3Y6.9)37 0.6 (0.05Y6.4)39
1.1 (0.3Y3.8)38
Hyperhomocysteinemia NA 1.4 (0.5Y3.5)38 NA
Elevated lipoprotein (a) NA 6.5 (4.5Y9.6)37 2.8 (1.1Y7.5)39
Elevated FVIII:C NA NA NA
37
Q2 Genetic traits NA 18.8 (6.5Y54.1) NA
37
APLA syndrome variable 7 (3.7Y13.1) NA
APLA = antiphospholipid antibody; FVIII:C = factor VIII activity; NA = not available.
a
Selected meta-analyses were of incident arterial ischemic stroke and cohort studies were of recurrent arterial ischemic stroke.
b
Heterozygous trait.

interpreted cautiously since the studies of 44 months. Elevated lipoprotein (a)

analyzed were small and observational, (relative risk 4.4; 95% confidence inter-
the relationship between the timing of val 1.9Y10.5) and congenital protein C
thrombophilia testing and stroke was deficiency (relative risk 3.5; 95% confi-
often not clear, and data linking stroke dence interval 1.1Y0.6) were associated
with certain thrombophilias were with an increased risk of recurrent
reported only from a single group. stroke.39 A retrospective study from the
In stark contrast to multiple case- Great Ormond Street Hospital examined
control and cohort studies investigating 212 children with arterial ischemic
the association between thrombophilia stroke (21 days to 19 years of age).
and incident stroke, few studies have After a median follow-up of 2.2 years,
evaluated the association of thrombo- 79 children (37%) had clinical recur-
philia with recurrent childhood arte- rence (TIA 46, arterial ischemic stroke
rial ischemic stroke. A prospective 29, death with reinfarction 4). In 115
German study of 301 infants and chil- children who had no acquired risk
dren (7 months to 18 years of age) factors for stroke, the prothrombin
found 20 children (6.6%) had a recur- F2 G20210A mutation was associated
rent stroke during a median follow-up with a significantly increased risk of

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 Stroke in Children and Young Adults

KEY POINT
h The authors offer stroke (hazard ratio 7.89; 95% confi- sickle cell screen/hemoglobin electro-
thrombophilia testing dence interval 1.78Y34.92).40 These phoresis.41 Similarly, the 2008 American
to patients with differing results indicate that large pro- Heart Association guidelines con-
childhood-onset stroke, spective studies are needed to clarify cluded that it was reasonable to test
particularly when other the association between thrombophilia for common prothrombotic conditions
risk factors are not and stroke recurrence in children. in childhood-onset stroke, even when
identified and after other risk factors for stroke are identi-
discussing risks and RELEVANCE OF THROMBOPHILIA fied.42 In contrast, in 2010 the British
benefits of such testing TESTING IN PEDIATRIC ARTERIAL Committee for Standards in Haema-
with the patient and ISCHEMIC STROKE tology suggested that testing for herita-
family. Testing is
Although studies and meta-analyses ble thrombophilia was not indicated in
typically done acutely
have indicated an association between children with stroke.43 Similarly, the
and repeated at
3 months if specific
congenital/acquired thrombophilia and 2012 American College of Chest Physi-
abnormalities pediatric stroke, the exact impact of cians (ACCP) guidelines do not rec-
are identified. thrombophilia on risk of recurrence ommend changing the duration or
and clinical outcome, the economic intensity of anticoagulation based on
effectiveness of testing, and the psy- the presence or absence of an identi-
chological impact of a thrombophilia fiable thrombophilia.44
diagnosis upon patient and family are In the absence of robust evidence
unclear. Except for very specific clinical or consistent guidelines, it is diffi-
scenarios (eg, antiphospholipid anti- cult to make recommendations on
body syndrome), the results of thrombo- thrombophilia testing in pediatric ar-
philia testing rarely impact treatment terial ischemic stroke. At the authors’
selection or duration of therapy. The institution, thrombophilia testing is
proposed potential benefits of testing offered to patients with childhood-
(guidance of testing in family members, onset stroke, particularly when other
informed decisions on future estrogen risk factors are not identified and after
therapy in girls, and guidance of throm- discussing risks and benefits of such
boprophylaxis recommendations for testing with the patient and family.
future high-risk situations) are not evi- Testing is typically done acutely and
dence based and have not been shown repeated at 3 months if specific ab-
to improve outcomes.34 normalities are identified. Given the
Interestingly, the ambiguity surround- low risk of recurrence, acute testing is
ing thrombophilia testing is reflected in rarely offered in cases of perinatal ar-
the divergent recommendations made terial ischemic stroke (with the excep-
by international consensus guidelines. tion of arterial ischemic stroke in the
In 2002, the perinatal/pediatric subcom- setting of neonatal purpura fulminans).
mittee of the International Society on Risks and benefits of thrombophilia
Thrombosis and Haemostasis (ISTH) testing are usually discussed with fam-
recommended that all children with ilies at 1-year follow-up and testing is
arterial or venous thrombosis be tested performed for specific cases, such
for genetic and acquired thrombotic as in patients with a strong family history
states, including complete blood cell of thrombosis or when a patient is
count, antithrombin activity, protein C perceived to be at high risk for recur-
activity, free and total protein S anti- rent thrombotic events (eg, complex
gen, F5 R506Q and F2 G20210A mutation congenital heart disease) in which there
testing, MTHFR T677T and/or fasting might be a role of future thrombopro-
homocysteine, lipoprotein (a), lupus anti- phylaxis during high-risk situations.
coagulant, anticardiolipin antibody, and Standard thrombophilia testing at the
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authors’ center includes antiphospholipid they should be suspected when char-
antibodies (ie, lupus anticoagulant, IgG acteristic periventricular infarcts are
and IgM isotype anticardiolipin anti- seen coupled with multisystem im-
bodies, IgG and IgM isotype $2 pairment (eye, hearing, cardiac, he-
glycoprotein-I antibodies), F5 R506Q patic, renal) or lactic acidosis. A 2015
and F2 G20210A mutation analysis, consensus statement described in
antithrombin activity, protein C and detail the steps to evaluate suspected
protein S activity, fibrinogen level, D- mitochondrial disease.46
dimer, FVIII:C, fasting lipoprotein (a), The necessary diagnostic testing in
and homocysteine level. Given that children who sustain a perinatal stroke
recent evidence suggests that polymor- is less clear. Since mother and fetus
phisms in the MTHFR gene do not are in relatively prothrombotic states
result in elevated levels of homocys- close to term,23 screening tests for
teine and are not, by themselves, as- thrombophilia may be abnormal, but
sociated with an increased risk of it is not clear that these abnormalities
thrombosis, we no longer test for translate into increased risk for future
MTHFR variants.45 strokes or specific management of
future pregnancies. Echocardiography
FURTHER DIAGNOSTIC to evaluate for congenital heart lesions
EVALUATIONS is appropriate. Imaging evaluation of
In some instances, the acute clinical the cervical vessels, particularly in those
setting provides obvious clues for the children who experienced a traumatic
cause of the stroke, eg, ischemic strokes birth, is also appropriate.
detected concurrent with extracorporeal The diagnostic evaluation for an ini-
membrane oxygenation or cortical ve- tial stroke in the young adult is similar
nous infarcts occurring with bacterial to that for the older adult. Illicit drug
meningitis. In such patients, the extent use should be considered as a possible
of the evaluation may be more tailored cause for stroke in the young adult. In a
and less protocol driven. Typically, case-control study of young adults with
though, the cause of the stroke is not stroke, acute cocaine use, particularly in
apparent at onset, so a lumbar puncture the smoked form, was associated with
should be considered, especially if the a nearly eightfold increase in stroke
patient is febrile. Additionally, a history risk.47 The role of a patent foramen
of varicella should be sought, and a ovale as a cause for stroke is still being
serum varicella titer should be consid- debated, but a large randomized trial
ered. Screens for autoimmune disease, in patients who had cryptogenic stroke
such as an erythrocyte sedimentation and patent foramen ovale comparing
rate, antinuclear antibody, and com- device closure with medical manage-
plement profile, should be considered, ment found no difference in stroke
particularly when multiple organ sys- recurrence between the two groups.48
tems appear to be affected. A large Genetic disorders are rare causes of
number of genetic disorders are associ- ischemic stroke but should be consid-
ated with stroke in children, such as ered in young adults when an obvious
neurofibromatosis type 1 or trisomy cause cannot be found and particularly
21 syndrome, but clinical clues that when clinical features suggest a diag-
the patient has a genetic disorder or a nosis. Fabry disease; cerebral autosomal
neurocutaneous syndrome usually ex- dominant arteriopathy with subcorti-
ist. Disorders of mitochondrial func- cal infarcts and leukoencephalopathy
tion can be difficult to diagnose,46 but (CADASIL) and the recessive form,
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 Stroke in Children and Young Adults

cerebral autosomal recessive arteri- adequate oxygenation, assurance of

opathy with subcortical infarcts and airway integrity, and maintenance of
leukoencephalopathy (CARASIL); adequate hydration while avoiding hy-
COL4A1 and TREX1 mutations; mito- potonic fluids. Blood pressure should
chondrial disorders, such as mito- be maintained to ensure adequate cere-
chondrial encephalomyopathy, lactic bral perfusion, and hypotension should
acidosis, and strokelike episodes be avoided. Mild hypertension can be
(MELAS) 5 ; Marfan syndrome; and tolerated to preserve cerebral perfu-
Ehlers-Danlos syndrome type IV can all sion as long as blood pressures are not
present with stroke in a young person severely elevated. If severely elevated
whose underlying diagnosis was not blood pressures must be lowered, treat-
previously recognized.49 In patients ment should be gradual to avoid pre-
with cryptogenic stroke, additional car- cipitous hypotension that could impair
diac rhythm monitoring may be indi- cerebral perfusion. Depending upon the
cated. Recent advances in cardiac size and location of the acute ischemic
telemetry have shown that paroxysmal infarct, monitoring for malignant MCA
atrial fibrillation may occur intermit- infarction syndrome, aspiration risk, or
tently and can be missed even with herniation risk are warranted. Patients
24-hour monitoring; these patients have with small cortical infarcts are less likely
a higher risk for stroke than patients to need intensive observation once
without atrial fibrillation.50 an aspiration risk has been excluded,
while patients with large MCA infarcts
ACUTE MANAGEMENT or cerebellar or brainstem infarcts need
The acute management of stroke in intensive observation until the acute
young adults is not fundamentally dif- cerebral edema has resolved.
ferent from that in older adults. Since If a child has acute stroke from
those details are covered extensively sickle cell anemia, acute transfusion or
elsewhere in this issue, they will not exchange transfusion with the guidance
be addressed here. Instead, acute man- of a hematologist is the treatment of
agement will focus upon aspects ger- choice.51 If the source of a stroke is
mane to children. unknown and cervical vessel dissection,
The majority of neonates with symp- focal arteriopathy, or cardiac embolism
tomatic arterial ischemic stroke present are suspected, anticoagulation with
with seizures, so the initial manage- unfractionated heparin/low-molecular-
ment involves seizure monitoring and weight heparin or antiplatelet therapy
acute treatment with antiepileptic with aspirin are appropriate for acute
drugs.28 About one-third require re- management.44 At the authors’ institu-
suscitation and almost one-quarter have tion, ongoing anticoagulation is pre-
systemic illness, so cardiorespiratory ferred for patients with extracranial
stabilization and treatment of associ- dissection and cardioembolic stroke
ated systemic illness are critical to acute (with low-molecular-weight heparin or
management. A source for recurrent vitamin K antagonist [warfarin]). The
cardioembolism and sustained pro- duration of anticoagulation therapy is
thrombotic states occur in less than about 3 months for cardioembolic
20%, so routine antithrombotic treat- stroke and 6 weeks to 3 months for
ment is not recommended unless one patients with extracranial dissection
of these conditions is identified.31 (based on follow-up radiologic assess-
After the neonatal period, initial man- ment).44 Once dissection and embo-
agement involves basic supportive care: lism have been excluded, we tend to
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 KEY POINT
offer antiplatelet therapy (aspirin) for inclusion and exclusion criteria are h Since the recurrence risk
secondary prophylaxis for a minimum rigorously followed and the patient is for most neonatal arterial
of 2 years. Thrombophilias that are managed according to well-established ischemic stroke appears
clinically significant must be distin- protocols.33 Thrombolysis in younger to be low, neonates are
guished from population polymor- children should be pursued with great not typically treated with
phisms, and their treatment should caution. Despite isolated case reports antithrombotic agents.
involve the input of a hematologist. of successful endovascular thrombec-
Patients who have moyamoya disease tomy in very young children, careful
or moyamoya syndrome (when the vas- technical consideration should be
culopathy occurs in association with given to what stent retrievers can be
diseases such as sickle cell disease, safely used in small cerebral vessels.
neurofibromatosis type 1, or trisomy At the authors’ institution, endovascular
21 syndrome) are candidates for sur- thrombectomy in preteen children is
gical revascularization, such as the in- not an option. Furthermore, since def-
direct pial synangiosis or the direct inite vasculopathy is a significant cause
superficial temporal artery-MCA anasto- of ischemic stroke in children, neuro-
mosis (Case 8-2).52 The timing of such interventionalists must be keenly aware
surgery is a matter of neurosurgical that they may be dealing with a very
judgment, particularly with the indirect abnormal cerebrovascular system.
pial synangiosis52; if a sufficient degree IV thrombolysis is most effective if
of cerebral ischemia does not exist, there a team follows a developed protocol
may be insufficient stimulus for vas- where key groups (emergency depart-
cular proliferation to occur. On the other ment, radiology, pharmacy, and inten-
hand, if clinical progression occurs with sive care) have well-identified tasks.
recurring strokes or TIAs, cognitive This is particularly true for endovascular
decline, or radiologic evidence of steady thrombectomy. Not only must the in-
vascular occlusion, the natural history is terventionalist be experienced with cere-
progressive deterioration if no interven- brovascular disease, but the anesthesia
tion occurs. When the patient is stable and catheterization laboratory teams
without clinical or radiologic evidence must be able to work safely and effec-
of progression, it is difficult to deter- tively with children. If these elements
mine when to operate. cannot be assembled within the requi-
In selected circumstances, children site time frames, it is far safer to pro-
with acute stroke may be candidates vide supportive care rather than work
for IV thrombolysis and endovascular outside existing guidelines. One should
thrombectomy.33,53 Publication bias not feel compelled to work outside
toward positive results was likely for guidelines simply because a child
reports of IV thrombolysis in children,54 is involved.
and the same may be true for reports
of endovascular revascularization. Ob- SECONDARY PREVENTION
stacles that limit acute thrombolysis in Since the recurrence risk for most
children are the delays in diagnosis and neonatal arterial ischemic stroke ap-
the need to distinguish a stroke mimic pears to be low,31 neonates are not
from a stroke. If an older adolescent typically treated with antithrombotic
has a confirmed acute arterial ischemic agents. Neonates who have had stroke
stroke and is within the time frame for may have few focal neurologic signs
IV thrombolysis (4.5 hours) or endovas- in the acute phase. Long-term manage-
cular thrombectomy (6 hours), throm- ment requires monitoring the infants
bolysis is reasonable if published for the later appearance of motor and
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 Stroke in Children and Young Adults

Case 8-2
A 7-year-old girl presented with long-standing headaches that became more severe and frequent.
When she developed a headache with right hand numbness, a brain MRI was performed and thought
to show an arteriovenous malformation. Magnetic resonance angiography (MRA) and catheter
angiography showed enlarged vertebral and basilar vessels, right internal carotid artery occlusion, left
middle cerebral artery (MCA) stenosis, and numerous collateral vessels consistent with moyamoya
disease, Suzuki stage III to IV (the Suzuki stages range from I to VI, with the higher score indicating a
greater severity of stenosis) (Figures 8-2A, 8-2B, and 8-2C). Scattered punctate T2 and fluid-attenuated
inversion recovery (FLAIR) positive areas in the deep white matter suggested prior ischemic injury. She
was initially treated with aspirin and soon had a left pial synangiosis; the right side was not addressed
because of the prominent collateral supply from the posterior circulation.
Eighteen months after the pial synangiosis, she developed recurring headaches, nausea, and
vomiting that varied in frequency. Topiramate 1.5 mg/kg/d was prescribed without change in headache
frequency. Two years after her initial
presentation, she reported an episode of right
hand numbness similar to her original
presentation. Her neurologic examination
remained normal. CT angiography showed stable
moyamoya pattern and a stable left external
carotid artery branch supplying the synangiosis
(Figure 8-2D). Magnetic resonance perfusion in
the left hemisphere showed 10% lower
perfusion than the right, but no focal area of
decreased perfusion. The headaches continued
with variable right hand numbness. Adding
clopidogrel yielded no change, so 3 to 4 months
after the headaches and right hand numbness
recurred, topiramate was increased to 5 mg/kg/d
and the headaches promptly decreased. She
remained free of severe headache for the
following 9 months.
Comment. This case illustrates that
moyamoya can occur without any identifiable
risk factors. Monitoring disease progression in
children can be challenging because of the
need for monitoring over many years and the
limited tools to predict which areas at risk will
progress to infarction. Indirect revascularization
(such as a pial synangiosis where the superficial FIGURE 8-2 Imaging of the patient in Case 8-2. A,
Catheter angiogram, left vertebral artery
temporal artery is sutured to the pia mater) is injection. The long arrow identifies
technically more feasible in young children, but moyamoya collateral vessels. The short arrow illustrates that
this is a left vertebral artery injection filling the right middle
to be successful, a pial synangiosis must be cerebral artery and both anterior cerebral arteries via a
performed where sufficient cerebral ischemia large right posterior communicating artery. B, Catheter
exists to promote the proliferation of collateral angiogram, right common carotid artery injection. Absent
flow into the internal carotid artery (short arrow) and
vessels. Patients with moyamoya syndrome may collateral flow via the middle meningeal artery (long arrow)
also have migraine, which can be extremely to the supraclinoid right internal carotid artery are seen. C,
difficult to distinguish from the patient’s Catheter angiogram, left internal carotid artery injection.
Severe stenoocclusive disease and prominent moyamoya
moyamoya symptoms. This child’s response to an collateral vessels are seen. D, CT angiogram. The red arrow
adequate trial of topiramate suggests that her identifies the external carotid artery branch supplying
headaches were more likely to be migraine than the anastomosis. The yellow arrow identifies the
craniotomy defect.
moyamoya-related symptoms.

172 ContinuumJournal.com February 2017

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 KEY POINT
tone deficits and delayed develop- although timing of the surgery, as h In children who sustained
mental milestones as well as providing mentioned previously, is a complex a stroke after the
appropriate interventions when those problem. In contrast to adults,55 in the neonatal period,
problems appear. A small proportion VIPS study, a 19% stroke recurrence treatment to prevent
of infants will develop epilepsy, but risk was seen in the small number of recurrent stroke varies
reliable predictors of poststroke epi- children with cervical artery dissec- with the associated
lepsy have not been established. tion. These limited data suggest that condition.
In children who sustained a stroke children should be treated with anti-
after the neonatal period, treatment to thrombotic agents to prevent acute
prevent recurrent stroke varies with the recurrence until the dissection has
associated condition. In the VIPS study, resolved.44 Children with stable focal
children who had definite arteriopathy, arteriopathy should be treated with
especially those with moyamoya disease/ antiplatelet agents, but the duration is
syndrome, had the highest recurrence uncertain (Case 8-3). One case series
risks; thus, children with moyamoya of 79 children noted that of the 74 with
disease/syndrome warrant long-term nonprogressive arteriopathy, 13 had
monitoring and long-term treatment recurrent stroke or TIA56 over a median
with antithrombotic medication, in par- follow-up of 1.4 years. The VIPS study
ticular antiplatelet agents. Those who showed that the 1-year recurrence risk
have moyamoya disease are likely can- was low, 4.5 %, for children without an
didates for revascularization surgery, identified cause for the initial stroke

Case 8-3
A 12-year-old girl presented with a 2-day history of headache. She became difficult to awaken and then
appeared disoriented. She was noted to have left-sided facial droop, drooling, and numbness as well
as weakness in her left arm and leg. Brain MRI showed an acute infarction in the right basal ganglia
(Figure 8-3A). Further history revealed that she had been started on an oral contraceptive 10 days
earlier. Family history was notable for deep venous thrombosis in the paternal grandmother when
she was in her forties; there was no family history of strokes or clotting disorders. Evaluation for
thrombophilia and an echocardiogram were normal. Antinuclear antibody was slightly elevated but
was considered a nonspecific finding. A magnetic resonance angiogram (MRA) showed arterial stenosis
within the proximal M1 segment of the right middle cerebral artery, confirmed by a catheter angiogram
(Figure 8-3B). She was treated with aspirin.
She was readmitted 5 times soon after initial presentation for recurring right frontal headache,
transient unsteadiness, or recurrence of the left-sided face and arm weakness coupled with intermittent
paresthesia and numbness. Each episode cleared within 24 hours, and no new diffusion changes were
noted on subsequent MRIs. In between these episodes, her neurologic examination was notable only for
stable mild weakness of her left foot extensors.
Since clinical suspicion was that the events reflected recurrent hemispheric TIAs, dipyridamole was
added to the aspirin. Angioplasty and bypass were considered but eventually not recommended. A
single-photon emission computed tomography (SPECT) perfusion scan showed no areas of reversible
hypoperfusion, and her MRA remained stable 5 months after initial presentation. She was treated with
topiramate and the episodes of headache and left-sided sensory symptoms stopped, although mild
headaches continued 3 to 4 times per week and she had a severe activity-limiting headache 2 to 3 times
per month. About 3 years after original presentation, she developed severe depression requiring
treatment but eventually responded to antidepressants and counseling. A follow-up MRA 5 years after
her incident stroke showed complete occlusion of the original focal stenosis at the mid right M1
segment (Figure 8-3C). The distal M1 segment beyond the stenosis was reconstituted by an inferior
collateral loop that had evolved.
Continued on page 174

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 Stroke in Children and Young Adults

Continued from page 173

FIGURE 8-3 Imaging of the patient in Case 8-3. A, Diffusion-weighted MRI sequence
demonstrates the subcortical location of the original infarction in the right basal
ganglia. B, Intracranial magnetic resonance angiography (MRA) demonstrates an
area of focal signal abnormality in the proximal right middle cerebral artery consistent with
focal stenosis (arrow). C, Intracranial MRA demonstrates absence of flow in the proximal right
middle cerebral artery suggestive of complete occlusion with reconstitution of the distal
segments from a collateral vessel (red arrow).

Comment. This case illustrates the focal nonatherosclerotic arteriopathy that can occur in children.
The patient did not have risk factors for moyamoya syndrome. The vasculopathy did not progress to a
moyamoya type, but the focal stenosis eventually progressed to become complete. This case also illustrates
that behavior/mood complications can occur in children and adolescents, just as in young adults.

(ie, idiopathic stroke). The duration of dren who have had stroke due to sickle
antithrombotic treatment in these cell disease, long-term transfusion ther-
children is uncertain, although a small apy is necessary to reduce recurrence;
study found no recurrence after 2 years stopping long-term transfusion therapy
following idiopathic stroke without results in an increased risk of stroke
arteriopathy.57 Children with cardiac recurrence.58 If the stroke occurred in
disease who have potential for further association with an acute provocation,
cardioembolism should be treated with such as central nervous system infec-
an antithrombotic agent until the risk tion, cardiac surgery/catheterization,
for embolism has resolved.44 For chil- or traumatic fat embolism, long-term

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 KEY POINTS
antithrombotic treatment is probably Outcomes After Neonatal Stroke h Secondary stroke
unnecessary unless a cause for thrombo- Relatively few long-term follow-up stud- prevention in young
embolism persists. ies of neonatal arterial ischemic stroke adults involves
Young adults have a significant risk have been conducted, and the results encouraging the same
of recurrent stroke and other cardio- can be somewhat contradictory be- lifestyle changes as in
vascular events. As noted earlier, one cause of differing follow-up periods. A older adults: avoiding
prospective European cohort study 2015 prospective study of 100 neonates smoking, increasing
found the 20-year cumulative risk of with arterial ischemic stroke reported physical activity, making
ischemic stroke recurrence was 19.4%, dietary modifications to
that at 2 years of age, 39% had cerebral
and the 20-year cumulative risk was achieve weight loss, and
palsy and 31% had delayed mental per-
avoiding recreational
32.8% for any vascular event (including formance of variable magnitude.3 Sig- drugs, especially
TIA, myocardial infarction, stroke).30 nificant associations existed between cocaine. Aggressive
One prospective multicenter European normal development and absence of treatment of
study found that young adults with cerebral palsy and epilepsy. In a study hypertension,
stroke had a number of modifiable risk of 31 school-aged children who had dyslipidemias, and
factors,21 such as smoking (55%), phys- neonatal MCA infarcts, 28 had normal diabetes mellitus are also
ical inactivity (48.2%), hypertension IQs; of this group, three had IQs in the obvious targets. These
(46.6%), dyslipidemias (34.9%), obesity low normal range.59 Another three had secondary prevention
(28.0%), and diabetes mellitus (10.3%). extremely low IQs, but they also had measures are particularly
Secondary stroke prevention thus in- hemiplegia or epilepsy. Lesion size did important in young
volves encouraging the same lifestyle adults because of their
not correlate with IQ.
changes as in older adults: avoiding longer potential lifespan
and the significant risk of
smoking, increasing physical activity, Outcomes After Stroke in
recurring vascular events
making dietary modifications to achieve Children
over that longer lifespan.
weight loss, and avoiding recreational Similar to neonates, few studies of long-
drugs, especially cocaine. Aggressive h Similar to neonates, few
term outcome after stroke have been
studies of long-term
treatment of hypertension, dyslipidemias, conducted in older children. The larg- outcome after stroke
and diabetes mellitus are also obvious est to date is a prospective cohort study have been conducted in
targets. These secondary prevention from Switzerland that had follow-up older children.
measures are particularly important data for 95 children for an average of
h In a prospective cohort
in young adults because of their 7 years after the incident stroke.60 study of 7 years of
longer potential lifespan and the sig- Mortality was 14% overall; those chil- follow-up data for
nificant risk of recurring vascular events dren who died in the first 6 months children after a stroke,
over that longer lifespan. Whether expired from the stroke, while those mortality was 14%
statin therapy is warranted in young who expired later died from a range of overall, and 6% had a
adults who have stroke from non- diseases, including infection, leukemia, recurrent stroke.
atherosclerotic events (such as cardiac and cardiac disease. Of the children Fifty-five percent had a
embolism) is uncertain.5 studied, 6% had a recurrent stroke. hemiparesis, although
Fifty-five percent had a hemiparesis, most (49% of those
OUTCOMES AND LONG-TERM although most (49% of those affected) affected) were mild in
MANAGEMENT severity, and 21% had
were mild in severity, and 21% had
speech impairments,
The challenge for managing patients speech impairments, but again, most
but again, most (59%
who have had stroke, particularly as (59% of those affected) were mild. of those affected) were
neonates or young children, is identify- Parents reported that 15% of the mild. Parents reported
ing those who have risks for significant children had some type of psycholog- that 15% of the
sequelae that might respond to appro- ical or psychiatric disorder. children had some type
priate intervention. A proportion will These investigators examined the of psychological or
have significant sequelae, but not all. relationship between poststroke deficits psychiatric disorder.

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 Stroke in Children and Young Adults

KEY POINTS
h Interest is growing in and cognitive outcomes.61 Total IQ for of a poorer mRS score. Poststroke epi-
the outcome of young the entire stroke group was not signif- lepsy occurred in 16% of survivors, and
adults who have had icantly different from population epilepsy was significantly associated
stroke, but the number norms; however, distinct subgroups with a poorer mRS score.65 The inves-
of studies with had significantly lower IQs. Total IQ tigators assessed subjective reports of
long-term follow-up is was significantly lower in children who memory and executive function impair-
relatively small. had more severe neurologic impair- ment in the survivors and compared
h A Dutch study of ment, poorer function as measured by them with objective measures of these
outcomes 9 years after a modified Rankin Scale (mRS) score of cognitive functions.66 Stroke survivors
the incident stroke 2 or more, or acute seizures with the reported subjective memory (86%) and
found that 10% of incident stroke or poststroke epilepsy. executive function (67%) impairments
young adult ischemic In specific cognitive domains, children at rates significantly greater than in
stroke survivors were who had infarcts involving both cortical stroke-free controls, but the magnitude
functioning at a and subcortical regions had signifi- of these self-reported impairments did
modified Rankin Scale
cantly lower verbal IQ and poorer work- not correlate with the magnitude of
score of 3 to 5 and 27%
ing memory and performance speed. objective measures of memory or exec-
were dead. As a group,
stroke survivors
Working memory and processing speed utive function. As a group, however,
performed worse than were significantly poorer in children stroke survivors performed worse than
controls in objective who had more severe neurologic im- controls in objective measures of pro-
measures of processing pairment or poorer mRS scores. cessing speed, working and immediate
speed, working and Our own work is consistent with memory, delayed memory, attention,
immediate memory, this finding.62 In a case-control study and executive function.67 When cog-
delayed memory, of children who had stroke compared nitive impairment was compared with
attention, and executive with controls, most of the children who mRS score, only impaired working
function. Depressive had stroke had mild neurologic deficits. memory was associated with poorer
symptoms were present Greater neurologic impairment corre- mRS scores.68
in 16% of men and
lated with lower total IQ and reduced In this same cohort, depression and
23% of women,
processing speed, adaptive behavior, anxiety occurred in a significant pro-
compared with 6% in
controls. Anxiety was
and social participation. In summary, portion of survivors. Depressive symp-
present in 15% of men while childhood stroke survivors typi- toms were present in 16% of men and
and 29% of women, cally have normal cognitive function, cer- 23% of women, compared with 6% in
compared with 12% tain subgroups will be at risk for greater controls.69 Anxiety was present in 15%
of controls. cognitive impairment, and physicians of men and 29% of women, compared
should anticipate the need for greater with 12% of controls. Lower educa-
assistance in these subgroups.63 tional level and unemployment were
Interest is growing in the outcome significantly associated with depressive
of young adults who have had stroke, symptoms and anxiety. Stroke survivors
but the number of studies with long- reported higher levels of fatigue (41%)
term follow-up is relatively small. One when compared with controls (18%);
large prospective Dutch study exam- fatigue was significantly associated with
ined a number of outcomes 9 years poorer functional outcome on the mRS.70
after the incident stroke in individuals When survivors of ischemic and hem-
aged 18 to 50 years. These investiga- orrhagic stroke (89% were ischemic
tors found that 10% of ischemic stroke strokes) were compared with the gen-
survivors functioned at an mRS score eral Dutch population regarding partial
of 3 to 5 and 27% were dead.64 Greater or full unemployment, 26% to 33% of
age and higher National Institutes of men and women 34 to 54 years of age
Health Stroke Scale scores at stroke were unemployed, compared with 5%
onset were associated with greater odds to 9% of the general population.71
176 ContinuumJournal.com February 2017

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 Review Article

Management of
Address correspondence to
Dr Kelly Flemming, Mayo Clinic,
200 First St SW, Rochester,
MN 55905-0001,

Unruptured Intracranial [email protected].

Relationship Disclosure:
Dr Flemming reports no

Aneurysms and disclosure. Dr Lanzino serves as

a consultant for Medtronic.
Unlabeled Use of

Cerebrovascular Products/Investigational
Use Disclosure: Drs Flemming
and Lanzino discuss the

Malformations
unlabeled/investigational
use of statins and fasudil
for the treatment of
cavernous malformation.
Kelly D. Flemming, MD; Giuseppe Lanzino, MD * 2017 American Academy
of Neurology.

ABSTRACT
Purpose of Review: Unruptured intracranial aneurysms and vascular malformations
are detected more frequently because of the increased use and availability of brain
imaging. Management of these entities requires knowledge of which patients are
at high risk for hemorrhage and what treatment options are available. This article
summarizes the epidemiology, natural history, and management strategies for
unruptured intracranial aneurysms, arteriovenous malformations, cavernous
malformations, developmental venous anomalies, and capillary telangiectasias.
Recent Findings: Pooled cohort studies and meta-analyses have improved the ability
to predict hemorrhage for each vascular abnormality. Scores and tools have been
developed to aid the practitioner in predicting hemorrhage risk for unruptured
intracranial aneurysms. Advances in endovascular techniques for unruptured intracra-
nial aneurysms have improved the ability to treat difficult wide-necked aneurysms.
Summary: Unruptured intracranial aneurysms are a common incidental finding. The
PHASES (population, hypertension, age, size of aneurysm, earlier subarachnoid
hemorrhage from another aneurysm, site of aneurysm) score and Unruptured Intra-
cranial Aneurysm Treatment Score may be useful tools for predicting natural history
and treatment recommendations. The overall risk of hemorrhage for both arteriove-
nous malformations and cavernous malformations is about 2% to 4% per year.
With both of these entities, prior hemorrhage predicts future hemorrhage. In addi-
tion, other select patient and radiologic factors influence risk of hemorrhage. The
risk of future hemorrhage should be compared to the risk of treatment. Develop-
mental venous anomalies and capillary telangiectasias are largely benign entities and
rarely symptomatic.

Continuum (Minneap Minn) 2017;23(1):181–210.

INTRODUCTION (Table 9-1), some common principles

With increased use of brain imaging, and management strategies may be
unruptured intracranial aneurysms and applied to all. Hemorrhage is the most
unruptured vascular malformations feared complication from each of the
have been detected with greater fre- entities, and management is aimed at
quency. While each of the vascular determining the risk of future hemor-
abnormalities of the brain has distin- rhage as compared to the risk of inter-
guishing clinical and radiologic features vention (surgery, endovascular therapy,

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 Aneurysms and Cerebrovascular Malformations

TABLE 9-1 Comparison of Unruptured Intracranial Aneurysms and Vascular Malformations of

the Brain

Developmental
Unruptured Arteriovenous Cavernous Venous Capillary
Aneurysm Malformation Malformation Anomaly Telangiectasia
Etiology Acquired Probably acquired Acquired, Congenital Possibly
sporadic (80%) congenital
Familial (20%) Acquired after
(autosomal brain radiation
dominant) (in some)

Presentation Incidental, cranial Incidental, seizure, Incidental, seizure, Incidental; Incidental;

nerve palsy, hemorrhage, focal hemorrhage, focal rarely, seizure, rarely, seizure,
compressive neurologic deficit neurologic deficit hemorrhage, hemorrhage,
symptoms focal neurologic focal neurologic
deficit deficit
Diagnosis MRA, CTA, MRI, MRA or MRI (include Contrast CT Contrast CT or
or DSA CTA, DSA hemosiderin- or MRI MRI (include
sensitive hemosiderin-
sequences and sensitive
contrast) sequences)
Overall Risk of Variable depending 2Y4% per year 1Y4% per year Rare (G1% Rare (G1%
Hemorrhage on risk factors per year) per year)
Risk Factors for Strongest risk Strongest risk Strongest risk NA NA
Hemorrhage factors: size, factors: prior factors: prior
location hemorrhage, hemorrhage,
presence of brainstem location
Additional
an associated
potential risk Additional
aneurysm
factors: prior potential risk
subarachnoid Additional factors: female
hemorrhage from potential risk sex, multiplicity
other aneurysm, factors: age,
family history, exclusive deep
morphology, venous drainage,
Japanese or deep location
Finnish heritage
CT = computed tomography; CTA = CT angiography; DSA = digital subtraction angiography; MRA = magnetic resonance angiography;
MRI = magnetic resonance imaging; NA = not applicable.

stereotactic radiosurgery). Thus, under- and management strategies of unrup-

standing the natural history and risk of tured intracranial aneurysms, arteriove-
hemorrhage of each of the vascular ab- nous malformations (AVMs), cavernous
normalities is important. Patients may malformations, developmental venous
have comorbid conditions or lifestyles anomalies, and capillary telangiectasias.
that potentially increase the risk of
bleeding; thus, individualized man- UNRUPTURED INTRACRANIAL
agement and counseling are important. ANEURYSM
This article reviews the epidemiology, Unruptured intracranial aneurysms are
clinical presentation, natural history, commonly encountered in clinical

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 KEY POINTS
neurology practice. Neurologists play an for surveillance to avoid repeated radi- h Rare disorders such as
important role in determining whether ation exposure and to limit the beam- polycystic kidney disease
an aneurysm is symptomatic, assessing hardening artifact. and coarctation of the
risk factors, and counseling patients aorta may predispose
about the natural history. The following Epidemiology patients to unruptured
section reviews useful tools for a practic- Estimates based on imaging studies intracranial aneurysm
ing neurologist encountering an unrup- suggest that approximately 3% of the formation.
tured intracranial aneurysm. US population harbor an unruptured h Unruptured intracranial
intracranial aneurysm. Unruptured aneurysms are more
Definition and Radiologic intracranial aneurysms are acquired common in women,
Appearance lesions, and risk factors for their tobacco users, and
Intracranial aneurysms can be character- development can be divided into patients with
ized by their shape or by their etiology. those that are modifiable and those hypertension.
In this article, the term unruptured that are nonmodifiable (Table 9-2).1
intracranial aneurysm specifically re- Most studies show a higher prevalence
fers to the most common type of brain of unruptured intracranial aneurysms
aneurysm, a saccular or berry aneurysm. in women compared to men and in
Saccular aneurysms are round arterial patients over the age of 30, with a
outpouchings typically located at ar- peak prevalence in the fifth and sixth
terial bifurcations involving vessels decades. In patients with a family
of the circle of Willis. They are believed history of an unruptured intracranial
to be acquired lesions. aneurysm or subarachnoid hemor-
Saccular unruptured intracranial rhage (SAH) in a first-degree relative,
aneurysms may be incidentally detected the prevalence is approximately 4%. If
at the time of rupture of another aneu- two or more family members had
rysm or during imaging performed for unruptured intracranial aneurysms or
another neurologic indication. Some SAHs, the incidence of detection in-
aneurysms are found on cross-sectional creases to approximately 8% to 11%.1
MRI or CT. However, smaller aneu- In one study, patients with two or
rysms may only be detected by MR an- more first-degree relatives with
giography (MRA), CT angiography unruptured intracranial aneurysms or
(CTA), or digital subtraction angiogra- SAHs were serially screened with MRA
phy. Digital subtraction angiography or CTA; new aneurysms continued to
remains the gold standard for aneu- be detected even after two early
rysm detection. It is superior to CTA or negative screens.2 In addition to age,
MRA for detecting aneurysms less than sex, and family history, certain rare
3 mm in diameter, but it does carry a disorders predispose to aneurysm for-
small risk (less than 0.1%) of bleeding, mation (Table 9-2), the most common
stroke, or renal failure and uses radi- of which is polycystic kidney disease;
ation.1 Three-dimensional rotational coarctation of the aorta may also
conventional arteriography is ideal predispose to aneurysm formation.
and can provide detail about the aneu- Modifiable risk factors include hyper-
rysm size, morphology, and potential tension, cigarette smoking, and poten-
perforating vessels near the aneurysm. tially excessive alcohol intake.
MRA and CTA have high sensitivity and Saccular unruptured intracranial an-
specificity for the detection of aneu- eurysms most commonly occur at
rysms over 3 mm in diameter and are bifurcation points in the circle of
reasonable tests for screening and fol- Willis. Most unruptured intracranial
lowing patients. MRA may be preferred aneurysms (about 80% to 85%) are in
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 Aneurysms and Cerebrovascular Malformations

TABLE 9-2 Risk Factors for Unruptured Intracranial Aneurysm

Formation

b Risk Factors
Nonmodifiable
Female sex
Increasing age
Family history of unruptured intracranial aneurysm or subarachnoid
hemorrhage in first-degree relatives
Modifiable
Hypertension
Cigarette smoking
Possibly excess alcohol use
b Rare Diseases/Conditions Associated With Increased Risk of Aneurysm Formation
Autosomal dominant polycystic kidney disease
Ehlers-Danlos syndrome type IV
Marfan syndrome
Coarctation of the aorta
Bicuspid aortic valve
Pseudoxanthoma elasticum
Hereditary hemorrhagic telangiectasia
Neurofibromatosis type 1
!1-Antitrypsin deficiency
Fibromuscular dysplasia
Pheochromocytoma
Klinefelter syndrome
Tuberous sclerosis
Noonan syndrome
!-D-Glucosidase deficiency
Microcephalic osteodysplastic primordial dwarfism
Intracranial arteriovenous malformation

the anterior circulation, with common circulation, common locations include

sites including the anterior communi- the top of the basilar artery, the
cating artery, middle cerebral artery superior cerebellar artery branch from
bifurcation or trifurcation, posterior the basilar artery, and the anterior
communicating artery origin, ophthal- inferior cerebellar artery branch from
mic artery origin, and internal carotid the basilar artery. Nearly 20% of pa-
artery bifurcation. In the posterior tients have multiple aneurysms, which

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 KEY POINT
are more common in patients who are ies have helped establish risk factors h In the United States, the
older or female or who use tobacco. for rupture so practitioners can try to prevalence of unruptured
select appropriate patients for treat- intracranial aneurysms is
Presentation ment. In the past 10 years, many new 3000 per 100,000, and
Unruptured intracranial aneurysms endovascular treatments have evolved the prevalence of
can be divided into three main to reduce the risk of treatment of subarachnoid hemorrhage
groups: (1) asymptomatic or incidental, unruptured intracranial aneurysms. is 10 per 100,000. Thus,
(2) symptomatic (not due to hemor- Several large cohort studies and the majority of unruptured
rhage), and (3) unruptured aneurysm(s) meta-analyses have provided impor- intracranial aneurysms
in patients with a prior SAH from a tant prospective natural history data do not rupture.
separate aneurysm. While the majority that allow prediction of the risk of
of unruptured intracranial aneurysms aneurysm rupture in individuals. The
are discovered incidentally or in pa- largest natural history study assessing
tients with prior SAH, a minority of patients from North America and
unruptured intracranial aneurysms Europe is the International Study of
present with acute or chronic neuro- Unruptured Intracranial Aneurysms
logic symptoms. Acute headache may (ISUIA).3,4 In the prospective arm of
occur as a result of sudden thrombosis, this study, 2686 patients were followed
dural compression, or local inflamma- over a mean time of 49.2 months. Two
tion. In addition, both acute and chronic main predictors were determined: size
headaches may result from compression and location (Table 9-3). With increas-
of the trigeminal nerve as with enlarge- ing size, the rupture risk was higher.
ment of carotid cavernous aneurysms. Aneurysms located in the posterior
Patients may also develop acute or circulation or posterior communicating
chronic cranial neuropathies due to segment of the carotid artery had a
compression. Most commonly, cranial higher risk than those in the anterior
nerves II, III, IV, V, and VI are involved. circulation. In addition, in patients who
Patients with extradural carotid cavern- had a prior SAH from another aneu-
ous aneurysms may present with eye rysm and also had a small (less than
pain in addition to cranial nerve III, IV, or 7 mm in diameter) incidental aneurysm,
VI involvement. Rarely, patients may the risk was higher than in a patient
develop cerebral ischemic symptoms. with no prior history of SAH. In the
Most often, this is due to a partially Unruptured Cerebral Aneurysm Study
thrombosed aneurysm with distal embo- (UCAS), 1930 Japanese patients were
lization, although other sources of ische- followed for 11,660 aneurysm-years.5
mia must always be ruled out. The overall risk of rupture was 0.95%
per year. Aneurysm size and location
Natural History and the presence of a daughter sac
Aneurysmal rupture is a serious and were predictive of rupture. In contrast
potentially fatal event. With increasing to the ISUIA, the UCAS found that
use of brain and cerebrovascular im- both anterior communicating artery
aging, it has been shown that approx- and posterior communicating artery
imately 3% (3000 per 100,000) of aneurysms had a higher risk of rupture
people in the United States harbor an compared to other locations. Given
unruptured intracranial aneurysm. Yet that the Japanese population has a
the annual incidence of SAH is about higher rate of SAH, it is not clear if
10 per 100,000.1 This means that the this translates to the North American
majority of unruptured intracranial population. Several other large pro-
aneurysms do not rupture. Many stud- spective natural history studies also
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 Aneurysms and Cerebrovascular Malformations

KEY POINT
h Risk factors for unruptured TABLE 9-3 Five-Year Cumulative Rupture Rates According to Size
intracranial aneurysms and Location of Unruptured Aneurysma
include size and location
(posterior circulation, Size
posterior communicating
G7 mm G7 mm
artery, anterior Location Group 1b Group 2c 7Y12 mm 13Y24 mm 25 mm
communicating artery),
Cavernous carotid 0 0 0 3.0% 6.4%
growth, and symptoms
artery (n = 210)
not due to rupture.
AC/MC/IC (n = 1037) 0 1.5% 2.6% 14.5% 40%
Post-P comm (n = 445) 2.5% 3.4% 14.5% 18.4% 50%
AC = anterior communicating or anterior cerebral artery; IC = internal carotid artery (not cavernous
carotid artery); MC = middle cerebral artery; Post-P comm = vertebrobasilar, posterior cerebral
arterial system, or the posterior communicating artery.
a
Reprinted with permission from Wiebers DO, Lancet.4 B 2003 Elsevier. thelancet.com/journals/
lancet/article/PIIS0140-6736(03)13860-3/abstract.
b
Patients with no prior history of subarachnoid hemorrhage.
c
Patients with a prior history of subarachnoid hemorrhage from another aneurysm.

suggest size and location as important Putting all the data together, the
factors. The Familial Intracranial Aneu- most impactful risk factors for aneu-
rysm study (FIA) followed 113 patients rysm rupture are size (greater risk with
with 148 familial unruptured intracra- increasing size), location (posterior cir-
nial aneurysms. In this study, the rate culation, posterior communicating, and
of rupture was approximately 1.2 per anterior communicating), and symp-
100 patients, higher than the nonfa- toms not due to rupture (Table 9-4).
milial rates from the ISUIA study.6 Other risk factors that may play a role
Given the small number of patients are also listed in Table 9-4. Aneurysmal
and outcome events as well as a short growth found on surveillance imaging
follow-up length, a definitive conclusion raises a concern for potential future
as to whether family history raises risk rupture as well. Risk factors for aneu-
was not possible. rysm growth include female sex, ciga-
A pooled analysis of individual data rette smoking, younger age, excessive
from six prospective cohort studies alcohol use, aneurysm location, multi-
yielded additional information on rup- plicity of aneurysms, history of stroke,
ture risk and risk factors. In this anal- and history of transient ischemic attack.
ysis, 8382 patients were followed for Emerging aneurysm vessel wall imaging
29,166 person-years.7 The overall 5-year techniques may be a future aid for the
risk of aneurysm rupture was 3.4%. Risk clinician in risk stratification for rupture.8
factors for rupture included age, hyper-
tension, history of SAH, aneurysm size Management and Treatment
and location, and country of origin of Management decisions for unruptured
the patient. Together, these risk factors intracranial aneurysms include: (1)
were modeled into an easy-to-use scor- when to screen a patient for an un-
ing system, the PHASES (population, hy- ruptured intracranial aneurysm; (2)
pertension, age, size of aneurysm, earlier whether a patient undergoes observa-
SAH from another aneurysm, site of tion versus treatment; (3) if treatment is
aneurysm) score, to aid in predicting selected, the type of treatment (surgical
rupture risk in individuals (Figure 9-1). or endovascular); (4) what type of

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FIGURE 9-1 PHASES (population, hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage from another
aneurysm, site of aneurysm) score and rupture risk.
Reprinted with permission from Greving JP, et al, Lancet Neurol.7 B 2014 Elsevier. thelancet.com/journals/laneur/article/PIIS1474-4422(13)70263-1/abstract.

KEY POINT
follow-up or surveillance is necessary; tomatic intracranial aneurysms, such as h Screening for unruptured
and (5) how to treat concurrent disease those with isolated cranial nerve palsy. intracranial aneurysms is
or comorbidities. Guidelines for the Treatment of an incidental asymptomatic recommended for those
management and treatment of unrup- unruptured intracranial aneurysm re- with two or more
tured intracranial aneurysms were pub- quires careful thought about the natural first-degree relatives
lished by the American Heart/Stroke history of that individual aneurysm com- with unruptured
Association in 2015.1 pared to the risk of treatment of the intracranial aneurysms
Screening. Patients with two or aneurysm.1,9 Patient factors such as age, or aneurysmal
more family members with unruptured medical history, history of SAH, life ex- subarachnoid
intracranial aneurysms or SAHs should pectancy, and family history should be hemorrhages.
be considered for screening with either considered. The size, location, growth,
CTA or MRA. This is especially important and morphologic characteristics of the
if the patient also has a history of hyper- aneurysm and whether the patient has
tension or tobacco use or is female.1 symptoms not due to rupture should
Other rare, but high-risk, groups that may also be considered. Patients selected for
require screening include patients with potential treatment should be seen by a
autosomal dominant polycystic kidney vascular neurosurgeon with expertise
disease, especially if they have a family in unruptured intracranial aneurysms
history of unruptured intracranial aneu- at a high-volume institution. In addition,
rysms, and patients with coarctation of the patient’s preference and concerns
the aorta or microcephalic osteo- should be considered.
dysplastic primordial dwarfism. Since Two scores may be useful for aiding
many unruptured intracranial aneu- the practitioner in decisions regarding
rysms do not need invasive treatment, treatment. One is the PHASES score (dis-
patients should receive counseling cussed previously). This score allows
about this before undergoing screening. prediction of natural history that can be
Determining whether to treat an weighed against the risk of treatment
unruptured intracranial aneurysm. (Case 9-1). The second scoring system
Treatment is generally favored in symp- is the Unruptured Intracranial Aneurysm

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 Aneurysms and Cerebrovascular Malformations

KEY POINT
h The natural history of clinical decision making in patients with
the unruptured TABLE 9-4 Risk Factors for unruptured intracranial aneurysms.
Intracranial Aneurysm Using the Delphi Method (a structured
intracranial aneurysm
Growth and Rupture
must be compared to technique in which experts approach
the individual treatment and answer specific well-defined ques-
b Risk Factors for Aneurysm
risk to make a tions in two or more rounds based on
Growth
determination on discussion and presentation of prior
whether treatment is Female sex research), investigators found that
recommended. The Cigarette smoking there was excellent consensus among
Unruptured Intracranial experts using this method.
Aneurysm Treatment Younger age
Treatment of unruptured intra-
Score may aid Excessive alcohol use cranial aneurysms. While treatment
the practitioner.
Aneurysm location recommendations for unruptured in-
Multiplicity of aneurysms tracranial aneurysms are beyond the
scope of this article, a few statements
History of stroke
can be made about the types of treat-
History of transient ischemic ments offered for unruptured intracranial
attack aneurysms. Treatment generally includes
Aneurysm size surgical and endovascular options.
b Risk Factors for Aneurysm
Surgical clipping of aneurysms has
Rupture been the mainstay of aneurysm treat-
ment for decades. In a meta-analysis of
Strongest risk factors
patients undergoing surgery for any
Size unruptured intracranial aneurysm, the
Location major morbidity rate was approximately
4% and the mortality rate was 1%.11 In
Symptoms not due to
rupture data from the ISUIA treated arm, the
morbidity rate, which included cogni-
Additional potential risk
tive impairment, was higher (more than
factors
10%). In that study, age was a key pre-
Younger age (G50 years) dictor of surgical outcome.3,4
Cigarette smoking Endovascular options generally in-
Hypertension
clude standard coiling but also can
include balloon and stent-assisted
Aneurysmal growth coiling and flow diversion, and parent
Morphology artery sacrifice with or without bypass.
Female sex Data on endovascular treatment come
from older studies and suggest a
Prior subarachnoid
combined morbidity/mortality rate of
hemorrhage
8% to 9%. This technology and user
Family history of expertise continues to evolve with
subarachnoid hemorrhage
time. Endovascular flow diversion for
Finnish or Japanese the treatment of aneurysms is a new
heritage and evolving option (Figure 9-3). Low-
porosity stent devices divert blood flow
in the usual direction and away from
Treatment Score (UIATS) (Figure 9-2).10 the aneurysmal wall. Ultimately, the
This scoring system was developed by aneurysm involutes, and the flow diverter
69 experts in the field to quantify provides a scaffold for intimal growth.
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 Case 9-1
A 71-year-old man of English descent with a history of hypertension
underwent brain magnetic resonance angiography (MRA) during the
investigation for an ischemic stroke. The MRA demonstrated a 5-mm right
middle cerebral artery aneurysm. The patient had no prior history of
subarachnoid hemorrhage and no family history of unruptured intracerebral
aneurysm or subarachnoid hemorrhage. The cause of the ischemic stroke
was atrial fibrillation.
Comment. Based on the International Study of Unruptured Intracranial
Aneurysms (ISUIA) criteria, the rupture risk of this patient’s aneurysm was very
close to 0. Based on his PHASES (population, hypertension, age, size of
aneurysm, earlier subarachnoid hemorrhage from another aneurysm, site of
aneurysm) score of 4 points (1 point for hypertension, 1 point for age older
than 70 years, 2 points for middle cerebral artery aneurysm location), the
5-year rupture risk was calculated to be 0.9% (or roughly 0.2% per year).
Because of this patient’s low risk of rupture compared to the morbidity/
mortality from either endovascular or surgical treatment, observation
would commonly be recommended. Anticoagulation is appropriate for his
atrial fibrillation and does not increase the risk of rupture. However, if
rupture did occur, the use of anticoagulation would carry a higher
morbidity and mortality. In this patient, surveillance with MRA or CT
angiography was recommended to be performed in 6 months, then every
1 to 2 years thereafter.

Multicenter prospective studies have of the aneurysm, and volume of aneu-

shown this method to be effective for rysms treated at the center. The age of
complex aneurysms (more than 10 mm the patient is important. In the surgi-
in size with a wide neck) of the internal cal arm of the ISUIA study, a clear
carotid artery proximal to the origin of gradient of older patients having worse
the posterior communicating artery. It is outcomes compared to younger patients
US Food and Drug Administration (FDA) existed. The size and location of the
approved for proximal intradural carotid aneurysm are also important. With in-
circulation aneurysms, such as those in creasing size, surgical risk increases. In
the cavernous paraclinoid-ophthalmic addition, a posterior circulation aneu-
segments.1 rysm location was associated with in-
The decision to consider surgical creased surgical risk as compared to
clipping versus aneurysm coiling for anterior circulation aneurysms. Other
an individual patient requires careful aneurysm features to consider include
examination of individual patient fac- the presence of thrombus, calcification,
tors and aneurysmal factors and the aneurysm neck size, and morphology.
expertise of practitioners, as both The expertise and volume of the treat-
options are effective treatments for ing institution is important. Centers that
unruptured intracranial aneurysms.1,9 perform treatment of more than 20
In some situations, either technique aneurysms per year have better out-
may be reasonable. However, in other comes than those that treat fewer than 20.
situations, one therapeutic modality While no randomized trials of sur-
may be safer or more effective. Con- gery versus endovascular treatment
siderations include age, comorbidities, exist for unruptured aneurysms, data
patient preference, size and location from the International Study of Aneurysm

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 Aneurysms and Cerebrovascular Malformations

FIGURE 9-2 Unruptured Intracranial Aneurysm Treatment Score (UIATS).

AcomA = anterior communicating artery; BasA = basilar artery; multiple = multiple-selection category;
PcomA = posterior communicating artery; SAH = subarachnoid hemorrhage; single = single-selection
category; UIA = unruptured intracranial aneurysm.
a
The minimal intervention-related risk is always added as a constant factor.
Reprinted with permission from Etminan N, et al, Neurology.10 B 2015 American Academy of Neurology. neurology.org/content/85/10/881.short.

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FIGURE 9-3 Treatment of an aneurysm with flow diversion. A, A flow diverter is placed in the parent artery of a
wide-necked aneurysm. B, Flow is diverted in the cephalad direction away from the aneurysm wall.
C, Ultimately, because of decreased flow into the aneurysm, it thromboses.

KEY POINT
Treatment (ISAT) suggest that the Treatment of concurrent disease
h Surveillance magnetic
endovascular procedural risk is less and lifestyle restrictions. Patients with
resonance angiography
than the surgical risk in patients with unruptured intracranial aneurysms or CT angiography is
ruptured intracranial aneurysms in often have other comorbidities that re- recommended for
which either treatment was felt to be quire treatment. Practitioners caring patients with an
a potential option.12 Overall, endovas- for patients with aneurysms may be unruptured intracranial
cular treatment may have lower peri- asked questions by primary care phy- aneurysm undergoing
procedural morbidity or mortality; sicians or obstetricians regarding par- observation.
however, surgical clipping has a lower ticular comorbidities and treatment.
rate of aneurysm remnant or aneu- Most recommendations come from
rysm recurrence. expert opinion as few data may exist
Follow-up surveillance. Surveil- on individual topics. In general, no
lance imaging with MRA or CTA is often evidence exists to indicate that patients
recommended in patients with an with stable unruptured intracranial an-
unruptured intracranial aneurysm who eurysms should restrict their level and
will undergo observation. If frequent type of activity in any way or form. Sim-
surveillance is necessary, MRA may be ilarly, these patients can undergo any
favored to avoid ongoing radiation ex- surgical procedure and take any indi-
posure. Surveillance allows the practi- cated medication without any particu-
tioner to determine if an aneurysm has lar restriction as no evidence exists to
grown, which may prompt consider- the contrary.
ation of treatment. In one study, the Some patients with unruptured in-
rate of growth was 6.9% over 4 years in tracranial aneurysms have a concomi-
patients with aneurysms less 8 mm in tant illness requiring anticoagulation
size, 25% in those with aneurysms (eg, pulmonary embolus, atrial fibrilla-
8 mm to 12 mm in size, and 83% in pa- tion). Anticoagulation does not pre-
tients with aneurysms larger than 12 mm. cipitate hemorrhage of an unruptured
While no exact studies exist to guide the intracranial aneurysm; however, if a
intervals of surveillance, the first repeat patient does have an aneurysmal hem-
image is recommended 6 to 12 months orrhage while on anticoagulation, the
after the initial discovery. Thereafter, morbidity/mortality is higher. Thus,
the interval depends on patient age the risk-benefit ratio needs to be con-
and aneurysm size and location. sidered. If patient had a small (less than

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 Aneurysms and Cerebrovascular Malformations

7 mm) incidental unruptured intracra- aneurysm, and this may not be

nial aneurysm and needed a novel warranted.13 In these rare situations,
anticoagulant for a pulmonary embo- evaluation by a cerebrovascular neurol-
lism, the benefit of the anticoagulation ogist and neurosurgeon is suggested.
would seem to outweigh the risk. If,
however, the patient had a symptom- ARTERIOVENOUS
atic enlarging unruptured intracranial MALFORMATIONS
aneurysm and a concomitant illness AVMs may come to the attention of a
requiring anticoagulation, treatment neurologist after a patient has a sei-
of the unruptured intracranial aneu- zure or an intracranial hemorrhage or
rysm may be considered first. Inter- after it is incidentally found on an MRI
estingly, exploratory data from large performed for an alternative indica-
cohorts suggest that aspirin use may tion. The following section reviews the
reduce rupture risk. More prospec- worrisome clinical and radiologic fea-
tive data or a clinical trial are neces- tures of patients with AVMs that may
sary to recommend such as treatment, require neurosurgical referral.
however.
Very few lifestyle restrictions need Definition and
to be put forth on patients with un- Radiologic Appearance
ruptured intracranial aneurysms. Pa- AVMs are vascular abnormalities consist-
tients who use tobacco should be ing of fistulous connections of arteries
encouraged to quit. In addition, all pa- and veins without normal intervening
tients should avoid secondhand smoke. capillary beds. Thus, arterial pressure
Periodic assessment of blood pressure is directly transmitted to venous struc-
is recommended. One may consider tures, leading to increased blood flow,
limiting heavy weightlifting that re- dilatation of vessels, and tortuosity.
quires the Valsalva maneuver. Routine Venous hypertension may result.
physical activity, such as aerobic activity, AVMs may appear as serpiginous
sexual activity, or contact sports, does vessels on contrast CT. Calcification of
not necessitate restriction. the AVM may also appear on CT in up
It is uncommon to encounter a to one-third of patients. In addition to
patient who is pregnant with a con- identifying the AVM, CT is useful for
comitant unruptured intracranial an- assessing for acute intracranial hemor-
eurysm; however, the same principles rhage. However, small AVMs may be
of management apply to patients who missed on CT alone. MRI is superior to
are pregnant (ie, weighing the risk of CT for identifying AVMs. It is important
hemorrhage against the risk of treat- to determine the size and location as
ment). In most cases, an incidental these features impact treatment choices.
aneurysm is small, and observation is In addition, MRI may show evidence of
recommended. A recent study sug- previous symptomatic or subclinical
gests the rate of rupture of cerebral hemorrhage as well as secondary
aneurysms is not higher during preg- changes, including mass effect, edema,
nancy as compared to the nonpregnant and ischemic changes in surrounding
state.13 Few data exist to guide the brain tissue. T1- and T2-weighted MRI
mode of delivery in these patients. A sequences often show flow voids that
recent study found that the rate of may be tightly packed or diffuse depend-
cesarean deliveries is higher in patients ing on the size (Figure 9-4). MRA or
harboring unruptured intracranial an- CTA can be useful in assessment of the
eurysms compared to those without an flow; however, cerebral angiography is
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 KEY POINT
tionally considered congenital lesions, h Arteriovenous
evolving evidence and several well- malformations
documented cases of de novo AVM commonly present with
formation have challenged this notion. hemorrhage in the
Most AVMs may, indeed, be acquired second through
lesions. AVMs may also have a genetic fourth decades.
basis in some populations, but this is
rare. The majority of AVMs are located
supratentorially, and they are typically
solitary. In the posterior fossa, the cere-
bellum is the most common site. AVMs
may rarely be associated with any of
the other vascular malformations.

Presentation
AVMs may be an incidental finding or
patients may present with neurologic
FIGURE 9-4 Arteriovenous malformation. symptoms and deficits due to hemor-
T2-weighted MRI of the
brain demonstrates multiple rhagic or nonhemorrhagic etiologies.
flow voids in the right hemisphere, suggestive With the increasing use of MRI, the
of a large arteriovenous malformation.
number of asymptomatic incidentally
discovered AVMs has increased. Ap-
the gold standard for assessing the proximately 10% to 20% of AVMs are
angioarchitecture of these lesions. On discovered as incidental findings.
cerebral arteriography, parenchymal If symptomatic, the most common
AVMs appear as tightly packed masses presentation is that of hemorrhage (ap-
of enlarged feeding arteries and dilated proximately 40% to 60% of patients).
tortuous veins with little or no interven- Most commonly, hemorrhage is within
ing parenchyma within the nidus. Arte- the brain parenchyma; however, sub-
riovenous shunting with abnormal early arachnoid or intraventricular bleeding
filling of veins that drain the lesion is can occur. Patients presenting with
characteristic of AVMs. Cerebral angiog- hemorrhage are more likely to have an
raphy is essential prior to determination AVM that is small (less than 3 cm) and in
of treatment to carefully assess the size a deep location and to have exclusive
of the AVM, determine if any nidal deep venous drainage. Approximately
aneurysms or feeding artery aneurysms 10% to 30% of patients present with
exist, establish eloquent location, and seizures. Patients presenting with sei-
determine feeding and draining vessels. zures have a supratentorial AVM, often
in a frontal or temporal location. Sei-
Epidemiology zures may be simple or partial complex
The estimated prevalence of AVMs is and may or may not generalize.
approximately 0.1% to 0.2%.14 Patients Less commonly, patients will initially
are typically diagnosed between 20 and have transient, permanent, or progres-
40 years of age. Nearly 40% of intra- sive focal neurologic deficits not due to
cerebral hemorrhage in patients 15 to hemorrhage or seizure. Mechanisms for
45 years of age is due to an AVM. Most this type of presentation may include
studies report an equal or slight male steal phenomena (ischemia due to a
preponderance in patients with AVMs. high-flow AVM “stealing” blood away
Although AVMs have been tradi- from local tissue), recurrent small
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 Aneurysms and Cerebrovascular Malformations

KEY POINTS
h Prior hemorrhage hemorrhages, local pressure or mass tion is often used as an adjunct treatment
increases the risk for effect from the AVM, or hydrocephalus. with either surgical resection or radio-
recurrent hemorrhage surgery. In some selected cases (often
Natural History small AVMs with a single draining vein),
in patients with
arteriovenous Hemorrhage due to AVM carries high embolization may be curative. Rec-
malformation. morbidity and mortality. Several natu- ommendations for management come
h Treatment for ral history studies, meta-analyses, and from natural history cohorts, a single
arteriovenous a single clinical trial have attempted to clinical trial, surgical series, and the
malformation depends estimate the risk of bleeding in AVMs American Heart Association Guide-
on patient factors to aid in management decisions about lines.18 Medical management for pa-
(presence of symptoms/ which patients require treatment. The tients with AVMs includes counseling
hemorrhage, age of overall risk of hemorrhage in patients regarding the natural history risk, treat-
patient, comorbidities) with AVMs has been estimated to be ing seizures associated with the AVM,
and angiographic factors 2% to 4% per year.15,16 and managing comorbidities and other
(location of feeding and An individual’s risk of rupture de- health conditions.
draining vessels, pends on several factors; prior hemor- Surgery can definitively remove
eloquence of the brain,
rhage is the most consistent risk factor AVMs and thereby eliminate the risk of
presence of feeding
for future hemorrhage.16 In patients future hemorrhage. When technically
artery or nidal aneurysms,
size of nidus). with a prior history of hemorrhage, possible, this technique is preferred in
the risk of ever-recurrent hemorrhage patients who have hemorrhaged, given
h Options for treating
is up to 44%. Furthermore, in these pa- their risk of subsequent hemorrhage.
an arteriovenous
malformation to reduce
tients, the risk of subsequent hemor- The Spetzler-Martin AVM grading system
hemorrhage risk or rhage is highest in the first year after is commonly used to assess surgical risk
seizures include surgery initial hemorrhage. One study found (Table 9-5 and Table 9-6).19 Surgical
or stereotactic that the bleeding rate in those who risk increases with higher Spetzler-
radiosurgery. presented with hemorrhage initially was Martin grade. In patients in whom
Endovascular higher in the first year (15.4%), falling surgery is performed because of intrac-
embolization is a to 5.3% in the next 4 years and 1.7% table seizures, up to 60% to 80% of
common adjunctive after 5 years.17 Radiologic risk factors patients may become seizure free 2 to
procedure. include deep location, exclusive deep 3 years postsurgery.
h The Spetzler-Martin venous drainage, and the presence of Stereotactic radiosurgery is also a con-
arteriovenous an associated aneurysm. sideration for the treatment of AVMs. It
malformation grading takes approximately 2 to 3 years for an
system can aid in Management and Treatment AVM to involute and obliterate by this
determining surgical risk. The natural history for an individual technique, thus the patient remains at
must be carefully weighed against the risk for hemorrhage during that time
risk of intervention. Consultations with frame. For this reason, surgery is gen-
cerebrovascular neurologists, vascular erally preferred if a patient has already
neurosurgeons, and interventionalists hemorrhaged. Although heavily de-
and radiosurgeons with expertise in bated, best evidence suggests that
AVM management should be sought. stereotactic radiosurgery neither in-
Patient preference, clinical factors, radio- creases nor decreases the risk of
logic factors, and neurosurgical exper- hemorrhage during the latency period
tise play a role in selecting the most between treatment and obliteration.
appropriate treatment for an individual. The Pollock-Flickinger score was
In general, treatment options to reduce developed to aid the practitioner in
the risk of hemorrhage from an AVM selecting patients with AVMs for stereo-
include surgical resection or stereotac- tactic radiosurgery (Table 9-7).20 Ste-
tic radiosurgery. Endovascular emboliza- reotactic radiosurgery is most successful
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 KEY POINT

TABLE 9-5 Spetzler-Martin and Spetzler-Martin Supplementary h Successful surgery will

Grading Scores for Arteriovenous Malformationsa immediately reduce the
risk for further
Spetzler-Martin Grading Points Supplementary Grading hemorrhage; however,
stereotactic radiosurgery
Size (cm) Age (years)
results in obliteration
G3 1 G20 of the arteriovenous
3Y6 2 20Y40 malformation only after
2 to 3 years.
96 3 940
Venous drainage Bleeding
Superficial 0 Yes
Deep 1 No
Eloquence Compactness
No 0 Yes
Yes 1 No
Total 5
a
Reprinted with permission from Kim H, et al, Neurosurgery.19 B 2015 Congress of Neurological
Surgeons. journals.lww.com/neurosurgery/pages/articleviewer.aspx?year=2015&issue=01000&
article=00003&type=abstract.

in patients with small lesions. In patients radiosurgery (to reduce the size of the
with AVMs smaller than 3 cm, approxi- AVM); no evidence exists that this ap-
mately 80% of patients will have com- proach is effective, and many studies
plete obliteration of the AVM with have actually demonstrated worse out-
radiosurgery after 2 to 3 years. Larger comes after radiosurgery with previ-
AVMs may have lower obliteration rates ously embolized AVMs. Embolization is
or require staged radiosurgery. Patients best performed by an interventionalist
with a large and diffuse AVM nidus are or surgeon with expertise in AVM treat-
less favorable candidates for stereotac- ment as careful selection of feeding
tic radiosurgery. Risk of subsequent branches is necessary to avoid occluding
radiation necrosis is approximately 1% branches that also feed normal brain.
to 3% and depends on the dose deliv- Only one clinical trial has been
ered and the volume treated. In patients performed to evaluate the safety and
who undergo radiosurgery and have had effectiveness of treating unruptured
seizures, seizure freedom is achieved in AVMs.21 This study was halted early
50% to 60%, depending on the size of for safety concerns. A Randomized
the AVM and other characteristics. Trial of Unruptured Brain Arteriovenous
Endovascular embolization is a com- Malformations (ARUBA) randomly
mon adjunct to surgical treatment of assigned patients with unruptured AVMs
AVMs and may be curative in isolation in to medical versus interventional (sur-
less than 5% of patients. Embolization gery, radiation therapy, or endovascular
reduces the nidus size and vascularity therapy) treatment. A total of 223
of the AVM, potentially decreasing sur- patients were followed for a mean
gical complications in complex AVMs. 33 months. The primary end point of
Preoperative embolization is rarely used death or symptomatic stroke was
in many centers prior to stereotactic higher in the intervention group as

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 Aneurysms and Cerebrovascular Malformations

TABLE 9-6 Patient Outcomes According to Spetzler-Martin Grade,

Supplementary Grade Scale, and Combined Gradesa

Neurologic Outcome
Worse or Dead Improved or Unchanged
N % N %
Spetzler-Martin Grade
I 5 8.9 51 91.1
II 30 24.4 93 75.6
III 27 30.0 63 70.0
IV 9 31.0 20 69.0
V 2 100.0 0 0.0
Supplemental Grade
I 1 3.7 26 96.3
II 8 11.9 59 88.1
III 25 22.1 88 77.9
IV 32 40.5 47 59.5
V 7 50.0 7 50.0
Combined Grade
1 0 0.0 0 0.0
2 0 0.0 7 100.0
3 0 0.0 21 100.0
4 5 9.1 50 90.9
5 19 21.1 71 78.9
6 19 27.1 51 72.9
7 24 54.5 20 45.5
8 4 50.0 4 50.0
9 2 40.0 3 60.0
10 0 0.0 0 0.0
a
Reprinted with permission from Kim H, et al, Neurosurgery.19 B 2015 Congress of Neurological Surgeons.
journals.lww.com/neurosurgery/pages/articleviewer.aspx?year=2015&issue=01000&article=
00003&type=abstract.

compared to the medical management may be considered in patients with small

group (30.7% versus 10.1%). A critique asymptomatic AVMs.
of the ARUBA study design was that the
relatively short duration of follow-up CAVERNOUS MALFORMATION
may have missed the longer-term Cavernous malformations are com-
benefit of intervention on hemor- monly encountered in clinical practice
rhage risk. These results suggest that after patients present with seizure
a cautious approach to intervention or brain hemorrhage or as an incidental

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TABLE 9-7 Pollock-Flickinger Score for Grading Arteriovenous
Malformation for Radiosurgerya

Arteriovenous 0.1  (Volume + 0.02) 

Malformation Formula (Age + 0.5)  Location

Where:
Volume: in mL
Age: in years
Location: superficial (hemispheric/corpus
callosum/cerebellar) = 0; deep (basal
ganglia/thalamus/brainstem) = 1
Chance (%) of excellent AVM score e1.00: 89 (79Y94)
outcome with 95%
AVM score 1.01Y1.50: 70 (59Y79)
confidence interval
AVM score 1.51Y2.00: 64 (51Y75)
AVM score 92.00: 46 (33Y60)
Chance (%) of modified AVM score e1.00: 0 (0Y8)
Rankin Scale decline with
AVM score 1.01Y1.50: 13 (7Y22)
95% confidence interval
AVM score 1.51Y2.00: 20 (12Y32)
AVM score 92.00: 36 (24Y50)
a
Data from Pollock BE, Flickinger JC, Neurosurgery.20 journals.lww.com/neurosurgery/pages/
articleviewer.aspx?year=2008&issue=08000&article=00014&type=abstract.

finding on an MRI scan. Unlike other malformation. CT is sensitive but not

vascular malformations, approximately specific for the diagnosis of cavernous
20% of cavernous malformations may malformations. Hemorrhage or mild
be familial. Neurologists play an impor- calcification seen on CT may be
tant role in distinguishing the type of suggestive of a cavernous malforma-
cavernous malformation (sporadic tion, but the CT may also be normal.
versus familial), counseling patients In addition, angiography is often
on the risk of bleeding, and initiating normal, as these lesions are low flow
symptomatic treatment. The following at the level of the capillary. Thus, MRI
section reviews these issues and ques- is the diagnostic study of choice. MRI
tions commonly asked by patients. scans should include standard T1- and
T2-weighted sequences and ideally
Definition and Radiologic should also include a hemosiderin-
Appearance sensitive sequence (gradient recalled
Cavernous malformations are angio- echo [GRE] or susceptibility-weighted
graphically occult vascular malfor- imaging [SWI]) and T1 with post-
mations composed of endothelial-lined contrast sequences. On T2-weighted
caverns. The endothelia have defec- MRI, a typical cavernous malforma-
tive tight junctions; thus, cavernous tion appears as a well-defined lesion
malformations may leak, often resulting with a central core of mixed signal
in symptoms.1,18,22 intensity surrounded by a rim of
An MRI is generally necessary to hypointensity (Figure 9-5). The re-
make the diagnosis of a cavernous ticulated appearance on T2 sequences
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 Aneurysms and Cerebrovascular Malformations

FIGURE 9-5 Cavernous malformation. T2-weighted MRI of the brain (A) demonstrates a
right midbrain-thalamic cavernous malformation of the brain. Note the
reticulated popcorn appearance. The associated susceptibility-weighted
sequence (B) demonstrates the large midbrain-thalamic lesion but also shows numerous
hypointensities. This patient had the familial form of cavernous malformation.

reflects the thrombosis, calcification, Epidemiology

and blood within the caverns. The Cavernous malformations account for
appearance has been likened to pop- approximately 5% to 10% of all vascular
corn or a mulberry. The surrounding T2 malformations. Approximately 0.3% to
hypointensity reflects hemosiderin 0.5% of the population may harbor a
deposition. If a cavernous malforma- cavernous malformation based on
tion has bled, it often appears bright autopsy and clinical and MRI studies.
on both T1 and T2 sequences with The overall prevalence in males and
mild associated mass effect. Some females is equal, and patients are typi-
cavernous malformations may appear cally diagnosed between the second
as hypointense lesions on T2 without and fourth decades.
a reticulated center, and others may The majority of cavernous malfor-
be only identified on hemosiderin- mations are supratentorial and are, on
sensitive sequences (GRE or SWI). average, 1.4 cm to 1.7 cm in size (range
While these sequences are sensitive, 0.1 cm to 9 cm). In the posterior fossa,
in isolation they are not specific, and the pons and cerebellum are the most
findings on these sequences can rep- common sites of involvement. Rarely,
resent calcium or microbleed from an they appear in the spinal cord.
alternative etiology. T1 with post- Association with developmental
gadolinium contrast sequences may venous anomalies, capillary telangi-
be useful in detecting a concomitant ectasias, and AVMs has also been
developmental venous anomaly. Al- described, with co-occurrence of cav-
though MRI is more specific than CT, ernous malformations and developmen-
the MRI appearance is not always tal venous anomalies reported most
pathognomonic (Table 9-8). commonly. Clinical studies estimate that

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 KEY POINTS
propose that thrombosis of a develop- h Approximately 30% of
TABLE 9-8 Differential Diagnosis mental venous anomaly with backflow patients with cavernous
of Cavernous into the thin-walled leaky cavernous mal-
Malformations malformations will
formation results in hemorrhage. have a concomitant
Cavernous malformations are ac- developmental
b Cavernous Malformation
Mimics
quired lesions. In general, 80% of pa- venous anomaly.
tients have cavernous malformations h Approximately 80% of
Thrombosed arteriovenous that are sporadic. In these patients, the cavernous malformations
malformation
etiology is largely unknown, although are acquired sporadic
Calcified tumor (eg, cavernous malformations have been lesions and 20% are
oligodendroglioma) described after radiation therapy to the familial (autosomal
Hemorrhagic metastases brain or spinal cord. Approximately dominant inheritance).

Granuloma 20% of patients with cavernous malfor-

mations have the familial form. While
Infectious/inflammatory
the radiologic and pathologic changes
nodules
are similar, the main difference is the
b Differential Diagnosis tendency for multiple lesions in patients
of a Hypointensity on
with the familial form.
Hemosiderin-sensitive
Sequences The genetics of familial cavernous
malformations have advanced our
Cavernous malformation
knowledge of the pathogenesis of
Calcium cavernous malformations. Three loci
Microbleed due to cerebral in patients with familial cavernous
amyloid angiopathy malformations have been identified,
Microbleed due to
and all are autosomal dominant with
hypertension incomplete penetrance. They include
CCM1 gene (also known as KRIT1) on
Trauma
chromosome 7q, CCM2 (also known
History of radiation to as malcavernin) on chromosome 7p,
the brain and CCM3 (also known as PDCD10)
Metallic particles on chromosome 3q (Table 9-9).24
CCM proteins are important in angio-
genesis and endothelial permeability
through actions in actin regulation
up to 30% of patients with cavernous and endothelial tight junction forma-
malformations have an associated de- tion and maintenance. In these patients
velopmental venous anomaly. How- with familial cavernous malformations,
ever, these studies may underestimate multiple cavernous malformations
the association as not all patients had are the rule, and skin lesions may
postcontrast studies. In addition, a also occur.
2013 7T MRI study found that 23 of
23 patients with cavernous malforma- Presentation
tions of the brain studied had an ab- Similar to other vascular malformations,
normal venous structure that was not patients with cavernous malformations
obvious on standard imaging.23 The pre- may present with seizures, focal neuro-
sence of an associated developmental logic deficits, or headaches, or the
venous anomaly has been implicated both malformation may be discovered inci-
in the potential pathogenesis and behav- dentally. The underlying cause of
ior of a cavernous malformation. Some symptoms may simply be mass effect

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 Aneurysms and Cerebrovascular Malformations

TABLE 9-9 Genetics of Familial Cavernous Malformations

CCM1 Also Known CCM2 Also Known CCM3 Also Known

Gene as KRIT1 as Malcavernin as PDCD10
Locus 7q11-22 7p15 3q25-27
Features Multiple cavernous Multiple cavernous Multiple cavernous
malformations malformations malformations
More prevalent in Often present in childhood
Hispanic population
More aggressive clinical course
Scoliosis may occur

or “leakiness” of the cavernous Clinical series report that 10% to

malformation or overt symptomatic 60% of patients with cavernous mal-
hemorrhage due to the cavernous formations present to medical atten-
malformation. tion with intracerebral hemorrhage.14
Seizures are the most common ini- Although patients with cavernous mal-
tial symptom at presentation, consis- formations most commonly have
tent with the fact that most cavernous intraparenchymal hemorrhage, sub-
malformations occur in a supratentorial arachnoid and intraventricular hemor-
location. Seizures are more likely in rhage have also been described.
patients with cavernous malforma- Patients with hemorrhage may present
tions located in the temporal lobe or with headache, seizure, or focal neuro-
with extensive hemosiderin deposi-
logic deficit. The deficit may be tran-
tion, calcification, or a thick gliomatous
sient, progressive, recurrent, or fixed.
capsule. The International League
The initial symptoms depend on the
Against Epilepsy (ILAE) has published
criteria for cavernous malformationY location and size of the lesion. The term
related epilepsy.25 Definite cavernous focal neurologic deficit (FND) is often
malformationYrelated epilepsy is diag- ascribed to patients with an acute to
nosed in a patient who has at least one subacute focal neurologic deficit with
cavernous malformation and evidence no imaging evidence of hemorrhage or
of a seizure-onset zone within the im- no imaging performed at the time of
mediate vicinity of the lesion. Probable the symptoms.
cavernous malformationYrelated epi- An estimated 10% to 40% of cav-
lepsy is defined as epilepsy that is focal ernous malformations are incidental
and arises from the same hemisphere findings on an MRI done for another
as the cavernous malformation with no reason. Often headaches are the indi-
evidence of an alternative cause for the cation for the MRI, and the relation-
seizure. Cavernous malformation unre- ship to the cavernous malformation
lated to epilepsy is diagnosed in a may be unclear. Use of International
patient with at least one cavernous Classification of Headache Disorders
malformation and evidence that the category, location, and whether acute
epilepsy is not related to the cavernous hemorrhage is present may be helpful
malformation (eg, the patient has a to distinguish primary headache dis-
generalized seizure disorder such as orders from those related to cavern-
juvenile myoclonic epilepsy). ous malformations.

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 KEY POINT
Natural History orrhage. The 5-year estimated risk of h The risk of hemorrhage
Many single-institution cavernous mal- hemorrhage was 30.8% (approximately from a cavernous
formation natural history studies and 6% per year) in patients with brainstem malformation is
two large meta-analyses have been cavernous malformations presenting approximately 1% to
published. Methodologic differences initially with hemorrhage or focal neu- 4% per year. Prior
in the studies make them difficult to rologic deficit, 18.4% (approximately hemorrhage and
compare. However, with the limita- 3.7% per year) in patients with nonbrain- brainstem location
tions considered, the overall annual stem cavernous malformations present- increase the risk of
ing initially with hemorrhage, 8.0% hemorrhage in patients
prospective hemorrhage risk in pa-
(approximately 1.6% per year) in patients with a cavernous
tients with cavernous malformations
malformation.
has been estimated to be between 1% with brainstem cavernous malforma-
and 4% per patient-year.14 It has been tions presenting without focal deficits
found that the prospective risk of or hemorrhage, and 3.8% (approximately
cavernous malformation hemorrhage 0.76% per year) in patients with nonbrain-
is strongly associated with the initial stem cavernous malformations present-
clinical presentation (hemorrhage ver- ing without focal deficit or hemorrhage.
sus no hemorrhage) and location Other risk factors for hemorrhage
(brainstem versus nonbrainstem). In suggested by some, but inconsistently
the Mayo Clinic study, patients who noted in other studies, include female
came to medical attention because of sex, pregnancy, presence of a coexis-
hemorrhage had a higher risk of hem- tent developmental venous anomaly,
orrhage compared to those presenting cavernous malformation multiplicity,
with other symptoms (Table 9-10). In and brainstem or deep location.
the two meta-analyses, prior hemor- Many studies have also found a
rhage significantly increased the risk of decline in hemorrhage rate with time.
future hemorrhage.16,26 Horne and col- In the Mayo Clinic natural history
leagues performed an individual data study, if a patient presented to medi-
meta-analysis including 1620 patients cal attention because of intracerebral
from seven published cohorts.26 In that hemorrhage, the risk of a recurrent
study, prior hemorrhage and brainstem hemorrhage in the first year was 18.3%,
location were predictors of future hem- falling to 9.22% in the second year

TABLE 9-10 Rate of Prospective Hemorrhage in Cavernous Malformations by Presenting

Symptoms and Overalla

Annual Rate of Prospective Hemorrhage (Confidence Interval)b

Symptoms Not Related Incidental or
Interval Hemorrhage to Hemorrhage Unclear Relationship Overall
0YG1 year 18.3% (8.80, 33.8) 2.30% (0.28, 8.29) 0.00% (0.00, 3.85) 5.06% (2.61, 8.83)
1YG2 years 9.22% (2.51, 23.6) 2.82% (0.34, 10.1) 1.14% (0.03, 6.30) 3.46% (1.39, 7.11)
2YG5 years 0.96% (0.02, 5.34) 2.98% (0.97, 6.94) 0.00% (0.00, 1.70) 1.23% (0.45, 2.67)
5YG10 years 3.07% (0.63, 8.95) 1.29% (0.16, 4.65) 0.52% (0.01, 2.90) 1.35% (0.50, 2.94)
Overall 6.19% (3.74, 9.67) 2.18% (1.09, 3.91) 0.33% (0.04, 1.18) 2.25% (1.54, 3.18)
a
Reprinted with permission from Flemming KD, et al, Neurology. B 2012 American Academy of Neurology. neurology.org/content/
15

78/9/632.short.
b
This table notes the risk as stratified by initial presenting symptoms and combined as a whole group during the specified yearly intervals.

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 Aneurysms and Cerebrovascular Malformations

KEY POINTS
h Surgical treatment is and down to 2% to 3% per year in lactic antiepileptic drug (AED) is
generally indicated in years 3 to 10.15 This temporal clustering recommended, even if the cavernous
patients with a of hemorrhages has been noted by malformation is in the temporal lobe.
symptomatic cavernous others. The declining rate of hemor- If, however, a patient has had a single
malformation in a rhage is important when comparing seizure, it is generally recommended
noneloquent area to the natural history of cavernous malfor- that the patient start an AED since the
reduce the risk of mations to that of treatment, includ- risk of a second seizure may be as high
hemorrhage or seizure ing radiation therapy. However, this as 94%. Approximately 60% of patients
due to the cavernous clustering effect has not been noted respond to a first AED. Early surgery
malformation. in all studies. may be considered to reduce the
h In patients with cavernous If patients have no seizures at diag- hemorrhage risk if the seizure was
malformations in nosis, the risk of future seizures is ap- actually caused by a hemorrhage or if
eloquent regions, proximately 1.5% to 3% per year.25 The it is felt that the patient may be poorly
surgery may be only established risk factors predict- compliant with medications.25 If a pa-
considered for a patient
ing development of seizures were mul- tient has breakthrough seizures despite
who has repeated
tiple cavernous malformations and adequate trials of AEDs, then surgery
hemorrhages and
increasing morbidity.
supratentorial location. could be considered to reduce the risk
of seizure and future hemorrhage.
Management and Treatment Surgery is generally considered in
Management of patients with cavern- patients with symptomatic surgically
ous malformations includes medical accessible lesions.31 If a cavernous mal-
management and surgical evaluation, formation is in an eloquent or deep
thus requiring a multidisciplinary team area (eg, thalamus, basal ganglia), sur-
of neurologists, neurosurgeons, and, gery would be considered in the setting
in some cases, geneticists. Management of recurrent hemorrhages or significant
is based on general recommenda- morbidity. The latter rationale is also
tions and expert opinion, as no clinical considered for brainstem cavernous
trials and few guidelines exist.27,28 The malformations. Some controversy exists
Cavernoma Alliance United Kingdom about this, and practice may vary. Some
published guidelines for the manage- brainstem cavernous malformations
ment of cavernous malformations in adjacent to the pial surface could be
adults in 2008. The ILAE has published removed after an initial hemorrhage.
a review and recommendations for man- In each individual, careful comparison
agement summary for seizures associ- of the risks of surgery versus the natural
ated with cavernous malformation. At history must be weighed (Case 9-2).
the time of this writing, the Angioma The risk of surgery depends on the
Alliance is updating guidelines pub- location of the cavernous malformation
lished previously in 2008.29 and the experience of the surgeon. In
Medical management for patients patients undergoing surgery for sei-
with cavernous malformations may in- zure, approximately 60% to 80% will
clude genetic counseling, managing sei- be seizure free at 1 to 2 years.25
zures if present, counseling on lifestyle Stereotactic radiosurgery is com-
and environmental risk factor modifica- monly used for dural arteriovenous
tion, managing comorbidities (eg, preg- fistulas and AVMs, but it is uncommonly
nancy, use of antithrombotics), and used for cavernous malformations. In
discussing natural history and individual many radiosurgery studies, none of
risks with the patient (Table 9-11). which have had a control arm, the risk
In patients with cavernous malfor- of hemorrhage is reduced at 2 to 3 years.
mations and no seizures, no prophy- However, a similar reduction in
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TABLE 9-11 Overview of the Management of Patients With
Cavernous Malformation(s)

Components of
Management Comments
Patient Management Issues
Genetic counseling Consider in patients with multiple cavernous
malformations or a family history of cavernous
malformations
Genetic testing available for CCM1, CCM2, and CCM3a
Lifestyle modification Patients with cavernous malformations and seizures
should avoid lifestyle activities that may reduce seizure
threshold or potentially result in injury if a seizure occurs.
For example, lack of sleep, medication noncompliance,
or alcohol use may precipitate seizures. In addition,
caution in water activities is recommended.
Very limited data may suggest intense exercise or
binge alcohol use may increase risk of hemorrhage30;
other data do not support limiting activity
Medications While data do not suggest antithrombotics increase
the risk of hemorrhage, in general, they should be
avoided unless the risk outweighs the benefit
(compare the natural history to the risk of
condition requiring antithrombotic)
Avoid medications that lower seizure threshold if a
history of seizure disorder exists
Pregnancy Provide prepregnancy counseling
If seizure disorder is present, consider antiepileptic
drugs (AEDs) with lower teratogenic potential
Advise folate supplementation if patient is on seizure
medication during pregnancy
MRI, if needed, during pregnancy
Vaginal delivery is an acceptable mode of delivery unless
recent hemorrhage or neurologic deficits preclude it
Seizure disorder AED treatment is warranted after a single seizure
in the presence of a cavernous malformation
Interventional Therapy
Surgery Surgery should be considered in symptomatic patients
to reduce future hemorrhage rate and seizure risk
if in a noneloquent area
Surgery may be considered in symptomatic patients
in eloquent or deep areas if repeated hemorrhages
occur or if there is significant morbidity
Observation is generally recommended for
asymptomatic patients with cavernous malformations
Continued on page 204

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 Aneurysms and Cerebrovascular Malformations

TABLE 9-11 Overview of the Management of Patients With

Cavernous Malformation(s) Continued from page 203

Components of
Management Comments
Radiosurgery Radiosurgery is reserved for patients with
repeated hemorrhages in surgically inaccessible
areas if the risk of radiosurgery is less than
the expected morbidity from the cavernous
malformation
Emerging Therapies/Techniques
Medical Animal and in vitro models have explored
use of simvastatin, fasudil, vitamin D, and
sulindac in reducing leakiness of cavernous
malformations
Radiologic Quantitative susceptibility mapping and
dynamic contrast-enhanced quantitative
perfusion to assess leakiness of cavernous
malformation
MRI = magnetic resonance imaging.
a
Genetests.org; search term: cavernous malformation.

hemorrhage rate is noted in natural At present, no alternatives to sur-

history studies. Thus, whether it is the gery exist to reduce lesion burden and
stereotactic radiosurgery or natural his- the risk of hemorrhage. Advances in
tory leading to the decreased hemor- the understanding of the molecular
rhage rate is uncertain. A controlled study pathways involved in formation of
is necessary to answer this question. cavernous malformations has resulted

Case 9-2
A 34-year-old man presented with acute left hemiplegia and hemisensory
loss. CT and subsequent MRI of the brain demonstrated a cavernous
malformation in the right thalamocapsular region that had acutely
hemorrhaged.
Comment. The 5-year risk of recurrent hemorrhage in this patient may
be estimated to be close to 20%, which must be weighed against the risk
of surgery. In general, the risk of a persistent or worse deficit with surgery
of a cavernous malformation in the deep structures (eg, basal ganglia,
thalamus) is about 20% to 30%. Thus, in this situation, it is common to
observe and, if a second bleed occurs with increasing morbidity, again
consider the risks and benefits. While no guidelines exist on when to
reimage, a follow-up image could be considered in 1 to 3 months to ensure
the correct diagnosis and to determine if any change has occurred.
Annual surveillance can be considered, although if the patient remains
asymptomatic, no change in management would occur at that time. In this
particular case, observation was recommended due to the morbidity of
surgery with a cavernous malformation in this location. Physical and
occupational therapy were initiated.

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 KEY POINTS
in candidate medications emerging as unknown, but they are estimated to h Developmental venous
possible alternatives to surgery, which occur in 2% to 3% of the general pop- anomalies are
may reach human clinical trials within ulation. The diagnosis is typically made congenital vascular
the next 1 to 3 years. in the third or fourth decade, with an anomalies that drain
equal prevalence in men and women. normal brain.
DEVELOPMENTAL VENOUS Developmental venous anomalies are h Developmental venous
ANOMALIES commonly solitary, but several cases anomalies commonly
Developmental venous anomalies are of multiple developmental venous co-occur with cavernous
commonly encountered in clinical anomalies have been reported. Devel- malformations.
practice, often as an incidental finding. opmental venous anomalies are most
They rarely cause symptoms and rarely commonly located supratentorially,
hemorrhage. However, a neurologist but when infratentorial occur frequently
can be useful in determining the rela- in the cerebellum.
tionship of a developmental venous The association of developmental
anomaly to the symptoms leading to venous anomalies with other vascular
the brain imaging study. The following malformations is well established. As-
section reviews the data regarding sociation has been most commonly
developmental venous anomalies. seen with cavernous malformations,33
but rarely the association has been
Definition and Radiologic found in patients with AVMs as well.
Appearance
Developmental venous anomalies are Presentation
congenital lesions. It is hypothesized Developmental venous anomalies
that an intrauterine event results in focal rarely cause symptoms and are often
arrest of venous development and re- incidental findings. They may be
tention of the primitive medullary considered symptomatic if the loca-
veins.32 The radially arranged medul- tion is consistent with the signs and
lary veins converge into a single venous symptoms of the initial illness and if
channel separated by normal brain
tissue and drain normal cerebral tissue.
Developmental venous anomalies
are rarely diagnosed without a contrast-
enhanced image (CT or MRI). Contrast-
enhanced imaging studies reveal a
caput medusae, or linear enhancement
of a transcerebral vein (Figure 9-6).
Cross-sectional imaging may also dem-
onstrate associated vascular malfor-
mations (most commonly cavernous
malformations) or pathology associated
with the developmental venous anom-
aly, such as venous congestion, throm-
bosis, or hemorrhage.

Epidemiology FIGURE 9-6 Developmental venous

anomaly. T1-weighted MRI with
Developmental venous anomalies contrast. This MRI demonstrates
the typical caput medusae appearance of a
are the most common type of vascular developmental venous anomaly near the left
malformation. The exact prevalence of basal ganglia.
developmental venous anomalies is

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 Aneurysms and Cerebrovascular Malformations

KEY POINTS
h Developmental venous radiologically or surgically no other anomaly is causative. For example, is
anomalies rarely cause cause is identified. 32 a primary seizure disorder or other
symptoms, and Patients with developmental venous lesion responsible? Developmental ve-
surveillance imaging is anomalies may rarely be seen initially nous anomalies may cause seizure if
generally not indicated. with focal neurologic deficits or seizure. an associated cavernous malformation
h Capillary telangiectasias Focal neurologic deficits may be due is present or if the developmental
are rare congenital to hemorrhage, venous thrombosis/ venous anomaly has thrombosed. In
vascular malformations infarction, or, very rarely, compressive these patients, appropriate evaluation
that rarely cause symptoms such as hemifacial spasm. of the seizure disorder and AED
symptoms. When hemorrhage is encountered, other therapy are recommended. If a patient
h Large capillary pathology (ie, an associated cavernous with a developmental venous anomaly
telangiectasias may malformation) should be sought (eg, presents with hemorrhage, the pos-
require the addition of by obtaining hemosiderin-sensitive sibility of an associated cavernous
hemosiderin-sensitive MRI sequences) before attributing signs malformation that bled should be
MRI sequences and and symptoms to a developmental considered. Consultation with a cere-
follow-up MRI to venous anomaly. brovascular neurosurgeon and a vas-
distinguish them from cular neurologist is recommended to
neoplasms. Natural History assess appropriate therapy in these
Few natural history studies assessing rare individual cases.
the risk of hemorrhage from a devel-
opmental venous anomaly exist. The CAPILLARY TELANGIECTASIA
studies suffer from small numbers, lack Capillary telangiectasias typically are
of long-term follow-up, and other meth- found incidentally on brain imaging.
odologic issues. With those caveats, the While occasionally mistaken for a
estimated rate of hemorrhage related to brain tumor because of the gadolini-
a developmental venous anomaly is be- um enhancement, these lesions have a
tween 0.15% and 0.61% per year.14,34 distinct appearance on hemosiderin-
This may be an overestimate because sensitive sequences. Thus, neurologists
of tertiary care referral bias. can be useful in assessing the relation-
ship of presenting symptoms to the
Management and Treatment capillary telangiectasia and aiding in the
Developmental venous anomalies correct diagnosis of the lesion by
drain normal brain. Attempting to assessing whether appropriate MRI se-
surgically remove them may result quences have been performed.
in venous infarction or hemorrhage.
Thus, in most cases, no treatment is Definition and Radiologic
indicated as developmental venous Appearance
anomalies are usually asymptomatic Capillary telangiectasias are angiograph-
and have a relatively benign natural ically occult vascular malformations
history.32 Surveillance imaging in pa- composed of dilated capillaries with
tients who are asymptomatic is gener- normal intervening neural tissue. These
ally not warranted since it would not vascular malformations are typically
alter management. visualized only on a contrast-enhanced
If a patient with a developmental MRI. A combination of a postcontrast
venous anomaly presents with seizure, T1-weighted MRI sequence with a
imaging should be conducted to as- hemosiderin-sensitive image (GRE or
sess whether a more common cause SWI) (Figure 9-7) is ideal for diagno-
of seizure is present before consider- sis.35 A telangiectasia often appears
ing that the developmental venous as a blushlike area of enhancement
206 ContinuumJournal.com February 2017

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FIGURE 9-7 Capillary telangiectasia. This contrast-enhanced T1-weighted image of the brain
(A) demonstrates a small blush of contrast in the pons consistent with a capillary
telangiectasia. The gradient recalled echo (GRE) sequence (B) shows a
hypointensity that helps distinguish capillary telangiectasia from other enhancing processes (eg,
tumor, inflammation).

on the postcontrast sequence with a cor- solitary lesions and located in the pons,
responding hypointense region on the but they may occur elsewhere in the
hemosiderin-sensitive sequence. Most central nervous system. These lesions
telangiectasias are punctate and smaller may be sporadic or part of a syndrome
than 1 cm; however, some are larger or such as Rendu-Osler-Weber syndrome
more diffuse. The latter can sometimes (hereditary hemorrhagic telangiecta-
be mistaken for neoplasm, subacute sia), ataxia-telangiectasia, or Wyburn-
infarction, or demyelinating or inflam- Mason syndrome.
matory disease. The lack of mass effect,
the stability over time, and the finding of Presentation
a hypointensity on SWI in association Capillary telangiectasias are common
with a contrast-enhancing lesion is incidental findings at autopsy and are
highly specific for capillary telangi- rarely symptomatic. 14 Vague non-
ectasia and can reassure the clinician specific neurologic symptoms often
about the benign nature of the lesion. lead to the incidental discovery of
capillary telangiectasia. Rare reports
Epidemiology of all types of neurologic symptoms
Capillary telangiectasias are rare. These have been described, including focal
lesions may be congenital, but they neurologic deficit due to hemor-
have also been described after radiation rhage, seizures, cranial nerve palsies,
to the brain; some feel they may be extrapyramidal disorders, and focal
on a continuum with other vascular hemispheric syndromes. Symptoms
malformations such as cavernous mal- may be episodic, persistent, and
formations. Most commonly, they are rarely progressive.

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 Aneurysms and Cerebrovascular Malformations

Natural History Stroke Association. Stroke

2015;46(8):2368Y2400. doi:10.1161/
The risk for hemorrhage is assumed to STR.0000000000000070.
be low; however, no large case series 2. Bor AS, Rinkel GJ, van Norden J, Wermer MJ.
with extensive follow-up have been Long-term, serial screening for intracranial
conducted. In the meta-analysis by aneurysms in individuals with a family
history of aneurysmal subarachnoid
Gross and colleagues, of 47 patients
haemorrhage: a cohort study. Lancet
over 65 patient-years of follow-up, Neurol 2014;13(4):385Y392. doi:10.1016/
none had hemorrhage or a change in S1474-4422(14)70021-3.
lesion morphology.36 3. Unruptured intracranial aneurysmsVrisk
of rupture and risks of surgical
Management and Treatment intervention. International Study of
Unruptured Intracranial Aneurysms
Management is generally conserva- Investigators. N Engl J Med
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doi:10.1016/S0140-6736(03)13860-3.

CONCLUSION 5. UCAS Japan Investigators, Morita A,

Kirino T, et al. The natural course of
While unruptured aneurysms and unruptured cerebral aneurysms in a
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features. First, it is important to deter- 6. Broderick JP, Brown RD Jr, Sauerbeck L, et al.
Greater rupture risk for familial as
mine the relationship of the symptom compared to sporadic unruptured
to the lesion. A symptomatic lesion is intracranial aneurysms. Stroke 2009;
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Development of the PHASES score for
tion provided. This must be weighed prediction of risk of rupture of intracranial
against the surgical or interventional aneurysms: a pooled analysis of six
risk. Together the team (patient, neu- prospective cohort studies. Lancet Neurol
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4422(13)70263-1.
tionalist) can then make a decision
regarding treatment. Practitioners also 8. Bhogal P, Uff C, Makalanda HL. Vessel
wall MRI and intracranial aneurysms.
must manage comorbid conditions,
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strictions. Finally, it is important to
9. Brown RD Jr, Broderick JP. Unruptured
determine the mode and timing of intracranial aneurysms: epidemiology,
surveillance imaging. natural history, management options,
and familial screening. Lancet Neurol
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30. Li D, Hao SY, Jia GJ, et al. Hemorrhage risks malformations: pathophysiological, diagnostic,
and functional outcomes of untreated and surgical considerations. Neurosurg Focus
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2014.3.JNS132537. Laster DW. The natural history of
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 Review Article

Inherited and
Address correspondence to
Dr Jennifer Juhl Majersik,
University of Utah,
175 N Medical Center

Uncommon Causes Dr, Third Floor,

Salt Lake City, UT 84132,
[email protected].

of Stroke Relationship Disclosure:

Dr Majersik receives
research/grant support from
the National Institutes of
Jennifer Juhl Majersik, MD, MS Health (5U10NS086606) and
Remedy Pharmaceuticals,
Inc. Dr Majersik has served
as an expert witness for
ABSTRACT FAVROS PLLC.
Purpose of Review: This article is a practical guide to identifying uncommon causes Unlabeled Use of
of stroke and offers guidance for evaluation and management, even when large Products/Investigational
Use Disclosure:
controlled trials are lacking in these rarer forms of stroke. Dr Majersik reports
Recent Findings: Fabry disease causes early-onset stroke, particularly of the ver- no disclosure.
tebrobasilar system; enzyme replacement therapy should be considered in affected * 2017 American Academy
patients. Cerebral autosomal dominant arteriopathy with subcortical infarcts and of Neurology.
leukoencephalopathy (CADASIL), often misdiagnosed as multiple sclerosis, causes
migraines, early-onset lacunar strokes, and dementia. Moyamoya disease can cause
either ischemic or hemorrhagic stroke; revascularization is recommended in some
patients. Cerebral amyloid angiopathy causes both microhemorrhages and macro-
hemorrhages, resulting in typical stroke symptoms and progressive dementia. Preg-
nancy raises the risk of both ischemic and hemorrhagic stroke, particularly in women
with preeclampsia/eclampsia. Pregnant women are also at risk for posterior reversible
encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome, and
cerebral venous sinus thrombosis. Experts recommend that pregnant women with
acute ischemic stroke not be systematically denied the potential benefits of IV re-
combinant tissue plasminogen activator.
Summary: Neurologists should become familiar with these uncommon causes of
stroke to provide future risk assessment and family counseling and to implement
appropriate treatment plans to prevent recurrence.

Continuum (Minneap Minn) 2017;23(1):211–237.

INTRODUCTION therapies to prevent recurrence. For

Historically, up to 30% of ischemic these reasons, it is incumbent upon the
strokes have been considered crypto- neurologist to be familiar with the un-
genic, without a cause found despite common causes of stroke and their
standard evaluation. However, an ex- recognition, evaluation, and treatment.
panded evaluation can lead to discov- This article is a practical guide to
ery of an uncommon cause of stroke. identifying such stroke causes, such as
Although some of the uncommon subtle historical clues of prior throm-
stroke causes are not currently treat- botic events, suggestive family history
able, particularly the monogenic etiol- or disorders of other organ systems, or
ogies, diagnosis of such a disorder unusual imaging findings. This article
allows appropriate future risk assess- offers guidance for evaluation and man-
ment and family counseling; many un- agement, although large controlled
common causes, such as infection, trials are generally lacking in these
vasculitis, and hypercoagulopathy, re- rarer forms of stroke. Table 10-1 lists
quire treatment distinct from standard some of the many uncommon causes
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 Inherited and Uncommon Stroke

TABLE 10-1 Uncommon Causes of Stroke

b Primarily Ischemic Stroke

Genetic causes
Fabry diseasea
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)a
Cerebral autosomal recessive arteriopathy with subcortical infarcts
and leukoencephalopathy (CARASIL)a
Retinal vasculopathy with cerebral leukodystrophya
COL4A1-related cerebral small vessel diseasea
Cervical and intracranial arterial dissection
Hypercoagulability (acquired and genetic)
Vasculopathy
Fibromuscular dysplasia
Radiation-induced vasculopathy
Cardioembolic
Endocarditis
Autoimmune valvular disease
Central nervous system infection
HIV
Varicella-zoster virus
Bacterial meningitis
Others
Migrainous infarction
b Intracerebral Hemorrhage
Cerebral amyloid angiopathya
Cerebral cavernous malformations (genetic and sporadic)
Hereditary cerebral hemorrhage with amyloidosis (Dutch type and
Icelandic type)
b Both Ischemic Stroke and Intracerebral Hemorrhage (Either or Mixed)
Moyamoya (disease and syndrome)a
Sickle cell anemia
Hereditary hemorrhagic telangiectasia
Vasculitis and inflammatory conditions
Posterior reversible encephalopathy syndrome (PRES)
Reversible cerebral vasoconstriction syndrome (RCVS)
Cerebral venous sinus thrombosis (CVST)
Pregnancy (preeclampsia/eclampsia, hypercoagulability, CVST, RCVS, PRES)a
Recreational drug use
HIV = human immunodeficiency virus.
a
Causes covered in this article.

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 KEY POINTS
of stroke by their typical presentation angiokeratomas (clustered in the bath- h Fabry disease is an
(ischemic versus hemorrhagic). ing trunk area and lips), corneal dys- X-linked lysosomal
trophy, and hypohidrosis, with renal storage disease
MONOGENIC DISORDERS impairment, cardiac conduction distur- with neurovascular
ASSOCIATED WITH STROKE bances, cardiomyopathy, and central manifestations of
Monogenic causes of stroke are felt nervous system (CNS) complications early-onset ischemic
to be rare, although their true inci- developing later in life. stroke, often in the
dence is unknown because of a lack The neurovascular manifestations posterior circulation;
of epidemiologic data. Strokes from of Fabry disease include early-onset is- dilatation of the
monogenic disorders tend to be part chemic stroke, often in the posterior vertebrobasilar vessels
up to extensive
of a multisystem disorder with other circulation; dilatation of the vertebro-
dolichoectasia;
organ involvement. One Italian study basilar vessels up to extensive doli-
and leukoaraiosis.
used a disease-specific phenotypic choectasia; and leukoaraiosis (white
tool to determine who to screen for matter hyperintensities seen on T2- h Fabry disease is a
multisystemic disorder,
one of five monogenic diseases asso- weighted brain MRI sequences and
causing acroparesthesia,
ciated with stroke: Fabry disease; cere- thought to represent cerebral small
angiokeratomas, corneal
bral autosomal dominant arteriopathy vessel disease).3 In prospective stud- dystrophy, hypohidrosis,
with subcortical infarcts and leukoen- ies, Fabry disease has been found in 1% renal impairment, cardiac
cephalopathy (CADASIL); mitochondrial to 4% of young patients with crypto- conduction disturbances,
encephalomyopathy, lactic acidosis, genic stroke.4 Although hyperintensity and cardiomyopathy.
and strokelike episodes (MELAS); he- in the pulvinar region on T1-weighted
reditary cerebral amyloid angiopathy; MRI sequences has been considered
and Marfan syndrome. Using this pre- pathognomonic for Fabry disease, it is
screening tool to narrow the number only found in a minority of patients,
of tested patients, they found 7% of with lower frequency in women than
their screened patients had one of the men and in those with early versus late
five monogenic disorders associated disease (Figure 10-1).5,6 The leuko-
with stroke.1 The sensitivity of their araiosis can be extensive but also
screening process could not be de- increases with disease duration, so it
termined as no center has genetically may not be present in young patients
tested all of their patients with stroke with stroke.5
because of the enormous cost that Other CNS manifestations include
would entail, but the study shows that hearing loss, vertigo, and neuropsy-
targeted testing can assist in finding a chiatric symptoms such as depression
higher yield for genetic testing and and neuropsychological deficits, while
reveal previously unknown diagnoses. peripheral nervous system involvement
includes hypohidrosis, intestinal dys-
Fabry Disease motility, and small fiber peripheral
Fabry disease is a multisystemic lyso- neuropathy with young-onset painful
somal storage disorder with an esti- acroparesthesia that increases with
mated birth prevalence of 1 per 40,000 heat and fever. While sensory and motor
to 1 per 70,000 and higher prevalence nerve conduction studies and EMG are
of late-onset disease.2 Inheritance is typically normal, sympathetic skin re-
X-linked, with men manifesting the sponses are often abnormal, which
major disease manifestations and might aid in diagnosis.7
women being more variably and mildly Fabry disease is caused by over
affected. Significant intrafamilial vari- 600 distinct mutations in the !-
ability in phenotype exists. Early systemic galactosidase A gene (GAL), most found
manifestations include acroparesthesia, in single families. The mutations result
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 Inherited and Uncommon Stroke

KEY POINT
h Fabry disease is most
easily diagnosed by
a readily available
and standardized
enzymatic test that
measures leukocyte
!-galactosidase A
activity. However,
women may require
molecular genetic
testing or skin biopsy
because of normal to
low enzymatic testing.

FIGURE 10-1 Fabry disease pulvinar hyperintensities.

Axial T1-weighted MRI shows abnormal
hyperintensity in bilateral pulvinar nuclei and
lentiform nuclei. Although seen in a minority of patients
with Fabry disease, it is considered pathognomonic for
Fabry disease when present.
Courtesy of Lubdha Shah, MD, University of Utah.

in deficient activity of lysosomal !- Fabry disease should be considered

galactosidase A, which leads to progres- when evaluating stroke in the young,
sive accumulation of glycosphingolipids particularly if the posterior circulation
in the vascular endothelium, smooth is involved and the patient has a family
muscle cells, and autonomic and dor- history of stroke. However, it should
sal root ganglia. It is likely that vessel, be noted that a magnetic resonance
tissue, and organ accumulation of the (MR) study of 3203 young patients with
glycolipid globotriaosylceramide leads stroke found that brain MRI findings
to the organ impairment and clinical did not distinguish the 1% of patients
disease, including stroke. who had Fabry disease from the pa-
Fabry disease is most easily diag- tients with nonYFabry disease causes of
nosed by a readily available and stan- stroke, including presence or extent of
dardized enzymatic test that measures white matter hyperintensities, stroke
leukocyte !-galactosidase A activity. localization, vertebrobasilar artery dila-
The !-galactosidase A activity assay is tation, and even T1-signal hyperinten-
nearly 100% sensitive and specific in sity of the pulvinar.5 Thus, at this time,
men, but only 50% of female carriers no clear screening guidelines exist, and
are identified, because of normal to low neurologists must use clinical suspicion
enzyme levels. In patients of either sex from family and personal history in pa-
with nondiagnostic !-galactosidase A tients with cryptogenic stroke with or
activity, molecular genetic testing can without peripheral neuropathy and
be used for diagnosis. A third diagnostic multiorgan involvement. Once a diag-
test option is skin biopsy or culture nosis is established, patients should be
of skin fibroblasts. A diagnosis of cared for by a multidisciplinary team
214 ContinuumJournal.com February 2017

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 KEY POINTS
and evaluated for proteinuria, renal dys- clinical events in the fourth and fifth h Recombinant
function, and structural and electro- decades and increased risk of prema- !-galactosidase A is
physiologic cardiac involvement. ture death by patients’ early sixth available as enzyme
Recombinant !-galactosidase A is decade. However, a Dutch study found replacement therapy
available as enzyme replacement ther- enzyme replacement therapy not to be for Fabry disease and
apy for Fabry disease and should be cost-effective because of both high is recommended by
considered for affected individuals. Re- treatment cost and limited improve- experts for all patients
placement therapy has been shown to ment in quality of life, with costs per with Fabry disease with
decrease left ventricular mass and renal additional quality-adjusted life-year ex- affected kidneys, heart,
accumulations,8 although beneficial ef- ceeding $7 million.12 or brain. Enzyme
replacement therapy has
fects on quality of life were not found
Cerebral Autosomal Dominant been shown to reduce
in a 2015 meta-analysis.9 Reduction of
disease progression but
stroke risk and mortality have also not Arteriopathy With
should be managed by a
been established, although white mat- Subcortical Infarcts
multidisciplinary team.
ter disease may be stabilized in patients and Leukoencephalopathy
h Cerebral autosomal
on enzyme replacement therapy.10 CADASIL is an autosomal dominant
dominant arteriopathy
Starting and stopping rules for enzyme neurovascular disorder that causes with subcortical infarcts
replacement therapy were recently de- ischemic subcortical stroke, migraine and leukoencephalopathy
rived by expert consensus and included with aura, depression and apathy, and (CADASIL) is an
initiation of enzyme replacement ther- dementia. CADASIL has a predicted pre- autosomal dominant
apy as soon as patients show early signs valence (symptomatic and asymptom- neurovascular disorder
of kidney, heart, or brain involvement,2 atic) of at least 10.7 per 100,000 adults13 that causes ischemic
with optimal supportive care according and is now recognized as the most subcortical stroke,
to chronic kidney disease guidelines common cause of inherited stroke and migraine with aura,
and antiplatelet agents and statins for vascular dementia in adults. The prev- depression and apathy,
those with a history of stroke or tran- alence of clinical features in CADASIL and dementia.
sient ischemic attack (TIA). Enzyme is reported as stroke or TIA in 61%, h Young-onset lacunar
replacement therapy is administered migraine in 70%, cognitive impairment stroke in a patient
as an IV infusion every 2 weeks and in 48%, psychiatric problems (including without vascular risk
continued indefinitely. Presence of depression and psychosis) in 47%, and factors and a personal
history of migraine
advanced disease, including cardiac seizures in 8%.13 Although the arterial
should prompt
fibrosis or severe renal dysfunction, affects are found throughout the body,
consideration of
may limit the effectiveness of enzyme for reasons unknown, only the rarest of CADASIL, particularly in
replacement therapy. However, a lon- reports of symptoms outside the ner- patients with a family
gitudinal study of 52 patients with Fabry vous system exist.14 history of stroke or
disease on enzyme replacement ther- Strokes and TIAs are typically clas- dementia. However,
apy for a median of 10 years found that sic lacunar syndromes and occur in up neurologists should
81% of patients had no severe clinical to 60% to 85% of symptomatic indi- consider the diagnosis
events during the treatment period, viduals at a median age of 49 to 57 years in anyone with
and 94% were still alive after 10 years. over a range covering the entire adult characteristic MRI
The severe clinical events in the remain- human lifespan.13,15 CADASIL has been findings of white matter
ing 19% were most often single or reported in 11.1% (95% confidence in- hyperintensities in the
anterior temporal poles
recurrent stroke (9.6% of all patients), terval 2.5Y44.5) of patients under 50 with
and external capsules.
typically occurring in those younger lacunar stroke and leukoaraiosis.16
than 40 years of age, followed by renal Migraine is an early sign, with aver-
events, which happened at older ages.11 age onset in the third decade of life,
This is in marked contrast to literature although it can begin in childhood.
from the preYenzyme replacement Migraine without aura is of no higher
therapy era, which reported severe prevalence in patients with CADASIL
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 Inherited and Uncommon Stroke

than in the general population; how- severe form of migraine, can be severe
ever, migraine with aura is typically enough to require hospitalization in
reported to occur in 20% to 40% of up to 11% of symptomatic patients with
patients,15 with one large 2016 series CADASIL (Case 10-1).17 This consists
reporting migraine with aura in 75% of prolonged (median of 8 days, range
of patients who were symptomatic,17 3 to 17 days) but ultimately reversible
a markedly high prevalence compared reduced consciousness without other
to the general population. Hemiplegic cause. CADASIL encephalopathy typi-
migraine occurs in 16% of patients cally begins with a migraine headache
with CADASIL and migraine,17 and and is often accompanied by nausea/
CADASIL encephalopathy, also called vomiting, seizures, fever, and even hal-
CADASIL coma, a particularly disabling lucinations.17 MR-based arterial spin

Case 10-1
A 46-year-old man presented to the emergency department with the
gradual onset of confusion and partial left hemiparesis following a severe
migraine that began the day before. He had a prior history of migraine
with aura, a family history of early-onset stroke, and a recent MRI with
leukoaraiosis, including anterior temporal lobe T2 hyperintensities but no
lacunes. These characteristics had led to molecular genetic testing 2 years
before the current presentation, which revealed a DNA sequence variation
in the NOTCH3 gene causing an odd number of cysteine residues within an
epidermal growth factor repeat, and the diagnosis of cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL). He vomited in the emergency department, and his examination
showed confusion and mild weakness on the left side. He was admitted,
and a brain MRI showed no acute ischemia or hemorrhage. Over the next
few days, his headache fluctuated and he continued to worsen, developing
visual hallucinations, mild fever to 38 -C (100.5 -F), and a fluctuating but
downward-trending neurologic examination, eventually becoming mute
and akinetic. His EEG showed slowing but no seizures. He was treated with
multiple nonergot, nontriptan acute migraine therapies, and after 3 days,
his mentation started to improve. He was discharged home on day 7 with
improved cognition, speech, and gait. He later reported in clinic that he was
back to his normal baseline 10 days after initial onset.
Comment. A severe form of CADASIL migraine, termed CADASIL
encephalopathy or CADASIL coma, consists of prolonged but ultimately
reversible reduced consciousness without other cause and without brain
ischemia. It typically evolves from a migraine headache; is commonly
accompanied by seizures, fever, hallucinations, or nausea/vomiting; and
lasts a median of 8 days (range 3 to 17 days).17 Magnetic resonanceYbased
arterial spin labeling in patients with CADASIL encephalopathy has
revealed reversible global and regional cerebral hyperperfusion.18
Although it has been hypothesized that patients with CADASIL with
migraine may represent a more severe phenotype, one study found that
patients with CADASIL without migraine had a higher cumulative
incidence of stroke and hypothesized that, through preconditioning,
cortical spreading depression in CADASIL may protect the brain against
subsequent ischemia.17

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 KEY POINT
labeling in patients with CADASIL en- and presymptomatic patients. In ad- h T2 hyperintensities
cephalopathy has revealed reversible dition to focal lacunar infarcts and involving the white
global and regional cerebral hyper- eventually confluent leukoaraiosis, T2 matter of the anterior
perfusion.18 Transgenic mice express- hyperintensities involving the white temporal poles are
ing a vascular NOTCH3 mutation or matter of the anterior temporal poles seen in 90% of patients
knockout mutation demonstrate en- (the O’Sullivan sign) are seen in 90% with CADASIL.
hanced cortical spreading depression, of patients with CADASIL and are a use-
which may explain the coprevalence of ful distinction from leukoaraiosis due
migraine with aura and CADASIL to hypertension or other traditional ce-
encephalopathy in patients with rebrovascular risk factors (Figure 10-2).22
CADASIL. 19 Although it has been Signal abnormalities in the external
hypothesized that patients with CADASIL capsule and corpus callosum are also
with migraine may represent a more distinctive of CADASIL. Up to 69% of
severe phenotype, one study found that patients have microbleeds detected on
patients with CADASIL without migraine MR gradient recalled echo (GRE) im-
had a higher cumulative incidence of ages (T2*)23 that increase in number as
stroke and hypothesized that through patients age and have significant over-
preconditioning, cortical spreading de- lap with the microbleeds in other types
pression in CADASIL may protect the of small vessel disease, such as cere-
brain against subsequent ischemia.17 bral amyloid angiopathy and hyper-
Depression (and sometimes mania) tensive vasculopathy.24 Case reports
is present in about 20% of patients with also exist of macrobleeds (intracerebral
CADASIL, and apathy, independent of
depression, is seen in 40%. These begin
in middle age and contribute to overall
reduction in quality of life. Cognitive
impairment in CADASIL typically begins
with reduction in executive function and
processing speed and progresses to a
more global dementia, often including a
pseudobulbar affect. Gait disturbance is
a strong predictor of subsequent cogni-
tive decline.20 CADASIL was previously
thought to be nearly uniformly cata-
strophic, but it is now known that sever-
ity is variable. Early reports showed a
high prevalence (over 50%) of severe
disability in patients over 65 years old21
with only 14% of older patients having
no disability, but a 2014 report found
that in CADASIL survivors 58 to 75 years
of age, 68% were mobile without aids
and 46% were entirely independent.13
In the vast majority of patients, brain FIGURE 10-2 The O’Sullivan sign in cerebral autosomal
MRI abnormalities precede the onset of dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL).
symptoms by 10 to 15 years (early-onset T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities
migraine with aura being the exception); involving the white matter of the anterior temporal poles
(the O’Sullivan sign, arrows) are seen in 90% of patients
thus, brain MRI is a useful screening tool with CADASIL.
for diagnosis for both symptomatic

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 Inherited and Uncommon Stroke

KEY POINT
h Molecular genetic hemorrhage [ICH]), with microbleeds a false-negative genetic result. In this
testing is the gold being present in the majority of pub- instance, if the neurologist remains
standard for the lished ICH cases.25 The MRI findings highly suspicious of CADASIL, he or
diagnosis of CADASIL, that best correlate with clinical impair- she should consider ordering a skin
with 100% specificity ment in CADASIL are the number of biopsy that includes vascular basal lam-
and nearly 100% lacunes and brain volume.20 Athero- ina to evaluate for granular osmophilic
sensitivity when sclerotic changes in the medium and material, a highly specific finding for
screening the 23 exons large cervicocephalic vessels are typ- CADASIL. A genetic test that finds a
for a mutation leading ically minimal or absent. sequence variant of unknown signifi-
to an odd number of The NOTCH3 gene encodes a trans-
cysteine residues within
cance not involving a cysteine residue
membrane receptor that contains 34 should also prompt skin biopsy. Given
an epidermal growth
epidermal growth factor repeats (EGFR), the clinical and radiographic overlap
factor repeat. For
patients in whom a high
a large transmembrane protein neces- between CADASIL and other disor-
suspicion of CADASIL sary for vascular smooth muscle differ- ders, a CADASIL scale has been devel-
exists but who have a entiation and development. Each EGFR oped to predict which patients should
negative genetic test, normally has six cysteine residues. Over undergo genetic testing for CADASIL.27
skin biopsy may reveal 150 causal mutations have been re- Although the initial study showed high
granular osmophilic ported, the vast majority of which are sensitivity (97%) and specificity (74%)
material in the vascular missense mutations and all of which in an Italian population, this predictive
basal lamina, which is lead to an odd number of cysteine res-
highly diagnostic
accuracy was not replicated in a Chinese
idues within a given EGFR. Although population.28 The decision to test
of CADASIL. the NOTCH3 gene has 33 exons,
asymptomatic individuals within a
more than 90% of CADASIL mutations
family with CADASIL is a very individ-
are found in exons 2 to 24, with more
ualized one that should be made with
than 70% of families harboring muta-
care and after patient education, pos-
tions in exons 3 and 4.15 New causa-
sibly with the assistance of a genetic
tive mutations continue to be regularly
counselor.29 Since CADASIL has no
discovered, and de novo mutations are
known treatment or prevention strategy,
not uncommon but of unknown fre-
quency. Much interfamilial phenotypic genetic testing is not recommended
heterogeneity exists despite sharing in asymptomatic children.
the same mutation, suggesting environ- Unfortunately, because of similarities
mental or epigenetic modifying factors. in clinical presentation and neuroimag-
Patients who are homozygous for the ing, CADASIL is often misdiagnosed as
NOTCH3 mutation have been shown multiple sclerosis and treated with im-
to have a slightly more severe clinical munomodulatory medications that con-
and radiologic phenotype with earlier fer risk without benefit (Figure 10-3).
onset as compared to their heterozy- This highlights the importance of
gous family members.26 performing a detailed family history
Molecular genetic testing is the focused on stroke, migraine, depression/
gold standard for the diagnosis of anxiety, and cognitive decline as well
CADASIL, with 100% specificity and as correct interpretation of CSF find-
nearly 100% sensitivity when screen- ings. In a study of CSF examination in
ing the 23 exons for a mutation leading 87 patients with CADASIL who were
to an odd number of cysteine residues genetically diagnosed, 29% had mildly
within an EGFR. Because of the large elevated protein (mean 40.4 mg/dL,
number of mutations, some of which range 12 mg/dL to 75 mg/dL), only
are located outside of the usually one had oligoclonal bands (1.1%), and
screened exons, it is possible to have none had pleocytosis.30

218 ContinuumJournal.com February 2017

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 KEY POINT
h Although no treatment
specific to CADASIL
exists, strict control of
hypertension in patients
with CADASIL may
prevent or delay onset
of functional disability.

FIGURE 10-3 MRI findings in cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) resembling multiple sclerosis. A,
Sagittal fluid-attenuated inversion recovery (FLAIR) MRI showing white matter
hyperintensities perpendicular to the ventricles, similar to those typically seen in multiple
sclerosis. B, Sagittal FLAIR MRI at the midline shows no hyperintensities in the corpus
callosum. C, Axial FLAIR MRI at the level of the lateral ventricles showing subcortical and
periventricular white matter changes. D, Axial FLAIR MRI at the level of the temporal lobes,
showing only minimal leukoaraiosis in the left anterior temporal lobe (arrow).

Specific treatment for CADASIL is not hypertension were unassociated with

currently available. Given that CADASIL latency of stroke onset. Yet controlling
is primarily a small vessel arteriopathy, hypertension may have other benefits;
many clinicians support aggressive this same study found a suggestion of
management of cerebrovascular risk earlier loss of independence by 16 years
factors while acknowledging the lack in patients with hypertension (median
of clinical trials to support this strat- age 55 versus 71 years, P=.096),13 and
egy. However, one observational study another study found that hypertension
found that clinical factors such as (alone among standard vascular risk
smoking status, hyperlipidemia, and factors) is associated with functional

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 Inherited and Uncommon Stroke

KEY POINT
h Patients with cerebral disability in patients with CADASIL.31 overall cognitive function as measured
autosomal recessive Antiplatelet therapy is often provided by the Vascular Dementia Assessment
arteriopathy with by vascular neurologists, although with Scale cognitive subscale (VADAS-cog)
subcortical infarcts and the recognition that its benefit has not score but did improve executive func-
leukoencephalopathy been rigorously studied and such use tion, so it is sometimes prescribed.36
(CARASIL) experience could increase the risk of microbleeds
early-onset lacunar or even ICH.32 One common but un- Cerebral Autosomal
stroke (onset in the third tested stroke prevention strategy is to Recessive Arteriopathy With
decade) in the absence prescribe aspirin only in patients with- Subcortical Infarcts and
of hypertension, out microbleeds on MRI. Short-term Leukoencephalopathy
progressive dementia
treatment with atorvastatin does not Cerebral autosomal recessive arteriop-
(onset in the third
improve hemodynamic parameters in athy with subcortical infarcts and leuko-
through fifth decades),
premature alopecia
patients with CADASIL but has not been encephalopathy (CARASIL) causes
(onset in the teen years), tested against the outcome of stroke symptoms similar to CADASIL but ear-
and spondylosis prevention or with long-term use.33 It is lier in life, without migraine, and with
deformans (disk also not known whether IV recombinant the addition of alopecia and low back
degeneration) (onset tissue plasminogen activator (rtPA) is pain. Patients with CARASIL experience
in the second and efficacious in patients with CADASIL, early-onset lacunar stroke (onset in the
third decades). and some controversy exists among third decade) in the absence of hyper-
experts regarding the safety of IV rtPA tension, progressive dementia (onset in
in this population, with fear of in- the third through fifth decades), pre-
creased risk of hemorrhagic transfor- mature alopecia (onset in the teen years),
mation, particularly in those with and spondylosis deformans (disk de-
microbleeds. However, at least one generation) (onset in the second and
case report exists of successful IV rtPA third decades). Early MRI findings are
treatment,25 and it is not unusual for similar to CADASIL: microbleeds as well
patients to be considered for IV rtPA as progressive leukoaraiosis with early
if presenting within the usual rtPA involvement of the external capsule,
window for an acute ischemic stroke. pons, and the frontal white matter.37
For migraine prevention, standard In late stages, a characteristic MRI fea-
medications are typically tried, with no ture of CARASIL is involvement of the
one medication preferred over another.17 pontocerebellar tract, called the arc
However, observational reports of par- sign since it appears as an arc-shaped
ticular benefit from acetazolamide exist, hyperintense lesion from the pons to
possibly because of the hypoperfusion the middle cerebellar peduncles.37
seen in CADASIL.34,35 For migraine treat- CARASIL is caused by mutations in
ment, serotonin (5-hydroxytryptamine 1 the HtrA serine peptidase 1 (HTRA1)
[5-HT1]) receptor agonists (triptans) gene on chromosome 10q.38 HTRA1
are not routinely used because of a pre- binds and cleaves the prodomain of
sumed potential to increase stroke risk, proYtransforming growth factor "1
particularly in patients with complicated (pro-TGF-"1), and the cleaved product
migraine. However, one observational is degraded by the endoplasmic retic-
study of migraine treatments in patients ulum. This mechanism regulates the
with CADASIL reported that 11% of pa- amount of mature TGF-"1.39 Originally
tients had tried triptans, with about a 50% found in Japanese patients, CARASIL is
response rate and no adverse events.17 now known to be present in multiple
In a randomized controlled trial of populations.40 Although CARASIL is
patients with CADASIL with cognitive considered an autosomal recessive con-
impairment, donepezil did not improve dition and quite rare, heterozygotes of
220 ContinuumJournal.com February 2017

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 KEY POINTS
HTRA1 mutations are now known to protein that retains exonuclease activ- h Retinal vasculopathy
have a milder version of the same pheno- ity but loses normal perinuclear local- with cerebral
type but with autosomal dominant in- ization, which is theorized to have leukodystrophy, a new
heritance.41 HTRA1 mutations as a cause detrimental effects on endothelial cells, term for what were
of cerebral small vessel disease thus may leading to a degenerative cerebral previously described as
be more prevalent than currently recog- microangiopathy causing stroke and three separate disorders
nized. No disease-specific therapy for dementia.43 Homozygotes have Aicardi- (cerebroretinal
CARASIL is available at this time. Goutieres syndrome, a severe enceph- vasculopathy syndrome;
alopathy and leukodystrophy. The hereditary vascular
Retinal Vasculopathy With proliferative retinopathy may respond retinopathy; and
Cerebral Leukodystrophy hereditary
to intravitreal bevacizumab.44
endotheliopathy,
What were previously thought to be
retinopathy,
three separate autosomal dominant COL4A1-Related Cerebral Small
nephropathy, and
causes of stroke and retinopathy (cere- Vessel Disease
stroke), is an autosomal
broretinal vasculopathy syndrome; he- Mutations in the COL4A1 gene, a gene dominant disorder
reditary vascular retinopathy; and encoding the type IV collagen alpha 1 caused by mutations in
hereditary endotheliopathy, retinopa- chain, cause an autosomal dominant the TREX1 gene. These
thy, nephropathy, and stroke [HERNS]) early-onset cerebral small vessel disease syndromes cause vision
have been found to all map to the that manifests in the fourth decade of loss, stroke, and
TREX1 gene and are now collectively life as diffuse leukoaraiosis (in 63% of dementia beginning
termed retinal vasculopathy with cere- reported patients, diffuse and not with in middle age, with
bral leukodystrophy. In these syndromes, the anterior temporal involvement that death occurring in
most patients 5 to
vision loss, stroke, and dementia be- is seen in CADASIL), microbleeds (53%),
10 years later.
gin in middle age, and death occurs in and lacunar stroke (13%).45 Additionally,
most patients 5 to 10 years later. The patients are prone to subcortical ICH, h Mutations in
retinopathy is characterized by neovas- particularly after mild environmental the COL4A1 gene, a
gene encoding the
cularization of the optic disc, retinal stresses such as vaginal birth, sports
type IV collagen alpha 1
hemorrhages, and macular edema. Non- activities, anticoagulant use, and head
chain, cause an
visual neurologic deficits are more var- trauma.46 Additional manifestations of autosomal dominant
iable and include strokelike episodes COL4A1 mutations can include infantile early-onset cerebral
following visual loss with multifocal hemiparesis and congenital poren- small vessel disease that
cortical and subcortical dysfunction. cephaly; cerebral aneurysms (44%, with manifests in the fourth
Brain MRI reveals multifocal white multiple aneurysms in half); migraine decade of life as diffuse
matter hyperintensities and, in about with aura; and systemic manifestations leukoaraiosis (without
50% of patients, an enhancing tumor- of the eye (48%, cataracts, retinal vessel the anterior temporal
like lesion with cortical sparing that may tortuosity, and retinal hemorrhages), involvement that is
resemble a primary CNS malignancy kidney (15%), and muscle (15%). Sim- seen in CADASIL),
on brain imaging but on pathology ilar to CADASIL, high intrafamilial vari- microbleeds, and
lacunar stroke.
reveals necrosis and reactive gliosis, of ability exists. Screening should be
Additionally, patients
which spontaneous regression has considered in patients with any of the
are prone to subcortical
been observed.42 Patients with TREX1 following: a personal or family history intracerebral hemorrhage,
mutations also have various combi- of either infantile hemiparesis or por- particularly after mild
nations of Raynaud phenomenon, encephaly, a personal history of leuko- environmental stresses
migraine, and mild kidney or liver encephalopathy with microbleeds but such as vaginal birth,
dysfunction. The TREX1 gene en- without hypertension, or a personal sports activities,
codes a DNA-specific 3¶-5¶ exonuclease. history of retinal arteriolar tortuosities. anticoagulant use, and
The retinal vasculopathy with cerebral Although no known treatment exists for head trauma.
leukodystrophyYassociated TREX1 mu- COL4A1 mutations, diagnosis is helpful
tations result in creation of a truncated in order to counsel patients regarding
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 Inherited and Uncommon Stroke

KEY POINT
h Moyamoya disease avoidance of even mild head trauma, between the external carotid artery
is a nonatherosclerotic, particularly women of childbearing age and ICA, with eventual disappearance
noninflammatory, since cesarean delivery is strongly rec- of both the moyamoya vessels and
progressive vasculopathy ommended for an affected fetus to the intracranial portion of the ICA.47
that causes narrowing avoid ICH from birth trauma. Moyamoya disease was initially thought
of the distal internal to be always bilateral but is now known
carotid artery and MOYAMOYA DISEASE to sometimes be unilateral. There can
development of small Moyamoya disease is a progressive also be development of posterior
collateral vessels at the occlusive vasculopathy consisting of circulation disease. Histopatholog-
base of the brain that stenosis or occlusion of the terminal ically, arteries in moyamoya disease
look like a puff of smoke
internal carotid artery (ICA), proximal reveal intimal hyperplasia, internal
on an angiogram. It is
anterior cerebral artery, or proximal elastic lamina interruption, and pro-
typically bilateral but can
be unilateral and include
middle cerebral artery, with the subse- liferation of smooth muscle cells.
the posterior circulation. quent development of abnormal vascu- Importantly, atherosclerosis and in-
lar networks at the site of stenosis/ flammation are absent.48 The term
occlusion that feed the basal ganglia moyamoya syndrome is used to de-
(Figure 10-4). In late stages, the so-called note moyamoya vascular changes oc-
internal carotid artery-external carotid curring secondary to atherosclerosis,
artery conversion develops, a compen- thyroid disease, radiation, sickle cell
satory development of anastomosis anemia, or other causes.

FIGURE 10-4 Conventional cerebral angiogram of bilateral internal carotid arteries in a

patient with moyamoya disease. Diffuse bilateral internal carotid artery
narrowing, left greater than right (long white arrows), with complete
supraclinoid internal carotid artery occlusion on the left and near-complete occlusion on
the right. The moyamoya appearance is most pronounced on the right. Extensive pial
collateralization is seen over the left frontoparietal convexity (short white arrow).
Courtesy of Scott McNally, MD, University of Utah.

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 KEY POINTS
Moyamoya disease causes both TIA/ lations and the incomplete penetrance h Moyamoya disease
ischemic stroke and ICH. In all pop- of the autosomal dominant transmission, causes ischemic stroke
ulations, ischemia is more prevalent screening of asymptomatic family mem- in children and adults
than hemorrhage in children. This is bers of patients with moyamoya disease of European/North
also true in adults of European and has been called for. Using transcranial American ancestry in a
North American ancestry, but in Doppler as the initial screening test, watershed distribution
East Asia, adults are more likely to pre- followed by MRA for positive screens, and intracerebral
sent with hemorrhage. Recurrent one Chinese study of asymptomatic hemorrhage or infarct in
stroke is usually of the same type as family members increased the percentage East Asian adults.
the initial stroke. Ischemic strokes are of familial moyamoya disease identified h Screening of
often in watershed distributions from in their population from 7% to 15%.52 asymptomatic family
cerebral hypoperfusion. In addition to In the absence of clinical trial data, members of patients
the common stroke effects of motor many clinicians prescribe antiplatelet with moyamoya disease
weakness and altered consciousness, agents to prevent ischemic stroke in may identify more
affected members and a
approximately 20% of patients with patients with moyamoya disease. To
familial cause.
moyamoya disease (and more in the augment blood flow in ischemic
pediatric/young adult population) expe- moyamoya disease, for decades neuro-
rience headaches. The headaches have surgeons have provided revascularization
migrainous features and are theorized directly through extracranial-intracranial
to be from chronic hypoperfusion; some artery bypass (EC-IC bypass), indirectly
have been reported to be relieved by through approximation of the superfi-
bypass surgery.49 Patients with mo- cial temporal artery to the ischemic
yamoya disease may also have movement hemisphere through dural defects via
disorders, possibly from hypoper- one of several methods in an attempt to
fusion of thalamo-cortico-basal ganglia promote neovascularization and im-
circuits. The representative type is proved blood flow over time,53 and via
chorea with limb shaking; dystonia and a combination of both methods. Al-
dyskinesia have also been reported. though numerous case series exist
In prior decades, a conventional showing benefit to revascularization
angiogram was considered necessary in terms of improved blood flow and
for diagnosis, but CT and MR angiog- reduced ischemic events, most are in
raphy (MRA) are now acceptable as pediatric populations, and no random-
well. Additionally, MR-based high- ized trials have been conducted to
resolution vessel wall imaging may compare efficacy of the various surgi-
play a valuable role in distinguishing cal options. Patients are often selected
moyamoya from other causes of intra- for surgery if they have had repeated
cranial vessel narrowing.50 TIAs or infarcts and show decreased
Moyamoya disease has an ethnic bias, regional blood flow, vascular response,
with the highest incidence in Japan and and perfusion reserve. Additionally, in
other East Asian countries, and is more patients with hemorrhagic moyamoya
common in women, with a 1.8 to 1 sex disease, the recently published Japan
ratio (female to male). Familial forms Adult Moyamoya Trial showed that
of moyamoya, which account for about direct EC-IC bypass surgery can re-
15% of cases, have been associated in duce recurrent ICH rates over 5 years
East Asians with mutations in the by 60% compared to medically man-
RNF213 gene on chromosome 17q25.3 aged patients, at least in experienced
and also in sporadic Asian cases.51 neurosurgical centers,54 likely by re-
Because of the high prevalence of ducing the stress on the moyamoya
RNF213 mutations in East Asian popu- collateral vessels.
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 Inherited and Uncommon Stroke

KEY POINTS
h Diseases of CEREBRAL AMYLOID crobleeds, cortical superficial siderosis,
small vessels in the ANGIOPATHY and even brain atrophy.56
brain clinically cause Approximately one-third of symptom- Sporadic small vessel disease is
both lacunar strokes atic strokes are due to diseases of the typically classified into two main types:
and intraparenchymal small vessels, defined as parenchymal cerebral amyloid angiopathy and hy-
hemorrhage and, on or leptomeningeal vessels 5 2m to pertensive arteriopathy. Because the
imaging, white matter 2 mm in diameter (1 mm is the typical latter is not always associated with
hyperintensities, limit of visualization on cerebral an- hypertension, some prefer the more
microbleeds, and giogram).55 These vessels either pen- descriptive but somewhat bulky term
atrophy. Very little sporadic nonamyloid microangiopathy.
etrate the cortex via short and long
evidenced-based
penetrating arterioles that supply the Both types can cause microhemor-
treatment exists for
cortex and subcortical white matter or rhages and macrohemorrhages, but
small vessel disease,
with treatment arise from deep perforators that sup- etiologic clues can be taken from lo-
complicated by the ply the base of the brain (basal ganglia, cation; sporadic nonamyloid micro-
need to prevent thalami, and brainstem). Small vessels angiopathy hemorrhages are located
both hemorrhage are end arterioles with their main col- deep (basal ganglia, internal capsule,
and infarct. lateral flow found in the capillary bed, thalamus, brainstem), while cerebral
h Cerebral amyloid not in adjacent arterioles. Thus, when amyloid angiopathyYrelated ICH is
angiopathy is these arteries fail, no vascular backup lobar (cortical-subcortical) and found
characterized system is in place. Additionally, these primarily in posterior cortical regions,
histologically by arteriolar systems do not interconnect followed by frontotemporal and parietal
amyloid-" fibril but meet in the junctional zone around lobes, and, more rarely, the cerebellum.
deposition in the the lateral ventricles, not coincidentally Cerebral amyloid angiopathyYrelated
media of primarily where leukoaraiosis is most prevalent. ICH makes up only 5% to 10% of deep
small to medium Charidimou55 provides an excellent ICH but 50% of lobar ICH.57
blood vessels. summary of the anatomy and patho- Cerebral amyloid angiopathy is char-
physiology of small vessel disease. acterized histologically by amyloid-"
Although evidence-based treatments fibril deposition in the media of primar-
exist for large artery atherosclerotic neu- ily small to medium blood vessels. De-
rovascular diseases, how best to pre- generative changes follow the amyloid
vent or treat diseases of small vessels is deposition, with fibrous thickening,
not yet known. Unlike most large artery necrosis, and wall thinning with possi-
disorders, diseases of the small vessels ble formation of microaneurysms. Un-
can cause both ischemia and hemor- like other forms of ICH, traditional
rhage, which complicates treatment. vascular risk factors other than increased
Clinically, small vessel disease is the age do not increase the risk of cerebral
primary cause of two main stroke types: amyloid angiopathyYrelated ICH. The
lacunar infarcts and intraparenchymal vast majority of cerebral amyloid angio-
hemorrhages. Small vessel diseases also pathy is sporadic, with only exceed-
cause nearly half of dementias and sub- ingly rare cases being monogenic.
stantially contribute to functional im- Future predictive models of cerebral
pairments in the elderly, including amyloid angiopathyYrelated ICH risk
cortical gait disorders, cognitive impair- may include results of genetic analy-
ment, and urinary symptoms.55 Imag- sis of specific risk-conferring variants,
ing sequelae of small vessel disease such as those in the CR1,58 ACE,59 and
include not only the well-studied white APOE genes,60 which predict risk of
matter hyperintensities of presumed cerebral amyloid angiopathyYrelated
vascular origin, but also enlargement ICH and recurrent cerebral amyloid
of perivascular spaces, cerebral mi- angiopathyYrelated ICH.
224 ContinuumJournal.com February 2017

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 KEY POINT
Cerebral amyloid angiopathy should due to seizures and EEGs are typi- h Magnetic resonanceY
be suspected when recurrent hemor- cally normal, antiepileptic medications based imaging is
rhages or multiple simultaneous corti- can be tried as treatment since they important after
cal hemorrhages are found in someone have been reported to reduce spell transient stereotypic
older than 55 years of age. Using the frequency.63 Convexity subarachnoid symptoms in the elderly
Boston Criteria, diagnosis of probable hemorrhage (SAH) associated with to look for cortical
cerebral amyloid angiopathy requires cerebral amyloid angiopathy can pre- superficial siderosis or
either multiple hemorrhages restricted sent with a similar migraine auraYlike convexity subarachnoid
to lobar, cortical, or cortical-subcortical symptomatology, and, in fact, convexity hemorrhage related
regions or a single such hemorrhage and SAH in an elderly person should sug- to cerebral amyloid
angiopathy amyloid spells.
focal or disseminated superficial side- gest cerebral amyloid angiopathy as a
rosis; additionally, the patient must be cause, particularly if imaging also re-
55 years of age or older and have no veals the presence of lobar microhemor-
other known cause of the ICH.61 Defi- rhages (Case 10-2).24
nite cerebral amyloid angiopathy adds In a minority of patients, cerebral
the requirement of pathologic confir- amyloid angiopathy is accompanied by
mation. Diagnostic sensitivity is in- a perivascular inflammatory response.
creased by MR-based T2*-weighted Such cerebral amyloid angiopathyY
GRE and susceptibility-weighted imag- associated angiitis is a clinicopathologic
ing (SWI) sequences that highlight entity causing alterations in mental
microhemorrhages. status, headaches, seizures, and focal
In addition to typical signs of spon- neurologic deficits. MRI reveals edema
taneous ICH, up to 20% of patients with surrounding microhemorrhages that
cerebral amyloid angiopathy have tran- resolves over time and is easily mis-
sient focal neurologic spells, often termed taken for infection or other edematous
amyloid spells, particularly in patients CNS processes. Patients typically re-
with cortical superficial siderosis. Amyloid spond well to immunosuppression with
spells last up to 30 minutes and consist IV steroids and only rarely require long-
of either positive (auralike) or negative term suppression with cyclophospha-
(TIA-like) symptoms, with the former mide because of recurrences.
thought to be from cortical spreading Unfortunately, no known treatment
depression from irritation from hemo- or prevention of cerebral amyloid
siderin deposition and the latter from angiopathyYrelated diseases exists.
vasospasm or cerebral vessel occlusion Based on observational data, tight
from amyloid deposition.62 A classic blood pressure control is likely indicated
presentation is stereotypic slowly pro- to prevent recurrent ICH.64 However,
gressive paresthesia. Because of their patients with primary lobar ICH (a proxy
transient nature, amyloid spells are for determining which ICHs are cere-
often misdiagnosed and treated as TIA bral amyloid angiopathyYrelated) have
or migraine equivalent in the elderly higher ICH recurrence rates than those
unless hemorrhage-sensitive MR-based with deep ICH (4.4% versus 2.1% per
imaging is done to raise suspicion of an year)65 and thus most experts agree
alternative diagnosis. Since TIA requires that patients with cerebral amyloid
antithrombotic treatment for stroke pre- angiopathyYrelated ICH should gener-
vention while cerebral amyloid angiop- ally not be anticoagulated with warfarin,
athy hemorrhage is worsened with even in the presence of an indication
antithrombotics, it is important to dis- such as nonvalvular atrial fibrillation.66
tinguish the two diagnoses. Although Although newer oral anticoagulants have
amyloid spells are not thought to be less overall risk of ICH, their rates in
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 Inherited and Uncommon Stroke

KEY POINT
h To prevent patients with cerebral amyloid angio- the cardiovascular benefits for both pri-
recurrent intracerebral pathy in particular is as of yet unknown. mary and secondary cardiovascular pre-
hemorrhage, most It is even less clear whether antiplatelet vention.69 It is not known if statins are
experts withhold agents are safe in patients with an in- contraindicated in patients with arterio-
anticoagulation and dication for such therapy (eg, myocar- losclerotic lobar ICH, which has differ-
statins in patients with dial infarction, ischemic stroke from ent pathophysiologic mechanisms. To
cerebral amyloid large artery atherosclerosis) but who also date, studies are mixed as to whether or
angiopathyYrelated have cerebral amyloid angiopathyY not cerebral microhemorrhages on pre-
intracerebral hemorrhage. related microhemorrhages without his- treatment MRI increase the risk of symp-
tory of lobar hemorrhage. tomatic ICH after rtPA in acute ischemic
Hypercholesterolemia is also associ- stroke, and experts do not currently rec-
ated with increased ICH risk, possibly ommend withholding rtPA in such
mediated by low triglyceride levels.57 patients if they are otherwise eligible,
The effects of statins on ICH risk re- but rather to include the presence of
main controversial, with some second- microhemorrhages as an additional
ary prevention trials showing increased piece of evidence in weighing potential
ICH risk in those on statins with prior risk versus benefit of thrombolysis.70
history of ICH67 but meta-analyses
refuting increased ICH rates in unse- PREGNANCY-ASSOCIATED
lected populations on statins.68 A deci- STROKE
sion analysis analyzed ICH rates in Pregnancy and the peripartum period
cerebral amyloid angiopathyYrelated are associated with an increased risk of
lobar ICH and found that statin avoidance both ischemic and hemorrhagic stroke.
was the preferred treatment strategy, A US-based study using nationwide
since statin therapy was predicted to sampling determined the overall prev-
increase the baseline annual probability alence of pregnancy-related stroke
of ICH recurrence from approximately hospitalizations as 71 per 100,000 deliv-
14% to approximately 22%, offsetting ery hospitalizations,71 nearly triple the

Case 10-2
A 75-year-old man without prior neurologic history began having episodes of right upper extremity
numbness, decreased coordination, and weakness that lasted 5 minutes and self-resolved. He was
diagnosed with transient ischemic attacks (TIAs) in an emergency department and started on aspirin.
However, the episodes increased in frequency and duration (lasting 15 to 30 minutes) and began to be
accompanied by right facial droop and dysarthria, but always with complete resolution of symptoms.
He again sought medical care and received multiple head CTs, brain MRIs, neck and head vessel
imaging, and an echocardiogram, all reported as normal. He was advanced to aspirin/extended-release
dipyridamole and begun on a statin. However, the episodes continued, and he presented to another
emergency department where review of prior imaging revealed subtle left central sulcus hemorrhage;
repeat brain MRI confirmed bilateral central sulcal subarachnoid hemorrhage (SAH) and showed
scattered areas of chronic microhemorrhage without acute ischemia or prior infarct (Figure 10-5A).
He was diagnosed with amyloid spells due to cortical superficial siderosis from cerebral amyloid
angiopathy. Antiplatelet agents were stopped, and an antiepileptic drug was started, with resolution
of his spells. He subsequently did well without further spells but with a slowly progressive cognitive
decline. He presented to the emergency department again at age 82 for several days of increasing
confusion, including walking into walls. A head CT revealed occipital lobar ICH as well as increased
microhemorrhages and superficial siderosis (Figures 10-5B and 10-5C). He received conservative
management, including tight blood pressure control, and was discharged to a skilled nursing facility.
Continued on page 227

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 Continued from page 226

FIGURE 10-5 Imaging of the patient in Case 10-2. A, Axial gradient recalled echo (GRE) MRI (left and middle) and
susceptibility-weighted imaging (SWI) (right) images at age 75 reveal bilateral central sulcus subarachnoid
hemorrhage, more prominent on the left (long arrows). Additionally, multiple punctate areas of greater
susceptibility artifact are seen diffusely, most of which are centered at the gray-white interface (short arrows). There was
associated reactive pial enhancement and neither acute ischemia nor prior infarct (not shown). B, Same patient at age 82 after
several days of confusion. Axial noncontrast head CT shows right occipital hemorrhage. C, Same patient. Comparison of axial
SWI MRI sequences at age 75 (left of each of the pairs) to those at the same level at age 82 (right of each of the pairs). In addition
to the new occipital ICH, at every level new microhemorrhages and increased superficial siderosis in the convexities are seen.

Comment. Up to 20% of patients with cerebral amyloid angiopathy have transient spells, often termed
amyloid spells, particularly in patients with cortical superficial siderosis. Amyloid spells last up to 30 minutes
and consist of either positive or negative symptoms, with a classic presentation being stereotypic slowly
progressive paresthesia. Amyloid spells can be easily misdiagnosed as TIA or migraine equivalent unless
hemorrhage-sensitive magnetic resonanceYbased imaging is done. Such misdiagnosis can result in
inappropriate antithrombotic treatments and worsening of cerebral amyloid angiopathy hemorrhage.

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 Inherited and Uncommon Stroke

KEY POINT
h New-onset seizures prevalence of stroke in nonpregnant, cardioembolic stroke from peripartum
in a woman in the nonYhormone-using young women cardiomyopathy.
latter half of pregnancy (24 per 100,000 person-years).72 Al- Eclampsia is thought to be due to
should not be assumed though overall age-adjusted stroke abnormal placental implantation that
to be eclampsia incidence is declining in the United causes placental hypoxia and subse-
but should prompt a States, the prevalence among preg- quent release of vascular mediators
complete evaluation for nant women has increased by 54% such as vascular endothelial growth
noneclamptic causes. compared to the decade prior, which factor, leading to endothelial cell injury
is at least partially explained by the and widespread vasospasm, which is
simultaneous increase in hyperten- considered central to the condition.
sive disorders.71 Vasoconstriction leads to increased resis-
The highest-risk time period for tance to blood flow with resultant
pregnancy-related stroke is during the hypertension and generalized endothe-
third trimester, delivery, and postpar- lial disruption. The endotheliopathy
tum period, with over half of strokes may also be partially responsible for
occurring postpartum and approxi- the lack of autoregulation in the pres-
mately two-thirds of antenatal strokes ence of hypertension, which could lead,
occurring in the third trimester.73,74 A in particular, to ischemic and hemor-
2014 study examined the postpartum rhagic stroke.76
thrombotic risk for 1 year postpartum Sudden focal neurologic deficits in a
and found that thrombotic risk, includ- pregnant woman should prompt rapid
ing stroke, is elevated 6 weeks post- evaluation. Although new-onset seizures
partum (odds ratio 10.8, 95% confidence are necessary for the diagnosis of
interval, 7.8Y15.1) with continued in- eclampsia, new seizures in a woman in
creased risk up to 12 weeks postpartum the latter half of pregnancy should not
(odds ratio 7 to 12 weeks postpartum of exclude evaluation for alternative expla-
2.2; 95% confidence interval, 1.5Y3.1) nations, with one study finding that
with return to baseline thrombotic risk presumption of eclampsia in pregnant
at 16 weeks postpartum.75 patients with seizure delayed correct
Hemorrhagic stroke is more com- diagnosis in 42%, of which ultimately
mon during pregnancy than in the non- only 20% met diagnostic criteria of
pregnant state: hemorrhagic stroke eclampsia.77 Thus rapid neuroimaging
accounts for 16% of antenatal strokes, is critical for proper evaluation of a preg-
11% of strokes during delivery, and 36% nant woman with new-onset neurologic
of postpartum stroke hospitalizations.71 symptoms, including vessel imaging,
Cerebral venous thrombosis is also more given the wide differential of stroke
common in pregnancy-associated stroke, causes in pregnancy.
accounting for 31%, 43%, and 24% of Although head CTs use ionizing
antenatal, delivery, and postpartum radiation, fetal exposure is very low.
stroke hospitalizations, respectively.71 CT-based angiograms and perfusion
Although pregnant women may have studies result in higher exposures. Pelvic
conventional causes of stroke, they are and abdominal shielding are typically
particularly at risk for stroke from un- required during CT, such as in the sit-
usual causes, including eclampsia (the uation of rapid evaluation for IV tissue
major contributor to stroke in preg- plasminogen activator, although fetal
nancy), posterior reversible encepha- exposure is actually due to internal
lopathy syndrome (PRES), reversible scatter within the mother that is not
cerebral vasoconstriction syndrome, reduced by external shielding. MRI is
cerebral venous sinus thrombosis, and far superior to CT to visualize the
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 KEY POINT
cytotoxic and vasogenic edema com- syndrome and cerebral venous throm- h MRI is considered
mon in preeclampsia/eclampsia and bosis (Case 10-3). safe in pregnancy;
PRES and aids in the diagnosis of Preeclampsia was redefined in however, gadolinium
nonstroke causes of neurologic clini- 2013 by the American College of Ob- is considered
cal syndromes. Fortunately, MRI is con- stetricians and Gynecologists as a contraindicated for all
sidered safe in pregnancy. However, syndrome in a previously normoten- but the rarest of
gadolinium not only crosses the placenta sive nonproteinuric pregnant woman circumstances in
but also deposits in fetal tissue, so MRI after 20 weeks’ gestation characterized pregnancy. Thus vessel
with contrast is considered contraindi- by new-onset hypertension (higher than imaging in the patient
cated for all but the rarest of circum- 140/90 mm Hg) plus proteinuria or any who is pregnant is
typically performed
stances in pregnancy. Vessel imaging is of the features of severe preeclampsia
by CT angiogram
generally accomplished with CT angio- (thrombocytopenia, impaired liver func-
or noncontrast
gram or noncontrast MR time-of-flight tion, renal insufficiency, pulmonary time-of-flight magnetic
sequences. Ultrasound-based modali- edema, or cerebral or visual distur- resonance angiography.
ties (eg, carotid duplex, transcranial bances).78 Eclampsia is a life-threatening
Doppler) are completely safe in preg- condition in a preeclamptic woman
nancy, although they are not available in with the addition of generalized seizure
most emergency settings for acute or persistent altered consciousness with
stroke decision making and are unable no other explanation for her seizures.78
to directly visualize intracranial vessels, Preeclampsia/eclampsia markedly in-
which is important for diagnosis of creases a woman’s incidence of stroke
reversible cerebral vasoconstriction during pregnancy and the puerperium,

Case 10-3
A 25-year-old woman in her third trimester of pregnancy presented to
the emergency department after a day of increasing headache and blurry
vision. Upon arrival, her blood pressure was 150/100 mm Hg and she was
confused. Her visual acuity was 20/20 and her pupils were reactive, but
she had difficulty reaching for objects (optic apraxia). She then had a
generalized tonic-clonic seizure. An immediately obtained head CT showed
no intracerebral hemorrhage, and CT angiography of the head and neck
revealed no arterial or venous abnormalities. However, a subsequent
noncontrast brain MRI revealed posterior occipital edema without infarct.
She was diagnosed with posterior reversible encephalopathy syndrome
(PRES) and given IV magnesium for seizure control, IV fluid hydration, and
IV labetalol for tight blood pressure control. She was admitted to the
neurocritical care unit for further management.
Comment. Seizures and any other sudden focal neurologic changes in a
pregnant woman require rapid evaluation, including imaging of the brain
parenchyma and head and neck vessels, to allow diagnosis of reversible
cerebral vasoconstriction syndrome, PRES, cerebral venous thrombosis, and
the usual considerations in nonpregnant patients, such as brain tumor.
Head CTs in a pregnant woman subject the fetus to low radiation levels
and are acceptable when necessary for the life of the mother. Brain MRIs
do not subject the fetus to any radiation or other risk and are the
preferred imaging modality if time allows due to their safety profile and
better diagnostic discrimination. However, gadolinium, the standard
contrast agent with MRI, is contraindicated in pregnancy since it crosses
the placenta and deposits in fetal tissue.

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 Inherited and Uncommon Stroke

KEY POINT
h Despite a lack of with a 24.7 times elevated risk of fits outweigh the anticipated increased
randomized trial data, hemorrhagic stroke and a 91.1 times risks of uterine bleeding, noting that
expert opinion suggests elevated risk of ischemic stroke in urgent consultation with obstetrics is
that IV recombinant women with preeclampsia/eclampsia highly recommended.84
tissue plasminogen compared to those without.79 Endovascular treatment has been de-
activator should not be Treatment of stroke in pregnancy finitively shown to be efficacious in pa-
withheld from a focuses on preserving the health of the tients with acute ischemic stroke from
pregnant woman who mother. Although pregnancy is listed as ICA or proximal middle cerebral artery
is otherwise eligible for a relative contraindication for IV rtPA,80 occlusions and in whom treatment can
the therapy. rtPA is too large to cross the placenta be initiated within 6 hours of symptom
and no maternal or fetal toxicity is ap- onset.85 Although the recommenda-
parent when dosed at 0.9 mg/kg, the tions are silent on eligibility of pregnant
standard dose in ischemic stroke.81 IV women, a handful of case reports have
rtPA risk in pregnancy is predominantly shown benefit to the pregnant woman
due to uterine hemorrhage, but IV rtPA with stroke.86 Fetal risk is increased
has been used successfully in many case mainly because of the procedural re-
reports, and expert opinion is clear that quirement of ionizing radiation. Endo-
it should not be withheld from a preg- vascular treatment is generally viewed
nant woman who is otherwise eligible as appropriate for the pregnant woman
for the therapy (Case 10-4).81Y83 The when chosen carefully according to
2016 updated American Heart Associ- guidelines laid out for patients who are
ation (AHA)/American Stroke Associa- not pregnant and may even be prefer-
tion (ASA) recommendations for rtPA in able if immediately available, as it can
ischemic stroke, which provide scien- avoid the risk of extracranial hemor-
tific rationale for each inclusion and ex- rhage from systemic thrombolysis.
clusion criterion including pregnancy, However, systemic rtPA should be
affirm that IV rtPA may be considered given if endovascular treatment will be
for use in disabling ischemic stroke in delayed more than 30 to 60 minutes
pregnancy when the anticipated bene- (eg, if waiting for the arrival of the

Case 10-4
A 30-year-old previously healthy woman who was 28 weeks
pregnant and recently diagnosed with preeclampsia presented to the
emergency department after the sudden onset of left-sided weakness
and vision loss. Her initial National Institutes of Health Stroke Scale
score was 10 for left homonymous hemianopia and left-sided hemiparesis
and partial sensory loss. Immediate noncontrast head CT revealed a
hyperdense right middle cerebral artery. As she was within 3 hours of
onset, she was given IV recombinant tissue plasminogen activator (rtPA) at
standard dosing of 0.9 mg/kg. During the infusion, she was transported to
a comprehensive stroke center for consideration of endovascular therapy.
Comment. Although it was initially unclear as to whether rtPA is
safe in pregnancy, expert opinion and the American Heart
Association/American Stroke Association now agree that rtPA should not
be withheld in disabling ischemic stroke in pregnancy if no other
contraindications exist. Endovascular therapy is also considered appropriate
in pregnant patients, using the same criteria as is standard for the
nonpregnant patient.

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 KEY POINT
angiographic team).83 The newer stent reduction, and lipid lowering if dyslip- h Preeclampsia and
retriever devices have shorter times to idemic.90 Given the increased risk of eclampsia are now
revascularization as compared to the future hypertension, the AHA/ASA rec- established risk factors
first-generation devices and thus may ommends that blood pressure screening for future vascular
be particularly appropriate for use in begin 6 to 12 months after preeclampsia/ disease, including a
patients who are pregnant. Both en- eclampsia with treatment initiation if doubling of the 10-year
dovascular treatment and fetal out- hypertension is present. It is important risk of stroke. Additional
comes are better when the procedure that health care providers inform women vascular risk factors
is performed under conscious sedation with preeclampsia/eclampsia of these should be aggressively
rather than general anesthesia.87 increased risks. Many barriers to imple- treated in women with a
It is now clear that a previous diag- history of preeclampsia
menting these guidelines exist, includ-
or eclampsia.
nosis of preeclampsia increases future ing lack of maternal reporting of her
cardiovascular risk in the affected history of preeclampsia/eclampsia be-
woman, including cerebrovascular dis- cause of lack of knowledge of its future
ease, even beyond the childbearing risk and lack of attendance at primary
years, with a 10-year risk of all-cause car- care clinics postpartum.96 However, one
diovascular disease of 18.2% in women study found that lifestyle interventions
with a history of preeclampsia versus have the potential to modestly reduce
only 1.7% in women with uncompli- cardiovascular disease risk after a pre-
cated pregnancies (odds ratio 13.1, 95% eclamptic pregnancy (odds ratio 0.91,
confidence interval 3.4Y85.5)88 and a interquartile range 0.87Y0.96),91 and
doubling of risk of cerebrovascular thus clinicians should seek to reduce
disease in particular (odds ratio 2.03, these barriers, possibly through post-
95% confidence interval 1.54Y2.67).89 pregnancy vascular clinics.
The reasons behind the increased risk
of future stroke in women with a his- CONCLUSION
tory of preeclampsia are uncertain but Uncommon causes of stroke are recog-
are likely a combination of factors that nizable by key clinical and radiographic
are not completely explained by shared features and require heightened aware-
vascular risk factors.90,91 Current theo- ness and additional diagnostic tech-
ries include that pregnancy acts as a niques in order to implement individual
“stress test” for previously silent vas- distinct treatment paradigms and pro-
cular disease, the failure of which vide future risk assessment.
manifests as preeclampsia or other Strokes from monogenic disorders
gestational syndromes92 or that pre- tend to be part of a multisystem dis-
eclampsia itself leads to future cerebro- order. They are thought to be rare, but
vascular disease by causing prolonged a lack of epidemiologic data leaves
vascular damage 93 or inducing a their true incidence unknown. Targeted
chronic inflammatory state.94 testing can assist in finding a higher
Regardless of causal pathway, history yield for genetic testing. The two most
of preeclampsia/eclampsia should be common genetic causes of stroke are
considered a vascular risk factor; it was Fabry disease and CADASIL. Fabry dis-
recognized by the AHA/ASA as such for ease, an X-linked lysosomal storage dis-
the first time in 2011.95 In 2014, the order, may affect up to 4% of young
AHA/ASA recommended that a history patients with cryptogenic stroke and has
of preeclampsia/eclampsia trigger ag- systemic manifestations of acropares-
gressive reduction of modifiable vascu- thesia, angiokeratomas, corneal dystro-
lar risks, including smoking cessation, phy, hypohidrosis, renal impairment,
increase in physical activity, weight cardiac conduction disturbances, and
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 Inherited and Uncommon Stroke

cardiomyopathy. CNS complications a degenerative vascular disorder caused

develop later in life and include early- by amyloid-" fibril deposition in the
onset ischemic stroke, often in the media of small to medium blood ves-
posterior circulation, and leukoaraiosis. sels, causes both microhemorrhages
Experts recommend enzyme replace- and macrohemorrhages, with the ma-
ment therapy in patients with renal, car- crohemorrhages typically occurring
diac, or brain manifestations. CADASIL, in lobar regions. Clinically, the disease
an autosomal dominant disorder caused causes typical stroke symptoms but also
by a NOTCH3 gene mutation, is ac- progressive dementia. Hemorrhage can
cepted as the most common cause of include convexity SAH and lead to
inherited stroke and vascular demen- amyloid spells that mimic TIA. There is
tia in adults. Often misdiagnosed as no known treatment of cerebral amy-
multiple sclerosis, CADASIL causes mi- loid angiopathy, but to reduce the risk
graines, early-onset lacunar stroke, and of hemorrhage, most experts avoid anti-
dementia. Although no treatment is thrombotics and statins and tightly con-
known to exist, control of hypertension trol blood pressure.
is likely important to reduce disability. Pregnancy raises the risk of both is-
There are several other known genetic
chemic and hemorrhagic stroke, par-
causes of ischemic stroke. CARASIL,
ticularly in women with preeclampsia/
which maps to the HTRA1 gene, is a
eclampsia. Pregnant women are also at
disorder similar to CADASIL but of
risk for PRES, reversible cerebral vaso-
earlier onset and also with alopecia and
constriction syndrome, and cerebral
spondylosis deformans. Retinal vascu-
lopathy with cerebral leukodystrophy venous sinus thrombosis. Experts rec-
maps to the TREX1 gene and causes ommend that pregnant women with
middle-age onset of vision loss, stroke, acute ischemic stroke not be system-
and dementia. On brain MRI, about half atically denied the potential benefits
of patients have an enhancing tumor- of IV rtPA.
like lesion that resembles a primary Neurologists should become famil-
CNS malignancy and of which sponta- iar with these uncommon causes of
neous regression has been observed. stroke to provide future risk assessment
COL4A1-related cerebral small vessel and family counseling and to imple-
disease is notable not only for early- ment appropriate treatment plans to
onset diffuse leukoaraiosis and lacunar prevent recurrence.
stroke but also for unique susceptibility
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 Review Article

Stroke Rehabilitation
Address correspondence to
Dr Samir R. Belagaje, Emory
University, 80 Jesse Hill Jr Dr
SE, Faculty Office Bldg, Room
375, Atlanta, GA 30303, Samir R. Belagaje, MD
[email protected].
Relationship Disclosure:
Dr Belagaje reports
no disclosure. ABSTRACT
Unlabeled Use of Purpose of Review: Rehabilitation is an important aspect of the continuum of care
Products/Investigational
Use Disclosure:
in stroke. With advances in the acute treatment of stroke, more patients will survive
Dr Belagaje discusses the stroke with varying degrees of disability. Research in the past decade has expanded
unlabeled/investigational use our understanding of the mechanisms underlying stroke recovery and has led to the
of fluoxetine for poststroke
motor recovery treatment,
development of new treatment modalities. This article reviews and summarizes the
cholinesterase inhibitors and key concepts related to poststroke recovery.
memantine for the treatment Recent Findings: Good data now exist by which one can predict recovery, especially
of aphasia, and dopaminergic
agents to aid in the treatment
motor recovery, very soon after stroke onset. Recent trials have not demonstrated a
of poststroke depression. clear benefit associated with very early initiation of rehabilitative therapy after stroke in
* 2017 American Academy terms of improvement in poststroke outcomes. However, growing evidence suggests
of Neurology. that shorter and more frequent sessions of therapy can be safely started in the first
24 to 48 hours after a stroke. The optimal amount or dose of therapy for stroke
remains undetermined, as more intensive treatments have not been associated with
better outcomes compared to standard intensities of therapy. Poststroke depression
adversely affects recovery across a variety of measures and is an important target for
therapy. Additionally, the use of selective serotonin reuptake inhibitors (SSRIs)
appears to benefit motor recovery through pleiotropic mechanisms beyond their
antidepressant effect. Other pharmacologic approaches also appear to have a benefit
in stroke rehabilitation.
Summary: A comprehensive rehabilitation program is essential to optimize poststroke
outcomes. Rehabilitation is a process that uses three major principles of recovery:
adaptation, restitution, and neuroplasticity. Based on these principles, multiple
different approaches, both pharmacologic and nonpharmacologic, exist to enhance
rehabilitation. In addition to neurologists, a variety of health care professionals are
involved in stroke rehabilitation. Successful rehabilitation involves understanding the
natural history of stroke recovery and a multidisciplinary approach with judicious use of
resources to identify and treat common poststroke sequelae.

Continuum (Minneap Minn) 2017;23(1):238–253.

INTRODUCTION and neurocritical care, more patients

Stroke is the fifth leading cause of now survive stroke, with varying de-
death and a leading cause of long- grees of disability.
term disability in the United States. In general, neurologists are familiar
The economic impact of a stroke is tre- with acute stroke treatments and
mendous. By 2030, total direct annual prevention strategies but tend to be
stroke-related medical costs are ex- less familiar with aspects of stroke
pected to increase from $71.55 billion rehabilitation. Because neurologists
in 2012 to $184.13 billion, and indi- are involved in the continuum of
rect annual costs are expected to stroke care in both inpatient and
rise from $33.65 billion in 2012 to outpatient settings, it is important to
$56.54 billion.1 Because of the recent be knowledgeable in this important
advances in acute stroke treatment aspect of stroke. At the very least, this

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 KEY POINT
knowledge will help neurologists to ing through rehabilitation, many stroke h Rehabilitation is a process
educate stroke survivors and their survivors obtain greater independence of stroke care that
families on the prognosis and sec- in activities of daily living and im- reduces disability and
ondary complications of stroke, proved functional capacity.2 Table 11-1 improves participation in
identify barriers to recovery, and lists the major rehabilitation ap- therapy. Recovery is
develop individualized plans to help proaches, the goals of each approach, defined as improvements
patients improve. and an example.3 across a variety
On the other hand, stroke recovery of outcomes.
STROKE REHABILITATION VERSUS may be best defined as improvement
STROKE RECOVERY across a variety of outcomes, begin-
It is important to differentiate be- ning with biological and neurologic
tween stroke recovery and stroke changes that manifest as improve-
rehabilitation. These two terms are ment on performance and activity-
often used interchangeably in the based behavioral measures. A variety
clinical setting and literature but im- of measures exist, and, depending
portant differences exist. Stroke reha- on the definition of successful recov-
bilitation has been broadly defined as ery, the proportion of patients classi-
any aspect of stroke care that aims to fied as recovered in stroke outcome
reduce disability and promote partici- studies can vary markedly. For exam-
pation in activities of daily living. ple, Duncan and colleagues4 com-
Stroke rehabilitation is a process; its pared patterns of recovery using
objectives are to prevent deterioration different outcome measures and vary-
of function, improve function, and ing thresholds for defining success-
achieve the highest possible level of ful recovery. The percentage of
independence (physically, psychologi- patients who achieved full recovery
cally, socially, and financially) within at 6 months differed based on the
the limits of the persistent stroke scale and how recovery was defined.
impairments. During this process, Therefore, recovery may not neces-
treatment and training are provided sarily reflect functional improvement
to stroke survivors to help them either behaviorally or biologically. It is
return to normal life. By regaining important to tailor the definition of
and relearning skills of everyday liv- recovery to the individual patient and

TABLE 11-1 Rehabilitation Approaches and Goals

Approach Goals Example

Restoration Retrain parts of the central nervous Home exercise program
system to engage lost functions; to improve hemiparesis
restore the function of damaged
brain tissue
Compensation Adapt behavior to the loss of Use of prisms in glasses
function without changing the to address poststroke
impairments, or reorganization diplopia
of partially spared brain pathways
to relearn lost functions
Modification Altering environmental setting to Adding rails in shower to
promote function and activities assist with transfers and
of daily living prevent falls

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 Stroke Rehabilitation

KEY POINTS
h The human brain develop a rehabilitation plan to reach questions, and regeneration holds
recovers from a stroke the defined recovery goals. hope for the future.
through adaptation, A human brain recovers from stroke Neuroplasticity, generally defined
regeneration, and in three main ways: adaptation, regen- as changes or a rewiring in the neural
neuroplasticity. eration, and neuroplasticity. Most network, is considered to be the main
h Neuroplasticity is driven successful rehabilitation techniques recovery process. Soon after a stroke,
by principles of task incorporate at least one of these activation is decreased in cortical areas
specificity, repetition, processes. Adaptation is the reliance directly affected by the stroke. This
and challenge. on alternative physical movements or reduced activity is associated with a
devices to compensate for poststroke change in the localization of certain
deficits. An example would be the use tasks such as movement. As time
of the nondominant hand to feed progresses through the acute and
oneself after hemiplegia affecting subacute period, the neural networks
dominant hand function. Assistive de- that had been disrupted by the
vices include a walker for poststroke stroke reconnect in areas adjacent to
gait and balance dysfunction and the area of stroke and coincide with
prisms in glasses to compensate for clinical recovery. For example, func-
visual field deficits. While adaptation tional neuroimaging techniques show
is helpful, it may also be harmful to the that as hand function improves, cor-
recovery process because of learned tical representation that once sub-
disuse. This phenomenon occurs served the hand moves toward the
when individuals do not use their cortical face area (Figure 11-15).6 This,
affected limb because they have de- in turn, causes an activation in the peri-
veloped habits to complete actions ischemic area/ischemic area with return
and tasks bypassing use of the limb, of laterality to functions and alteration
even though they have the capacity to of representative cortical maps. Fur-
use it. Limiting use of the limb can also thermore, the amount of recovery
limit its recovery. correlates with the degree of activation
Regeneration is the growth of neu- in the peri-infarct areas. In general, less
rons and associated cells and circuity functional poststroke recovery is seen
to replace those damaged from a in neural networks that have activation
stroke. This approach has historically in areas more widely distributed be-
been considered least useful in stroke yond the peri-infarct territory.
rehabilitation as it was believed that Research studies have demonstrated
central nervous system tissue did not that neuroplasticity is driven by sev-
have the capacity for regrowth after eral key principles. For plasticity to
injury. However, regeneration has fully occur, rehabilitation interven-
been the focus of attention in recent tions must be task specific and goal
years because of research advances in directed rather than general and
stem cell and growth factor interven- nonspecific movements. Furthermore,
tions. At this time, it is not con- the goal-directed tasks must be chal-
sidered a standard clinical aspect of lenging and interesting enough to
stroke recovery. Questions still exist maintain an individual’s attention,
regarding the type of stem cell to and the task should allow for repeti-
use, how to deliver it (intravenously, tion through multiple attempts.7Y9
via surgical resection, or endovas-
cularly), dosing, and long-term safety NATURAL HISTORY OF STROKE
effects. Nevertheless, ongoing clinical Most stroke deficits will see the
trials are attempting to answer these highest rate of recovery during the
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FIGURE 11-1 Three patterns of evolution of functional MRI (fMRI) activation after middle
cerebral artery stroke and use of the affected hand for three different patients.
As time progresses, the activated sites become more consolidated, lateralized,
and smaller.
Modified with permission from Feydy A, et al, Stroke.5 B 2002 American Heart Association, Inc. stroke.ahajournals.org/
content/33/6/1610.long.

first 3 to 6 months after stroke. After to facilitate continued recovery in the

6 months, recovery then reaches a plateau phase remain an active area of
plateau phase without additional sig- clinical research.
nificant improvement. However, ex- Swallowing, facial movement, and
ceptions exist, and improvement can gait tend to demonstrate better recov-
continue for several years after stroke. ery than other deficits. One hypothesis
Models to predict potential for recov- to explain this observation is that these
ery beyond 6 months and interventions deficits have bihemispheric representation

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 Stroke Rehabilitation

KEY POINTS
h Different functions in the cortex as part of their normal TIMING AND INTENSITY OF
recover differently. functional anatomy.10,11 On the other REHABILITATION
Swallowing, facial hand, cortical functions, such as lan- Uncertainty remains as to the optimal
movement, and gait guage and spatial attention as well as timing and intensity of rehabilitation.
tend to have better dominant hand movement, are more In a study examining differences in
recovery than language lateralized in functional anatomy and outcomes for patients for whom ther-
and dominant hand consequently recover more slowly.10 apy was initiated 20 days apart, a
function. In addition to the limitations of spon- strong inverse relationship between
h Upper extremity motor taneous recovery, multiple factors play the start date and functional outcome
recovery can be predicted a role in the plateau of recovery. Limited was observed, albeit with wide confi-
very early at the bedside therapy or absence of therapy often dence intervals.15 In other words,
through the presence/ leads to learned disuse and hinders those who initiated therapy soon after
absence of voluntary improvement.12 Poststroke depression stroke onset exhibited significantly
finger extension and has been shown to impede recovery higher effectiveness of treatment than
shoulder abduction.
across a variety of measures such as did the medium- or late-initiating groups.
cognitive deficits and mortality. Other Treatment initiated within the first
factors that can hinder recovery include 20 days was associated with a signifi-
side effects of medications, such as cantly higher probability of excellent
excessive benzodiazepine use, and phys- therapeutic response compared to treat-
ical comorbidities, such as cervical ment beginning at 20 or 40 days. These
spine disorders. Neurologists manag- findings should not be surprising given
ing the patient with stroke in the acute, the natural history of stroke recovery
subacute, and chronic settings should as previously discussed.
attempt to ensure that patients are re- Consensus is lacking as to when to
ceiving appropriate therapy and are start rehabilitation after stroke as
periodically screened for depression. specific guidelines for early mobiliza-
Good data exist to predict recovery tion do not exist. Patients with stroke
very soon after stroke onset. Motor who receive thrombolytic therapy are
recovery tends to begin in the proxi- often immobilized for at least 24 hours
mal musculature of the upper and to minimize complications from re-
lower extremities and progresses. combinant tissue plasminogen activa-
The Early Prediction of Functional tor. One reason is that strict blood
Outcome After Stroke (EPOS) study pressure guidelines are placed on
found that recovery of upper extrem- patients after thrombolysis to reduce
ity function at 6 months could be the risk of hemorrhage. Therefore,
accurately predicted if voluntary finger clinicians may be hesitant to increase
extension and shoulder abduction physical activity in these patients for
were present at 48 hours poststroke.13 fear that an elevation in blood pres-
In fact, if these movements were sure may result. In addition, patients
present, the probability of a good treated with endovascular arterial re-
outcome was 98%; if finger extension perfusion are often confined to bedrest
was not present within 48 hours, the to minimize the risk of complications
probability of a good outcome was 25%. related to femoral access. However,
If the movements did not improve prolonged bedrest increases the risk
by day 9 poststroke, the likelihood of of complications related to immobility,
complete upper extremity recovery including pressure sores, aspiration
decreased to 14%.13 Similar predictive pneumonia, and deep vein thrombosis.
models are being developed for recov- In the A Very Early Rehabilitation
ery of lower extremity deficits.14 Trial (AVERT), 2104 patients who were

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 KEY POINT
hospitalized with either ischemic or the course of 2 weeks in 52 patients h The generally accepted
hemorrhagic strokes were randomly with upper extremity weakness from practice for stroke
assigned to receive customary therapy either ischemic or hemorrhagic strokes. rehabilitation at this
or a very early intervention. In the The therapy was started in the first time involves using less
intervention arm, the first mobilization 28 days after a stroke. Improvement, intense therapy in the
was aimed to begin within 24 hours as measured by the Action Research acute/hyperacute
following stroke onset, with the addi- Arm Test (ARAT) score, was demon- setting and increasing
tional goals of the patient being strated in all groups; the high-intensity the intensity for those
upright and out of bed at least twice constraint-induced movement ther- who can tolerate it in
daily. This intervention continued for apy group had significantly less im- the rehabilitation/
outpatient setting.
the first 14 days poststroke or until provement at day 90 compared to
discharge from the acute stroke unit the dose-matched constraint-induced
and was delivered by a physical ther- movement therapy and control groups
apy team, including a trained nurse. at day 90.19 Similarly, animal models
Those who were mobilized had a have demonstrated enlargement in
worse outcome, defined as a modified areas of ischemia correlating with
Rankin Score of less than 3, compared poor function when constraint ther-
to standard care (46% versus 50%; apy is applied early after a stroke.20 It
adjusted odds ratio = 0.73, P = .004).16 is not clear why early use of constraint
However, in a prespecified dose- therapy impairs early recovery; how-
response analysis of the trial, it appears ever, as this therapy is more intense
that shorter but more frequent sessions than conventional therapies, greater
of early mobilization improved patients’ ischemic demand exists, which can
chances of regaining independence.17 cause neurologic injury. Based on these
Similarly, early rehabilitation starting results, it appears that more data are
within 48 hours demonstrated benefit needed before any definite conclusions
in 6-month survival and functional out- can be made about the early application
comes in patients with intracerebral of intense therapy such as constraint-
hemorrhage.18 induced movement therapy.
Once therapy is initiated, unan- In the 2016 Interdisciplinary Com-
swered questions exist regarding the prehensive Arm Rehabilitation Evalua-
‘‘dose’’ of rehabilitation. Analogous to tion (ICARE) trial, 361 subjects were
medications prescribed for stroke, given rehabilitation in one of three
variations in the duration and intensity arms: an Accelerated Skill Acquisition
of rehabilitation therapy affect recov- Program, dose-equivalent usual and
ery outcomes. However, the exact customary occupational therapy, or
nature of this relationship in unclear. usual and customary occupational
Data from the Very Early Constraint- therapy. Motor outcomes were not
Induced Movement During Stroke significantly different between the
Rehabilitation (VECTORS) trial, a study three groups.21
of the amount of therapy and motor Based on the results of these
improvement after stroke, suggest that studies, answers to the dosing ques-
more therapy does not always result in tion remain elusive. Generally ac-
significantly better outcomes. This cepted practice at this time includes
single-blind phase 2 randomized trial consulting therapists to first evaluate
compared traditional upper extremity patients within the first 48 hours,
therapy with dose-matched and high- using less intense therapy practices
intensity constraint-induced movement as determined by the rehabilitation
therapy protocols administered over teams and tolerated by patient, and,
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 Stroke Rehabilitation

KEY POINT
h Based on current for those who can tolerate it, increas- unfortunately, many stroke survivors
guidelines, inpatient ing the intensity of rehabilitation in who are uninsured or underinsured,
rehabilitation facilities the rehabilitation/outpatient setting. despite being good candidates for inpa-
are appropriate tient rehabilitation facilities, are dis-
posthospital discharge THERAPY APPROACHES TO charged to a skilled nursing facility.
locations for patients REHABILITATION The importance of posthospital dis-
who are able to actively A goal of stroke rehabilitation should charge disposition on outcomes is
participate in two be to facilitate relearning of skills that discussed later in this article.
disciplines of therapy for were possible before the stroke, but in Rehabilitation is often provided in a
3 hours per day, have some cases the focus of rehabilitation team-based approach and involves
medical issues requiring
must be adaptation and compensation various disciplines, such as physical
physician supervision,
for deficits. This process begins while therapy, occupational therapy, and
and have a reasonable
expectation of resuming
the patient is hospitalized for stroke speech and language therapy. The
community living. and involves motor skill retraining, role of the team involves setting goals,
preventing complications, and teach- reevaluating these goals on a regular
ing adaptive techniques using a com- basis, and making adjustments to the
prehensive approach. In the US health rehabilitation plan as needed. In addi-
care system, stroke survivors in need tion to improving the function of the
of further rehabilitation following the patient, caregiver training is an impor-
acute hospitalization have three pos- tant aspect of rehabilitation.
sible posthospital dispositions: (1) Physical therapists perform evalua-
home with outpatient therapy, (2) tions to detect problems with move-
home with home health therapy, or ment and balance. They work with the
(3) inpatient rehabilitation facility or patient and the rehabilitation team to
skilled nursing facility placement. The perform exercises to strengthen mus-
disposition is based on the nature and cles for walking, standing, and other
severity of deficits, comorbidities, and activities. Occupational therapists help
insurance/reimbursement. For exam- stroke survivors learn strategies to
ple, inpatient rehabilitation facilities manage daily activities such as eating,
are available to patients who are able bathing, dressing, writing, and cook-
to actively participate in at least two ing. One simple way to differentiate
disciplines of therapy (physical ther- between physical and occupational
apy, occupational therapy, or speech therapy is that the focus of physical
and language therapy) for 3 hours therapy is on the lower extremities,
per day, have medical issues requir- while occupational therapy focuses on
ing physician supervision, and have a upper extremity impairments, but it is
reasonable expectation of resuming important to note that this is a gener-
community living. The length of stay alization and there are exceptions and
in these settings is dependent on a nuances in this difference.
variety of factors, including the sever- Speech and language pathologists
ity of neurologic deficits, medical (ie, speech therapists) help stroke
comorbidities, and rehabilitation prog- survivors learn strategies to overcome
ress; on average, the length of stay is swallowing and language deficits. In
about 2 weeks. It is important to note the acute setting, they are involved
that in many areas of the United States, with dysphagia and swallowing evalu-
the presence and type of third-party ations and may make recommenda-
insurance will determine where pa- tions for alternative methods of oral
tients continue rehabilitation following intake, such as nasogastric tubes or
acute hospital discharge. Consequently, percutaneous endoscopic gastrostomy
244 ContinuumJournal.com February 2017

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 KEY POINTS
tubes. In the subacute and outpatient preserved singing abilities in the h Constraint-induced
settings, aphasia tends to be the focus unaffected hemisphere and engage movement therapy is an
of speech and language therapy. language-capable regions in the non- alternative motor
Following the initial evaluation, dominant (usually right) hemisphere. rehabilitation therapy
therapists develop a program and While robust evidence for this ap- technique for the upper
provide exercises that use the princi- proach is lacking, it appears that this extremity in which the
ples of neuroplasticity mentioned pre- therapy is most beneficial in stroke unaffected extremity is
viously (task specificity, repetition, survivors with expressive (Broca) constrained with a mitt,
challenging). Teaching of compensa- aphasia but with some retained ex- thereby forcing use of
tory and adaptive techniques is an- pressive abilities as well as absent bi- the affected hand.
other important goal. Therapists train hemispheric damage. h Melodic intonation
the patient and family in activities Functional electrostimulation is an- therapy is an alternative
such as safe transfers, assisted ambu- other technique than can be used to therapy technique that
lation, proper feeding, and provision enhance motor recovery in patients has been shown to
enhance recovery of
of appropriate adaptive techniques. with stroke.27,28 This technique in-
poststroke aphasia. It
Device-based and adjunctive thera- volves applying electrical stimulation
involves the use of
pies, such as robotic arms and body- to muscles of interest. Functional musical elements,
weight support treadmills, have been electrostimulation devices are commer- including melody and
proposed; however, studies have cially available, and improving these rhythm, to improve
failed to demonstrate their superior- types of devices is an area of active language production.
ity over currently used therapies and research interest. An example of a
evidence to support regular clinical functional electrostimulation device is
use is lacking.22,23 shown in Figure 11-2.
Several nontraditional strategies Following a stroke, it is important
have demonstrated improved efficacy that the rehabilitation setting is ap-
compared to traditional therapy. propriate and optimized for the indi-
Constraint-induced movement ther- vidual patient. Patients who receive
apy is a motor rehabilitation therapy their posthospital rehabilitation in an
technique in which the unaffected
extremity is constrained with a mitt,
thereby forcing use of the affected
hand. This approach, even in a modi-
fied dose using a decreased frequency
of constraint-induced movement ther-
apy, has been shown to be more ef-
fective than standard therapy in the
3- to 9-month poststroke window.24,25
Melodic intonation therapy has
been shown to enhance recovery of
poststroke aphasia.26 Melodic intona-
tion therapy uses musical elements,
including melody and rhythm, to
FIGURE 11-2 An example of a functional electrostimulation
improve language production. The device that provides electrical stimulation to
theoretical basis of this approach is muscles of the forearm and hand to enable a
that language is localized in the dom- stroke survivor to extend the wrist and flex fingers. The
stimulation intensity can be adjusted depending on the level
inant hemisphere, but singing and of the patient’s weakness and progress with therapy. It is
melody localize to the nondominant portable and can be used at home.
hemisphere. Consequently, advocates Courtesy of Bioness Inc.
of this therapy take advantage of
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 Stroke Rehabilitation

KEY POINT
h When patients with inpatient rehabilitation facility have oxetine for Motor Recovery After
stroke are unable to improved outcomes following endo- Acute Ischaemic Stroke (FLAME) trial
return home following vascular therapy compared to those in was a randomized double-blind
their acute hospitalization, a subacute or skilled nursing facility.29 placebo-controlled trial comparing
discharge to an inpatient In a cohort with no significant differ- fluoxetine 20 mg/d and placebo be-
rehabilitation facility ences in age, comorbidities, infarct ginning 5 to 10 days after stroke on-
will likely result in volume, or recanalization rates, pa- set in patients with hemiplegia or
a better outcome. tients who went to a skilled nursing hemiparesis.31 In the intervention
facility had significantly worse out- group, the change in motor func-
comes than those patients who went tion, as measured by the Fugl-Meyer
to an inpatient rehabilitation facility.30 Assessment of Sensorimotor Recov-
These points are important for clini- ery After Stroke score, was significant-
cians to remember when deciding on ly higher than in the placebo group.31
appropriate postacute care and dis- The study results suggest that, rather
charge disposition for patients with than just treating poststroke depres-
stroke as there may be confounders sion (which was addressed in the
and the appropriate destination may trial), selective serotonin reuptake
not be immediately clear. These inhibitors (SSRIs) may also impact
points are illustrated in Case 11-1. motor recovery, likely through neu-
roplastic mechanisms. Other antide-
PHARMACOLOGIC APPROACHES pressant or neuro-modulating agents
TO STROKE REHABILITATION have also been examined with posi-
Medications can also play a role in tive benefits. For example, clinical trials
promoting stroke recovery. The Flu- using cholinesterase inhibitors and

Case 11-1
An 80-year-old woman presented with a right middle cerebral artery
distribution acute ischemic stroke. She received both IV recombinant tissue
plasminogen activator and mechanical thrombectomy. She was admitted
to the hospital for further testing and close monitoring. Despite the acute
therapy she still had deficits from her stroke. On hospital day 3, she was
evaluated by the therapy team and found to be lethargic and participating
poorly in therapy. Because of her lethargy, the therapy team determined
that she was unable to participate in her 3 hours of therapy per day and
recommended skilled nursing facility placement. Evaluation by the primary
team revealed that she had a low-grade fever and leukocytosis and a
urinalysis suggestive of a urinary tract infection. Antibiotics were started,
and she improved over the next 2 days. Her ability to participate in therapy
sessions improved, and the discharge recommendation was upgraded to
an inpatient rehabilitation facility.
Comment. This case is an example of how neurologic status can be
confounded by infection-induced encephalopathy, a condition that is
reversible with appropriate treatment, and illustrates the potential
mutability of posthospital discharge recommendations in a short period
of time. Had the primary team just proceeded with the initial discharge
recommendations and not addressed and treated her confounders to
participation in therapy, and had not pursued a repeat evaluation by
the therapy team, it is likely that her poststroke recovery would have
been compromised.

246 ContinuumJournal.com February 2017

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 KEY POINTS
glutamatergic agents suggest improve- proton pump inhibitors are preferable h Caution and careful
ments in aphasia rehabilitation.32Y34 to H2 blockers in this setting. consideration must be
Similarly, it appears that dopaminergic used when prescribing
medications may help address post- SPECIFIC ISSUES IN STROKE antiepileptic medications
stroke depression and attention.35,36 REHABILITATION and antihistaminergic
The trials are limited by their small medications as they
While each stroke presents its own may adversely affect
numbers, heterogeneity of stroke size,
individual issues in rehabilitation due stroke recovery.
and locations. Given these limitations,
to factors such as stroke size, stroke
insufficient evidence exists to imple- h Shoulder pain is a
location, and patient comorbid factors,
ment the medications in routine clini- common sequela after a
several common themes or issues stroke and may be
cal practice. However, as the safety
often present. This section reviews the caused by a variety
profile of these interventions is reason-
most common sequelae and issues of conditions.
ably demonstrated, in certain situations
impeding overall recovery and qual-
it would be reasonable to consider
ity of life.
these pharmacologic agents as part
of the rehabilitation plan of patients
after discussion with patients and Shoulder Syndrome
care teams. Loss of arm function is a common
Certain medications can impair poststroke outcome and results in
poststroke recovery, in particular when shoulder pain in up to 70% of patients
used in the acute period. Based on with upper extremity dysfunction.39
their mechanistic effect on neuro- Shoulder pain delays recovery as the
transmitters, older antiepileptic agents, painful joint limits participation in
such as phenobarbital, diazepam, and rehabilitation and may mask improve-
phenytoin, can impede synaptic for- ments in motor function. Shoulder
mation in animal models.37 To avoid pain can result from multiple causes,
such detrimental effects on poststroke including subluxation, impingement,
recovery, newer-generation antiepi- complex regional pain syndrome, tha-
leptic drugs should be considered lamic pain syndrome, spasticity, or
as the first-line treatment for post- other conditions such as radiculopa-
stroke seizures. thies. To discern between the various
H2 blockers (such as famotidine or causes of shoulder pain, careful as-
ranitidine) are a type of antihistamine sessments of both normal and affected
used during hospitalizations to reduce shoulders and ranges of motion (pas-
the risk of gastric reflux and counter sive and active) are required. A palpa-
the potential gastrointestinal side ef- ble fingerbreadth gap between the
fects of antithrombotic medications acromion and humeral head suggests
such as aspirin. Since antithrombotics joint subluxation. A restricted range of
are an evidence-based intervention for movement without pain at rest but
secondary stroke prevention, the use present on limited movement sug-
of H2 blockers is widespread. However, gests adhesive capsulitis as the pri-
antihistamines can cause sedation in mary pathology.
patients who are elderly and compro- Treatment for shoulder pain should
mise attention vital for effective perfor- begin early by recognizing patients at
mance of motor and cognitive tasks. risk for shoulder syndromes. Patients
Evidence suggests that these medica- with flaccid upper extremity paresis
tions can impede plasticity through are prone to shoulder subluxation and
inhibition of long-term potentiation.38 traction in the glenohumeral capsule,
Given this potential risk of treatment, which lead to damage of surrounding

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 Stroke Rehabilitation

KEY POINT
h Depression is a common soft tissues. Proper positioning that counteract them. Studies show that
sequela after a stroke includes supporting the distal forearm higher rates of mortality and morbid-
and adversely affects from the elbow down to reduce strain ity are seen in stroke patients diag-
outcomes. Medications at the shoulder reduces the tension nosed with poststroke depression,43,44
such as selective serotonin on the shoulder; slings can be used to while treatment of depression leads to
reuptake inhibitors can provide additional support. Strapping improved functional recovery after
be effectively used in or taping of the upper arm to the stroke. Moreover, by restoring the
the treatment of shoulder and clavicle has been used balance of central neurotransmitters,
poststroke depression. routinely in the management of sub- improving motivation to work with re-
luxation. An intraarticular cortisone habilitation therapists, and increasing
injection (1 mg to 5 mg) into the gle- compliance with medications, treat-
nohumeral joint can be used to treat ment of depression leads to improved
pain in patients with adhesive capsulitis. functional recovery after stroke.
Functional electrostimulation can be SSRIs are the most studied agents
used for muscle contraction and pain for the treatment of poststroke de-
relief. The management of spasticity is pression. Evidence exists for the use
discussed later in this article. of citalopram (20 mg/d), sertraline
(50 mg/d to 100 mg/d), and fluoxetine
Depression (20 mg/d), which are superior to
Poststroke depression is increasingly placebo in treating poststroke depres-
recognized as a common sequela sion and producing improvement in
of stroke. The prevalence of clini- quality-of-life measures.45Y47 Evidence
cally diagnosed poststroke depression also supports the efficacy of tricyclic
ranges from 20% to 40%, and it is antidepressants for the treatment of
likely underdiagnosed.40Y42 The inter- poststroke depression.48 Case 11-2
action between depression and stroke is a clinical example of how post-
recovery is complex, but when de- stroke depression affects recovery and
pression is untreated or undertreated its treatment.
in patients, poststroke recovery is not
optimized. Depression symptoms (eg, Spasticity
fatigue, reduced motivation, loss of Spasticity is a motor disorder generally
confidence, and attention and con- defined as a velocity-dependent in-
centration difficulties) limit the bene- crease in tonic stretch reflexes leading
fits of rehabilitation and can even to increased tone. It is often identified

Case 11-2
A 45-year-old man was admitted to the hospital with a basal ganglia lacunar
stroke. Despite having a small stroke with minimal comorbidities and mild
to moderate deficits, the patient was not improving. His therapists reported
decreased participation and minimal functional gains in therapy sessions.
The patient reported increased fatigue and somnolence, and his family noted
poor engagement and a change in personality. Poststroke depression was
diagnosed. He was started on citalopram 20 mg/d, with gradual improvement
in his mood and other symptoms.
Comment. This case illustrates the importance of screening for poststroke
depression and having a low threshold to treat it. It is important to note
that the effect of selective serotonin reuptake inhibitors (SSRIs) may not be
seen for 1 to 2 weeks.

248 ContinuumJournal.com February 2017

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 KEY POINTS
during the chronic phase of post- addition to financial independence h Spasticity adversely affects
stroke recovery. At 12 months, patients and full integration into society, pa- poststroke outcomes.
without spasticity have shown signifi- tients enjoy subtle benefits from em-
h Botulinum toxin
cantly better motor and activity scores, ployment, such as improvement in
and intrathecal baclofen
have lower Barthel Index scores, and self-esteem and confidence. Clinicians are the preferred
are less likely to receive institutional often concentrate on the severity of treatments of spasticity
care (PG.0001) compared to those with physical and cognitive impairments in patients with
spasticity.49 Likewise, another study when considering a patient’s ability chronic stroke.
demonstrated that modified Rankin to return to work; however, studies h Studies show that the
Scale and Barthel Index scores were have demonstrated that other factors, severity of physical and
greater for patients with spasticity than such as younger age, educational cognitive impairments is
for patients without spasticity.50 These level, level of skill, and prestroke pro- not associated with a
studies show that spasticity adversely fessional status, appear to be strong stroke survivor’s ability
affects functional outcomes in the influencers of a patient’s ability to to return to work. More
chronic phase of stroke; therefore, return to work.53,54 Vocational reha- important factors
management of spasticity is an essen- bilitation programs are available for include age, educational
tial part of stroke rehabilitation. patients, and often neuropsychologi- level, and prestroke
Historically, treatment of spasticity cal testing can help assess a patient’s professional status.
has involved oral medications such as cognitive ability to return to work. For
baclofen, nerve blocks, and serial patients who are deemed unable to
casting, but these interventions are return to work, health care teams
limited because of side effects. Alter- should assist patients with completing
natively, botulinum toxin and intrathe- temporary disability forms or long-
cal baclofen are now widely accepted term disability forms, if needed.
in the management of spasticity in pa-
tients with chronic stroke. Compared Return to Driving
to the oral route, intrathecal baclofen The ability to drive plays an important
achieves muscle-relaxing properties at role in routine activities and frequently
significantly lower doses, thus limiting serves as the key to independence.
systemic side effects. In studies of Stroke survivors are often restricted
intrathecal baclofen in patients who in their driving ability because of
were poststroke with spasticity, im- hemiparesis; visual field, cognitive, and
provement was seen in mobility, activ- coordination deficits; and poststroke
ities of daily living, and quality of life.51 seizures. The ability to return to driving
Botulinum toxin is beneficial for is often viewed by patients as their
poststroke spasticity, demonstrating metric for return to normalcy and
improvement in upper limb muscula- independence, and inability to return
ture tone. In studies supporting its use, to driving can affect their ability to
botulinum toxin was administered into return to work. Consequently, patients
muscles of interest in the hand, wrist, often ask for clearance to return to
and upper arm at least 6 weeks post- driving or ask when they can anticipate
stroke. Study participants had a Modi- this clearance. A clearance to return to
fied Ashworth Scale score of 2 to 3 in driving should involve both a medical
upper extremity muscles of interest and clearance and a functional assessment
were followed for at least 10 weeks.52 clearance. The medical clearance evalu-
ation can be performed by a health care
Return to Work professional; it should ensure that vi-
A common concern of stroke survi- sual field, cognitive, and motor defi-
vors regards return to employment. In cits are not severe enough to impact

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 Stroke Rehabilitation

KEY POINT
h A formal driving driving ability and that seizure control is CONCLUSION
assessment is helpful compliant with local laws. The medical Stroke rehabilitation is a complex
in determining a clearance evaluation should also assess process that involves multiple health
stroke survivor’s other medical comorbidities, such as care specialties and multiple ap-
ability to drive. cardiac conditions, that could poten- proaches, depending on the nature
tially affect the patient’s driving and of the patient’s deficits. While the
lead to harm for the patient or others timing and dosing of therapy and
on the road. However, more complex novel approaches have not been fully
aspects of driving, such as planning, validated and established, it is clear
motor coordination, and reaction that successful rehabilitation can make
times, are difficult to ascertain in the a positive impact on the outcome of
office. A formal driving assessment stroke survivors. Neurologists can play
can be helpful to evaluate these skills a role in rehabilitation by advising
and can be conducted on a driving sim- patients on the natural history of
ulator or by in-car evaluation by a stroke, ensuring that the appropriate
specialist assessor. therapy and therapy location are
provided, screening for poststroke
EMERGING TECHNIQUES IN depression, and recognizing and man-
STROKE REHABILITATION aging specific issues in stroke rehabil-
Further advances in stroke recovery itation. Stroke rehabilitation is the
and rehabilitation will likely occur in next frontier in stroke care, and phy-
the next decade. On a systems of care sicians involved in this field will have
level, telemedicine is currently playing more knowledge and many more tools
a role in the acute management of at their disposal in the coming years.
stroke but will likely expand to the
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 LIFELONG LEARNING IN NEUROLOGY ®
\

Stroke Epidemiology and Risk Factor

Management
Amy Guzik, MD; Cheryl Bushnell, MD, MHS. Continuum (Minneap Minn). February
2017; 23 (1 Cerebrovascular Disease):15Y39.

Abstract
Purpose of Review:
Death from stroke has decreased over the past decade, with stroke now the fifth leading cause
of death in the United States. In addition, the incidence of new and recurrent stroke is
declining, likely because of the increased use of specific prevention medications, such as statins
and antihypertensives. Despite these positive trends in incidence and mortality, many strokes
remain preventable. The major modifiable risk factors are hypertension, diabetes mellitus,
tobacco smoking, and hyperlipidemia, as well as lifestyle factors, such as obesity, poor
diet/nutrition, and physical inactivity. This article reviews the current recommendations for
the management of each of these modifiable risk factors.

Recent Findings:
It has been documented that some blood pressure medications may increase variability of
blood pressure and ultimately increase the risk for stroke. Stroke prevention typically includes
antiplatelet therapy (unless an indication for anticoagulation exists), so the most recent
evidence supporting use of these drugs is reviewed. In addition, emerging risk factors, such
as obstructive sleep apnea, electronic cigarettes, and elevated lipoprotein (a), are discussed.

Summary:
Overall, secondary stroke prevention includes a multifactorial approach. This article incorporates
evidence from guidelines and published studies and uses an illustrative case study throughout the
article to provide examples of secondary prevention management of stroke risk factors.

Key Points
& Stroke incidence and mortality have declined in recent decades, correlating with
improved risk factor management.

* 2017 American Academy of Neurology.

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 & Disparities in stroke incidence and mortality still exist, particularly in the stroke belt and
among blacks and Mexican Americans.
& Hypertension is the most common modifiable risk factor for stroke.
& The recommended blood pressure targets are less than 140/90 mm Hg in patients
with an ischemic stroke and less than 130/80 mm Hg in patients with a small vessel
distribution ischemic stroke.
& Avoiding blood pressureYlowering medications that lead to variability is recommended.
Treatment with atenolol shows more variability, while treatment with amlodipine is
associated with less variability.
& Atherosclerotic causes of ischemic stroke or the finding of a low-density lipoprotein level
higher than 100 mg/dL should be treated with a high-potency statin.
& Intolerance to statins, a common problem, can be addressed by stopping the medications,
checking for muscle enzymes, and reducing the dose upon reinitiation.
& Disorders of glucose metabolism are highly prevalent in patients with stroke. Patients
with new-onset stroke or transient ischemic attack should be screened for diabetes
mellitus with hemoglobin A1c or an oral glucose tolerance test.
& Diabetes mellitus and metabolic syndrome are key risk factors for first-ever and recurrent
ischemic stroke; therefore, management for these conditions should include lifestyle
and pharmacologic strategies to reduce the hemoglobin A1c to less than 7%.
& Cigarette smoking is a significant risk factor, at least doubling the risk of stroke.
& Nicotine replacement therapy, bupropion, and, in particular, varenicline are effective
treatments for smoking cessation. While electronic cigarettes may pose less potential
stroke risk than traditional cigarettes, insufficient evidence exists to counsel patients
to use electronic cigarettes as a primary form of smoking cessation.
& Environmental exposure to secondhand smoke increases stroke risk by as much as
30% among nonsmokers.
& While the risk of stroke from smokeless tobacco products and electronic cigarettes is
less clear than from cigarette smoking, poststroke risk modification provides an
opportune time for counseling on cessation from all forms of tobacco and nicotine.
& The Mediterranean diet is associated with lower risk of stroke. It is characterized by
high intake of olive oil, fruits and vegetables, nuts, and whole grains; moderate intake of
fish and poultry; and low intake of dairy, red and processed meats, and sweets.
& Diet and nutrition can affect not only risk factors such as hypertension and hyperlipidemia
but also stroke risk specifically. The Dietary Approaches to Stop Hypertension diet
is effective in lowering blood pressure and low-density lipoprotein, with reduction of
sodium intake to 2400 mg/d or less recommended for those with hypertension.
& Obesity is an established risk factor for ischemic stroke. With every 1-unit increase
in body mass index (about 7 pounds), the risk for ischemic stroke rises by about 5%.
& Patients with stroke should engage in three to four sessions of moderate- to
vigorous-intensity aerobic exercise per week, with sessions lasting an average of
40 minutes.
& Obstructive sleep apnea has been linked to increased risk of incident stroke, higher
poststroke mortality, and worse functional outcome. Polysomnography should be
considered with high suspicion of apnea, even without typical signs or symptoms.
& Lipoprotein (a) is a lipoprotein that has been associated with both atherosclerosis
and thrombogenesis. While it has been associated with increased stroke risk in children,
association in adults is less clear.
& In patients without a cardioembolic source, aspirin monotherapy at doses of 50 mg to
325mg is an appropriate strategy for secondary stroke prevention.

* 2017 American Academy of Neurology.

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Clinical Evaluation of the Patient With
Acute Stroke
Andrew M. Southerland, MD, MSc. Continuum (Minneap Minn). February 2017;
23 (1 Cerebrovascular Disease):40Y61.

Key Points
& Establishing time of stroke onset, or last known well time, starts the clock on all further
decision making for the patient with acute stroke. Confirming last known well time
with the patient or a reliable witness, or identifying an associated event, is key to
informing accurate treatment decisions going forward.
& Symptom chronology is an important feature to help distinguish acute stroke from
common stroke mimics. Stroke tends to be abrupt and maximal at onset, with the
exception of stuttering transient ischemic attacks or small vessel strokes that may
fluctuate in intensity in the acute period.
& Patients with acute stroke with decreased level of consciousness or respiratory distress
may require rapid intubation. Prior to sedation, rapid assessment of pupillary
function, gaze deviation, blink to threat, motor tone, and purposeful movements can
help formulate the neurologic syndrome.
& Patients in atrial fibrillation with focal neurologic deficits should be assumed to have
cardioembolic ischemic stroke until proven otherwise. Inquiring about anticoagulation
and medication compliance in the acute stroke history is essential to informing an
appropriate treatment decision.
& The National Institutes of Health Stroke Scale is biased toward left hemispheric and
anterior circulation strokes. Therefore, careful vigilance should be employed when
assessing stroke severity in patients with nondominant, right hemisphere, brainstem,
or isolated cerebellar strokes to guide treatment.
& Evidence-based guidelines suggest the only laboratory test absolutely required prior
to initiation of IV recombinant tissue plasminogen activator is a finger-stick blood
glucose. Other laboratory tests, such as complete blood cell count and metabolic
panel, should not delay head CT or initiation of IV recombinant tissue plasminogen
activator. Exceptions include patients taking warfarin or with known hematologic
abnormalities, for whom rapid coagulation profiling is warranted. Obtaining proper
vascular access in the emergency department may also delay door-to-CT time, so using
prehospital access or point-of-care testing may be beneficial.
& Strokes involving the frontal eye fields create a conjugate deviation of the eyes to the
ipsilateral ischemic hemisphere, ie, ‘‘looking at your stroke.’’
& The classic left middle cerebral artery syndrome presents with left gaze preference, right
visual field cut, aphasia, and right hemiparesis/hemianesthesia.
& Determining handedness in patients with stroke is key to defining hemispheric dominance
and characterizing stroke syndromes. Only a minority of primarily left-handed
individuals are right hemisphere dominant for language.
& Listening intently for phonemic or semantic paraphasic errors is important to recognize
subtle aphasia in the patient with acute stroke.
& Diagnosing aphasia from other forms of encephalopathy may be distinguished by a
patient’s level of attentiveness.

* 2017 American Academy of Neurology.

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 & Mild hemispatial neglect from a right middle cerebral artery stroke can be elicited at
the bedside by double simultaneous stimulation, during which the patient extinguishes the
contralateral sensory stimulus.
& Bilateral medial thalamic strokes result in a state of depressed level of consciousness
or coma and often occur secondary to occlusion of a single thalamoperforator trunk off
the top of the basilar artery, known as the artery of Percheron.
& When examining patients with stroke who are tetraplegic or appear to be comatose,
the examiner must always ensure they are not actually ‘‘locked in’’ from bilateral
pontine infarction and able to communicate with vertical eye movements or other
subtle signs.
& Alexia without agraphia classically results from a left posterior cerebral artery territory
stroke causing infarction of the splenium of the corpus callosum and left occipital lobe,
leading to a disconnection of visual and language integration.
& Patients presenting with acute-onset dysequilibrium or gait ataxia should prompt a
thorough examination of eye movements, postural stability, and gait to rule out a
paramedian cerebellar stroke.
& The HINTS methodology (head impulse test, pattern of nystagmus, and test of skew)
helps distinguish central from peripheral vestibulopathy in patients presenting with
an acute vestibular syndrome.

Treatment of Acute Ischemic Stroke

Alejandro A. Rabinstein, MD, FAAN. Continuum (Minneap Minn). February 2017;
23 (1 Cerebrovascular Disease):62Y81.

Abstract
Purpose of Review:
This article provides an update on the state of the art of the emergency treatment of acute ischemic
stroke with particular emphasis on the alternatives for reperfusion therapy.
Recent Findings:
The results of several randomized controlled trials consistently and conclusively demonstrating
that previously functional patients with disabling strokes from a proximal intracranial artery
occlusion benefit from prompt recanalization with mechanical thrombectomy using a retrievable
stent have changed the landscape of acute stroke therapy. Mechanical thrombectomy within
6 hours of symptom onset should now be considered the preferred treatment for these patients
along with IV thrombolysis with recombinant tissue plasminogen activator (rtPA) within the
first 4.5 hours for all patients who do not have contraindications for systemic thrombolysis.
Patients who are ineligible for IV rtPA can also benefit from mechanical thrombectomy.
Collateral status and time to reperfusion are the main determinants of outcome.
Summary:
Timely successful reperfusion is the most effective treatment for patients with acute ischemic
stroke. Systems of care should be optimized to maximize the number of patients with acute
ischemic stroke able to receive reperfusion therapy.

* 2017 American Academy of Neurology.

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

Key Points

& Prompt reperfusion is the most effective treatment for patients with acute ischemic stroke.
& The three principles of acute stroke therapy are to achieve recanalization of the occluded
vessel (and reperfusion of the ischemic tissue), to optimize collateral flow, and to
avoid secondary brain injury.
& The ischemic penumbra is the region of hypoperfused brain that can still be viable with
prompt recanalization of the occluded artery.
& Collateral flow is responsible for the temporary preservation of the ischemic penumbra.
& No neuroprotective agent has been proven to be beneficial for acute ischemic stroke
in clinical trials.
& IV thrombolysis with rtPA and endovascular thrombectomy with a retrievable stent are both
solidly established treatments for appropriate candidates with acute ischemic stroke.
& Time to reperfusion is a major determinant of outcome in acute ischemic stroke.
& Randomized placebo-controlled trials have demonstrated that IV thrombolysis with rtPA is
beneficial for patients with acute ischemic stroke up to 4.5 hours from symptom onset.
& Some previously cited contraindications for IV thrombolysis have been revisited, thus
expanding the pool of patients who can be considered good candidates for this treatment.
& Benefit from IV thrombolysis is much greater in the first 90 minutes from symptom onset.
& Most cases of symptomatic intracerebral hemorrhage are caused by reperfusion injury
causing hemorrhagic transformation of an already severe stroke.
& Six recent randomized controlled trials have conclusively proven that endovascular
therapy with mechanical thrombectomy improves functional outcomes in patients with
acute stroke from a proximal intracranial artery occlusion (internal carotid artery, M1 or
M2 segments) when the intervention is performed within 6 hours of symptom onset.
& Candidates for endovascular stroke therapy are patients with severe neurologic
symptoms, no major ischemic changes on the baseline CT scan, good prestroke functional
status, and early presentation.
& Mechanical thrombectomy can be attempted when IV thrombolysis does not result in
rapid clinical improvement and also in patients who are ineligible for IV rtPA.
& Careful assessment of brain imaging is necessary to exclude a large established
infarction (core).
& The optimal radiologic method to select candidates for endovascular therapy is not yet
established, but the Alberta Stroke Programs Early CT Score, evaluation of collaterals on
CT angiography, and CT perfusion or MRI diffusion/perfusion are all available options.
& Endovascular interventions for acute stroke should be performed under conscious
sedation whenever possible.
& Patients with wake-up strokes and those with stroke of unknown time of onset might
benefit from acute reperfusion if a large infarct core can be reliably excluded.
& It is prudent not to administer IV thrombolysis in patients taking the novel oral
anticoagulants (dabigatran, rivaroxaban, apixaban, edoxaban) because readily available
tests in the emergency department cannot quantify the degree of active anticoagulation.
& Patients with mild or rapidly improving strokes who present within the time window
for IV thrombolysis and still have disabling symptoms at the time of the evaluation should
probably be offered treatment with rtPA.
& Although patients with basilar artery occlusion were not included in the randomized
controlled trials of IV thrombolysis or mechanical thrombectomy, these patients should
be treated with acute reperfusion therapies because of their dismal prognosis if
recanalization cannot be achieved.

* 2017 American Academy of Neurology.

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

 & Mobile stroke units have been shown to provide a safe way to start thrombolysis in the
prehospital setting.

Diagnosis and Management of Transient

Ischemic Attack
Shelagh B. Coutts, MD, MSc, FRCPC. Continuum (Minneap Minn). February 2017;
23(1Cerebrovascular Disease):82Y92.

Abstract
Purpose of Review:
This article reviews the diagnosis, investigation, and recommended management after a
transient ischemic attack (TIA) and discusses how to make an accurate diagnosis, including
the diagnosis of mimics of TIAs.
Recent Findings:
Up to a 10% risk of recurrent stroke exists after a TIA, and up to 80% of this risk is preventable
with urgent assessment and treatment. Imaging of the brain and intracranial and extracranial
blood vessels using CT, CT angiography, carotid Doppler ultrasound, and MRI is an important
part of the diagnostic assessment. Treatment options include anticoagulation for atrial fibrillation,
carotid revascularization for symptomatic carotid artery stenosis, antiplatelet therapy, and
vascular risk factor reduction strategies.
Summary:
TIA offers the greatest opportunity to prevent stroke that physicians encounter. A TIA should be
treated as a medical emergency, as up to 80% of strokes after TIA are preventable.

Key Points
& Minor ischemic stroke and transient ischemic attack should be managed similarly.
& Making the correct diagnosis of transient ischemic attack is key, as 50% of patients
assessed for possible transient ischemic attack will have an alternative diagnosis
(ie, are a mimic).
& Atrial fibrillation is a common cause of transient ischemic attack and ischemic stroke.
& All patients with possible transient ischemic attack require structural imaging of the brain
to rule out mimics.
& Urgent imaging using CT/CT angiography can identify patients at high risk for recurrent
stroke.
& Although the presence of a lesion seen on diffusion-weighted imaging can be helpful by
proving that ischemia occurred, the absence of a lesion does not rule out ischemia.
& Finding out why a transient ischemic attack occurred is the key to preventing a
recurrent stroke.
& Recognition and management of transient ischemic attack offers the greatest opportunity
to prevent disabling stroke.

* 2017 American Academy of Neurology.

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

Prevention and Management of
Poststroke Complications
Josephine F. Huang, MD. Continuum (Minneap Minn). February 2017;
23(1 Cerebrovascular Disease):93Y110.

Abstract
Purpose of Review:
This article provides a synopsis of the immediate and delayed medical complications of stroke,
with an emphasis on prevention and management of these complications.
Recent Findings:
Meta-analysis of the trials for endovascular treatment of acute stroke shows no significant
increase in hemorrhagic events. Rehabilitation guidelines published by the American Heart
Association and American Stroke Association in 2016 aid in providing the best clinical practice
for patients with stroke, from the time of their initial hospitalization to their return to
the community.
Summary:
Medical complications from stroke are common and are associated with poor clinical outcomes,
increased length of hospital stays and higher rates of readmission, increased cost of care, delayed
time to rehabilitation, and increased mortality. Being cognizant of the common complications
encountered, taking appropriate measures to prevent them, and knowing how to manage them
when they do occur are essential to the continued care of patients with stroke.

Key Points
& Angioedema resulting from use of recombinant tissue plasminogen activator often
involves the unilateral tongue and lips contralateral to the side of the infarct. It is often
mild and transient, but in severe cases, IV recombinant tissue plasminogen activator
should be stopped immediately and anaphylaxis appropriately treated.
& The peak incidence of deep venous thrombosis formation is in the first week after stroke,
while pulmonary embolism is most commonly seen in weeks 2 to 4. Prevention of deep
venous thrombosis and pulmonary embolism starts with early initiation of venous
thromboembolism prophylaxis.
& Patients with stroke who are at high risk of developing deep venous thrombosis and
pulmonary embolism include those who are immobilized, dehydrated, or elderly
and those who have a history of malignancy, previous deep venous thrombosis, or
clotting disorders.
& Contraindications to unfractionated heparin or low-molecular-weight heparin for deep
venous thrombosis prophylaxis or therapy for symptomatic deep venous thrombosis
or pulmonary embolism include intracranial hemorrhage, recent thrombolytic therapy,
and active extracranial hemorrhage. Alternatives include intermittent pneumatic
compression or aspirin for prophylaxis and inferior vena cava filter or surgical
embolectomy for symptomatic deep venous thrombosis or pulmonary embolism.

* 2017 American Academy of Neurology.

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 & Aspiration may be prevented with early dysphagia screening.
& Provide adequate hydration and early nutrition in patients who are unable to take
anything by mouth. Dehydration carries an increased risk of deep venous thrombosis,
while early nutrition through a nasogastric tube is associated with improved survival.
& Up to 70% of patients with stroke will have a fall, thus all patients with stroke should
have a formal fall prevention program.
& Fractures in patients who are poststroke often occur on the paretic side and are secondary
to accidental falls.
& Decreased mobility is associated with decreased bone mineral density.
& Balance training can help to reduce falls.
& Patients with stroke in long-term care facilities should be assessed for calcium and
vitamin D supplementation.
& Seizures after stroke are often focal in onset and can have secondary generalization. They
may have early or late onset; late-onset seizures are associated with a higher rate of
developing chronic epilepsy.
& Prophylactic antiepileptic drugs are not recommended after stroke.

Cardioembolic Stroke
Cumara B. O’Carroll, MD, MPH; Kevin M. Barrett, MD, MSc. Continuum (Minneap Minn).
February 2017; 23 (1 Cerebrovascular Disease):111Y132.

Abstract
Purpose of Review:
Cardioembolic stroke is common and disproportionately more disabling than nonembolic
mechanisms of stroke. Its incidence is expected to rise because of the age-related incidence of
atrial fibrillation and an aging population. This article summarizes the different causes of
cardioembolism and outlines current management guidelines.
Recent Findings:
Since cardioembolic stroke is not a single disease entity, its diagnosis requires initial clinical
suspicion and a comprehensive evaluation, including ECG, echocardiography, brain imaging,
and cardiac monitoring. Atrial fibrillation is the most common cause of cardioembolic stroke, and
anticoagulation is usually recommended. This article reviews risk stratification models to assist in
the decision-making process and highlights the increased use of novel oral anticoagulants for
stroke prevention in atrial fibrillation. New data support the importance of prolonged cardiac
monitoring for diagnosing occult atrial fibrillation. Current data on other mechanisms of
cardioembolic stroke, such as prosthetic heart valves and aortic arch atherosclerosis, are also
presented, and the available evidence regarding patent foramen ovale closure in cryptogenic
stroke is summarized.
Summary:
Cardioembolism is an important cause of ischemic stroke, with diverse underlying mechanisms
requiring a tailored approach to diagnosis, management, and prevention.

* 2017 American Academy of Neurology.

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

Key Points
& Cardioembolism accounts for 20% to 30% of all ischemic strokes.
& Multiple cortical infarcts in different vascular distributions in an individual patient should
raise suspicion for a proximal source of embolus.
& Transesophageal echocardiography is superior to transthoracic echocardiography in
assessing the anatomy of the ascending aorta/aortic arch; evaluating for the presence
of thrombus in the left atrium; and detecting and measuring an atrial septal defect, atrial
septal aneurysm, or patent foramen ovale.
& Atrial fibrillation is associated with left atrial enlargement, resulting in stasis of blood and
increased propensity for clot formation, with subsequent embolization to the brain.
& Paroxysmal atrial fibrillation seems to present a similar risk of stroke as persistent or
permanent atrial fibrillation.
& For both the CHADS2 and CHA2DS2VASc scores, a previous history of stroke
or transient ischemic attack usually confers a high enough annual risk to
warrant anticoagulation.
& Warfarin is superior to aspirin in preventing stroke for high-risk patients with atrial
fibrillation, and thus anticoagulation is preferred over antiplatelet agents for secondary
stroke prevention in these patients.
& Patients with atrial fibrillation may require medications for control of rate and rhythm,
but this does not preclude the need for antithrombotic therapy for stroke prevention.
& All of the novel oral anticoagulants were found to be noninferior to warfarin, with
dabigatran (high dose) and apixaban meeting superiority end points. Apixaban also
resulted in lower mortality and less major bleeding.
& Potential benefits of the novel oral anticoagulants over warfarin include fixed dosing,
rapid onset of action, fewer drug interactions, no dietary restrictions, lack of laboratory
monitoring, and lower rates of intracerebral hemorrhage.
& The selection of an appropriate method of anticoagulation should be based on the
individual’s risk factors, cost, tolerability, potential for drug interactions, and
patient preference.
& Idarucizumab is the newly approved reversal agent for dabigatran.
& A patient with atrial fibrillation on oral anticoagulation would have to fall approximately
295 times a year for the risk of a traumatic subdural hematoma to outweigh the benefit
of stroke prevention.
& For most patients with acute ischemic stroke and underlying atrial fibrillation, it is
reasonable to initiate oral anticoagulation within 14 days of symptom onset, but the exact
timing is unclear and often varies in clinical practice.
& Patients with cryptogenic stroke or transient ischemic attack should have prolonged
cardiac monitoring within 6 months of the initial vascular event.
& All patients with mechanical valve prostheses should be on daily aspirin therapy in
addition to anticoagulation as this lowers the risk of stroke.
& Novel oral anticoagulants are not indicated in patients with mechanical heart valves, and
warfarin remains the preferred treatment.
& Staphylococcus aureus, Streptococcus viridans, and Enterococcus are the most common
organisms in infective endocarditis.
& Transthoracic echocardiography will not definitely exclude vegetations or abscesses in
infective endocarditis, and transesophageal echocardiography is considered superior
for making the diagnosis.
& Patients with infective endocarditis often have multifocal infarcts of differing ages with
superimposed microhemorrhages on brain MRI.

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 & Antithrombotic therapy (antiplatelet or anticoagulant agents) in patients with infective
endocarditis does not reduce the risk of embolization and is instead associated with a higher
risk of intracerebral hemorrhage.
& Full-dose unfractionated heparin or low-molecular-weight heparin is recommended over
warfarin in patients with nonbacterial thrombotic endocarditis to reduce embolization.
& Available data do not support patent foramen ovale closure for patients with cryptogenic
stroke or transient ischemic attack.
& Anticoagulation is recommended for at least 3 months in patients with myocardial
infarction and left ventricular thrombus because of high risk of embolization.
& The effectiveness of anticoagulation compared to antiplatelet therapy for secondary
stroke prevention in patients with heart failure and sinus rhythm is uncertain.
& Until further randomized data are obtained, guidelines suggest the use of antiplatelet
and statin therapy for patients with ischemic stroke or transient ischemic attack and aortic
arch atheroma, since the effectiveness of warfarin compared to antiplatelet therapy
is uncertain.

Large Artery Atherosclerotic

Occlusive Disease
John W. Cole, MD, MS. Continuum (Minneap Minn). February 2017; 23 (1 Cerebrovascular
Disease):133Y157.

Abstract
Purpose of Review:
Extracranial or intracranial large artery atherosclerosis is often identified as a potential etiologic
cause for ischemic stroke and transient ischemic attack. Given the high prevalence of large
artery atherosclerosis in the general population, determining whether an identified atherosclerotic
lesion is truly the cause of a patient’s symptomatology can be difficult. In all cases, optimally
treating each patient to minimize future stroke risk is paramount. Extracranial or intracranial large
artery atherosclerosis can be broadly compartmentalized into four distinct clinical scenarios
based upon the individual patient’s history, examination, and anatomic imaging findings:
asymptomatic and symptomatic extracranial carotid stenosis, intracranial atherosclerosis, and
extracranial vertebral artery atherosclerotic disease. This review provides a framework for
clinicians evaluating and treating such patients.

Recent Findings:
Intensive medical therapy achieves low rates of stroke and death in asymptomatic carotid
stenosis. Evidence indicates that patients with severe symptomatic carotid stenosis should
undergo carotid revascularization sooner rather than later and that the risk of stroke or death
is lower using carotid endarterectomy than with carotid stenting. Specific to stenting, the risk
of stroke or death is greatest among older patients and women. Continuous vascular risk
factor optimization via sustained behavioral modifications and intensive medical therapy is
the mainstay for stroke prevention in the setting of intracranial and vertebral artery
origin atherosclerosis.

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Summary:
Lifelong vascular risk factor optimization via sustained behavioral modifications and intensive
medical therapy are the key elements to reduce future stroke risk in the setting of large artery
atherosclerosis. When considering a revascularization procedure for carotid stenosis, patient
demographics, comorbidities, and the periprocedural risks of stroke and death should be
carefully considered.

Key Points
& Continuous vascular risk factor optimization via sustained behavioral modifications
and intensive medical therapy is critical to prevent stroke in the setting of large artery
atherosclerosis.
& It is important to determine if the identified large artery atherosclerotic lesion is proximal
to a vascular territory that corresponds to the patient’s stroke on imaging or symptoms
in the setting of a transient ischemic attack.
& Population-wide improved control of hypertension, dyslipidemia, and diabetes mellitus,
coupled with a reduction in tobacco use, has resulted in a decline in stroke mortality
from the third to the fifth leading cause of death in the United States.
& Hypertension and diabetes mellitus remain undertreated, and personalized approaches
to lifestyle changes and medical therapy are critical for successful stroke prevention.
& Physicians should consider each patient on an individual basis, working to optimize
their risk factor profile over the long term while inferring upon the most recent
professional society statement recommendations.
& Current surgical best practice restricts carotid endarterectomy for asymptomatic
carotid stenosis to patients with 70% or greater carotid stenosis if the surgery can be
performed with a 3% or less risk of perioperative complications.
& As consistent with recent guidelines, patients with asymptomatic carotid stenosis should
be prescribed a daily aspirin and statin and screened for other treatable risk factors
with appropriate medical therapies and lifestyle changes instituted.
& For patients with a transient ischemic attack or ischemic stroke within the past 6 months
and ipsilateral severe (70% to 99%) carotid artery stenosis, carotid endarterectomy is
recommended; for those with moderate (50% to 69%) carotid stenosis, carotid
endarterectomy is recommended depending on patient-specific factors, such as age, sex,
and comorbidities; and for those with a degree of stenosis of less than 50%, carotid
endarterectomy and carotid artery stenting are not recommended.
& The optimal timing of carotid revascularization via carotid endarterectomy after
a completed nondisabling stroke has been defined to be within 2 weeks if no
contraindications exist.
& Carotid artery stenting can be considered as an alternative to carotid endarterectomy
for patients who are symptomatic with greater than 70% stenosis if the anticipated rate
of periprocedural stroke or death is less than 6%; age should be considered when
choosing between carotid endarterectomy and carotid artery stenting.
& For patients who are older (70 years of age or older), carotid endarterectomy may be
associated with improved outcome compared with carotid artery stenting, in particular
when arterial anatomy is unfavorable for endovascular intervention. For patients who
are younger, carotid artery stenting is equivalent to carotid endarterectomy in terms of risk
for periprocedural complications (eg, stroke, myocardial infarction, or death) and
long-term risk for ipsilateral stroke.

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 & Extracranial-intracranial bypass surgery is not recommended for patients with a recent
transient ischemic attack or ischemic stroke ipsilateral to a stenosis or occlusion of
the middle cerebral or carotid artery and is considered investigational for those with
progressive symptoms despite optimal medical management.
& Current guidelines recommend that patients with a stroke or transient ischemic attack
caused by 50% to 99% stenosis of a major intracranial artery be treated with aspirin
325 mg/d in preference to warfarin.
& Routine preventive therapy with an emphasis on antithrombotic therapy, lipid lowering,
blood pressure control, and lifestyle optimization is recommended for all patients
with recently symptomatic extracranial vertebral artery stenosis.
& Current guidelines indicate that endovascular stenting of patients with extracranial
vertebral stenosis may be considered when patients are having symptoms despite optimal
medical treatment.
& While vertebral artery transposition and vertebral artery endarterectomy are performed
rarely, they can be considered in patients with persistent symptoms despite intensive
medical therapy.

Arterial Ischemic Stroke in Children

and Young Adults
Warren D. Lo, MD; Riten Kumar, MD, MSc. Continuum (Minneap Minn). February
2017;23(1 Cerebrovascular Disease):158Y180.

Abstract
Purpose of Review:
This article reviews risk factors, recurrence risk, evaluation, management, and outcomes
of arterial ischemic stroke in children and young adults.
Recent Findings:
The risk for recurrence and mortality appear to be low for neonatal and childhood stroke.
Most children have relatively mild deficits, but those who have greater neurologic deficits,
poststroke epilepsy, or strokes early in life are at risk for lower overall cognitive function. Stroke
recurrence and long-termmortality after stroke in young adults are greater than originally thought.
Cognitive impairments, depression, and anxiety are associated with higher levels of poststroke
unemployment and represent targets for improved poststroke care. Poststroke care in young
adults involves more than medical management. Self-reported memory and executive function
impairments may be more severe than what is detected by objective measures. Assessment of
possible cognitive impairments and appropriate management of psychological comorbidities are
key to maximizing the long-term functional outcome of stroke survivors.
Summary:
Childhood and young adult stroke survivors survive for many more years than older patients
with stroke. To ensure that these survivors maximize the productivity of their lives, neurologists
must not only optimize medical management but also recognize that impairments in
cognition and mood may be remediable barriers to long-term functional independence.

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Key Points

& In children, the group with the highest incidence of ischemic stroke is neonates, where
the estimated incidence ranges from 1 in 4400 to 1 in 7700 live births.
& Strokes also occur in utero. While the incidence is unknown, the US prevalence of
cerebral palsy is 3.1 per 1000 children at eight years of age. Unilateral spasticity accounts
for 19% to 35% of the total, and many of these cases are due to in utero stroke.
& The relative rarity of ischemic stroke in children and young adults contributes to delays
in diagnosis.
& The striking difference between stroke in children and young adults is the pattern of
identified risk factors and associated diseases.
& In neonatal stroke, the immediate recurrence risk appears to be very low, unless a
congenital heart lesion associated with cardiogenic embolism or a hypercoagulable
disorder associated with systemic thrombosis exists.
& Brain imaging is essential in children to confirm the presence of an ischemic stroke and
to rule out a hemorrhagic stroke, but each modality has benefits and disadvantages
to consider.
& The authors offer thrombophilia testing to patients with childhood-onset stroke,
particularly when other risk factors are not identified and after discussing risks and
benefits of such testing with the patient and family. Testing is typically done acutely and
repeated at 3 months if specific abnormalities are identified.
& Since the recurrence risk formost neonatal arterial ischemic stroke appears to be low,
neonates are not typically treated with antithrombotic agents.
& In children who sustained a stroke after the neonatal period, treatment to prevent recurrent
stroke varies with the associated condition.
& Secondary stroke prevention in young adults involves encouraging the same lifestyle
changes as in older adults: avoiding smoking, increasing physical activity, making
dietary modifications to achieve weight loss, and avoiding recreational drugs,
especially cocaine. Aggressive treatment of hypertension, dyslipidemias, and diabetes
mellitus are also obvious targets. These secondary prevention measures are particularly
important in young adults because of their longer potential lifespan and the significant
risk of recurring vascular events over that longer lifespan.
& Similar to neonates, few studies of long-term outcome after stroke have been conducted in
older children.
& In a prospective cohort study of 7 years of follow-up data for children after a stroke,
mortality was 14% overall, and 6% had a recurrent stroke. Fifty-five percent had a
hemiparesis, although most (49% of those affected) were mild in severity, and
21% had speech impairments, but again, most (59% of those affected) were mild.
Parents reported that 15% of the children had some type of psychological or
psychiatric disorder.
& Interest is growing in the outcome of young adults who have had stroke, but the number of
studies with long-term follow-up is relatively small.
& A Dutch study of outcomes 9 years after the incident stroke found that 10% of young
adult ischemic stroke survivors were functioning at a modified Rankin Scale score of
3 to 5 and 27% were dead. As a group, stroke survivors performed worse than controls in
objective measures of processing speed, working and immediate memory, delayed
memory, attention, and executive function. Depressive symptoms were present in 16%
of men and 23% of women, compared with 6% in controls. Anxiety was present in 15% of
men and 29% of women, compared with 12% of controls.

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Management of Unruptured Intracranial
Aneurysms and Cerebrovascular
Malformations
Kelly D. Flemming, MD; Giuseppe Lanzino, MD. Continuum (Minneap Minn).
February 2017;23(1 Cerebrovascular Disease):181Y210.

Abstract
Purpose of Review:
Unruptured intracranial aneurysms and vascular malformations are detected more frequently
because of the increased use and availability of brain imaging. Management of these entities
requires knowledge of which patients are at high risk for hemorrhage and what treatment options
are available. This article summarizes the epidemiology, natural history, and management
strategies for unruptured intracranial aneurysms, arteriovenous malformations, cavernous
malformations, developmental venous anomalies, and capillary telangiectasias.
Recent Findings:
Pooled cohort studies and meta-analyses have improved the ability to predict hemorrhage for
each vascular abnormality. Scores and tools have been developed to aid the practitioner in
predicting hemorrhage risk for unruptured intracranial aneurysms. Advances in endovascular
techniques for unruptured intracranial aneurysms have improved the ability to treat difficult
wide-necked aneurysms.
Summary:
Unruptured intracranial aneurysms are a common incidental finding. The PHASES (population,
hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage from another aneurysm,
site of aneurysm) score and Unruptured Intracranial Aneurysm Treatment Score may be
useful tools for predicting natural history and treatment recommendations. The overall risk of
hemorrhage for both arteriovenous malformations and cavernous malformations is about 2%
to 4% per year. With both of these entities, prior hemorrhage predicts future hemorrhage. In
addition, other select patient and radiologic factors influence risk of hemorrhage. The risk of future
hemorrhage should be compared to the risk of treatment. Developmental venous anomalies and
capillary telangiectasias are largely benign entities and rarely symptomatic.

Key Points
& Rare disorders such as polycystic kidney disease and coarctation of the aorta may
predispose patients to unruptured intracranial aneurysm formation.
& Unruptured intracranial aneurysms are more common in women, tobacco users, and
patients with hypertension.
& In the United States, the prevalence of unruptured intracranial aneurysms is
3000 per 100,000, and the prevalence of subarachnoid hemorrhage is 10 per 100,000.
Thus, themajority of unruptured intracranial aneurysms do not rupture.

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 & Risk factors for unruptured intracranial aneurysms include size and location (posterior
circulation, posterior communicating artery, anterior communicating artery), growth,
and symptoms not due to rupture.
& Screening for unruptured intracranial aneurysms is recommended for those with two
or more first-degree relatives with unruptured intracranial aneurysms or aneurysmal
subarachnoid hemorrhages.
& The natural history of the unruptured intracranial aneurysm must be compared to the
individual treatment risk to make a determination on whether treatment is recommended.
The Unruptured Intracranial Aneurysm Treatment Score may aid the practitioner.
& Surveillance magnetic resonance angiography or CT angiography is recommended for
patients with an unruptured intracranial aneurysm undergoing observation.
& Arteriovenous malformations commonly present with hemorrhage in the second through
fourth decades.
& Prior hemorrhage increases the risk for recurrent hemorrhage in patients with
arteriovenous malformation.
& Treatment for arteriovenous malformation depends on patient factors (presence of
symptoms/hemorrhage, age of patient, comorbidities) and angiographic factors
(location of feeding and draining vessels, eloquence of the brain, presence of feeding
artery or nidal aneurysms, size of nidus).
& Options for treating an arteriovenous malformation to reduce hemorrhage risk or seizures
include surgery or stereotactic radiosurgery. Endovascular embolization is a common
adjunctive procedure.
& The Spetzler-Martin arteriovenous malformation grading system can aid in determining
surgical risk.
& Successful surgery will immediately reduce the risk for further hemorrhage; however,
stereotactic radiosurgery results in obliteration of the arteriovenous malformation only
after 2 to 3 years.
& Approximately 30% of patients with cavernous malformations will have a concomitant
developmental venous anomaly.
& Approximately 80% of cavernous malformations are acquired sporadic lesions and 20%
are familial (autosomal dominant inheritance).
& The risk of hemorrhage from a cavernous malformation is approximately 1% to 4% per year.
Prior hemorrhage and brainstem location increase the risk of hemorrhage in patients
with a cavernous malformation.
& Surgical treatment is generally indicated in patients with a symptomatic cavernous
malformation in a noneloquent area to reduce the risk of hemorrhage or seizure due to
the cavernous malformation.
& In patients with cavernous malformations in eloquent regions, surgery may be considered
for a patient who has repeated hemorrhages and increasing morbidity.
& Developmental venous anomalies are congenital vascular anomalies that drain
normal brain.
& Developmental venous anomalies commonly co-occur with cavernous malformations.
& Developmental venous anomalies rarely cause symptoms, and surveillance imaging
is generally not indicated.
& Capillary telangiectasias are rare congenital vascular malformations that rarely
cause symptoms.
& Large capillary telangiectasias may require the addition of hemosiderin-sensitive
MRI sequences and follow-up MRI to distinguish them from neoplasms.

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Inherited and Uncommon Causes
of Stroke
Jennifer Juhl Majersik, MD, MS. Continuum (Minneap Minn). February 2017;
23(1 Cerebrovascular Disease):211Y237.

Abstract
Purpose of Review:
This article is a practical guide to identifying uncommon causes of stroke and offers guidance
for evaluation and management, even when large controlled trials are lacking in these rarer
forms of stroke.
Recent Findings:
Fabry disease causes early-onset stroke, particularly of the vertebrobasilar system; enzyme
replacement therapy should be considered in affected patients. Cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), often misdiagnosed
as multiple sclerosis, causes migraines, early-onset lacunar strokes, and dementia. Moyamoya
disease can cause either ischemic or hemorrhagic stroke; revascularization is recommended in
some patients. Cerebral amyloid angiopathy causes both microhemorrhages and
macrohemorrhages, resulting in typical stroke symptoms and progressive dementia. Pregnancy
raises the risk of both ischemic and hemorrhagic stroke, particularly in women with preeclampsia/
eclampsia. Pregnant women are also at risk for posterior reversible encephalopathy syndrome
(PRES), reversible cerebral vasoconstriction syndrome, and cerebral venous sinus thrombosis.
Experts recommend that pregnant women with acute ischemic stroke not be systematically denied
the potential benefits of IV recombinant tissue plasminogen activator.
Summary:
Neurologists should become familiar with these uncommon causes of stroke to provide future risk
assessment and family counseling and to implement appropriate treatment plans to prevent
recurrence.

Key Points
& Fabry disease is an X-linked lysosomal storage disease with neurovascular manifestations
of early-onset ischemic stroke, often in the posterior circulation; dilatation of the
vertebrobasilar vessels up to extensive dolichoectasia; and leukoaraiosis.
& Fabry disease is a multisystemic disorder, causing acroparesthesia, angiokeratomas,
corneal dystrophy, hypohidrosis, renal impairment, cardiac conduction disturbances,
and cardiomyopathy.
& Fabry disease is most easily diagnosed by a readily available and standardized enzymatic
test that measures leukocyte >-galactosidase A activity. However, women may require
molecular genetic testing or skin biopsy because of normal to low enzymatic testing.
& Recombinant >-galactosidase A is available as enzyme replacement therapy for Fabry
disease and is recommended by experts for all patients with Fabry disease with affected

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 kidneys, heart, or brain. Enzyme replacement therapy has been shown to reduce disease
progression but should be managed by a multidisciplinary team.
& Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) is an autosomal dominant neurovascular disorder
that causes ischemic subcortical stroke, migraine with aura, depression and apathy,
and dementia.
& Young-onset lacunar stroke in a patient without vascular risk factors and a personal
history of migraine should prompt consideration of CADASIL, particularly in patients
with a family history of stroke or dementia. However, neurologists should consider the
diagnosis in anyone with characteristic MRI findings of white matter hyperintensities
in the anterior temporal poles and external capsules.
& T2 hyperintensities involving the white matter of the anterior temporal poles are seen in
90% of patients with CADASIL.
& Molecular genetic testing is the gold standard for the diagnosis of CADASIL, with
100% specificity and nearly 100% sensitivity when screening the 23 exons for a mutation
leading to an odd number of cysteine residues within an epidermal growth factor repeat.
For patients in whom a high suspicion of CADASIL exists but who have a negative genetic
test, skin biopsy may reveal granular osmophilic material in the vascular basal lamina,
which is highly diagnostic of CADASIL.
& Although no treatment specific to CADASIL exists, strict control of hypertension in
patients with CADASIL may prevent or delay onset of functional disability.
& Patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL) experience early-onset lacunar stroke (onset in the
third decade) in the absence of hypertension, progressive dementia (onset in the third
through fifth decades), premature alopecia (onset in the teen years), and spondylosis
deformans (disk degeneration) (onset in the second and third decades).
& Retinal vasculopathy with cerebral leukodystrophy, a new term for what were previously
described as three separate disorders (cerebroretinal vasculopathy syndrome; hereditary
vascular retinopathy; and hereditary endotheliopathy, retinopathy, nephropathy, and
stroke), is an autosomal dominant disorder caused by mutations in the TREX1 gene. These
syndromes cause vision loss, stroke, and dementia beginning in middle age, with death
occurring in most patients 5 to 10 years later.
& Mutations in the COL4A1 gene, a gene encoding the type IV collagen alpha 1 chain,
cause an autosomal dominant early-onset cerebral small vessel disease that manifests in
the fourth decade of life as diffuse leukoaraiosis (without the anterior temporal
involvement that is seen in CADASIL), microbleeds, and lacunar stroke. Additionally,
patients are prone to subcortical intracerebral hemorrhage, particularly after mild
environmental stresses such as vaginal birth, sports activities, anticoagulant use, and
head trauma.
& Moyamoya disease is a nonatherosclerotic, noninflammatory, progressive vasculopathy
that causes narrowing of the distal internal carotid artery and development of small
collateral vessels at the base of the brain that look like a puff of smoke on an angiogram.
It is typically bilateral but can be unilateral and include the posterior circulation.
& Moyamoya disease causes ischemic stroke in children and adults of European/North
American ancestry in a watershed distribution and intracerebral hemorrhage or infarct in
East Asian adults.
& Screening of asymptomatic family members of patients with moyamoya disease may
identify more affected members and a familial cause.
& Diseases of small vessels in the brain clinically cause both lacunar strokes and
intraparenchymal hemorrhage and, on imaging, white matter hyperintensities,

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 microbleeds, and atrophy. Very little evidenced-based treatment exists for small vessel
disease, with treatment complicated by the need to prevent both hemorrhage and infarct.
& Cerebral amyloid angiopathy is characterized histologically by amyloid-A fibril
deposition in the media of primarily small to medium blood vessels.
& Magnetic resonanceYbased imaging is important after transient stereotypic symptoms
in the elderly to look for cortical superficial siderosis or convexity subarachnoid
hemorrhage related to cerebral amyloid angiopathy amyloid spells.
& To prevent recurrent intracerebral hemorrhage, most experts withhold anticoagulation
and statins in patients with cerebral amyloid angiopathyYrelated intracerebral
hemorrhage.
& New-onset seizures in a woman in the latter half of pregnancy should not be assumed
to be eclampsia but should prompt a complete evaluation for noneclamptic causes.
& MRI is considered safe in pregnancy; however, gadolinium is considered contraindicated
for all but the rarest of circumstances in pregnancy. Thus vessel imaging in the patient who
is pregnant is typically performed by CT angiogram or noncontrast time-of-flight
magnetic resonance angiography.
& Despite a lack of randomized trial data, expert opinion suggests that IV recombinant tissue
plasminogen activator should not be withheld from a pregnant woman who is otherwise
eligible for the therapy.
& Preeclampsia and eclampsia are now established risk factors for future vascular
disease, including a doubling of the 10-year risk of stroke. Additional vascular risk
factors should be aggressively treated in women with a history of preeclampsia
or eclampsia.

Stroke Rehabilitation
Samir R. Belagaje, MD. Continuum (Minneap Minn). February 2017;23(1 Cerebrovascular
Disease):238Y253.

Abstract
Purpose of Review:
Rehabilitation is an important aspect of the continuum of care in stroke. With advances in the
acute treatment of stroke, more patients will survive stroke with varying degrees of disability.
Research in the past decade has expanded our understanding of the mechanisms underlying
stroke recovery and has led to the development of new treatment modalities. This article reviews
and summarizes the key concepts related to poststroke recovery.

Recent Findings:
Good data now exist by which one can predict recovery, especially motor recovery, very
soon after stroke onset. Recent trials have not demonstrated a clear benefit associated with
very early initiation of rehabilitative therapy after stroke in terms of improvement in
poststroke outcomes. However, growing evidence suggests that shorter and more frequent
sessions of therapy can be safely started in the first 24 to 48 hours after a stroke. The optimal
amount or dose of therapy for stroke remains undetermined, as more intensive treatments
have not been associated with better outcomes compared to standard intensities of therapy.
Poststroke depression adversely affects recovery across a variety of measures and is an

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important target for therapy. Additionally, the use of selective serotonin reuptake inhibitors
(SSRIs) appears to benefit motor recovery through pleiotropic mechanisms beyond
their antidepressant effect. Other pharmacologic approaches also appear to have a benefit
in stroke rehabilitation.

Summary:
A comprehensive rehabilitation programis essential to optimize poststroke outcomes.
Rehabilitation is a process that uses three major principles of recovery: adaptation, restitution, and
neuroplasticity. Based on these principles, multiple different approaches, both pharmacologic
and nonpharmacologic, exist to enhance rehabilitation. In addition to neurologists, a variety of
health care professionals are involved in stroke rehabilitation. Successful rehabilitation involves
understanding the natural history of stroke recovery and amultidisciplinary approach with
judicious use of resources to identify and treat common poststroke sequelae.

Key Points
& Rehabilitation is a process of stroke care that reduces disability and improves
participation in therapy. Recovery is defined as improvements across a variety
of outcomes.
& The human brain recovers from a stroke through adaptation, regeneration, and
neuroplasticity.
& Neuroplasticity is driven by principles of task specificity, repetition, and challenge.
& Different functions recover differently. Swallowing, facial movement, and gait tend
to have better recovery than language and dominant hand function.
& Upper extremity motor recovery can be predicted very early at the bedside through
the presence/absence of voluntary finger extension and shoulder abduction.
& The generally accepted practice for stroke rehabilitation at this time involves using less
intense therapy in the acute/hyperacute setting and increasing the intensity for those
who can tolerate it in the rehabilitation/outpatient setting.
& Based on current guidelines, inpatient rehabilitation facilities are appropriate
posthospital discharge locations for patients who are able to actively participate in
two disciplines of therapy for 3 hours per day, have medical issues requiring physician
supervision, and have a reasonable expectation of resuming community living.
& Constraint-induced movement therapy is an alternative motor rehabilitation therapy
technique for the upper extremity in which the unaffected extremity is constrained
with a mitt, thereby forcing use of the affected hand.
& Melodic intonation therapy is an alternative therapy technique that has been shown to
enhance recovery of poststroke aphasia. It involves the use of musical elements,
including melody and rhythm, to improve language production.
& When patients with stroke are unable to return home following their acute
hospitalization, discharge to an inpatient rehabilitation facility will likely result in a
better outcome.
& Caution and careful consideration must be used when prescribing antiepileptic
medications and antihistaminergic medications as they may adversely affect
stroke recovery.
& Shoulder pain is a common sequela after a stroke and may be caused by a variety
of conditions.

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 & Depression is a common sequela after a stroke and adversely affects outcomes.
Medications such as selective serotonin reuptake inhibitors can be effectively used in
the treatment of poststroke depression.
& Spasticity adversely affects poststroke outcomes.
& Botulinum toxin and intrathecal baclofen are the preferred treatments of spasticity in
patients with chronic stroke.
& Studies show that the severity of physical and cognitive impairments is not associated
with a stroke survivor’s ability to return to work. More important factors include age,
educational level, and prestroke professional status.
& A formal driving assessment is helpful in determining a stroke survivor’s ability to drive.

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 Ethical and Medicolegal Issues

Discussing
Address correspondence to
Dr David Y. Hwang, Division
of Neurocritical Care and
Emergency Neurology,
Department of Neurology, Yale
School of Medicine, PO Box
208018, New Haven, CT 06520,
Life-sustaining Therapy
[email protected].
Relationship Disclosure:
Dr Hwang has received
With Surrogate
personal compensation for
speaking engagements for the
Mayo Clinic and The
Pennsylvania State University
Decision Makers
and research/grant support David Y. Hwang, MD
from the American Brain
Foundation, the Apple Pickers
Foundation, the Neurocritical
Care Society, and the National ABSTRACT
Institute on Aging, via its Loan Clinicians caring for patients with severe stroke in intensive care units often grapple with
Repayment Program.
Unlabeled Use of
requests from surrogate decision makers for life-prolonging treatment that members of
Products/Investigational the care team may believe to be futile. An example is a surrogate decision maker’s request
Use Disclosure: Dr Hwang to place a tracheostomy and feeding tube in a patient who, in the clinical judgment
reports no disclosure.
of the neurocritical care team, is very unlikely to recover interactive capacity. This article
B 2017 American Academy
of Neurology. presents a case, discusses definitions of medical futility, and summarizes recommended
steps for mediating conflict regarding potentially inappropriate treatment.

Continuum (Minneap Minn) 2017;23(1):254–258.

Case
A 46-year-old man with an extensive past medical history, including
insulin-dependent diabetes mellitus, chronic kidney disease, severe coronary
artery disease status postYcoronary artery bypass grafting, peripheral
vascular disease, and prior hypertensive cerebellar hemorrhage that required
decompressive craniectomy 10 years previously, sustained a devastating
occlusion of the basilar artery that could not be revascularized. He was
admitted to the neurocritical care unit in a coma and on mechanical
ventilation, with an MRI of the brain revealing restricted diffusion not only in
the majority of the midbrain and bilateral posterior cerebral artery vascular
territories but also in scattered areas of both middle cerebral artery
territories, indicative of an embolic shower likely of cardioembolic origin.
The neurocritical care team held several meetings with the patient’s
wife, during which the team told her that the patient’s prognosis for a
meaningful neurologic recovery was poor and introduced options for
limitations of life-sustaining therapy. The patient’s wife repeatedly told
the neurocritical care unit team that she wanted ‘‘everything done’’ and
was unwilling even to consider a do-not-resuscitate order. The patient had
no advance directive.
During the second week of hospitalization, the patient developed
worsening acute renal failure and gradually became more oliguric. A
consulting nephrologist told the neurocritical care team he was unwilling
to offer dialysis to the patient because his medical situation was ‘‘futile.’’
The neurocritical care team had further meetings with the patient’s
wife, who not only repeated her desire to have ‘‘everything done’’ but
Continued on page 255

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 Continued from page 254
demanded that dialysis be initiated if the patient became anuric.
She also demanded that a surgical consult be called so that the patient
could undergo tracheostomy and permanent feeding tube placement.
She stated that in prior situations doctors had been pessimistic about her
husband’s medical condition and ‘‘he proved them wrong.’’

DISCUSSION
Clinicians who care for patients with severe stroke in neurocritical care units will
inevitably encounter surrogate decision makers who request aggressive care
that the clinicians believe should not be offered.1 An awareness of professional
consensus for best practices in such situations is critical for an ethical resolu-
tion to the conflict. The American Thoracic Society recently released a statement
of updated recommendations for clinicians involved in such disputes.2 This
policy statement, which was released after input and approval from the American
Association for Critical Care Nurses (AACN), the American College of Chest
Physicians (ACCP), the European Society for Intensive Care Medicine (ESICM),
and the Society of Critical Care Medicine (SCCM), is the framework for the
discussion that follows.

Definitions
Futile care has had multiple formal definitions in the medical literature, rang-
ing from interventions for which ‘‘reasoning and experience indicate that the
intervention[s] would be highly unlikely to result in meaningful survival,’’3 to
those that ‘‘will not accomplish their intended goal, ie, treatments that have no
beneficial physiologic effect.’’4 This case is an example of the first definition,
which some may label as quality-of-life futility. A concrete example of the second
narrower definition of futility would be a situation in which the wife in this case
requests that the medical team administer antibiotics to cure her husband of
his stroke. Drawing a distinction between the two definitions is important, as it
is generally agreed that clinicians should neither offer nor provide strictly
futile care under any circumstances. For situations in which medical interventions
requested by a surrogate may indeed prolong a patient’s life but which clinicians
have ethical concerns in providing, the American Thoracic Society guidelines
recommend using the term potentially inappropriate treatment. This phrase
not only draws a distinction between these situations and strict futility but also
acknowledges that such judgments from clinicians are indeed preliminary and may
be subject to an institutional review process.2

The Need for Fair Process

In providing justification for their recommendations, the American Thoracic Society
guidelines writing committee discusses the ethical issues that arise when treat-
ing clinicians drive goals-of-care decisions unilaterally in situations in which they
perceive that surrogates are requesting potentially inappropriate treatment. The
literature documents wide variability among hospitals and clinicians in the care
provided to patients, such as the one described in this case, who have suffered a
severe stroke and require feeding tube placement.5 Some may argue that a
paternalistic approach to goals-of-care discussions may lighten the significant

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

 Discussing Life-sustaining Therapy

emotional and psychological decision-making burden the distressed surrogate is

carrying. However, allowing clinicians to make unilateral decisions about life
support may ultimately encourage some clinicians to circumvent the often
difficult and time-consuming process of attempting to find common ground
with surrogates when conflict exists.6 By the very nature of their acute brain
injury, patients with severe stroke who are intubated in neurocritical care units are
a vulnerable group, as both they and their family members are often not in situations
where they can simply select medical care providers who share their perspectives on
end-of-life care. A process-based approach to resolving such ethical conflicts, facilitated
by an interdisciplinary hospital committee, allows multiple perspectives to weigh in
and ideally promotes transparency of decision making.2

Steps for Conflict Resolution

In a situation in which extensive discussion between the stroke patient’s
surrogate and the primary treatment team fails to resolve an impasse about legal
but ultimately futile treatment, the American Thoracic Surgery guidelines
recommend the following practical steps2:
1. Seek the help of consultants skilled in negotiating agreements and mediating
conflict. For example, at many hospitals, the palliative care service may be
able to serve in this role and facilitate finding common ground between
clinicians and surrogates.
2. Give formal notice to the surrogate, both in writing and verbally, that a
process has been initiated for conflict resolution. Make sure the surrogate
understands that he or she is welcome to participate in this process.
3. Obtain a second medical opinion from an expert in the patient’s condition that
addresses both the patient’s prognosis and the primary clinician’s opinion
regarding the inappropriateness of the requested treatment.
4. Have the situation reviewed by an interdisciplinary hospital ethics committee
to assess (after input from both the primary team and patient’s surrogate)
the extent to which broad consensus exists from various perspectives that a
requested treatment is indeed inappropriate.
5. For situations in which the hospital ethics committee rules against the surrogate
but the surrogate still wishes to request the treatment, offer a good-faith
opportunity to explore transfer of the patient to another institution.
6. For patients who cannot be transferred, let surrogates know that they have
a right to pursue an independent appeal through judicial processes, to
be initiated within a reasonable defined time frame (eg, 2 business days).
7. Withhold or withdraw the potentially inappropriate treatment if the hospital
ethics committee agrees with the clinician’s opinion, the patient cannot
be transferred, and the surrogate either does not seek a court opinion or
the court agrees with the hospital ethics committee.

Time Pressure in Decision Making

While the approach outlined may apply when a clinician has an objection to a
request regarding tracheostomy and feeding tube placement for a stable patient
with severe stroke, clinical situations may arise in neurocritical care units in which
potentially inappropriate treatment is requested but completing all steps of the
recommended process is truly not practical. For example, in the case presented,

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the decision to initiate or withhold dialysis may become urgent to keep the
patient alive, despite the primary team’s and nephrologist’s attempts to keep the
patient stable by less invasive means. In such situations, clinicians should carefully
assess their level of certainty regarding whether the requested treatment is
indeed outside of the boundaries of accepted practice and engage other clinicians
to ensure consensus as time allows. Equally important as acknowledging a
willingness to have the withholding of potentially inappropriate treatment re-
viewed in court is for a clinician to self-assess whether factors such as sex, race, or
socioeconomic status are affecting the decision. Reasons for treatment refusal
should be clearly explained to surrogates.2

CONCLUSION
The majority of deaths in neurocritical care units involve decisions to limit life-
sustaining therapy and pursue comfort care.7 While the steps outlined may seem
straightforward at face value, the frequency at which surrogate requests for poten-
tially inappropriate treatment occur is a key reason that critical care organizations
such as the American Thoracic Society and others have focused on standardizing
the professional approach to such situations. Whenever possible, ‘‘clinicians should
conceptualize their judgments that requested treatments are inappropriate as
preliminary claims in need of confirmation, rather than conclusions to be
immediately acted on.’’2 An early introduction of palliative care principles into the
care of hospitalized patients with severe stroke may help avoid such situations of
conflict between care teams and patient surrogates.8
The patient described in the case died of a cardiac arrest before a formal
hospital ethics committee consult was called. According to his wife’s wishes, he
underwent a brief resuscitation attempt before being declared dead, an out-
come that, in and of itself, many clinicians may question from an ethical
perspective. This case thus also highlights the practical challenges of balancing a
fair, protocolized process for conflict resolution with the reality of the critically
ill patient’s condition. Time windows for decision making in the neurocritical
care unit are often brief, and unpredictable factors may affect the extent to
which clinicians can participate in processes of external review regarding the
appropriateness of treatments. With this caveat in mind, clinicians faced with
treatment requests from patients’ families that are potentially inappropriate
should nonetheless strive to avoid unilateral decisions that may be susceptible
to bias and follow a stepwise transparent approach to ensure that multiple
viewpoints are considered whenever possible.

REFERENCES
1. Cai X, Robinson J, Muehlschlegel S, et al. Patient preferences and surrogate decision making in
neuroscience intensive care units. Neurocrit Care 2015;23(1):131Y141. doi:10.1007/s12028-015-0149-2.
2. Bosslet GT, Pope TM, Rubenfeld GD, et al. An official ATS/AACN/ACCP/ESICM/SCCM policy
statement: responding to requests for potentially inappropriate treatments in intensive care units.
Am J Respir Crit Care Med 2015;191(11):1318Y1330. doi:10.1164/rccm.201505-0924ST.
3. American Thoracic Society. Withholding and withdrawing life-sustaining therapy. Ann Intern Med
1991;115(6):478Y485. doi:10.7326/0003-4819-115-6-478.
4. Consensus statement of the Society of Critical Care Medicine’s Ethics Committee regarding futile
and other possibly inadvisable treatments. Crit Care Med 1997;25(5):887Y891.
5. George BP, Kelly AG, Schneider EB, Holloway RG. Current practices in feeding tube placement for US
acute ischemic stroke inpatients. Neurology 2014;83(10):874Y882. doi:10.1212/WNL.0000000000000764.

Continuum (Minneap Minn) 2017;23(1):254–258 ContinuumJournal.com 257

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

 Discussing Life-sustaining Therapy

6. Hwang DY, Bernat JL. Neurologists and end-of-life decision-making: the role of ‘‘protective
paternalism.’’ Neurol Clin Pract 2015;5(1):6Y8. doi:10.1212/CPJ.0000000000000096.
7. Diringer MN, Edwards DF, Aiyagari V, Hollingsworth H. Factors associated with withdrawal of mechanical
ventilation in a neurology/neurosurgery intensive care unit. Crit Care Med 2001;29(9):1792Y1797.
8. Holloway RG, Arnold RM, Creutzfeldt CJ, et al. Palliative and end-of-life care in stroke: a
statement for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke 2014;45(6):1887Y1916. doi:10.1161/STR.0000000000000015.

258 ContinuumJournal.com February 2017

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

 Practice Issues

Remote Evaluation of
Address correspondence to
Dr Bart M. Demaerschalk,
Mayo Clinic Hospital,
5777 E Mayo Blvd,

the Patient With Phoenix, AZ 85054,

demaerschalk.
[email protected].

Acute Stroke Relationship Disclosure:

Dr Demaerschalk has
received personal compensation
as editor-in-chief of The
Bart M. Demaerschalk, MD, MSc, FAHA, FRCPC Neurologist and has received
publishing royalties from
Springer Publishing Company
and John Wiley & Sons, Inc.
ABSTRACT Unlabeled Use
of Products/Investigational
This article describes advances related to the successful remote evaluation of the Use Disclosure:
patient with acute stroke. Telestroke is a connected care approach that brings Dr Demaerschalk reports
expert stroke care to remote, neurologically underserved urban or rural locations. no disclosure.
Recent findings reveal strong evidence showing that telestroke is equivalent to in- * 2017 American Academy
of Neurology.
person care. Time is critical in treating patients with acute stroke, and telestroke
networks must assure that technology improvesVnot delaysVdelivery of care. The
stroke center and the spoke site must work collaboratively to develop and institute
protocols and policies to ensure that eligible patients are identified, assessed, and
treated swiftly. Adverse outcomes, such as intracranial hemorrhage and mortality,
must be monitored to assess safety metrics. An additional goal of telestroke
networks is to screen patients who might be candidates for potential endovascular
or neurosurgical therapy and transfer these patients for these procedures.

Continuum (Minneap Minn) 2017;23(1):259–267.

INTRODUCTION
Telestroke is an application of telemedicine that brings the expertise and ex-
perience of vascular neurologists and other stroke experts directly to hospitals that
are neurologically underserved. This article presents the rationale and evidence
supporting the use of telemedicine for the remote evaluation of patients with acute
stroke and discusses the practical aspects of a telemedicine evaluation.

Case
A 75-year-old woman living in a rural area was witnessed by her family to
have the sudden onset of dysarthria and left-sided weakness, which
persisted. She was transported by emergency medical services to her local
acute strokeYready community hospital within 60 minutes of the onset of
symptoms, where she was evaluated by an emergency department
physician. The hospital had a telestroke service agreement with a tertiary
care hospital; the emergency department physician initiated the system,
and a telestroke consultation was provided by a vascular neurologist at a
comprehensive stroke center hospital. A video-audio link was established
over the Internet, and a virtual face-to-face consult was performed by the
neurologist with the help of an emergency department nurse who assisted
in obtaining the history and performed the National Institutes of Health
Stroke Scale examination under the supervision of the neurologist.
Continued on page 260

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 Remote Stroke Evaluation

Continued from page 259

After performing a 15-minute evaluation, the vascular neurologist
conferred with the emergency department physician. Together they
reviewed the neurovascular imaging and no intracranial hemorrhage or
early ischemic changes were noted, but an occlusion of the right middle
cerebral artery was identified. They determined that the patient was a
candidate for IV thrombolytic treatment, which was initiated immediately
in the emergency department. The patient was then transferred by
helicopter to the comprehensive stroke center hospital for consideration
of endovascular treatment and ongoing care. The neurologist dictated a
full consultation note, which was available in the medical records system
of both the community spoke hospital and the destination hospital. The
neurologist communicated with the destination hospital transfer center to
coordinate hand-off communication and preparation among vascular
neurology, vascular neurosurgery, neuroradiology, neurocritical care, and
nursing before the patient arrived.

DISCUSSION
Levine and Gorman first suggested the term telestroke in 1999 to describe the
use of telemedicine for patients with stroke.1 In the earliest experiences with IV
recombinant tissue plasminogen activator (rtPA) treatment for acute ischemic
stroke, complication rates were highest among hospitals inexperienced with
stroke.2 Telemedicine for stroke was developed to assist as a neurologic con-
sultative modality for hospitals without neurologic expertise on-site.3 Studies
revealed that IV rtPA protocols were more rigorously applied, stroke mimics were
more accurately identified, brain scans were more regularly assessed in a timely
fashion, and thrombolysis rates in eligible patients were higher when telestroke
was adopted in stroke systems of care.4Y6 Telestroke is designed to provide any
patient who manifests symptoms and signs consistent with acute stroke access to
an expert and swift clinical evaluation, a review of diagnostic tests, a diagnosis,
emergency treatment recommendations, and disposition decision making. A
telestroke consultation is best performed in collaboration with bedside
physicians and nurses, regardless of hospital location, emergency department
versus other unit, rural or urban community, time of day, and proximity to the
nearest stroke center.7 Because IV rtPA and endovascular treatments each have
narrow time windows of effectiveness, stroke is a time-sensitive emergency. The
availability of a range of effective treatments, the paucity of stroke experts in
emergency departments, the opportunity to improve access and quality of care,
the narrow window of treatment efficacy, the resources required for air and ground
ambulance transportation, and the advancements in connected care technology
have all contributed to optimal conditions for telestroke.8

Telestroke Networks
Most telestroke networks are fashioned either as a distributed model or as a hub-
and-spoke model. In the typical distributive model, telestroke consultations are
delivered to hospitals from groups of providers who may be located at multiple
distant sites on a contractual basis. The providers typically have no other affiliation
with the telestroke hospital. If a patient requires a higher level of care following the

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telestroke evaluation, a transfer to a nearby stroke center is facilitated. In a hub-
and-spoke network, the stroke center hub is frequently an academic medical
center and provides telestroke services to distant spoke sites within its geographic
region. The stroke physicians are credentialed at the spoke hospitals. Whenever
transfers are indicated, the hub stroke center typically receives the patient from the
spoke hospital and can provide continuity of care, having already observed the
patient virtually.
Telestroke professionals should be licensed and credentialed with their
respective regulatory, licensing, and accrediting agencies, with consideration to
legislative requirements of the site where the patient and spoke site health care
professional are located. This consideration should include all federal and state
regulations. Credentialing by proxy processes should be adopted to minimize
administrative burden. State licensure and regulation rules are undergoing national
debate. The American Telemedicine Association (americantelemed.org), the
Federation of State Medical Boards ( fsmb.org), and the Robert J. Waters Center
for Telehealth & e-Health Law (ctel.org) provide helpful resources for locating the
most up-to-date state requirements for practicing telemedicine.

Telestroke and Stroke Systems of Care

In 2009, the American Heart Association and American Stroke Association pub-
lished a pair of articles that reviewed the available evidence for telemedicine within
stroke systems of care and made recommendations for telestroke implementa-
tion.9,10 The 2009 policy statement included guidelines with 14 recommendations,
the majority of which were based on Class I evidence.9 Key recommendations
expressed the value of telestroke to support the assessment of acute stroke
severity via the National Institutes of Health Stroke Scale (NIHSS), its equivalence
to that of a bedside evaluation, the review of brain CT scans by remotely located
stroke specialists in the context of thrombolysis eligibility decision making, and
urgent decisions about thrombolysis eligibility during telestroke. As expressed
in current stroke guidelines, telestroke remains standard care in hospitals that
cannot provide an in-hospital acute stroke team.11 Practice Table 1 9Y13 lists
current guidelines for telestroke practice.
In some instances, local hospitals are capable of administering IV rtPA with the
audio-video support of a vascular neurologist but are not capable of the obligatory
subsequent stroke care. Disposition decision making is an integral function of a
telestroke network. In hospitals without critical care units or on-site physicians and
nurses trained in stroke treatment, the IV rtPA is usually initiated on-site, but pa-
tients are transported to a nearby stroke center for subsequent care.14 The out-
comes of patients with stroke who have remote supervision of thrombolysis and
are subsequently transferred to a stroke center are comparable to those of pa-
tients with stroke who are directly admitted to a stroke center.8
Five recently published randomized trials have demonstrated the benefit of
endovascular treatment of stroke.15 Successful endovascular care requires the
resources, expertise, and experience housed only in comprehensive stroke cen-
ters. Telemedicine can serve to effectively triage patients with ischemic stroke
with proximal intracranial arterial occlusion who may benefit from transport to a
comprehensive stroke center to undergo endovascular treatment. Patients who
were transported from telemedicine-linked hospitals had a shorter time of

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 Remote Stroke Evaluation

PRACTICE TABLE 1 Guidelines and Recommendations Pertaining

to Telestroke Practice

b Wechsler LR, Demaerschalk BM, Schwamm LH, et al. Telemedicine quality

and outcomes in stroke: a scientific statement from the American Heart
Association/American Stroke Association [published online ahead of print
November 3, 2016]. Stroke. doi:10.1161/STR.0000000000000114.12
b Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale
for the inclusion and exclusion criteria for intravenous alteplase in acute
ischemic stroke: a statement for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke
2016;47(2):581Y641. doi:10.1161/STR.0000000000000086.13
b Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early
management of patients with acute ischemic stroke: a guideline for
healthcare professionals from the American Heart Association/American
Stroke Association. Stroke 2013;44(3):870Y947. doi:10.1161/
STR.0b013e318284056a.11
b Schwamm LH, Audebert HJ, Amarenco P, et al. Recommendations
for the implementation of telemedicine within stroke systems of care:
a policy statement from the American Heart Association. Stroke
2009;40(7):2635Y2660. doi:10.1161/STROKEAHA.109.192361.9
b Schwamm LH, Holloway RG, Amarenco P, et al. A review of the evidence
for the use of telemedicine within stroke systems of care: a scientific
statement from the American Heart Association/American Stroke
Association. Stroke 2009;40(7):2616Y2634.
doi:10.1161/STROKEAHA.109.192360.10

symptom onset to groin puncture and had superior outcomes compared to

patients who were transported from hospitals lacking a telemedicine connection.16
Likewise, telestroke networks serve to triage patients with malignant hemispheric
ischemic stroke for consideration of decompressive hemicraniectomy and to
triage patients with intracerebral hemorrhage for consideration of craniotomy
and hematoma evacuation. Despite limited reimbursement from payers, telestroke
networks are cost-effective, even for severe stroke, from the perspective of both
society and the hospital.17Y20 The American Telemedicine Association website lists
current states with parity laws for private insurance coverage for telemedicine,
and the list is updated regularly.21
In the acute stroke setting, the interpretation of CT images is an essential
component of the overall assessment, diagnosis, and treatment. Imaging data from
a remote site that are then transmitted in the digital imaging and communications
in medicine (DICOM) standard have a quality equivalent to that of on-site review. A
trained neurologist’s structured assessment of CT scans of the brain and inter-
pretations related to acute stroke are similar to those of radiologists.22 Interpre-
tation of CT angiography using a smartphone teleradiology system has resulted in
nearly the same accuracy as that of a traditional diagnostic workstation.23 Pre-
hospital stroke ambulance projects have reported the ability to perform CT
angiography along with CT imaging on specially equipped ambulances.24Y26
Accurate focused history taking, NIHSS evaluation, and the interpretation of lab-
oratory and neurovascular imaging diagnostic tests can all be conducted through

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telemedicine. Low-cost tablet-based platforms are available to provide the pre-
hospital evaluations.27

Metrics
Because of the critical importance of rapid treatment with IV rtPA of all eligible
patients with acute ischemic stroke, recording of time elements is key. Similar to
in-person acute stroke care, monitoring and recording critical time points in the
stroke chain of survival is compulsory (eg, patient arrival at originating site [spoke
site], time of CT, and start time of IV rtPA treatment) (Practice Table 2). Ad-
ditionally, the telestroke network should record the times of telestroke hotline
activation, telestroke team response by telephone, video start, diagnosis and
treatment decision making, and conclusion of the video consultation. Telestroke
networks generally record whether or not transfer from spoke to hub is indi-
cated, the nature of the indication, the transportation mode (air or ground), and
the name of the destination hospital.
Characteristics of the patient as well as characteristics of the telemedicine
encounter should be recorded, including age, gender, time variables, NIHSS score,
diagnosis, treatment decision making, disposition postemergency evaluation, and
transfer. Patient outcomes could include hospital length of stay, whether at hub or
at spoke, and in-hospital complications, including symptomatic and asymptomatic
intracerebral hemorrhage, extracranial hemorrhage, hemilingual edema, and

PRACTICE TABLE 2 Suggested Time Points for Telestroke

Documentation

b Time of patient’s stroke symptom onset or time last known to be at

baseline state
b Time of patient arrival at the originating hospital site (door) emergency
department
b Time of CT and laboratory studies conducted
b Time of telestroke request to the distant site
b Time of response by the telestroke consultant via phone and video
b Time of commencement of the telestroke clinical evaluation
b Time of review of CT via DICOM
b Time of review of other requisite diagnostic tests
b Time of diagnosis
b Time of emergency treatment eligibility decision making (IV rtPA/
endovascular treatment)
b Time of start of treatment with IV rtPA
b Time of disposition determination
b Time of transfer, if indicated, to a destination stroke center
b Time of arrival, if applicable, to a destination stroke center
CT = computed tomography; DICOM = digital imaging and communications in medicine;
IV = intravenous; rtPA = recombinant tissue plasminogen activator.

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 Remote Stroke Evaluation

mortality. At discharge, the modified Rankin Scale, NIHSS, or Functional Inde-

pendence Measure score and discharge location (eg, home, rehabilitation, assisted
living center) should be recorded. Telestroke systems should record IV rtPA treat-
ment rates and IV rtPA protocol adherence at all hospitals within the network.
Patient and provider satisfaction surveys should be a component of a telestroke
network. Patient surveys should record satisfaction with the providers and with the
technology. Provider feedback on adequacy of the technology and its operation,
troubleshooting, and help desk is encouraged.

Quality Monitoring
Audio, video, and Internet connectivity technical observations, failures, and limit-
ations should be recorded, and a backup system should be available.28 Any security
breach or violation of protected health information policy should be investigated.
Monitoring of neurovascular image transmission and quality should be a part of
technology workflow. Telestroke network hub-and-spoke sites should measure
quality of clinical performance in a standardized manner.29 Practice Table 3 lists
suggested quality monitoring measures for telestroke.

Licensing, Credentialing, and Privileging

Efforts to alleviate the administrative burden of attaining and maintaining in-
dividual provider state licenses are necessary for telestroke to grow to its full
potential.30,31 Small hospitals may wish to rely on the credentialing and pri-
vileging process done by proxy that has been approved by the Centers for
Medicare & Medicaid Services. Privileges for telestroke providers should include
fulfillment of telemedicine and stroke-training standards.
The necessary clinical personnel for a successful telestroke system provider
include a stroke center physician director, a program administrator, and physician
and nurse champions at the spoke partner hospitals.32,33

Documentation and Coding

Clinical telestroke encounters (eg, video, phone, neurovascular image data
transfer) should be documented in an electronic note format and provided to
the spoke site. The Centers for Medicare & Medicaid Services has written a
guideline that provides information for health care professionals providing
telehealth services. For more information on telestroke coding, refer to the article
‘‘Coding for Telestroke’’ by Timothy Ingall, MBBS, PhD, and Bart M. Demaerschalk,
MD, MSc, FAHA, FRCPC,34 in the April 2014 Continuum issue on Cerebrovas-
cular Disease.

CONCLUSION
Telestroke is a connected care approach to bringing expert stroke care to
remote, neurologically underserved urban or rural locations. Strong evidence
exists supporting the equivalence of telestroke to in-person care. Time is criti-
cal in treating patients with acute stroke, and telestroke networks must assure
that technology improvesVnot delaysVdelivery of care. The stroke center and
the spoke site must work collaboratively to develop and institute protocols
and policies to be sure that eligible patients are identified, assessed, and treated
swiftly. Adverse outcomes, such as intracranial hemorrhage and mortality, must be

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PRACTICE TABLE 3 Suggested Telestroke Measures

b Timeliness Measures
Hub measures: response time, consult time, transfer time
Spoke measures: time from door to telestroke consult activation and initiation,
time from door to CT, time from door to CT interpretation, time from door to
laboratory tests drawn, time from door to preliminary diagnosis, time from
door to treatment decision making or time from door to downgrade, time from
door to consult completion, time from door to start of IV rtPA, time from door
to consult completion and transfer (if applicable)
b Organizational Measures
Baseline National Institutes of Health Stroke Scale score, rtPA protocol
adherence (3 and 4.5 hours), transfers for higher level of care (to hub, to other
primary stroke center, to other comprehensive stroke center, to other),
endovascular treatment, advanced neurovascular imaging (CT/CTA/CTP or
MRA/DWI/PWI/MRI) completion at spoke, patient and family satisfaction
b Technology Measures
Connectivity, quality of video, quality of audio, neuroimaging transmission
(teleradiology), time needed to make connection, resolution of technical issues,
equipment downtime, IT response time (spoke, hub, and vendor IT support),
percentage of consults with technical observations (or problems), percentage
of technical problems that delayed diagnosis and decision making, percentage
of technical problems that prevented diagnosis and decision making
b Patient Measures
Hospital admission, hospital length of stay, discharge disposition, 90-day
outcome, modified Rankin Scale score, National Institutes of Health Stroke
Scale score, Functional Independence Measure score, diagnostic accuracy,
stroke mimics, percentage of patients with acute stroke evaluated within
3 hours of stroke onset, percentage of patients with acute stroke evaluated
within 4.5 hours of stroke onset, percentage of all patients appropriate for
telestroke calls initiated, percentage of all eligible patients for IV rtPA treated,
safety, mortality, postYIV rtPA hemorrhage
CT = computed tomography; CTA = computed tomography angiography; CTP = computed
tomography perfusion; DWI = diffusion-weighted imaging; IT = information technology;
IV = intravenous; MRA = magnetic resonance angiography; MRI = magnetic resonance
imaging; PWI = perfusion-weighted imaging; rtPA = recombinant tissue plasminogen activator.

monitored to assess safety metrics. Screening of patients for potential endo-

vascular or neurosurgical therapy and transferring patients who might benefit
from these procedures is now an additional goal of telestroke networks.

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doi:10.1197/j.aem.2004.08.014.
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20. Nelson RE, Okon N, Lesko AC, et al. The cost-effectiveness of telestroke in the Pacific Northwest
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23. Kostopoulos P, Walter S, Haass A, et al. Mobile stroke unit for diagnosis-based triage of persons
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from societal perspective. Am J Manag Care 2013;19(12):976Y985.
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WNL.0b013e318234332d.
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in-ambulance telemedicine: a pilot feasibility study. Stroke 2014;45(8):2342Y2347.
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30. Weinstein RS, Lopez AM, Joseph BA, et al. Telemedicine, telehealth, and mobile health
applications that work: opportunities and barriers. Am J Med 2014;127(3):183Y187.
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31. Gobis LJ. Licensing and liability: crossing borders with telemedicine. Caring 1997;16(7):18Y20, 22, 24
32. Federation of State Medical Boards. Model policy for the appropriate use of telemedicine
technologies in the practice of medicine. 2014. fsmb.org/Media/Default/PDF/FSMB/Advocacy/
FSMB_Telemedicine_Policy.pdf. Published April 2014. Accessed December 5, 2016.
33. Federation of State Medical Boards. Interstate medical licensure compact. fsmb.org/policy/
advocacy-policy/interstate-model-proposed-medical-lic. Accessed December 12, 2016.
34. Ingall TJ, Demaerschalk BM. Coding for telestroke. Continuum (Minneap Minn)
2014;20(2 Cerebrovascular Disease):441Y443. doi:10.1212/01.CON.0000446113.43409.b3.

Continuum (Minneap Minn) 2017;23(1):259–267 ContinuumJournal.com 267

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 Practice Issues

Coding in
Address correspondence to
Dr Pearce J. Korb,
University of Colorado,
Leprino Building, 12401 E

Stroke and Other 17th Ave, Mail Stop L950,

Aurora, CO, 80045,
[email protected].

Cerebrovascular Diseases Relationship Disclosure:

Drs Korb and Jones
report no disclosures.
Unlabeled Use of
Pearce J. Korb, MD; William Jones, MD Products/Investigational
Use Disclosure:
Drs Korb and Jones report
no disclosures.
ABSTRACT * 2017 American Academy
Accurate coding is critical for clinical practice and research. Ongoing changes to of Neurology.
diagnostic and billing codes require the clinician to stay abreast of coding updates.
Payment for health care services, data sets for health services research, and reporting
for medical quality improvement all require accurate administrative coding. This article
provides an overview of coding principles for patients with strokes and other cere-
brovascular diseases and includes an illustrative case as a review of coding principles in
a patient with acute stroke.

Continuum (Minneap Minn) 2017;23(1):e1–e11.

INTRODUCTION
It is important to code accurately in the care of people with strokes and other
cerebrovascular diseases not only to ensure the financial health of the practice but
also to provide better patient care. The International Classification of Diseases,
Tenth Revision, Clinical Modification (ICD-10-CM) must be used for diagnosis-
or problem-based coding.1 In addition to the diagnosis codes, Current Pro-
cedural Terminology (CPT) provides codes for Evaluation and Management
(E/M) services as well as procedures.2 This article summarizes the relevant codes
in ICD-10-CM, CPT codes for common and special procedures, and the issues
associated with accurate documentation. A case vignette is included to illustrate
these principles.
DIAGNOSIS CODING STANDARDS
Since the article ‘‘Coding for Telestroke’’ by Timothy J. Ingall, MBBS, PhD, and Bart
M. Demaerschalk, MD, MSc FRCPC,3 in the 2014 Continuum Cerebrovascular
Disease issue, the new ICD-10-CM, the alphanumeric coding system for clinical
diagnoses, has gone live in the United States. It is far more granular than the
prior edition, the International Classification of Diseases, Ninth Revision, Clin-
ical Modification (ICD-9-CM), with an expansion of codes from approximately
14,000 to 69,000. The increased specificity of codes allows for improved disease
tracking. In addition to the more systemic public health rationale, ICD-10-CM
may play a role in more accurate representation of disease acuity or risk when
considering how value is going to play a larger part in reimbursement.4
In the transition from ICD-9-CM to ICD-10-CM, stroke and other cerebrovascular
diseaseYrelated codes became much more complex. With this new code structure,
over 400 different possible combinations exist for stroke. The first three characters
(A12.----) are common traits, and the following characters (up to four: ---.3456)

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

contribute increasing specificity (Coding Table 1). The cerebral infarction codes
are within the common group Diseases of the Circulatory System denoted with
the letter I (I00YI99). More specifically, cerebrovascular diseases are included in
I60YI69, which includes I63, Cerebral infarction, the main focus of this article, and
codes for hemorrhagic strokes and other forms of intracranial bleeding.
Cerebral infarction can be further codified in an increasingly specific manner.
After I63, the decimal is placed and the following characters have specific clinical
meaning. The fourth digit denotes mechanism (eg, embolism, thrombosis) and
whether the arterial source is precerebral (extracranial) or cerebral (intracranial).
Once this is established, the fifth character identifies a specific artery, if known.
The sixth digit can specify laterality, if known or applicable to the localization
(Coding Table 2).
The codes listed in Coding Table 2 are the most common for ischemic
stroke, but less common causes of stroke and conditions are coded separately.
Several conditions within other code categories, such as I67, Other cerebro-
vascular diseases, and I68, Cerebrovascular disorders in diseases classified else-
where, cover strokes from other mechanisms or from other causes.
In addition, I65, Occlusion and stenosis of precerebral arteries, not resulting in
cerebral infarction, is a set of analogous codes with parallel specificity (eg, artery,
side). These codes are useful in encounters of transient ischemic attack (TIA) when
the vascular pathology is known. Importantly, TIAs and related conditions are
listed with Diseases of the Nervous System (G00YG99) instead of with Diseases of
the Circulatory System (Coding Table 3). In most cases, when the pathology is
known, G45, Transient cerebral ischemic attacks and related syndromes, would
be coded separately as a manifestation code secondary to the main code (eg, a TIA
due to stenosis of the basilar artery would be coded I65.1, Occlusion and stenosis
of basilar artery, with G45.0, Vertebro-basilar artery syndrome). If the pathology is
not known at the time, then G45.9, Transient cerebral ischemic attack, unspecified,
could be used as a primary code.
Unlike ICD-9-CM, ICD-10-CM no longer includes a time frame for what qual-
ifies for a condition to be considered a late effect from a stroke. If specifically
managing effects of a prior stroke, use I69, Sequelae of cerebrovascular disease
codes, but note that a new stroke code cannot be used concurrently (eg, I63,

CODING TABLE 1 ICD-10-CM Code Structure

Category Details Etiology, Anatomic Site, or Severity

First digit
(alpha) Second digit Third digit Decimal Fourth digit Fifth digit Sixth digit
I 6 3 . 3 1 2
Diseases of the I63, Cerebral I63.3, Cerebral I63.31, Cerebral I63.312, Cerebral
circulatory Infarction infarction due infarction due infarction due
system (I60YI69) to thrombosis to thrombosis to thrombosis
of the cerebral of middle of left middle
arteries cerebral artery cerebral artery
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

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CODING TABLE 2 ICD-10-CM Common Codes for Ischemic Stroke

Term Code
Cerebral infarction I63
Precerebral arteries
Cerebral infarction due to thrombosis of precerebral arteries I63.0
Cerebral infarction due to embolism of precerebral arterials I63.1
Cerebral infarction due to unspecified occlusion or stenosis of I63.2
precerebral arteries
Specific arteries for I63.0YI63.2 must be identified with a fifth character
Unspecified precerebral artery I63.-0
Vertebral artery I63.-1
Basilar artery I63.-2
Carotid artery I63.-3
Other precerebral artery I63.-9
Cerebral arteries
Cerebral infarction due to thrombosis of cerebral arteries I63.3
Cerebral infarction due to embolism of cerebral arteries I63.4
Cerebral infarction due to unspecified occlusion or stenosis of I63.5
cerebral arteries
Specific arteries for I63.3YI63.5 must be identified with a fifth character
Unspecified cerebral artery I63.-0
Middle cerebral artery I63.-1
Anterior cerebral artery I63.-2
Posterior cerebral artery I63.-3
Cerebellar artery I63.-4
Other cerebral artery I63.-9
Laterality, when applicable, for I63.0YI63.5 must be identified
with a sixth character
Right I63.--1
Left I63.--2
Unspecified I63.--9
Other or unspecified vascular source
Cerebral infarction due to cerebral venous thrombosis, nonpyogenic I63.6
Other cerebral infarction I63.8
Cerebral infarction, unspecified I63.9
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

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 Coding in Stroke

CODING TABLE 3 ICD-10-CM Codes for Other Cerebrovascular

Diseases and Transient Ischemic Attack

Term Code
Other cerebrovascular diseases I67
Dissection of cerebral arteries, nonruptured I67.0
Cerebral aneurysm, nonruptured I67.1
Cerebral atherosclerosis I67.2
Progressive vascular leukoencephalopathy I67.3
Hypertensive encephalopathy I67.4
Moyamoya disease I67.5
Nonpyogenic thrombosis of intracranial venous system I67.6
Cerebral arteritis, not elsewhere classified I67.7
Other specified cerebrovascular diseases I67.8
Cerebrovascular disorders in diseases classified elsewhere I68
Cerebral amyloid angiopathy I68.0
Cerebral arteritis in other diseases classified elsewhere I68.2
Other cerebrovascular disorders in diseases classified elsewhere I68.8
Transient cerebral ischemic attacks and related syndromes G45
Vertebro-basilar artery syndrome G45.0
Carotid artery syndrome (hemispheric) G45.1
Multiple and bilateral precerebral artery syndromes G45.2
Amaurosis fugax G45.3
Transient global amnesia G45.4
Other transient cerebral ischemic attacks and related syndromes G45.8
Transient cerebral ischemic attack, unspecified G45.9
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

Cerebral infarction). Also, if a personal history of TIA or a stroke without residual

deficits exists, then Z86.73, Personal history of transient ischemic attack (TIA),
and cerebral infarction without residual deficits can be used (Coding Table 4).
This code is also particularly useful when no deficits exist after recombinant tissue
plasminogen activator (rtPA) administration.
In addition to the primary diagnosis codes, additional codes should be
commonly used, if applicable to the care of stroke. When the stroke is likely
contributed to by certain risk factors, their presence should be documented and
coded. The most common risk factor codes are listed in Coding Table 5. If
the patient has been given rtPA either in the emergency department or another
facility within the past 24 hours and usually on admission, then a specific code
(Z92.82) should be used by the reporting hospital (Coding Table 5). Adding

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CODING TABLE 4 ICD-10-CM Sequelae Codes

Term Code
Sequelae of cerebral infarction I69.3
Unspecified sequelae of cerebral infarction I69.30
Cognitive deficits following cerebral infarction I69.31
Speech and language deficits following cerebral infarction I69.32
Aphasia following cerebral infarction I69.320
Dysphasia following cerebral infarction I69.321
Dysarthria following cerebral infarction I69.322
Fluency disorder following cerebral infarction I69.323
Other speech and language deficits following cerebral infarction I69.328
Monoplegia of upper limb following cerebral infarction I69.33
Monoplegia of lower limb following cerebral infarction I69.34
Hemiplegia and hemiparesis following cerebral infarction I69.35
Other paralytic syndrome following cerebral infarction I69.36
Laterality and dominance for I69.33YI69.36 must be identified
with sixth character
Right dominant side I69.3-1
Left dominant side I69.3-2
Right non-dominant side I69.3-3
Left non-dominant side I69.3-4
Unspecified side I69.3-9
Other sequelae of cerebral infarction I69.39
Apraxia following cerebral infarction I69.390
Dysphagia following cerebral infarction I69.391
Facial weakness following cerebral infarction I69.392
Ataxia following cerebral infarction I69.393
Other sequelae of cerebral infarction I69.398
Personal history of transient ischemic attack (TIA), and cerebral Z86.73
infarction without residual deficits
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

the manifestation/sequelae codes, risk factor codes, and any related clinical
syndromes (listed under G46, Vascular syndromes of brain in cerebrovas-
cular diseases) to the primary codes of cerebral pathology (eg, I63, Cerebral
infarction), besides the clinical value of increased specificity, may influence the
Hierarchical Condition Categories risk adjustment and reimbursement in the
near future.

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 Coding in Stroke

CODING TABLE 5 ICD-10-CM Risk Factor and Treatment Codes

Term Code
Use additional codes to identify presence of:
Alcohol related disorders F10
Nicotine dependence F17
Hypertension I10YI15
Occupational exposure to environmental tobacco smoke Z57.31
Tobacco use Z72.0
Contact with and (suspected) exposure to environmental tobacco Z77.22
smoke (acute) (chronic)
Personal history of nicotine dependence Z87.891
Status post administration of tPA (rtPA) in a different facility within Z92.82
the last 24 hours prior to admission to current facility
ICD-10-CM = International Classification of Diseases, Tenth Revision, Clinical Modification.

EVALUATION AND MANAGEMENT CODING

Coding for stroke varies according to the setting and phase of care. Specific coding
issues exist depending on whether the care is delivered inpatient, outpatient, or
via telemedicine.

Inpatient Coding
Stroke is one of the most common neurologic diagnoses warranting inpatient
admission; therefore, much of the care of these patients occurs in the inpatient
setting.5 The majority of a stroke provider’s services fall under E/M in CPT. The
fundamentals and elements of E/M coding have been covered extensively else-
where.2,3,6,7 One should be familiar with the specific differences in documentation
requirements based on the location and context of the encounter (eg, inpatient versus
outpatient/emergency department, new patient versus established patient visit).
One of the three major elements of E/M is medical decision making, which is
further divided into three areas: the number of conditions being addressed and
their status, the amount and intensity of data reviewed or ordered, and risk. Risk
may be the area most specifically important for those caring for patients with
stroke. This is determined by a table of risk and is labeled minimal, low, moderate,
or high. The level of risk is determined by three elements: presenting problems,
diagnostic procedures, and management options selected. It should be noted that
any abrupt change in neurologic status is one of the elements in presenting
problems for high level of risk. This would be applicable to the first encounter in
acute stroke. Drug therapy requiring intensive monitoring for toxicity is another
element considered to qualify for high level of risk. The use of and monitoring of
rtPA could be considered high risk, although as discussed later in this article, the
acute use of the medication can be considered critical care and coded in a different
way. Subsequent encounters during the admission may not qualify for high risk;
the provider must use this table in addition to the other elements of medical
decision making to determine risk (Coding Table 6).

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CODING TABLE 6 Table of Risk as a aPart of Medical Decision Making in Evaluation
and Management

Risk Level Presenting Problems Diagnostic Procedures Management Options Selected

Minimal One self-limited or minor Laboratory tests, chest x-rays, Rest, gargles, elastic bandages,
problem (eg, cold, insect ECG/EEG, urinalysis, ultrasound/ superficial dressings
bite, tinea corporis) echocardiogram, potassium
hydroxide test preparation
Low Two or more self-limited or Physiologic tests not under Over-the-counter drugs, minor
minor problems stress (eg, pulmonary function surgery with no identified risk
tests); noncardiovascular factors, physical therapy,
One stable chronic imaging studies with contrast occupational therapy, IV fluids
illness (eg, well-controlled (eg, barium enema); superficial without additives
hypertension, type 2 needle biopsy; arterial blood
diabetes mellitus, cataract) gases; skin biopsies
Acute uncomplicated injury
or illness (eg, cystitis,
allergic rhinitis, sprain)
Moderate Two stable Physiologic tests under stress Minor surgery with identified
chronic illnesses (eg, cardiac stress test, fetal risk factors; elective major surgery
One chronic illness contraction stress test); diagnostic (open, percutaneous, or endoscopic)
with mild exacerbation endoscopies with no identified with no identified risk factors;
or progression risk factors; deep needle or prescription drug management;
incisional biopsies; cardiovascular therapeutic nuclear medicine;
Undiagnosed new problem imaging studies, with contrast, IV fluids with additives; closed
with uncertain prognosis with no identified risk factors treatment of fracture or dislocation
(eg, lump in breast) (eg, arteriogram, cardiac without manipulation
Acute complicated injury catheterization); obtain fluid
(eg, head injury with brief from body cavity (eg, lumbar
loss of consciousness) puncture/thoracentesis)
High One or more chronic illness Cardiovascular imaging Elective major surgery
with severe exacerbation with contrast with identified (open, percutaneous, endoscopic)
or progression risk factors, cardiac with identified risk factors;
electrophysiologic studies, emergency major surgery (open,
Acute or chronic illness
diagnostic endoscopies percutaneous, endoscopic);
or injury that poses a
with identified risk parenteral controlled substances;
threat to life or bodily
factors, discography drug therapy requiring intensive
function (eg, multiple
monitoring for toxicity; decision
trauma, acute myocardial
not to resuscitate or to de-escalate
infarction, pulmonary
care because of poor prognosis
embolism, severe respiratory
distress, progressive severe
rheumatoid arthritis,
psychiatric illness with
potential threat to self
or others, peritonitis,
acute kidney injury)
An abrupt change in
neurologic status (eg, seizure,
transient ischemic attack,
weakness, sensory loss)
ECG = electrocardiogram; EEG = electroencephalogram; IV = intravenous.
a
Reprinted from Department of Health and Human Services, Centers for Medicare & Medicaid Services.6
cms.gov/Outreach-and-Education/Medicare-Learning-Network-MLN/MLNProducts/Downloads/eval-mgmt-serv-guide-ICN006764.pdf.

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 Coding in Stroke

If the patient is unstable and critically ill, critical care CPT codes can be used
instead of or in addition to E/M codes. Several situations exist in which this could
be true in the care of patients with acute stroke. Use of IV rtPA and certainly use of
intraarterial rtPA and possible mechanical thrombectomy qualifies for this high
probability of life-threatening deterioration. In addition to documenting this risk,
critical care coding requires detailed documentation of the time spent on care. The
code for the first hour of the time spent is 99291, Critical care, evaluation and
management; for each additional half hour, 99292, each additional 30 minutes
should be used (multiple times as applicable to the total time spent). The patient
does not have to be in a critical care unit. The codes can be applied if the clini-
cal work and patient are in any setting as long as the time spent is with the
patient or immediately available at bedside (eg, physician and patient in the
emergency department during rtPA and other acute care).8 If the patient is being
comanaged by different specialists responsible for different aspects of care,
then all can bill for critical time, but all must be considered primary providers of
care (as opposed to consultants), and any time spent by a trainee does not count
toward the total time.6
The case example in this article illustrates the critical nature of the care of
patients with stroke and the complexity of coding. In this scenario, the provider
determined and documented the critical and unstable nature of the patient
having received a therapy with a high rate of complication. Assuming complete
documentation of the critical status of the patient, time spent with the patient or
immediately available, and a description of the work done in that time, the
provider could code for critical care time. The appropriate coding for this case as
presented is summarized in Coding Table 7, Scenario 1.

Case
A 62-year-old right-handed man with a history of essential hypertension and
tobacco use presented with the sudden onset of aphasia and severe right
hemiplegia within 2 hours of onset, concerning for ischemic stroke. He underwent
a stroke code in the emergency department. His National Institutes of Health
Stroke Scale (NIHSS) score was 13, and his blood pressure was 162/95 mm Hg.
He had no contraindications to thrombolytic therapy. He had a family history of
myocardial infarction. His wife was present and was able to give urgent but
informed consent. She provided a complete medical history, social history, and
review of systems for the previous 2 weeks. His head CT was negative for bleeding
and was both independently reviewed and discussed with the on-call radiologist.
A head CT angiogram was also performed, and an occlusion of the left middle
cerebral artery was found. IV recombinant tissue plasminogen activator (rtPA)
was given at 2.5 hours after the last time the patient was known to be at his
neurologic baseline. After the infusion, a complete screening neurologic
examination beyond the NIHSS score was conducted. The patient was admitted
to the medical intensive care unit for close medical and neurologic observation,
with a neurologist as the primary provider in the open unit but a medical
intensive care unit physician and team managing any other medical issues.
All of these issues were documented, including the risk for deterioration from
potential hemorrhagic complications of the rtPA. The time spent with the patient
or immediately available to the bedside in the emergency department prior to
transfer was also documented, which totaled 120 minutes.

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 If the patient in the case described had not received rtPA or thrombectomy
because it was outside the therapeutic window and the provider felt he was stable,
spending 110 minutes of face-to-face time with him including patient care coor-
dination and counseling, the provider then could have billed based on medical
decision making or on time spent with the patient (Coding Table 7, Scenario 2).
Complete documentation of a comprehensive history and examination would have
warranted a level III E/M code for new patient admission (99223). Additionally, if
the total time spent on patient care was at least 50% on counseling or patient care
coordination, then one prolonged service code would be appropriate (99356).

Outpatient Coding
The principles of coding E/M for outpatient encounters are the same as for
inpatient encounters. The issues of coding in the prevention of stroke have
been covered in a previous Continuum article,7 with appropriate emphasis put
on diagnostic specificity, inclusion of code for the effects of stroke being managed
(Coding Table 4), and the importance of documentation of time spent on

CODING TABLE 7 Case Vignette Coding Summary

Code Type Source/Code Notes

Diagnosis ICD-10-CM

Primary
Cerebral infarction due to unspecified occlusion I63.512 Be as specific as possible. Note
or stenosis of left middle cerebral artery mechanism is unknown at this time.
Risk factors
Essential (primary) hypertension I10
Tobacco use Z72.0
Aphasia R47.01
Hemiplegia, unspecified affecting right G81.91
dominant side
Procedures CPT
Scenario 1
E/M
Critical care, evaluation and management of 99291 First 74 of 120 total minutes
the critically ill or critically injured patient; documented are used on this code.
first 30-74 minutes
Critical care, evaluation and management 99292 x 1 Next 30 minutes are used on this code,
of the critically ill or critically injured patient; leaving 16 minutes. If at least 30 additional
each additional 30 minutes (List separately minutes had been documented, then
in addition to code for primary service) additional 99292 codes should be submitted.
Continued on page e10

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 Coding in Stroke

CODING TABLE 7 Case Vignette Coding Summary Continued from page e 9

Code Type Source/Code Notes

Scenario 2
Initial hospital care, per day, for the 99223
evaluation and management of a patient, which
requires these 3 key components:

& A comprehensive history;

& A comprehensive examination;
& Medical decision making of high complexity.
Counseling and/or coordination of care with
other physicians, other qualified health care
professional, or agencies are provided consistent
with the nature of the problem(s) and the
patient’s and/or family’s needs.
Usually, the problem(s) requiring admission
are of high severity. Typically, 70 minutes are
spent at the bedside and on the patient’s
hospital floor or unit.
Prolonged service in the inpatient or observation 99356 x 1
setting, requiring unit/floor time beyond the
usual service; first hour (List separately in addition
to code for inpatient Evaluation and
Management service)
CPT = Current Procedural Terminology; E/M = evaluation and management; ICD-10-CM = International Classification of Diseases, Tenth
Revision, Clinical Modification.
CPT B 2016 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

counseling on risk factor prevention. This is all still true; the only change is the
increased specificity of ICD-10-CM, as previously discussed.

Telestroke
Parity between payment of in-person care and telehealth from third-party payers
is now required by law in 29 states and the District of Columbia. The statues
vary from state to state in regard to the licensing requirements, types of
services, and technologic restrictions.9 Despite the variable adoption of tele-
medicine, it is gaining acceptance and becoming eligible for reimbursement.

CONCLUSION
Caring for patients with strokes and cerebrovascular disease is complex, espe-
cially in the acute setting. The diagnostic coding system reflects this specificity;
accuracy is increasingly important as level of risk will be increasingly used in
reimbursement models. The stability of the patient, level of care delivered, and
setting of the care (eg, telehealth) determine the unique coding standards and
should be understood to ensure compliance.

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REFERENCES
1. Centers for Medicare & Medicaid Services, National Center for Health Statistics. International
classification of diseases, tenth revision, clinical modification (ICD-10-CM). cdc.gov/nchs/icd/
icd10cm.htm. Updated June 28, 2016. Accessed December 1, 2016.
2. American Medical Association. Current procedural terminology (CPT) 2016. Chicago, IL:
American Medical Association Press, 2016.
3. Ingall T, Demaerschalk B. Coding for telestroke. Continuum (Minneap Minn)
2014;20(2 Cerebrovascular Disease):441Y443. doi:10.1212/01.CON.0000446113.43409.b3.
4. Meyer H. Coding complexity: US health care gets ready for the coming of ICD-10. Health Aff
(Millwood) 2011;30(5):968Y974. doi:10.1377/hlthaff.2011.0319.
5. Hall MJ. National hospital discharge survey: 2007 summary. National health statistics reports;
no 29. Hyattsville, MD: National Center for Health Statistics, 2010.
6. Department of Health and Human Services, Centers for Medicare & Medicaid Services. Evaluation
and management services guide. cms.gov/Outreach-and-Education/Medicare-Learning-Network-
MLN/MLNProducts/Downloads/eval-mgmt-serv-guide-ICN006764.pdf. Published August 2015.
Accessed December 1, 2016.
7. Powers LB. Coding issues: current procedural terminology evaluation and management coding for
neurologic consultations. Continuum (Minneap Minn) 2011;17(5 Neurologic Consultation in the
Hospital):1129Y1134. doi:10.1212/01.CON.0000407065.34694.f1.
8. APPENDIX: stroke coding guide for critical care coding. Continuum (Minneap Minn)
2008;14(6 Acute Ischemic Stroke):133Y136. doi:10.1212/01.CON.0000300005.72222.21.
9. Thomas L, Capistrant G. State telemedicine gaps analysis: coverage and reimbursement.
higherlogicdownload.s3.amazonaws.com/AMERICANTELEMED/3c09839a-fffd-46f7-916c-692c11d78933/
UploadedImages/Policy/State%20Policy%20Resource%20Center/Coverage%20-%202016_50-state-
telehealth-gaps-analysis–coverage-and-reimbursement.pdf. American Telemedicine Association,
2016. Published May 2015. Accessed December 1, 2016.

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 Self-Assessment and CME

Postreading Self-Assessment and CME Test

Douglas J. Gelb, MD, PhD, FAAN; Adam Kelly, MD

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b 1. Which of the following causes of pediatric stroke is associated with the highest risk of recurrence?
A. cervical artery dissection
B. migraine
C. moyamoya disease
D. postinfectious vasculopathy
E. reversible cerebral vasoconstriction syndrome

b 2. A 34-year-old woman is seen in consultation after developing a right subcortical hemorrhage during labor. Her
neurologic history is notable for a prior left subcortical hemorrhage at age 18 that was attributed to mild head trauma. She
was not hypertensive during her pregnancy. Her examination shows a mild left hemiparesis and is otherwise normal;
blood pressure is 113/70 mm Hg. MRI of her brain shows a small acute hemorrhage in the right basal ganglia, diffuse white
matter hyperintensities through both cerebral hemispheres, a small chronic hemorrhage in the left putamen and several
subcortical microhemorrhages. Which of the following is the most likely diagnosis?
A. chronic untreated hypertension
B. COL4A1 mutation
C. inflammatory cerebral amyloid angiopathy
D. preeclampsia
E. reversible cerebral vasoconstriction syndrome

b 3. Which of the following categories of patients with stroke should have a standard swallow screen before they are
allowed to eat after a stroke?
A. all patients
B . only patients who are older than 65 years
C. only patients who have had a brainstem stroke
D. only patients who have had a large dominant hemisphere stroke
E . only patients with reduced levels of consciousness

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 Postreading Test

b 4. An 81-year-old man is seen in the emergency department after an episode of expressive aphasia and right facial
weakness lasting 15 minutes. His electrocardiogram shows atrial fibrillation, which has not been documented in
the past. Which of the following characteristics, if present, would make the use of a novel oral anticoagulant
challenging in this patient?
A. age 80 or older
B. body mass index of 35 or more
C. history of poor medication adherence
D. use of a cane as an assistive device
E. vegetarian diet

b 5. When using antihypertensive medication for secondary stroke prevention, which of the following medication
effects should be avoided because it is associated with an increased risk of stroke?
A. high blood pressure variability
B. low pulse pressure
C. low systolic blood pressure
D. rapid heart rate
E. short QT interval

b 6. A 33-year-old man is seen in clinic for evaluation of a recent cerebellar stroke. His stroke workup is most notable
for a dilated and tortuous appearance of his vertebral and basilar arteries seen on magnetic resonance angiography
(MRA). He has three siblings, including one brother who had a reportedly cryptogenic cerebellar stroke in his
20s. His two sisters are well. Which of the following would be most likely to be found in this patient?
A. café au lait spots
B. early alopecia
C. hemiplegic migraines
D. painful small fiber neuropathy
E. tall stature with long extremities

b 7. A 67-year-old woman is seen in the emergency department for evaluation of language dysfunction. She was
reportedly in her normal state of health when she and her son had dinner at 7 PM the night before. He went out
afterward and found her sleeping in a recliner when he returned at 10 PM, and he thinks he heard her go to the
bathroom around 2 AM (although he did not speak with her at those times). She usually awakens around 6 AM, and
he found her with nonsensical speech at 8 AM. Her examination is notable for receptive language dysfunction
(National Institutes of Health Stroke Scale score of 5) but no other focal neurologic deficits. Which of the following
times should she be considered to have last been well?
A. 7 PM yesterday
B. 10 PM yesterday
C. 2 AM today
D. 6 AM today
E. 8 AM today

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b 8. A 78-year-old man is seen in clinic 2 months after a left temporal lobe stroke. He still has some residual receptive
aphasia, with occasional paraphasic errors but otherwise largely preserved comprehension. The initial right
superior quadrantanopia seen during his hospitalization has now completely resolved. The patient inquires about
the possibility of resuming driving. His son, who accompanied him to this visit, thinks his father is nearly back to
baseline, but he and his sister had some concerns about the patient’s driving even prior to the stroke, although he
has no history of accidents. Which of the following is the most appropriate next step?
A. instruct the patient that stroke patients should not drive for 1 year
B. order formal visual field testing
C. prescribe donepezil
D. refer for formal driving evaluation
E. refer for 24-hour EEG

b 9. In patients with 70% stenosis of the extracranial portion of an internal carotid artery who have no history of
ischemic symptoms, which of the following tests is most reliable for identifying patients who have a higher risk of
future stroke?
A. EEG
B. functional MRI (fMRI)
C. magnetoencephalogram (MEG)
D. somatosensory evoked responses
E. transcranial Doppler

b 10. A 68-year-old man is seen in the emergency department with the acute onset of left-sided weakness and left
hemineglect beginning 1 hour ago. His blood pressure is 154/90 mm Hg; his vital signs are otherwise unremarkable.
His National Institutes of Health Stroke Scale score is 9. Which of the following medications, if taken earlier that
morning, would represent an exclusion to IV thrombolysis?
A. aspirin
B. clopidogrel
C. dabigatran
D. lisinopril
E. warfarin (with international normalized ratio [INR] of 1.6)

b 11. Which of the following best describes the relationship between the size of an unruptured aneurysm and
the risk of rupture?
A. consistently negative slope: the larger the aneurysm, the lower the risk
B . consistently positive slope: the larger the aneurysm, the greater the risk
C. inverted U-shaped curve: the risk is greatest with midsized aneurysms and lower with very small or
very large aneurysms
D. no relationship
E . U-shaped curve: the risk is lowest with midsized aneurysms and greater with very small or very
large aneurysms

b 12. Which of the following clinical factors is associated with lower total IQ following pediatric stroke?
A. congenital heart disease as a cause of stroke
B. development of poststroke epilepsy
C. earlier age of stroke
D. presence of motor findings
E. subcortical location of stroke

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 Postreading Test

b 13. A 5-year-old boy is admitted to the hospital with a 2-day history of left-sided weakness and numbness. Brain
imaging shows an acute stroke in the right hemisphere and subcortical white matter. Which of the following
mechanisms is the most common cause of stroke in children this age?
A. acquired heart disease
B. definite or suspected arteriopathy
C. hypercoagulable state
D. infection/sepsis
E. small vessel disease due to type 1 diabetes mellitus

b 14. Based on the best clinical evidence to date, which of the following medications is associated with enhanced
motor recovery when started 5 to 10 days after stroke in patients with hemiparesis or hemiplegia?
A. carbidopa/levodopa
B. donepezil
C. fluoxetine
D. methylphenidate
E. modafinil

b 15. A 75-year-old man is seen in the emergency department with the acute onset of aphasia and right-sided
weakness starting 1 hour ago. His blood pressure is 150/73 mm Hg, and his pulse is 90 beats/min and irregularly
irregular. His National Institutes of Health Stroke Scale score is 19, with points for left gaze preference, right-sided
weakness, right-sided sensory dysfunction, and global aphasia. Head CT shows a hyperdense left middle cerebral
artery sign. Which of the following is the most appropriate next step in management?
A. decompressive hemicraniectomy
B. IV heparin infusion
C. IV recombinant tissue plasminogen activator alone
D. IV recombinant tissue plasminogen activator and consideration of mechanical clot retrieval
E. referral for mechanical clot retrieval

b 16. In a patient with short-lived neurologic symptoms, presence of which of the following symptoms is associated
with the highest risk of development of subsequent stroke?
A. aphasia
B. dizziness
C. generalized weakness
D. left arm numbness
E. loss of consciousness

b 17. Which of the following is a contraindication to starting intermittent pneumatic compression for deep venous
thrombosis prophylaxis in a 72-year-old man hospitalized for a right frontoparietal stroke with a history of an
upper gastrointestinal bleed 3 weeks ago?
A. endovascular stent retrieval less than 12 hours ago
B. onset of stroke symptoms less than 24 hours ago
C. peripheral polyneuropathy
D. severe hemineglect and anosognosia
E. severe lower extremity edema

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b 18. Which of the following characterizations best summarizes the current evidence regarding the effects of
smokeless tobacco and electronic cigarettes on the risk of stroke?
A. compelling evidence exists that both smokeless tobacco and electronic cigarettes increase stroke risk
B . compelling evidence exists that neither smokeless tobacco nor electronic cigarettes increase stroke risk
C. compelling evidence exists that smokeless tobacco does not increase stroke risk, but insufficient evidence
exists to determine the effect of electronic cigarettes on stroke risk
D. compelling evidence exists that smokeless tobacco increases stroke risk, but insufficient evidence
exists to determine the effect of electronic cigarettes on stroke risk
E . insufficient evidence exists to determine the effect of either smokeless tobacco or electronic
cigarettes on stroke risk

b 19. Which of the following valve types and locations is thought to confer the highest thromboembolic risk and, as a
result, is generally treated with warfarin at a higher goal international normalized ratio (INR)?
A. bioprosthetic aortic valve
B . bioprosthetic mitral valve
C. bioprosthetic tricuspid valve
D. mechanical aortic valve
E . mechanical mitral valve

b 20. An 84-year-old right-handed woman is seen in the emergency department for the acute onset of visual dysfunction,
noted upon awakening this morning. She went to bed in good health, but when she awoke, she found herself bumping
into things on her right side while walking. She also had profound difficulty reading the newspaper this morning.
On examination, she has fluent language and preserved ability to write but is unable to read and has slight trouble with
naming. She also has a right homonymous hemianopia. In addition to the left occipital lobe, which of the following
structures is most likely affected in this patient?
A. Broca area
B. left hippocampus
C. pulvinar of the left thalamus
D. right occipital lobe
E. splenium of the corpus callosum

b 21. In which of the following settings is the risk-benefit tradeoff between carotid endarterectomy and purely
medical management most balanced and therefore most likely to be swayed by the patient’s overall surgical risk?
A. asymptomatic 40% stenosis of proximal left internal carotid artery
B. asymptomatic 100% stenosis of proximal right internal carotid artery
C. symptomatic 40% stenosis of proximal left internal carotid artery
D. symptomatic 60% stenosis of proximal right internal carotid artery
E. symptomatic 90% stenosis of proximal left internal carotid artery

b 22. A 7-year-old boy is admitted to the hospital with a 1-day history of facial weakness and slurred speech. His
examination reveals weakness of the left lower face with mild associated dysarthria, as well as slowed finger taps of
the left hand and a slight left pronator drift. MRI of the brain shows an acute stroke in the right hemisphere;
magnetic resonance angiography (MRA) of the head and neck is unremarkable. Which of the following is the most
appropriate next diagnostic step?
A. blood work for fasting lipids
B. carotid ultrasound
C. catheter angiography
D. implantable cardiac monitor
E. transthoracic echocardiogram

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 Postreading Test

b 23. Which of the following is the most common cause of elevated body temperature in the first 48 hours after an
ischemic stroke?
A. anhydrosis
B. damage to the hypothalamic thermoregulatory center
C. drug reaction
D. intraventricular blood due to hemorrhagic conversion
E. pneumonia

b 24. Endovascular flow diversion is US Food and Drug Administration (FDA)-approved for treating aneurysms in
which of the following arterial sites?
A. anterior communicating artery
B. intracavernous carotid artery
C. M2 segment of the middle cerebral artery
D. posterior communicating artery
E. top of the basilar artery

b 25. A 64-year-old woman with hypertension and hyperlipidemia had a 5-minute episode of left hemiparesis that
resolved completely before she reached the emergency department. In the emergency department 8 hours after the
episode, her neurologic examination is normal. Which of the following is the most important reason to perform a brain
imaging study on this patient?
A. determine the size of the lesion
B. differentiate between transient ischemic attack and stroke
C. look for nonischemic causes of her symptoms
D. reassure her that her symptoms are being taken seriously
E. satisfy requirements for billing at a high level of complexity

b 26. A patient with which of the following features of cavernous malformation has the greatest risk
of future hemorrhage?
A. brainstem cavernous malformation discovered during evaluation for headache
B. brainstem cavernous malformation presenting with acute hemorrhage
C. occipital lobe cavernous malformation presenting with visual field defect
D. temporal lobe cavernous malformation presenting with acute hemorrhage
E. temporal lobe cavernous malformation presenting with seizures

b 27. A 64-year-old man is seen in the emergency department with left-sided weakness that started roughly 24 hours
ago. On examination, he has 2/5 power in the left leg, a very subtle pronator drift of the left arm, and no weakness of the
left face. Which of the following associated features is most likely to be found in this patient?
A. abulia
B. alexia without agraphia
C. dyscalculia
D. extinction to double simultaneous stimulation on the left
E. right gaze preference

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b 28. A 51-year-old bus driver is seen in the emergency department for the acute onset of right-sided vision changes
that started 2 hours ago. He has no known medical problems and currently takes no medications. His blood
pressure is 141/79 mm Hg. On examination, he has a complete right homonymous hemianopia but no other focal
neurologic deficits; his National Institutes of Health Stroke Scale score is 2. Which of the following is the best
next step in the care of this patient?
A. catheter angiogram and embolectomy if proximal vessel occlusion is seen
B. IV recombinant tissue plasminogen activator
C. oral loading dose of aspirin and clopidogrel
D. oral sumatriptan for presumed migraine
E. urgent echocardiogram to look for intracardiac thrombus

b 29. A 33-year-old woman, currently at 36 weeks’ gestation, presents to the emergency department with acute-onset
left-sided weakness that began 90 minutes ago. She has weakness of the left face and arm, sensory loss in the left arm,
and mild dysarthria; her National Institutes of Health stroke scale score is 6. Blood pressure is 110/67 mm Hg. CT of
her brain is negative for hemorrhage but does show a possible hyperdense vessel sign in an M3 branch of the right
middle cerebral artery. Which of the following is the best next step in management?
A. induction of labor
B. IV recombinant tissue plasminogen activator
C. IV magnesium
D. referral for mechanical embolectomy
E. subcutaneous enoxaparin

b 30. A 33-year-old woman is seen in clinic for management of a recent right occipital stroke. Her diagnostic workup is
notable only for a transesophageal echocardiogram showing a small patent foramen ovale. No evidence of lower
extremity venous thrombosis is found, and testing for hypercoagulable states is negative. Which of the following is the
most appropriate next step for secondary stroke prevention in this patient?
A. aspirin
B. percutaneous patent foramen ovale closure
C. placement of an inferior vena cava filter
D. rivaroxaban
E. warfarin

b 31. A 65-year-old man is admitted to the hospital with a right internal capsule stroke resulting in a left hemiparesis. At
the end of the second hospital day, he has regained some limited movement in the left leg but does not have any
movement in the right arm or hand. Based on the Early Prediction of Functional Outcome After Stroke study (EPOS),
what is the likelihood of him recovering to a good functional outcome?
A. 10%
B. 25%
C. 40%
D. 50%
E. 75%

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 Postreading Test

b 32. A 56-year-old man is seen in the emergency department with the acute onset of vertigo beginning 6 hours ago.
He reports a nearly constant sensation of movement associated with significant nausea and vomiting. His motor,
sensory, and cerebellar examinations are all normal; he is not able to stand during gait testing. Which of the following
additional findings on history or examination would be most supportive of a stroke or other central cause of
his symptoms?
A. lack of skew deviation
B. normal head impulse test
C. presence of tinnitus
D. unidirectional nystagmus
E. worsening of vertigo with positional changes

b 33. Melodic intonation therapy is a rehabilitation strategy thought to have potential benefit in the recovery from
which of the following poststroke deficits?
A. dysprosody
B. expressive aphasia
C. flaccid dysarthria
D. receptive aphasia
E. spastic dysarthria

b 34. For which of the following dietary interventions is there evidence from a controlled trial to indicate a
reduction in stroke risk?
A. Atkins diet
B. elimination of coffee
C. elimination of soda
D. Mediterranean diet
E. moderate (5 ounces a day) wine consumption

b 35. Which of the following treatments is most appropriate for treating symptomatic intracranial hemorrhage
that develops within 24 hours of receiving IV recombinant tissue plasminogen activator?
A. cryoprecipitate
B. dexamethasone
C. hypertonic saline
D. mannitol
E. pentoxifylline

b 36. Which patients with symptomatic 80% stenosis of the M1 segment of the left middle cerebral artery should be
treated with angioplasty and stenting together with aggressive medical management rather than aggressive medical
management alone?
A. all
B. none
C. those who have had more than five transient ischemic attacks or minor strokes
D. those whose ischemic symptoms lasted longer than 30 minutes
E. those with low-density lipoprotein higher than 100 mg/dL

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b 37. In a patient who has had a recent left parietal ischemic stroke, which of the following factors would be a
reason to refrain from initiating high-potency statin therapy?
A. age younger than 75 years
B. diabetes mellitus
C. low-density lipoprotein lower than 100 mg/dL
D. myasthenia gravis
E. nonatherosclerotic cause of stroke

b 38. A 41-year-old man with a history of IV drug use is admitted to the hospital with fever and left-sided weakness.
Brain imaging shows multiple small bihemispheric acute infarcts, more so in the right hemisphere. His blood
cultures are positive for Enterococcus, and his transesophageal echocardiogram shows a vegetation adherent to
the aortic valve. Which of the following is the most appropriate antithrombotic therapy in this patient?
A. IV heparin
B. no antithrombotic therapy
C. oral aspirin
D. oral aspirin and clopidogrel
E. subcutaneous enoxaparin

b 39. A 47-year-old woman is seen in clinic for evaluation of multiple lacunar strokes and abnormal brain imaging.
She has experienced three separate subcortical strokes over the past 5 years, despite no known stroke risk factors
and good adherence to healthy lifestyle habits. Her personal medical history is notable for migraine with aura
dating back to adolescence; family history is remarkable for severe migraines in her sister and early strokes and
cognitive impairment in her mother. Brain MRI in this patient is most likely to show which of the following?
A. abnormal lenticulostriate vessels in the basal ganglia
B. diffuse subcortical T2 hyperintensity, including the anterior temporal lobes
C. dolichoectasia of the posterior circulation
D. loss of flow voids in the distal internal carotid arteries
E. superficial siderosis over both cerebral hemispheres

b 40. Which of the following features would be the most compelling reason to recommend treatment to a patient
with an unruptured posterior communicating artery aneurysm?
A. age younger than 50 years
B. history of diabetes mellitus
C. history of migraine with aura
D. presence of an isolated third nerve palsy
E. presence of a 2-mm unruptured internal carotid artery aneurysm

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 Self-Assessment and CME

Postreading Self-Assessment and CME

Test—Preferred Responses
Douglas J. Gelb, MD, PhD, FAAN; Adam Kelly, MD

Following are the preferred responses to the questions in the Postreading Self-Assessment and CME Test in this
Continuum issue. The preferred response is 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.
Upon completion of the Postreading Self-Assessment and CME Test and issue evaluation online at aan.com/
continuum/cme, participants 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
February 29, 2020.

b 1. The preferred response is C (moyamoya disease). Arteriopathy is a common cause of pediatric stroke. Several
different causative mechanisms can result in arteriopathy, but nonatherosclerotic forms of arteriopathy, such as
moyamoya disease, pose a higher risk of recurrent strokes than other causes such as cervical artery dissection,
transient arteriopathy, and postinfectious processes. For more information, refer to page 163 of the Continuum article
‘‘Arterial Ischemic Stroke in Children and Young Adults.’’

b 2. The preferred response is B (COL4A1 mutation). This patient is presenting with a subcortical hemorrhage of
unclear mechanism, likely provoked by the stress of childbirth. Her past history is notable for another brain
hemorrhage triggered by relatively mild head trauma. This history of multiple subcortical microhemorrhages
caused by mild trauma, in addition to the white matter disease without clear vascular risk factors, is suggestive of a
COL41A mutation. Preeclampsia and chronic hypertension both seem less likely in this case, given the lack of any
history of hypertension, either during or prior to her pregnancy. Reversible cerebral vasoconstriction syndrome
can be associated with intracerebral hemorrhage but would not be expected to cause the white matter changes
described here. Amyloid angiopathy is unlikely in a patient of this age. For more information, refer to page 221 of
the Continuum article ‘‘Inherited and Uncommon Causes of Stroke.’’

b 3. The preferred response is A (all patients). Every patient who has had a stroke should have a swallow evaluation before
being allowed to eat, drink, or take oral medications. A prospective trial demonstrated that use of a standard swallow
screen protocol was associated with a significantly reduced risk of aspiration pneumonia. For more information,
refer to pages 100Y101 of the Continuum article ‘‘Prevention and Management of Poststroke Complications.’’

b 4. The preferred response is C (history of poor medication adherence). This patient is presenting with a left
hemispheric transient ischemic attack, which is most likely cardioembolic in nature in the setting of his newly
discovered atrial fibrillation. He would benefit from anticoagulation for secondary stroke prevention, and his
options include warfarin or a novel oral anticoagulant. Given their relatively short half-lives and the lack of a widely
available means to measure their effect, novel oral anticoagulants may not be the best choice for anticoagulation
in patients with medication nonadherence. Age, obesity, and the use of a cane would not pose clear
contraindications to use of a novel oral anticoagulant (or warfarin). A vegetarian lifestyle might pose a challenge to the
use of warfarin, given the high intake of vitamin K, but no dietary restrictions have been identified for patients using
novel agents. For more information, refer to pages 118 and 120 of the Continuum article ‘‘Cardioembolic Stroke.’’

b 5. The preferred response is A (high blood pressure variability). In the course of lowering overall blood pressure
for secondary stroke prevention, variability in blood pressure should be avoided. Atenolol is a medication that
appears to be associated with high blood pressure variability. For more information, refer to page 19 of the
Continuum article ‘‘Stroke Epidemiology and Risk Factor Management.’’

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b 6. The preferred response is D (painful small fiber neuropathy). This patient is presenting with a posterior
circulation stroke at a young age, with imaging findings describing dolichoectasia of the vertebrobasilar system.
These features, along with stroke at a young age in his brother (suggesting a possible X-linked inheritance
pattern), are strongly suggestive of Fabry disease. Testing for "-galactosidase A activity would confirm the diagnosis,
but the presence of additional historical or examination elements, such as an associated painful small fiber neuropathy
or kidney disease, would increase the yield of testing. Café au lait spots are seen in neurofibromatosis, which would
be less likely to cause this presentation. Similarly, hemiplegic migraine would be more common with cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), early alopecia is associated with
cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and tall stature is
most commonly associated with Marfan syndrome. For more information, refer to page 213 of the Continuum
article ‘‘Inherited and Uncommon Causes of Stroke.’’

b 7. The preferred response is A (7 PM yesterday). This patient is presenting with an acute stroke manifesting with
receptive language dysfunction. Since her only neurologic deficits are in the language domain, her last known well
time should be considered to be the last time she communicated normally with someone. As a result, 7 PM yesterday
(when she had dinner with her son) should be considered as the last known well time; based on her current
examination, she would have been physically able to get up and around at 10 PM, 2 AM, and 6 AM. The time of symptom
discovery is 8 AM, but that should not be considered as the time of symptom onset. For more information, refer
to page 42 of the Continuum article ‘‘Clinical Evaluation of the Patient With Acute Stroke.’’

b 8. The preferred response is D (refer for formal driving evaluation). This patient has had a fair recovery from his
stroke but still has some lingering deficits that might impact his ability to operate a motor vehicle. This is also
occurring in the context of some baseline concerns about his ability to drive at a high level. In situations where the
safety of a return to driving is unclear, a formal driving assessment can be of assistance. Without a clear history of
episodes resembling seizures, there does not appear to be a clear role for an EEG or withholding his driving for an
arbitrary period of time, such as 1 year. Formal visual field testing may be beneficial, but the likelihood that a small defect
that was not detected on bedside testing would significantly impact his driving is probably low. If the baseline driving
concerns or any other symptoms were felt to be related to memory dysfunction, donepezil could be considered, but
it should not be prescribed solely to allow the patient to resume driving. For more information, refer to pages 249Y250
of the Continuum article ‘‘Stroke Rehabilitation.’’

b 9. The preferred response is E (transcranial Doppler). Transcranial Doppler embolus detection is probably the
best validated method for identifying patients with asymptomatic carotid stenosis who have an increased risk of
future ischemic events. For more information, refer to page 141 of the Continuum article ‘‘Large Artery
Atherosclerotic Occlusive Disease.’’

b 10. The preferred response is C (dabigatran). The novel oral anticoagulant medications (dabigatran, rivaroxaban,
apixaban, and edoxaban) are commonly used for stroke prevention in the setting of atrial fibrillation as well as
in other clinical scenarios. Since no method to measure the anticoagulant effect of these medications in a timely
fashion is available, thrombolytic therapy is usually withheld for patients who have taken a dose of these medications
within the past 48 hours. Patients taking warfarin can be treated within 3 hours of symptom onset if the international
normalized ratio (INR) is 1.7 or less. Aspirin, clopidogrel, and other antiplatelet medications do not represent a
contraindication to IV thrombolysis. Although angiotensin-converting enzyme inhibitors (such as lisinopril) are
associated with a higher risk of thrombolysis-related angioedema, recombinant tissue plasminogen activator is
typically not withheld in that setting. For more information, refer to page 75 of the Continuum article
‘‘Treatment of Acute Ischemic Stroke.’’

b 11. The preferred response is B (consistently positive slope: the larger the aneurysm, the greater the risk).
The strongest predictors of rupture of an unruptured aneurysm are size (the larger the aneurysm, the greater
the risk), location (greatest risk with aneurysms in the posterior circulation or posterior communicating artery),
and symptoms not due to rupture. For more information, refer to pages 185Y186 of the Continuum article
‘‘Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations.’’

b 12. The preferred response is B (development of poststroke epilepsy). As a group, pediatric patients with stroke
do not have different long-term cognitive outcomes than what would be expected based on population estimates;
however, some subgroups of patients with stroke are at risk for lower IQ scores. Specifically, children with
more severe neurologic impairment, those with impaired functional capacity (modified Rankin Scale score of 2 or
more), and either acute seizures or poststroke epilepsy are at risk for long-term cognitive dysfunction. For more
information, refer to pages 175Y176 of the Continuum article ‘‘Arterial Ischemic Stroke in Children and
Young Adults.’’

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 Postreading Test—Preferred Responses

b 13. The preferred response is B (definite or suspected arteriopathy). In cross-sectional studies of children beyond
the perinatal period, known or suspected arteriopathy is the most common cause of stroke, accounting for
roughly 46% of strokes (36% due to known arteriopathy, 10% due to suspected arteriopathy). The combination of
congenital plus acquired heart disease is estimated to cause approximately 30% of strokes in this age group, mostly
due to congenital lesions. The other causes listed account for small proportions of the stroke burden in children of this
age. For more information, refer to pages 160Y161 of the Continuum article ‘‘Arterial Ischemic Stroke in Children
and Young Adults.’’

b 14. The preferred response is C (fluoxetine). In the Fluoxetine on Motor Rehabilitation After Ischemic Stroke
(FLAME) trial, patients with strokes resulting in hemiparesis or hemiplegia were randomly assigned to either fluoxetine
20 mg/d or placebo, starting 5 to 10 days after their stroke. In patients receiving fluoxetine, motor recovery scores
were significantly higher, even after adjusting for the anticipated antidepressant effect of this medication. This has led to
the theory that fluoxetine (and potentially other selective serotonin reuptake inhibitors [SSRIs]) may enhance
neuroplasticity after stroke. For more information, refer to page 246 of the Continuum article ‘‘Stroke Rehabilitation.’’

b 15. The preferred response is D (IV recombinant tissue plasminogen activator and consideration of mechanical
clot retrieval). This patient has a clinical presentation and brain imaging that is concerning for a large left middle
cerebral artery infarction. He is a candidate for IV thrombolytic therapy, and this should be started immediately.
However, rates of complete middle cerebral artery recanalization with IV thrombolysis are relatively low, so there is a
fairly high likelihood that this patient will also be a candidate for mechanical embolectomy if he does not have early
improvement in symptoms. Recent data show a large clinical benefit to endovascular therapy in the setting of large
intracranial vessel occlusion; it should be emphasized that the majority of patients in these recent studies were treated
with IV thrombolysis prior to embolectomy. Therefore, patients who are otherwise good candidates for thrombolysis
should still receive this treatment as opposed to proceeding directly to endovascular therapy. For more information,
refer to page 69 of the Continuum article ‘‘Treatment of Acute Ischemic Stroke.’’

b 16. The preferred response is A (aphasia). The likelihood that an episode of transient symptoms represents a
transient ischemic attack is greater when the symptoms are focal, such as hemiparesis or aphasia, than when they
are diffuse, such as loss of consciousness or generalized weakness. Although dizziness and numbness can
represent focal symptoms, these terms are used by patients to mean so many different things that they are less
specific than weakness or aphasia. For more information, refer to pages 83Y84 of the Continuum article
‘‘Diagnosis and Management of Transient Ischemic Attack.’’

b 17. The preferred response is E (severe lower extremity edema). Prophylaxis for deep venous thrombosis should
be initiated at the time patients present with a stroke that restricts mobility. Most patients treated with an
endovascular stent retriever also receive IV recombinant tissue plasminogen activator, so they should not receive
heparin prophylaxis for the first 24 hours after thrombolytic therapy, but no reason exists to delay intermittent
pneumatic compression. Contraindications to intermittent pneumatic compression include peripheral vascular disease
causing leg ischemia, leg ulcerations, dermatitis, and severe leg edema. For more information, refer to pages 99Y100 of
the Continuum article ‘‘Prevention and Management of Poststroke Complications.’’

b 18. The preferred response is E (insufficient evidence exists to determine the effect of either smokeless tobacco
or electronic cigarettes on stroke risk). The effect of smokeless tobacco on stroke risk is unclear, and the effect
of newer forms of nicotine delivery such as electronic cigarettes is even less clear. For more information, refer to
pages 25Y26 of the Continuum article ‘‘Stroke Epidemiology and Risk Factor Management.’’

b 19. The preferred response is E (mechanical mitral valve). Prosthetic valves contribute to thromboembolic risk
through thrombogenicity of the valve material in addition to altered flow dynamics around the valve replacement.
Bioprosthetic valves are less thrombogenic than mechanical valves and patients are generally treated with aspirin
(except immediately after mitral replacement). Among mechanical valves, the mitral position is associated with a
higher risk of thromboembolism; therefore, warfarin with a goal international normalized ratio (INR) of 3.0 is
recommended in these patients (as opposed to a goal of 2.5 in patients with a mechanical aortic valve and no other
risk factors for thromboembolism). For more information, refer to page 123 of the Continuum article
‘‘Cardioembolic Stroke.’’

b 20. The preferred response is E (splenium of the corpus callosum). This patient is presenting with the clinical
syndrome of alexia without agraphia. In this syndrome, patients are unable to provide any visual information to the
language centers of the dominant hemisphere, since the dominant occipital lobe is damaged and information from the
remaining occipital lobe is unable to be communicated across a damaged splenium. For more information, refer
to page 54 of the Continuum article ‘‘Clinical Evaluation of the Patient With Acute Stroke.’’

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b 21. The preferred response is D (symptomatic 60% stenosis of proximal right internal carotid artery). For patients
with less than 50% stenosis of an internal carotid artery, whether symptomatic or asymptomatic, endarterectomy does
not reduce stroke risk relative to medical therapy alone. For patients with total occlusion of an internal carotid artery,
endarterectomy is not an option. For patients with symptomatic internal carotid artery stenosis of 70% to 99%,
endarterectomy dramatically reduces the risk of major stroke relative to medical therapy alone. For patients with
symptomatic internal carotid artery stenosis in the 50% to 69% range, endarterectomy also reduces the risk of major
stroke and the benefit is statistically significant, but the magnitude of the benefit is much smaller. In the 70% to 99%
symptomatic group, the number needed to treat (NNT) to prevent one major stroke at 2 years is 6, whereas in the 50%
to 69% symptomatic group, the NNT to prevent one major stroke at 5 years is 15. Thus, the risk-benefit tradeoff in
the 50% to 69% symptomatic group is heavily influenced by the individual patient’s surgical and anesthetic risks,
whereas the risk-benefit tradeoff almost always favors endarterectomy in the 70% to 99% symptomatic group, even
in patients with fairly substantial surgical risks. For more information, refer to pages 141Y145 of the Continuum
article ‘‘Large Artery Atherosclerotic Occlusive Disease.’’

b 22. The preferred response is E (transthoracic echocardiogram). This patient is presenting with symptoms and brain
imaging of a small right hemispheric stroke. Given the normal appearance of his magnetic resonance angiogram (MRA),
an arteriopathy affecting his medium to large arteries is highly unlikely. An embolic cause of his stroke thus becomes
most likely, so proceeding with either a transthoracic or transesophageal echocardiogram should be the next step.
Atherosclerotic causes of stroke are very unlikely in patients this age, and so fasting lipids and carotid ultrasound are
low-yield tests in this case. Likewise, atrial fibrillation and other dysrhythmias are unlikely to be causative or
detected with long-term cardiac monitoring in patients like this (unlike adults with cryptogenic strokes). If a small
artery vasculitis remains a possibility, then catheter angiography can be considered once a cardioembolic cause
is ruled out. For more information, refer to page 164 of the Continuum article ‘‘Arterial Ischemic Stroke in
Children and Young Adults.’’
b 23. The preferred response is E (pneumonia). Pneumonia is the most common cause of fever in the first 48 hours
after an acute stroke. For more information, refer to page 102 of the Continuum article ‘‘Prevention and
Management of Poststroke Complications.’’

b 24. The preferred response is B (intracavernous carotid artery). Endovascular flow diversion is US Food and
Drug Administration (FDA)-approved for proximal intradural carotid circulation aneurysms such as those in the
cavernous, paraclinoid-ophthalmic segments. For more information, refer to pages 188Y189 of the Continuum article
‘‘Management of Unruptured Intracranial Aneurysms and Cerebrovascular Malformations.’’

b 25. The preferred response is C (look for nonischemic causes of her symptoms). Brain imaging can identify
structural lesions that may produce symptoms that mimic transient ischemic attacks but require very different
management approaches. The diagnostic evaluation and management plan is generally the same for transient
ischemic attack and stroke, regardless of the size of the lesion. For more information, refer to page 86 of the
Continuum article ‘‘Diagnosis and Management of Transient Ischemic Attack.’’

b 26. The preferred response is B (brainstem cavernous malformation presenting with acute hemorrhage).
Patients with cavernous malformations who come to medical attention because of hemorrhage have a higher risk of
future hemorrhage than patients who present with other symptoms, and the risk of future hemorrhage is greater for
cavernous malformations located in the brainstem than for those located elsewhere. For more information, refer to
page 201 of the Continuum article ‘‘Management of Unruptured Intracranial Aneurysms and Cerebrovascular
Malformations.’’

b 27. The preferred response is A (abulia). This patient is presenting with features that are strongly suggestive of a
right hemispheric stroke affecting the territory of the anterior cerebral artery. Strokes in this area classically present
with contralateral weakness that affects the leg much more than the arm, without any involvement of the face. In
addition, patients often demonstrate abulia or other neuropsychological features given the involvement of the frontal
lobe. Alexia without agraphia is seen in lesions of the dominant occipital lobe plus the splenium of the corpus
callosum. Gaze preferences are seen with strokes involving the lateral aspect of the frontal lobe, usually from
involvement of the superior division of the middle cerebral artery. Dyscalculia is commonly seen with Gerstmann
syndrome, which affects the dominant inferior parietal lobe, and extinction to double simultaneous stimulation is also
seen primarily with parietal lesions. For more information, refer to pages 51Y52 of the Continuum article ‘‘Clinical
Evaluation of the Patient With Acute Stroke.’’

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 Postreading Test—Preferred Responses

b 28. The preferred response is B (IV recombinant tissue plasminogen activator). This patient is presenting with
symptoms of a left posterior cerebral artery territory stroke affecting the left occipital lobe. Although his stroke severity
is relatively mild based on the National Institutes of Health Stroke Scale score, his deficits would be considered
disabling in nature (given his employment as a bus driver). In the setting of mild but potentially disabling symptoms
and no contraindications to IV thrombolysis, treatment should be carried out. No evidence exists to support
mechanical embolectomy at this time point in this patient, since the patient is a candidate for thrombolysis. While
he will likely need antiplatelet therapy (although not specifically dual antiplatelet therapy) and a cardiac workup,
initiating thrombolytic therapy is the first priority. This patient’s symptoms should not be assumed to be migrainous
in nature. For more information, refer to pages 75 and 77 of the Continuum article ‘‘Treatment of Acute
Ischemic Stroke.’’

b 29. The preferred response is B (IV recombinant tissue plasminogen activator). This patient is presenting with signs
and symptoms of a right hemispheric stroke late in pregnancy, with imaging concerning for an acute occlusion
of a right middle cerebral artery branch. The health of the mother is critical in this situation, and given the severity of
the stroke symptoms described here, IV recombinant tissue plasminogen activator should be administered.
Mechanical embolectomy is unlikely to be indicated in what appears to be a branch occlusion of the right middle
cerebral artery and should not be done first in this patient who is otherwise eligible for IV recombinant tissue
plasminogen activator. IV heparin or injections of low-molecular-weight heparins are not indicated in the routine
management of acute stroke, especially in patients eligible for thrombolysis. Her symptoms are not consistent with
preeclampsia or eclampsia, so no clear indication for magnesium infusion or induction of labor exists. For more
information, refer to page 230 of the Continuum article ‘‘Inherited and Uncommon Causes of Stroke.’’

b 30. The preferred response is A (aspirin). This patient has experienced a cryptogenic stroke in the setting of a
patent foramen ovale. At present, no evidence exists to support the routine closure of patent foramen ovale
for secondary stroke prevention, although it can be considered in patients who have recurrent cerebrovascular events
while on intensive medical management. Current guidelines support the use of antiplatelet therapy (such as aspirin)
for most patients in this setting, with anticoagulation being recommended when a coexistent deep vein thrombosis or
underlying hypercoagulable state is discovered. Although strokes in patients with patent foramen ovale can occur
due to paradoxical embolism of deep vein thromboses, no role exists for placement of an inferior vena cava filter
for stroke prevention. For more information, refer to page 127 of the Continuum article ‘‘Cardioembolic Stroke.’’

b 31. The preferred response is B (25%). Predictors of stroke recovery are a valuable tool for neurologists and
rehabilitation providers for counseling patients and families on the most likely outcome after the stroke. The Early
Prediction of Functional Outcome After Stroke study (EPOS) found that in patients with no finger extension or
shoulder abduction activity after 2 days, the likelihood of gaining significant dexterity in that limb was only 25%.
If no movement was present by 9 days, the likelihood dropped to only 14%. For more information, refer to
page 242 of the Continuum article ‘‘Stroke Rehabilitation.’’

b 32. The preferred response is B (normal head impulse test). Acute onset of dizziness or vertigo can be related
to either a central etiology (such as stroke) or a peripheral process involving the inner ear. The HINTS approach
(head impulse test, pattern of nystagmus, and test for skew) can be used to help distinguish these two possibilities.
Patients with normal head impulse testing, multidirectional nystagmus, and skew deviations are more likely to have a
central cause of their symptoms. Vertigo of both central and peripheral etiologies is likely to worsen with movement and
thus does not assist much in the diagnostic process. Tinnitus is also relatively nonlocalizing, although it may be more
likely with peripheral lesions. For more information, refer to page 56 of the Continuum article ‘‘Clinical Evaluation of
the Patient With Acute Stroke.’’

b 33. The preferred response is B (expressive aphasia). Melodic intonation therapy is a rehabilitation technique
that uses melody, rhythm, and other musical elements to enhance language production. This is specifically used
in patients with expressive aphasia who do not have significant bihemispheric damage. The theory behind melodic
intonation therapy is that singing appears to primarily localize to the nondominant hemisphere and that language that
is expressed in a musical sense may be able to originate from these unaffected areas. For more information, refer to
page 245 of the Continuum article ‘‘Stroke Rehabilitation.’’

b 34. The preferred response is D (Mediterranean diet). In a controlled trial, the risk of a composite cardiovascular
disease end point was lower in the group assigned to the Mediterranean diet than in the group assigned to a
control low-fat diet. Secondary end point analysis also showed a significant decline in stroke risk in the group
assigned to the Mediterranean diet. Although some evidence indicates that soda intake is associated with an increased
stroke risk and moderate consumption of coffee or wine may be associated with a reduced stroke risk, these have
not been investigated in controlled trials. The Atkins diet has not been studied extensively in controlled trials. For more
information, refer to pages 26Y28 of the Continuum article ‘‘Stroke Epidemiology and Risk Factor Management.’’

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b 35. The preferred response is A (cryoprecipitate). Although no controlled trials have been conducted to determine the
best management of symptomatic intracranial hemorrhage after IV recombinant tissue plasminogen activator,
many protocols include the use of cryoprecipitate to restore decreased fibrinogen levels, since a fibrinogen level less
than 150 mg/dL was the only significant factor associated with hematoma expansion in a retrospective study.
For more information, refer to pages 94Y95 of the Continuum article ‘‘Prevention and Management of
Poststroke Complications.’’

b 36. The preferred response is B (none). Angioplasty and stenting have not been found to be more effective than
aggressive medical management alone for stroke prevention in patients with intracranial atherosclerosis or in
any subgroup of those patients, even patients who were already taking aspirin at the time of their ischemic
symptoms. For more information, refer to pages 149Y150 of the Continuum article ‘‘Large Artery Atherosclerotic
Occlusive Disease.’’

b 37. The preferred response is E (nonatherosclerotic cause of stroke). High-potency statin therapy is indicated
in patients with clinical manifestations of atherosclerotic cardiovascular disease, regardless of low-density lipoprotein
level; this includes patients who have had a transient ischemic attack or stroke. Moderate-potency statin therapy is an
acceptable alternative in patients older than 75 years, but high-potency statin therapy is recommended for patients
younger than 75 years. Diabetes mellitus is not a contraindication to high-potency statin therapy; in fact, patients with
diabetes mellitus should receive either moderate-potency or high-potency statin therapy, depending on their 10-year
risk for atherosclerotic cardiovascular disease. Strokes from nonatherosclerotic causes do not require high-potency
statin therapy. For more information, refer to pages 21Y22 of the Continuum article ‘‘Stroke Epidemiology and Risk
Factor Management.’’

b 38. The preferred response is B (no antithrombotic therapy). This patient is presenting with strokes due to septic
emboli in the setting of enterococcal endocarditis. Although his strokes are embolic in nature, antithrombotic therapy
is often held in the setting of endocarditis because of a higher incidence of intracranial hemorrhage in these patients.
For more information, refer to page 126 of the Continuum article ‘‘Cardioembolic Stroke.’’

b 39. The preferred response is B (diffuse subcortical T2 hyperintensity, including the anterior temporal lobes).
This patient’s presentation is highly suggestive of cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL). This is based on her history of subcortical infarcts without the typical
risk factors associated with this vascular disease (eg, hypertension, diabetes mellitus); her history of migraine
with aura; and her family history of migraines, stroke, and early cognitive impairment. Imaging in CADASIL shows
diffuse T2 white matter hyperintensities, often including the anterior temporal region and the external capsule.
Posterior circulation dolichoectasia is most commonly associated with Fabry disease. Loss of flow voids in the distal
internal carotid arteries and abnormal lenticulostriate vessels is seen in moyamoya disease. Superficial siderosis
is seen in a number of conditions, including cerebral amyloid angiopathy. For more information, refer to
pages 217Y218 of the Continuum article ‘‘Inherited and Uncommon Causes of Stroke.’’

b 40. The preferred response is D (presence of an isolated third nerve palsy). Treatment of an unruptured
intracranial aneurysm is generally recommended when the aneurysm is causing symptoms, such as an isolated
cranial nerve palsy. Patients younger than 70 years of age have a lower risk of aneurysmal rupture than patients
older than 70. The risk of aneurysmal rupture is not substantially affected by a history of migraine, diabetes mellitus,
or the presence of an additional small unruptured aneurysm in the internal carotid artery. For more information,
refer to pages 187Y188 of the Continuum article ‘‘Management of Unruptured Intracranial Aneurysms and
Cerebrovascular Malformations.’’

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 Self-Assessment and CME

Address correspondence to
Dr Kevin M. Barrett, Mayo
Clinic, 4500 San Pablo Rd S,
Patient Management Problem
Cannaday 2EVNeurology,
Jacksonville, FL 32224, Kevin M. Barrett, MD, MSc
[email protected].
Relationship Disclosure:
Dr Barrett serves on the
editorial board of Neurology,
has received research/grant
The following Patient Management Problem was chosen to reinforce the subject matter
support from the National presented in the issue. It emphasizes decisions facing the practicing physician. As you
Institute of Neurological read through the case you will be asked to complete 12 questions regarding history,
Disorders and Stroke for examination, diagnostic evaluation, therapy, and management. For each item, select the
serving on the executive
committees of the CREST-2 single best response.
and SHINE clinical trials, and To obtain CME credits for this activity, subscribers must complete this Patient
receives publishing royalties Management Problem online at aan.com/continuum/cme. A tally sheet is provided
from Wiley Blackwell.
Unlabeled Use of
with this issue to allow the option of marking answers before entering them online. A
Products/Investigational faxable scorecard is available only upon request to subscribers who do not have
Use Disclosure: computer access or to nonsubscribers who have purchased single back issues (send an
Dr Barrett reports email to [email protected]).
no disclosure.
* 2017 American Academy
Upon completion of the Patient Management Problem, participants may earn up
of Neurology. to 2 AMA PRA Category 1 Creditsi. Participants have up to 3 years from the date of
publication to earn CME credits. No CME will be awarded for this issue after
February 29, 2020.

Learning Objectives:
Upon completion of this activity, the participant will be able to:
& Identify patients with acute ischemic stroke who are eligible for acute
reperfusion therapy
& Interpret and describe the utility of advanced neuroimaging to select
patients who may benefit from mechanical thrombectomy
& Recognize and manage early poststroke complications

Case
The acute stroke team receives prehospital notification from emergency
medical services regarding a 78-year-old man with left-sided weakness en route
to the emergency department for stroke evaluation. The patient had lunch
with his wife from 1:00 to 1:45 PM and seemed fine. Immediately after lunch,
he went to take his usual 1-hour afternoon nap. When he awoke from his nap
at 2:45 PM, he fell while trying to get out of bed, and his wife noted that
he was not moving his left side. She called emergency medical services, and
an ambulance arrived at 3:15 PM. At the time of prehospital assessment,
the patient was noted to have no movement of his left arm or left leg
and slurred speech.
He arrives at the hospital at 3:50 PM. His past medical history is remarkable
for hypertension, hyperlipidemia, type 2 diabetes mellitus, and obstructive
sleep apnea. He has no prior history of transient ischemic attack or stroke.
On examination, the patient has a right head and gaze preference, decreased
blink to threat from the left visual hemifield, left lower facial weakness, no
antigravity power in the left arm and left leg, moderate dysarthria, and
left-sided hemispatial neglect. His National Institutes of Health Stroke
Scale (NIHSS) score is 16.

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b 1. Which of the following is the most accurate time to document for stroke onset?
A. 1:00 PM
B. 1:45 PM
C. 2:45 PM
D. 3:15 PM
E. 3:50 PM

b 2. Which of the following etiologies is the most likely cause of the patient’s symptoms?
A. basilar artery occlusion
B. right middle cerebral artery (MCA) occlusion
C. right posterior cerebral artery occlusion
D. small vessel occlusion (eg, penetrating artery disease)
E. superior sagittal sinus thrombosis
b 3. Which of the following is the most appropriate next step in this patient’s management?
A. brain MRI
B. carotid duplex ultrasound
C. cerebral angiography
D. endovascular neurosurgical consultation
E. noncontrast head CT

The patient is emergently sent for a noncontrast head CT.

b 4. Which of the following is a radiographic contraindication to treatment with IV recombinant tissue

plasminogen activator (rtPA)?
A. chronic small vessel ischemic changes in the subcortical white matter
B. hyperdense MCA sign
C. intracranial hemorrhage
D. loss of gray-white differentiation in the insular cortex
E. sulcal effacement in the cortical ribbon

Additional history is obtained by the stroke team while the patient is undergoing CT. He has no
prior history of intracranial hemorrhage, transient ischemic attack, or stroke. No convulsions were
witnessed at symptom onset, and he has no history of any recent surgical procedure, gastrointestinal
or genitourinary bleeding, oral anticoagulant use, or bleeding diathesis. His initial blood pressure
is 173/87 mm Hg and finger stick blood glucose is 190 mg/dL. Laboratory results are pending.
Head CT is remarkable for a hyperdense right MCA sign, loss of gray-white differentiation in the
insular cortex, and mild sulcal effacement in the right MCA distribution. There is no evidence of acute
intracranial hemorrhage.

Continuum (Minneap Minn) 2017;23(1):288–292 ContinuumJournal.com 289

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 Patient Management Problem

b 5. Which of the following is the most appropriate next step in management?

A. prepare weight-based dose of IV rtPA and await results of platelet count, prothrombin time (PT), and
international normalized ratio (INR) before bolus administration
B . recommend direct transfer to angiography suite in preparation for mechanical thrombectomy
C. treatment with IV heparin with goal partial thromboplastin time of 50 to 70
D. treatment with IV labetalol 10 mg to reduce pretreatment blood pressure
E . treatment with IV rtPA 0.9 mg/kg

As part of the brain attack protocol at the comprehensive stroke center, the patient undergoes CT
angiography (CTA) of the head and neck and CT perfusion study of the brain. The acute stroke team
reviews the images in the CT control room (PMP Figure 1).

PMP FIGURE 1 Imaging of patient. A, Maximum intensity projection coronal CT angiography; B, CT perfusion cerebral
blood flow map; C, CT perfusion blood volume map.

b 6. Which of the following is the most accurate interpretation of the CT angiogram (PMP Figure 1A)?
A. no relevant occlusion is seen to explain the patient’s symptoms
B. occlusion of the proximal right anterior cerebral artery (ACA)
C. occlusion of the proximal right MCA
D. occlusion of the proximal right MCA and ACA with inadequate collateral flow
E. occlusion of the right internal carotid artery with distal reconstitution

b 7. Which of the following is the most accurate interpretation of the CT perfusion study (PMP Figures 1B
and 1C)?
A. normal blood flow, normal blood volume, normal mean transit time in the right MCA territory
B. normal blood flow, normal blood volume, prolonged mean transit time in the right MCA territory
C. preserved blood flow and reduced blood volume in the right MCA territory
D. reduced blood flow and preserved blood volume in the right MCA territory
C. reduced blood flow and reduced blood volume in the right MCA territory

290 ContinuumJournal.com February 2017

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b 8. What is the most appropriate next evidence-based step in the management of this patient?
A. admission to the intensive care unit and withholding of antithrombotic therapy for 24 hours
B. echocardiography to evaluate for the proximal source of embolism
C. induced hypertension to augment collateral flow during infusion of IV rtPA
D. intensive monitoring for 24 hours following treatment with IV thrombolysis
E. mechanical thrombectomy with retrievable stent technology

After treatment with IV rtPA followed by mechanical thrombectomy with good recanalization,
the patient is transferred to the intensive care unit for continuous neurologic assessment. His
NIHSS score has improved from 16 to 5. His examination is remarkable for mild dysarthria, mild
hemisensory disturbance, and mild weakness of the left face, arm, and leg. Approximately 6 hours
after monitoring in the intensive care unit, he begins to report headache and nausea, and he is
unable to lift his left arm off the bed. At the time of neurologic deterioration, his blood pressure is
108/75 mm Hg and his pulse is 103.

b 9. Which of the following is the most appropriate next emergent diagnostic step?
A. bedside EEG
B. complete blood cell count, PT, and INR
C. lumbar puncture
D. MRI brain without contrast
E. noncontrast head CT

Noncontrast head CT shows no evidence of acute intracranial hemorrhage. The patient receives
150 mL of normal saline, and his blood pressure responds with a repeat measurement of
130/80 mm Hg. Strength in his left arm improves, with only a minor drift on neurologic reassessment.
One poststroke day 2, he undergoes a carotid duplex, which demonstrates significant atheromatous
plaque on the B-mode imaging and a peak systolic velocity of 330 cm/s at the origin of the right
internal carotid artery. Transthoracic echocardiogram shows mitral annular calcification and
estimated left ventricular ejection fraction of 55%. His low-density lipoprotein is 130 mg/dL.

b 10. Which of the following is the most likely ischemic stroke mechanism?
A. artery-to-artery embolism from high-grade right internal carotid artery stenosis
B. cardiogenic embolism due to mitral annular calcification
C. cryptogenic stroke
D. inherited or acquired prothrombotic state
E. small vessel arteriopathy due to hyperlipidemia

Continuum (Minneap Minn) 2017;23(1):288–292 ContinuumJournal.com 291

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

 Patient Management Problem

b 11. Which of the following is the optimal evidence-based approach to secondary stroke prevention in
this patient?
A. carotid revascularization
B. dual antiplatelet therapy with aspirin 325 mg/d plus clopidogrel 75 mg/d
C. high-dose statin therapy
D. oral anticoagulation with dosage-adjusted warfarin (goal INR 2 to 3)
E. treatment with a direct oral anticoagulant (direct thrombin inhibitor or factor Xa inhibitor)

The patient undergoes uncomplicated right carotid endarterectomy on hospital day 5. He is

discharged to acute inpatient rehabilitation and subsequently to home with his wife. At the time of
outpatient neurology follow-up 3 months poststroke, he is able to walk without assistance and does
not require assistance with activities of daily living.

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 Self-Assessment and CME

Patient Management Problem— Address correspondence to

Dr Kevin M. Barrett, Mayo
Clinic, 4500 San Pablo Rd S,
Preferred Responses Cannaday 2EVNeurology,
Jacksonville, FL 32224,
[email protected].
Kevin M. Barrett, MD, MSc Relationship Disclosure:
Dr Barrett serves on the
editorial board of Neurology,
has received research/grant
Following are the preferred responses for the Patient Management Problem in support from the National
this Continuum issue. The case, questions, and answer options are repeated, and Institute of Neurological
the preferred response is given, followed by an explanation and a reference with Disorders and Stroke for
serving on the executive
which you may seek more specific information. You are encouraged to review the committees of the CREST-2
responses and explanations carefully to evaluate your general understanding of and SHINE clinical trials, and
the material. The comment and references included with each question are receives publishing royalties
from Wiley Blackwell.
intended to encourage independent study.
Unlabeled Use of
To obtain CME credits for this activity, subscribers must complete this Patient Products/Investigational
Management Problem online at aan.com/continuum/cme. Upon completion of Use Disclosure:
the Patient Management Problem, participants may earn up to 2 AMA PRA Category 1 Dr Barrett reports
no disclosure.
Creditsi. Participants have up to 3 years from the date of publication to earn CME
* 2017 American Academy of
credits. No CME will be awarded for this issue after February 29, 2020. Neurology.

Learning Objectives:
Upon completion of this activity, the participant will be able to:
& Identify patients with acute ischemic stroke who are eligible for acute
reperfusion therapy
& Interpret and describe the utility of advanced neuroimaging to select patients
who may benefit from mechanical thrombectomy
& Recognize and manage early poststroke complications

Case
The acute stroke team receives prehospital notification from emergency medical
services regarding a 78-year-old man with left-sided weakness en route to the
emergency department for stroke evaluation. The patient had lunch with his wife
from 1:00 to 1:45 PM and seemed fine. Immediately after lunch, he went to take his
usual 1-hour afternoon nap. When he awoke from his nap at 2:45 PM, he fell while
trying to get out of bed, and his wife noted that he was not moving his left side.
She called emergency medical services, and an ambulance arrived at 3:15 PM. At the
time of prehospital assessment, the patient was noted to have no movement of his
left arm or left leg and slurred speech.
He arrives at the hospital at 3:50 PM. His past medical history is remarkable for
hypertension, hyperlipidemia, type 2 diabetes mellitus, and obstructive sleep
apnea. He has no prior history of transient ischemic attack or stroke. On examination,
the patient has a right head and gaze preference, decreased blink to threat from the
left visual hemifield, left lower facial weakness, no antigravity power in the left arm
and left leg, moderate dysarthria, and left-sided hemispatial neglect. His National
Institutes of Health Stroke Scale (NIHSS) score is 16.

Continuum (Minneap Minn) 2017;23(1):293–299 ContinuumJournal.com 293

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

 PMP—Preferred Responses

b 1. Which of the following is the most accurate time to document for stroke onset?
A. 1:00 PM
B. 1:45 PM
C. 2:45 PM
D. 3:15 PM
E. 3:50 PM

The preferred response is B (1:45 PM). The most appropriate time to document for stroke onset is the last time
the patient was known to be well. In this case, although he noted the symptoms upon awakening from his nap,
he was last known well at 1:45 PM before taking a nap, so that would be the correct time to document as time
of onset. Determining last known well time should be a priority during the initial acute stroke evaluation.1
For patients who have symptoms upon awakening, last known well time is often the time when they went to bed.
Time of onset provided by prehospital personnel should be verified, as initial reports may not be accurate or
new information may become available during transportation to the emergency department or after family arrival.
Advanced neuroimaging may play a role in patients with unknown time of onset or when symptoms present upon
awakening, but the optimal evidence-based neuroimaging approach has yet to be established.

1. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline
for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870Y947.
doi:10.1161/STR.0b013e318284056a.

b 2. Which of the following etiologies is the most likely cause of the patient’s symptoms?
A. basilar artery occlusion
B. right middle cerebral artery (MCA) occlusion
C. right posterior cerebral artery occlusion
D. small vessel occlusion (eg, penetrating artery disease)
E. superior sagittal sinus thrombosis

The preferred response is B (right middle cerebral artery [MCA] occlusion). The combination of right gaze
preference, left homonymous hemianopia, left hemiplegia, and hemispatial neglect is most suggestive of ischemia
in the right MCA distribution secondary to occlusion of the proximal M1 segment.1,2 Right posterior cerebral
artery occlusion would be expected to cause contralateral homonymous hemianopia without hemiplegia or gaze
preference. Lacunar infarction due to small vessel occlusion involves subcortical structures and would not be
expected to result in cortical signs such as gaze preference, homonymous hemianopia, or hemispatial neglect. Basilar
artery occlusion generally presents with prominent bulbar signs (eg, ocular motility impairment, facial weakness,
dysarthria) and motor deficits that may be bilateral in cases of ventral pontine ischemia. Superior sagittal sinus
thrombosis may cause venous infarction with clinical signs and symptoms that are not referable to
defined arterial territories.

1. Brazis PW, Masdeu JC, Biller J. Localization in clinical neurology. 5th edition. Philadelphia, PA: Lippincott Williams & Wilkins, 2007.
2. Southerland AM. Clinical evaluation of the patient with acute stroke. Continuum (Minneap Minn) 2017;23(1 Cerebrovascular
Disease):40Y61.

b 3. Which of the following is the most appropriate next step in this patient’s management?
A. brain MRI
B. carotid duplex ultrasound
C. cerebral angiography
D. endovascular neurosurgical consultation
E. noncontrast head CT

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 The preferred response is E (noncontrast head CT). The most appropriate next step in the management of this
patient is to exclude hemorrhagic stroke as the cause of the symptoms. CT is sensitive to acute hemorrhage,
readily available in stroke centers, and cost-effective.1 Brain MRI, although used as the first-line imaging modality
for acute stroke evaluation in some academic medical centers, is not widely available emergently, and screening for
potential contraindications to MRI may introduce unnecessary delays in diagnosis and treatment. Noncontrast
head CT should precede consideration of other vascular studies and neurosurgical consultation.

1. Powers WJ, Derdeyn CP, Biller J, et al. 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines
for the early management of patients with acute ischemic stroke regarding endovascular treatment. Stroke 2015;46(10):3020Y3035.
doi:10.1161/STR.0000000000000074.

The patient is emergently sent for a noncontrast head CT.

b 4. Which of the following is a radiographic contraindication to treatment with IV recombinant tissue plasminogen
activator (rtPA)?
A. chronic small vessel ischemic changes in the subcortical white matter
B. hyperdense MCA sign
C. intracranial hemorrhage
D. loss of gray-white differentiation in the insular cortex
E. sulcal effacement in the cortical ribbon

The preferred response is C (intracranial hemorrhage). Intracranial hemorrhage on noncontrast head CT is

an absolute contraindication to treatment with IV rtPA. Early ischemic changes evident on noncontrast head CT
include loss of gray-white differentiation in the insular cortex or lentiform nucleus and sulcal effacement in the
cortical ribbon due to cytotoxic edema; these early changes are not associated with increased risk of hemorrhage
following administration of IV rtPA.1 The hyperdense MCA sign is associated with thrombus within the vessel
and angiographic evidence of occlusion. Hypodensity in the periventricular and subcortical white matter is often
the consequence of chronic small vessel ischemia and is frequently identified in patients with atherosclerotic
risk factors such as hypertension, hyperlipidemia, and tobacco abuse.

1. Patel SC, Levine SR, Tilley BC, et al. Lack of clinical significance of early ischemic changes on computed tomography in acute stroke.
JAMA 2001;286(22):2830Y2838. doi:10.1001/jama.286.22.2830.

Additional history is obtained by the stroke team while the patient is undergoing CT. He has no prior history of
intracranial hemorrhage, transient ischemic attack, or stroke. No convulsions were witnessed at symptom onset,
and he has no history of any recent surgical procedure, gastrointestinal or genitourinary bleeding, oral
anticoagulant use, or bleeding diathesis. His initial blood pressure is 173/87 mm Hg and finger stick blood glucose
is 190 mg/dL. Laboratory results are pending. Head CT is remarkable for a hyperdense right MCA sign, loss of
gray-white differentiation in the insular cortex, and mild sulcal effacement in the right MCA distribution. There is
no evidence of acute intracranial hemorrhage.

Continuum (Minneap Minn) 2017;23(1):293–299 ContinuumJournal.com 295

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

 PMP—Preferred Responses

b 5. Which of the following is the most appropriate next step in management?

A. prepare weight-based dose of IV rtPA and await results of platelet count, prothrombin time (PT), and international
normalized ratio (INR) before bolus administration
B . recommend direct transfer to angiography suite in preparation for mechanical thrombectomy
C. treatment with IV heparin with goal partial thromboplastin time of 50 to 70
D. treatment with IV labetalol 10 mg to reduce pretreatment blood pressure
E . treatment with IV rtPA 0.9 mg/kg

The preferred response is E (treatment with IV rtPA 0.9 mg/kg). In the absence of absolute contraindications to
treatment, IV rtPA 0.9 mg/kg should be initiated without delay. IV rtPA remains the mainstay of evidence-based
reperfusion therapy for acute ischemic stroke.1 The results of platelet count, PT, and INR should not delay
administration of rtPA in patients without history of oral anticoagulant use or bleeding diathesis. The results
should be monitored as they become available, but the likelihood of identifying a previously unknown laboratory
contraindication to rtPA is low, and the overall benefit of earlier administration of thrombolysis outweighs the
risk.2 Extreme elevation of blood pressure (higher than 185/110 mm Hg) warrants initiation of antihypertensive
therapy before administration of thrombolysis but is not an absolute contraindication to therapy. IV heparin has
no evidence-based role in the early management of acute ischemic stroke. The patient’s clinicoradiographic syndrome
is suggestive of large vessel occlusion that may be amenable to mechanical thrombectomy, but consideration
of endovascular therapy should not preclude or delay administration of IV rtPA.

1. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic
stroke. N Engl J Med 1995;333(24):1581Y1587. doi:10.1056/NEJM199512143332401.
2. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous
alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke 2016;47(2):581Y641. doi:10.1161/STR.0000000000000086.

As part of the brain attack protocol at the comprehensive stroke center, the patient undergoes CT angiography
(CTA) of the head and neck and CT perfusion study of the brain. The acute stroke team reviews the images in the
CT control room (PMP Figure 1).

PMP FIGURE 1 Imaging of patient. A, Maximum intensity projection coronal CT angiography; B, CT perfusion cerebral
blood flow map; C, CT perfusion blood volume map.

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b 6. Which of the following is the most accurate interpretation of the CT angiogram (PMP Figure 1A)?
A. no relevant occlusion is seen to explain the patient’s symptoms
B. occlusion of the proximal right anterior cerebral artery (ACA)
C. occlusion of the proximal right MCA
D. occlusion of the proximal right MCA and ACA with inadequate collateral flow
E. occlusion of the right internal carotid artery with distal reconstitution

The preferred response is C (occlusion of the proximal right MCA). CTA has excellent sensitivity to diagnose
proximal intracranial large vessel occlusion (as seen in this patient) in patients with suspected stroke.1 In cases
of partial occlusion, the filling defect is accompanied by evidence of some contrast filling in an antegrade
fashion beyond the area of thrombosis. CTA is not sensitive to assessment of collateral flow without additional
information from perfusion studies.

1. van Seeters T, Biessels GJ, Kappelle LJ, et al. The prognostic value of CT angiography and CT perfusion in acute ischemic stroke.
Cerebrovasc Dis 2015;40(5Y6):258Y269. doi:10.1159/000441088.

b 7. Which of the following is the most accurate interpretation of the CT perfusion study (PMP Figures 1B and 1C)?
A. normal blood flow, normal blood volume, normal mean transit time in the right MCA territory
B. normal blood flow, normal blood volume, prolonged mean transit time in the right MCA territory
C. preserved blood flow and reduced blood volume in the right MCA territory
D. reduced blood flow and preserved blood volume in the right MCA territory
E. reduced blood flow and reduced blood volume in the right MCA territory

The preferred response is D (reduced blood flow and preserved blood volume in the right MCA territory).
The cerebral blood flow map shows diminished blood flow in the distribution of the right MCA (PMP Figure 1B)
and preserved to increased blood volume in the right MCA territory (PMP Figure 1B), a pattern suggestive
of brain at risk (ie, penumbra) that could be potentially salvageable if recanalization can be achieved in a timely
fashion.1 The two CT perfusion sequences shown in PMP Figure 1 are the cerebral blood flow (PMP Figure 1B)
and blood volume (PMP Figure 1C) maps; the mean transit time is not included in the figure.

1. Biesbroek JM, Niesten JM, Dankbaar JW, et al. Diagnostic accuracy of CT perfusion imaging for detecting acute ischemic stroke: a
systematic review and meta-analysis. Cerebrovasc Dis 2013;35(6):493Y501. doi:10.1159/000350200.

b 8. What is the most appropriate next evidence-based step in the management of this patient?
A. admission to the intensive care unit and withholding of antithrombotic therapy for 24 hours
B. echocardiography to evaluate for the proximal source of embolism
C. induced hypertension to augment collateral flow during infusion of IV rtPA
D. intensive monitoring for 24 hours following treatment with IV thrombolysis
E. mechanical thrombectomy with retrievable stent technology
The preferred response is E (mechanical thrombectomy with retrievable stent technology). Multiple randomized
clinical trials and meta-analyses have demonstrated the superiority of mechanical thrombectomy with retrievable
stent technology combined with IV rtPA compared to IV rtPA alone in patients with large vessel occlusion.1 Patients
with CTA evidence of proximal MCA occlusion within 6 hours of symptom onset and a favorable perfusion profile
should be offered this therapeutic option. No evidence supports induced hypertension in acute ischemic stroke,
and severe hypertension is associated with increased risk of hemorrhage in patients treated with IV thrombolysis.
Post-thrombolysis monitoring for neurologic deterioration, avoidance of antithrombotic therapy, and evaluation for
stroke mechanism are all acceptable practices but should not preclude the patient being treated with mechanical
thrombectomy at a comprehensive stroke center with the necessary resources for acute stroke intervention.

1. Goyal M, Menon BK, van Zwam WH, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual
patient data from five randomised trials. Lancet 2016;387(10029):1723Y1731. doi:10.1016/S0140-6736(16)00163-X.

Continuum (Minneap Minn) 2017;23(1):293–299 ContinuumJournal.com 297

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 PMP—Preferred Responses

After treatment with IV rtPA followed by mechanical thrombectomy with good recanalization, the patient is
transferred to the intensive care unit for continuous neurologic assessment. His NIHSS score has improved from
16 to 5. His examination is remarkable for mild dysarthria, mild hemisensory disturbance, and mild weakness
of the left face, arm, and leg. Approximately 6 hours after monitoring in the intensive care unit, he begins to
report headache and nausea, and he is unable to lift his left arm off the bed. At the time of neurologic
deterioration, his blood pressure is 108/75 mm Hg and his pulse is 103.

b 9. Which of the following is the most appropriate next emergent diagnostic step?
A. bedside EEG
B. complete blood cell count, PT, and INR
C. lumbar puncture
D. MRI brain without contrast
E. noncontrast head CT

The preferred response is E (noncontrast head CT). Noncontrast head CT should be ordered without delay
in patients treated with acute reperfusion therapy (IV rtPA, mechanical thrombectomy, or combined) and
neurologic deterioration to promptly exclude intracranial hemorrhage.1 Laboratory assessment of coagulopathy
may be part of the overall management strategy but should not delay CT imaging to exclude intracranial
hemorrhage. If no evidence of intracranial hemorrhage or recurrent ischemia exists, then one could consider EEG
to evaluate for epileptiform activity. MRI is usually not practical in the acute setting to exclude an intracerebral
hemorrhage. No indication for lumbar puncture exists in this patient, and it would be contraindicated in
the immediate post-rtPA period.

1. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for
healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44(3):870Y947. doi:10.1161/
STR.0b013e318284056a.

Noncontrast head CT shows no evidence of acute intracranial hemorrhage. The patient receives 150 mL of
normal saline, and his blood pressure responds with a repeat measurement of 130/80 mm Hg. Strength in his left
arm improves, with only a minor drift on neurologic reassessment. One poststroke day 2, he undergoes a
carotid duplex, which demonstrates significant atheromatous plaque on the B-mode imaging and a peak systolic
velocity of 330 cm/s at the origin of the right internal carotid artery. Transthoracic echocardiogram shows mitral
annular calcification and estimated left ventricular ejection fraction of 55%. His low-density lipoprotein is
130 mg/dL.

b 10. Which of the following is the most likely ischemic stroke mechanism?
A. artery-to-artery embolism from high-grade right internal carotid artery stenosis
B. cardiogenic embolism due to mitral annular calcification
C. cryptogenic stroke
D. inherited or acquired prothrombotic state
E. small vessel arteriopathy due to hyperlipidemia

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 The preferred response is A (artery-to-artery embolism from high-grade right internal carotid artery stenosis).
The peak systolic velocity measured in the right internal carotid artery is greater than 230 cm/s, suggestive of
a greater than 70% stenosis. Given the ipsilateral location of the stenosis to the symptomatic hemisphere, the
most likely mechanism would be artery-to-artery embolism. Mitral annular calcification is not considered a
high-risk cardiac source of embolism. Although the patient may have concomitant small vessel occlusive disease
or an inherited or acquired prothrombotic state, these would not be considered primary mechanisms in a
patient with a high-grade ipsilateral carotid stenosis and large vessel occlusion. The classification of cryptogenic
stroke is reserved for those without a determined stroke mechanism following a comprehensive evaluation.1

1. Mohr JP, Wolf PA, Grotta JC, et al. Stroke: pathophysiology, diagnosis, and management. Philadelphia, PA: Elsevier Saunders, 2011.

b 11. Which of the following is the optimal evidence-based approach to secondary stroke prevention in this patient?
A. carotid revascularization
B. dual antiplatelet therapy with aspirin 325 mg/d plus clopidogrel 75 mg/d
C. high-dose statin therapy
D. oral anticoagulation with dosage-adjusted warfarin (goal INR 2 to 3)
E. treatment with a direct oral anticoagulant (direct thrombin inhibitor or factor Xa inhibitor)

The preferred response is A (carotid revascularization). Carotid revascularization is an established safe and
effective approach to secondary stroke prevention in high-grade symptomatic internal carotid artery stenosis.1
Carotid endarterectomy and carotid angioplasty and stenting are equally effective in preventing the composite
outcome of stroke, myocardial infarction, and death when performed by skilled operators. For the outcome
of stroke alone, carotid endarterectomy is more effective than carotid angioplasty and stenting and is the favored
procedure in individuals older than 70 years of age. Oral anticoagulation is indicated to prevent stroke in patients
with nonvalvular atrial fibrillation.2 Dual antiplatelet therapy is the most effective secondary stroke prevention
strategy in patients with high-grade symptomatic intracranial atherosclerotic occlusive disease.3 High-dose statin
is the mainstay of intensive medical therapy but should not preclude carotid revascularization in this case.

1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a
guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45(7):2160-2236.
doi:10.1161/STR.0000000000000024.
2. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365(10):883Y891.
doi:10.1056/NEJMoa1009638.
3. Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med
2011;365(11):993Y1003. doi:10.1056/NEJMoa1105335.

The patient undergoes uncomplicated right carotid endarterectomy on hospital day 5. He is discharged to
acute inpatient rehabilitation and subsequently to home with his wife. At the time of outpatient neurology
follow-up 3 months poststroke, he is able to walk without assistance and does not require assistance with
activities of daily living.

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 Cerebrovascular Disease

* 2017 American Academy of

Neurology. All rights reserved.
INDEX cavernous malformation and, 203t
in HAS-BLED score, 115, 115c, 118t, 130r
intracranial aneurysm and, 183, 184t, 186, 188t
stroke in young adults and, 161t
Page numbers in boldface type indicate major toxic encephalopathy due to, 59t
discussions. Letters after page numbers refer to Alopecia, in CARASIL, 220, 232
the following: c = case study; f = figure; Alteplase. See Recombinant tissue plasminogen
r = reference; t = table. activator
Amaurosis fugax, 47, 48t
A American Academy of Sleep Medicine, 32
A Phase 3, Randomized, Double-Blind, American Association for Critical Care Nurses
Double-Dummy, Parallel Group, Multi-Center, (AACN), 255
Multi-National Study for Evaluation of Efficacy American College of Cardiology management
and Safety of Edoxaban (DU-176b) Versus guidelines
Warfarin in Subjects With Atrial Fibrillation for atrial fibrillation, 130r
(ENGAGE-AF TIMI-48), 118 for diet, 28
A Phase II Safety Study of Intravenous for echocardiography use, 129r
Thrombolysis With Alteplase in MRI-Selected for hyperlipidemia, 21, 22, 36r, 155r
Patients (MR WITNESS), 75, 77, 80r for hypertension, 36r
A Prospective, Multicenter, Randomized for lifestyle modifications, 38r
Controlled Trial to Evaluate the Safety and for valvular heart disease, 131r
Efficacy of the STARFlex Septal Closure System American College of Chest Physicians (ACCP),
Versus Best Medical Therapy in Patients With 129r, 130r, 131r, 168, 178r, 255
a Stroke and/or Transient Ischemic Attack Due American Diabetes Association, 24, 36r
to Presumed Paradoxical Embolism Through a American Heart Association (AHA), 52
Patent Foramen Ovale (CLOSURE I), 126Y127 definition of ischemic stroke, 47
A Randomized Trial of Unruptured Brain management guidelines for acute stroke, 40,
Arteriovenous Malformations (ARUBA), 195Y196 41t, 44
A Very Early Rehabilitation Trial (AVERT), in pregnancy, 230, 231
242Y243 rtPA, 64
AACN (American Association for Critical Care management guidelines for atrial fibrillation, 130r
Nurses), 255 management guidelines for stroke
ABCD2 score, 61r, 86Y87, 89c, 90, 92r prevention, 135
Abulia, 52 antiplatelet therapy, 34Y35
ACAS (Asymptomatic Carotid Atherosclerosis Study), diabetes mellitus screening, 24
141Y142, 147, 156r diet, 28
ACCP (American College of Chest Physicians), exercise, 29Y30, 30tY31t
129r, 130r, 131r, 168, 178r, 255 hyperlipidemia management, 21, 22, 36r, 155r
ACES (Asymptomatic Carotid Emboli Study), hypertension treatment, 18
141, 155r lifestyle factors, 38r
ACST (Asymptomatic Carotid Surgery Trial), 141 lipoprotein (a) screening, 33
Action Research Arm Test (ARAT) score, 243 obesity screening, 29
ACTIVE A (Atrial Fibrillation Clopidogrel Trial tobacco use/e-cigarettes, 25, 26
With Irbesartan for Prevention of Vascular management guidelines for valvular heart
Events), 116 disease, 131r
Acute vestibular syndrome, 56, 57t, 61r American Stroke Association (ASA), 52
Adaptation, poststroke, 238, 240, 244 definition of ischemic stroke, 47
AEDs. See Antiepileptic drugs management guidelines for acute stroke, 40,
AF. See Atrial fibrillation 41t, 44
Aging in pregnancy, 230, 231
atrial fibrillation and, 112, 120 management guidelines for stroke
stroke risk and, 16, 17f, 35r prevention, 135
Agraphesthesia, 48t, 51 antiplatelet therapy, 34Y35
AHA. See American Heart Association diabetes mellitus screening, 24
AICA. See Anterior inferior cerebellar artery exercise, 29Y30
Aicardi-Goutieres syndrome, 221 hypertension treatment, 18
Alberta Stroke Program Early CT Score lipoprotein (a) screening, 33
(ASPECTS), 45, 61r, 70t, 72, 72c, 72t, 74f, 80r, 97 obesity screening, 29
Alcohol intake American Telemedicine Association, 261, 262, 266r
blood pressure and, 21, 136t American Thoracic Society, 255, 257, 257r

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(-Aminocaproic acid, for intracerebral hemorrhage, for patients with patent foramen ovale, 127
68, 94 for patients with unruptured intracranial
Amlodipine, for stroke prevention, 19, 20f, 21c aneurysm, 191Y192
AMPLATAZER PFO Occluder, 127 rtPA use and, 66t, 75, 100
Amyloid spells, 225, 227c for venous thromboembolism, 100
Aneurysms. See Intracranial aneurysms, prophylaxis, 99Y100, 101t
unruptured Antidepressants, 106, 110r, 246Y247, 248,
Angiography. See Catheter angiography; 248c, 252r
Computed tomography angiography; Digital Antiepileptic drugs (AEDs)
subtraction angiography; Magnetic resonance in cerebral amyloid angiopathy, 225, 225c
angiography for children, 170
Angiotensin-converting enzyme inhibitors, 18, 68, effect on poststroke recovery, 247
93, 145 for patients with cavernous malformations,
Angiotensin II receptor antagonists, 145 202, 203t
Anglo-Scandinavian Cardiac Outcomes for patients with developmental venous
TrialYBlood PressureYLowering Arm anomalies, 206
(ASCOT-BPLA), 19 in pregnancy, 203t
Anosognosia, 50, 51, 52c, 61r, 102 prophylaxis, 103
Anterior cerebral artery (ACA) Antihypertensives, 15, 16, 18Y19, 19f, 20f, 21c
aneurysm, 186t Antiphospholipid antibody (APLA) syndrome,
occlusion/infarction, 47, 48t, 51Y52 126, 161, 164, 166t, 167t, 168, 169
Anterior circulation syndromes, 47Y52 Antiplatelet therapy for stroke prevention, 15,
anterior cerebral artery, 51Y52 34Y35, 39r. See also specific drugs
internal carotid artery, 47Y48 in aortic arch atherosclerosis, 128Y129
middle cerebral artery, 48Y51 in atrial fibrillation
Anterior inferior cerebellar artery (AICA) after acute stroke, 122
aneurysm, 184 in elderly patients, 121
occlusion/infarction, 48t, 56 risk stratification and, 116tY118t
Antibiotics vs. warfarin, 116Y117
futile, 255 in CADASIL, 220
for infection-induced encephalopathy, 246c in cerebral amyloid angiopathy, 226, 226c
for infective endocarditis, 125, 126 in children and young adults, 164, 170Y171, 173
for pediatric sepsis, 162c in extracranial vertebral artery atherosclerosis,
poststroke prophylaxis, 102 152, 153c
Anticoagulation. See also specific drugs in Fabry disease, 215
after acute MI with left ventricular thrombus, in heart failure, 128, 132r
127Y128 in infective endocarditis, 126
in atrial fibrillation, 60r, 82, 88, 89, 111, 114Y122, in intracranial atherosclerosis, 149Y150,
136t, 190c 151c, 155r
after acute stroke, 121Y122 in large artery atherosclerosis, 135, 136t,
cerebral amyloid angiopathyYrelated 137Y138
intracranial hemorrhage and, 225 in moyamoya disease, 173, 223
in elderly persons, 120Y121 in patients with patent foramen ovale, 127, 132r
warfarin vs. antiplatelet therapy, 116Y117 after TIA, 34, 82, 88Y90, 127, 129, 137, 149,
warfarin vs. novel oral anticoagulants, 151, 155r
118Y120, 119tY120t, 121c in valvular heart disease, 122
in children, 170 Antithrombin deficiency, 166, 166t, 167t, 168, 169
in heart failure, 128 Aortic arch atherosclerosis, 128Y129, 132r
in intracranial atherosclerosis, 149 Aortic Arch Related Cerebral Hazard Trial
in large artery atherosclerosis, 136t (ARCH), 128
novel oral anticoagulants, 120t Aortic valve replacement, 123
cost of, 120 Apathy, 52, 215, 217, 252r
to prevent stroke in atrial fibrillation, 111, Aphasia, poststroke, 29, 48t
115c, 118Y120, 119t, 131r conduction, 50f, 50t
rtPA use and, 75, 120 vs. encephalopathy, 58
use in cerebral amyloid angiopathy, 225Y226 global, 50t, 72c
use in patients with mechanical heart valves, graphic aphasia box, 50f
124, 125t impact on NIHSS, 44
for patients with mechanical and bioprosthetic left middle cerebral artery stroke and, 48, 48t,
heart valves, 123Y124, 124tY125t 49, 72c, 105c, 115c

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 Cerebrovascular Disease

mixed, 50t ASPECTS (Alberta Stroke Program Early CT

motor/expressive (Broca), 49, 50f, 50t, 115c, Score), 45, 61r, 70t, 72, 72c, 72t, 74f, 80r, 97
163c, 245 Aspiration pneumonia, 101, 102, 242
rehabilitation for, 245 Aspirin
medications, 247, 252r to lower lipoprotein (a), 33
melodic intonation therapy, 245 prophylaxis for deep vein thrombosis, 100, 101t
sensory/receptive (Wernicke), 49, 50f, 50t, 163c to reduce risk of intracranial aneurysm
thalamic, 49 rupture, 192
transcortical motor, 48t, 50f, 50t for stroke prevention, 19, 21c, 34Y35, 39r,
transcortical sensory, 50f, 50t 96c, 155r
Apixaban in aortic arch atherosclerosis, 128, 132r
for acute MI and left ventricular thrombus, 128 in atrial fibrillation, 115c, 116Y117, 122,
to prevent stroke in atrial fibrillation, 118, 120t, 123c, 130r
121c, 131r in CADASIL, 220, 234r
rtPA use and, 75 CAPRIE study, 34, 39r, 155r
Apixaban for the Prevention of Stroke in Subjects in carotid stenosis, 143c, 144, 148c, 155r
With Atrial Fibrillation (ARISTOTLE) trial, 118, in cerebral amyloid angiopathy, 226c
121c, 131r in children, 170Y171, 172c, 173c
APLA (antiphospholipid antibody) syndrome, 126, in extracranial vertebral artery
161, 164, 166t, 167t, 168, 169 atherosclerosis, 153c
Apnea-hypopnea index, 32 in heart failure, 128, 132r
APOA gene, 33 in intracranial arterial atherosclerosis,
ARAT (Action Research Arm Test) score, 243 149Y150, 151c, 157r
Arc sign on MRI, in CARASIL, 220 in large artery atherosclerosis, 136t, 137
ARCH (Aortic Arch Related Cerebral Hazard in patients with mechanical or bioprosthetic
Trial), 128 heart valves, 124, 124tY125t
ARIC (Atherosclerosis Risk in Communities) after TIA, 89Y90, 89c, 92r, 155r
study, 25, 33, 39r United Kingdom Transient Ischemic Attack
ARISTOTLE (Apixaban for the Prevention of trial, 19, 19f
Stroke in Subjects With Atrial Fibrillation) trial, use of H2 blockers with, 247
118, 121c, 131r Astereognosis, 48t, 51
Arteriovenous malformation (AVM), 181, 182, Asymptomatic Carotid Atherosclerosis Study
182t, 192Y196, 193f, 209r (ACAS), 141Y142, 147, 156r
in child, 172c Asymptomatic Carotid Emboli Study (ACES),
clinical presentation of, 193Y194 141, 155r
as contraindication for rtPA, 66t Asymptomatic Carotid Surgery Trial (ACST), 141
definition and radiologic appearance of, Ataxia-telangiectasia, 207
192Y193, 193f Atenolol, for stroke prevention, 19, 20f, 21c
epidemiology of, 193 Atherosclerosis Risk in Communities (ARIC)
incidental discovery of, 182t, 192, 193 study, 25, 33, 39r
intracerebral hemorrhage due to, 192, 193, 194 Atkins diet, 28c
locations of, 193 Atorvastatin, 22, 22t, 23c, 36c, 143c, 220,
management and treatment of, 194Y196 234r, 235r
endovascular embolization, 195 Atrial fibrillation (AF), 112Y122, 129rY131r
Pollock-Flickinger score to select patients for age-related incidence of, 112, 120
stereotactic radiosurgery, 194Y195, 197t anticoagulation in, 60r, 82, 88, 89, 111,
Spetzler-Martin grading system to assess 114Y122, 136t, 190c
surgical risk, 194, 195t, 196t after acute stroke, 121Y122
unruptured AVM, 195Y196 cerebral amyloid angiopathyYrelated
natural history of, 194 intracranial hemorrhage and, 225
as risk factor for intracranial aneurysm, 184t in elderly persons, 120Y121
risk of rupture, 194 warfarin vs. antiplatelet therapy, 116Y117
seizures due to, 192, 193, 194, 196 warfarin vs. novel oral anticoagulants,
Artery of Percheron, 53 118Y120, 119tY120t, 121c
ARUBA (A Randomized Trial of Unruptured Brain diagnosis of, 111
Arteriovenous Malformations), 195Y196 ECG in, 45c, 85, 115c, 122
ASA. See American Stroke Association heart failure and, 128
ASCOT-BPLA (Anglo-Scandinavian Cardiac hemorrhage risk after rtPA in, 95, 97
Outcomes TrialYBlood PressureYLowering occult, monitoring for, 122, 123c
Arm), 19 stroke due to, 15, 44, 46cY47c, 111, 112Y122, 129

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 antithrombotic therapy for prevention of, of developmental venous anomalies, 205, 205f
114Y122 in TIA evaluation, 87Y88
in children and young adults, 160t, 164, 170 of unruptured intracranial aneurysm, 182t, 183
Mediterranean diet and risk of, 27, 38f Brainstem stroke syndromes, 44, 52Y54, 53t, 56,
previous TIA and, 114 57, 92r
risk stratification tools for, 114Y115, 115c, in children, 170
116tY118t Brainstem vascular malformations
sleep apnea and, 32 arteriovenous malformations, 197t
TIA and, 86, 87, 114, 122 cavernous malformations, 182t, 201, 202, 210r
unruptured intracranial aneurysm and, Bupropion, for smoking cessation, 25, 37r
190c, 191
valvular vs. nonvalvular, 112, 114 C
wake-up stroke and, 76c
C-reactive protein, 28, 114t, 138
Atrial Fibrillation Clopidogrel Trial With Irbesartan
CADASIL. See Cerebral autosomal dominant
for Prevention of Vascular Events
arteriopathy with subcortical infarcts and
(ACTIVE A), 116
leukoencephalopathy
AVERT (A Very Early Rehabilitation Trial), 242Y243
California risk stratification tool, 86
AVM. See Arteriovenous malformation
Capillary telangiectasia, 181, 182t, 206Y208,
207f, 210r
B clinical presentation of, 207
Baclofen, for poststroke spasticity, 249, 253r definition and radiologic appearance of,
Barthel Index score, 70t, 249 206Y207, 207f
BASICS (Basilar Artery International Cooperation epidemiology of, 207
Study), 77, 81r management and treatment of, 208
Basilar artery aneurysm, 184, 186t, 189f natural history of, 208
Basilar Artery International Cooperation Study CAPRIE (Clopidogrel Versus Aspirin in Patients at
(BASICS), 77, 81r Risk of Ischaemic Events) trial, 34, 39r, 155r
Basilar artery occlusion/infarction, 48t, 52Y53, 53t, CARASIL (cerebral autosomal recessive
54, 55c, 55f, 254c, 266r. See also arteriopathy with subcortical infarcts and
Vertebrobasilar occlusive disease leukoencephalopathy), 170, 212t, 220Y221,
dense basilar artery sign, 55c, 55f 232, 234r
lacunar syndromes, 58t Cardioembolic stroke, 35r, 45, 91r, 111Y129,
prognosis for, 157r 129rY132r
reperfusion strategies for, 77, 81r after acute MI and left ventricular thrombus,
SAMMPRIS study of, 150, 151c 127Y128
top of the basilar syndrome, 53 aortic arch atherosclerosis and, 128Y129
WASID study of, 149 atrial fibrillation and, 15, 44, 46cY47c, 111,
Bell’s palsy, 159, 159t 112Y122
Benedikt syndrome, 53t in children and young adults, 160t, 164, 170
Bevacizumab, for retinal vasculopathy with Mediterranean diet and risk of, 27, 38f
cerebral leukodystrophy, 221, 234r sleep apnea and, 32
Bioprosthetic and mechanical heart valves, brain imaging findings in, 111, 112
123Y124, 124tY125t causes of, 111
Bleeding. See Intracerebral hemorrhage; diagnostic approach to, 112, 113tY114t
Subarachnoid hemorrhage diagnostic evaluation of, 111
Body mass index (BMI), 21c, 28Y29, 32, 38r in heart failure, 128
Boston Criteria for cerebral amyloid patent foramen ovale and, 112, 123c
angiopathy, 225 in children, 160t, 169
Botulinum toxin, for poststroke spasticity, closure for cryptogenic stroke, 111,
249, 253r 126Y127, 131rY132r, 179r
Brain Attack Surveillance in Corpus Christi valvular heart disease and, 122Y126, 131r
Project, 36r infective endocarditis, 124Y126
Brain imaging. See also specific imaging modalities mechanical and bioprosthetic heart valves,
in acute stroke evaluation, 45, 46cY47c, 46t 123Y124, 124tY125t
in children, 164Y165, 165t nonbacterial thrombotic endocarditis, 126
telestroke interpretation, 261, 262Y263, 263t, Carotid and Vertebral Artery Transluminal
265t, 266r Angioplasty Study (CAVATAS), 146, 151, 156r
of arteriovenous malformation, 192Y193, 193f Carotid atherosclerosis, extracranial, 139Y147,
of capillary telangiectasias, 206Y207, 207f 154rY156r
of cavernous malformation, 197Y198, 198f assessment of, 139Y140, 140f

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 Cerebrovascular Disease

asymptomatic, 133, 141Y144, 143c exercise, 31c

angioplasty and stenting for, 142Y144, 143c health effects of e-cigarettes, 26c
carotid endarterectomy for, 141Y142 sodium intake, 28c
microemboli detection and stroke risk statins, 23c
for, 141 telestroke, 259cY260c
symptomatic, 133, 144Y147, 148c treatment of cavernous malformation, 204c
endarterectomy for, 144Y145 wake-up stroke, 76c
endovascular treatment for, 145Y147, 148c Catheter angiography
extracranial-intracranial bypass for, 147 internal carotid stenosis on, 140, 148f
follow-up imaging and restenosis after in moyamoya disease, 222f, 223
treatment of, 147 for stroke evaluation in children, 164, 165t,
Carotid endarterectomy (CEA), 48, 133, 134, 138, 172c, 172f, 173c
141Y147, 154rY156r CAVATAS (Carotid and Vertebral Artery
for asymptomatic extracranial carotid stenosis, Transluminal Angioplasty Study), 146, 151, 156r
141Y142 Cavernoma Alliance United Kingdom, 202
vs. endovascular treatment, 142Y144, 143c Cavernous malformation, 181, 182, 182t,
follow-up imaging and restenosis after, 147 196Y205, 198f, 209rY210r
for symptomatic carotid stenosis, 144Y145, 154 clinical presentation of, 199Y200
vs. endovascular treatment, 145Y147, 148c definition and radiologic appearance of,
NASCET, 137Y138, 144Y145 197Y198, 198f
after TIA, 89, 89c developmental venous anomalies and,
Carotid Revascularization Endarterectomy Versus 198Y199, 205
Stenting Trial (CREST), 142Y143, 145, 146, differential diagnosis of, 199t
147, 156r epidemiology of, 198Y199
Carotid Revascularization Endarterectomy Versus familial, 197, 199
Stenting Trial 2 (CREST-2), 142, 143, 143c, 156r genetics of, 199, 200t
Carotid ultrasound, 23c, 82, 87, 112, 134, 140, incidental discovery of, 182t, 200
142, 143c, 143f, 155r, 164 intracerebral hemorrhage due to, 181, 196, 200,
Case studies 201Y202, 201t, 212t
acute brain imaging, 46cY47c locations of, 198
acute treatment decision making, 51cY52c management and treatment of, 202Y205,
atrial fibrillation 203tY204t
monitoring for occult AF, 123c antiepileptic drugs, 202
novel oral anticoagulants for, 121c in pregnancy, 203t
risk stratification for stroke, 115c surgery, 202Y205, 204c
CADASIL, 216c mimics of, 199t
carotid atherosclerosis natural history of, 201Y202, 201t
asymptomatic, 143c seizures due to, 196, 199Y200, 202, 203t
symptomatic, 148c sporadic, 197, 199
carotid endarterectomy, 89c CCM1 gene, 199, 200t
cerebral amyloid angiopathy, 226cY227c CCM2 gene, 199, 200t
childhood ischemic stroke, 162cY163c CCM3 gene, 199, 200t
moyamoya disease, 172c CEA. See Carotid endarterectomy
secondary prevention, 173cY174c Center for Epidemiological StudiesYDepression
determining whether to treat an unruptured Scale (CES-D), 106
intracranial aneurysm, 189c Centers for Medicare & Medicaid Services (CMS),
discussing life-sustaining therapy with 21, 264
surrogate decision makers, 254cY255c Cerebral amyloid angiopathy, 199t, 211, 212t, 213,
effect of poststroke depression on recovery, 248c 217, 224Y226, 227f, 232, 235r
intracranial hemorrhage after rtPA, 96c amyloid spells in, 225, 227c
locked-in syndrome, 55c Boston Criteria for diagnosis of, 225
malignant cerebral edema, 98c histopathology of, 224, 225
mechanical thrombectomy, 72cY73c intracerebral hemorrhage in, 212t, 224Y226, 226c
MRI detection of transient ischemic attack, 83c TIA due to, 225, 226c
poststroke depression, 105cY106c treatment of, 225Y226
pregnancy-associated stroke, 229c Cerebral autosomal dominant arteriopathy with
rtPA, 68c subcortical infarcts and leukoencephalopathy
stroke rehabilitation, 246c (CADASIL), 169, 211, 212t, 213, 215Y220, 216c,
stroke risk factor management 221, 231, 232, 233rY234r
antihypertensives, 21c clinical features of, 215Y217

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 genetics of, 216c, 217, 218, 234r risk factors and comorbidities for, 160Y162,
lacunar syndromes in, 215 160tY161t
migraine in, 211, 215Y216, 216c, 234r secondary prevention of, 171Y175, 173cY174c
misdiagnosis as multiple sclerosis, 211, 218, Children’s Hemiplegia and Stroke Association, 177
219f, 232 Cholesterol
MRI in, 214, 216Y218, 216c, 217f, 219f, 220, 233r dietary management, 28
prevalence of, 215 intracerebral hemorrhage risk and, 226
treatment of, 219Y220 LDL
Cerebral autosomal recessive arteriopathy with recurrent stroke risk and, 149
subcortical infarcts and leukoencephalopathy target for, 21
(CARASIL), 170, 212t, 220Y221, 232, 234r vascular risk factors and, 135, 138
Cerebral edema after stroke, 62 lipoprotein (a) screening and, 33
in child, 162c, 170 low HDL-C, metabolic syndrome and, 24
decompressive hemicraniectomy for, 98c, management for stroke prevention, 15, 16,
98f, 99 36r, 155r
malignant, 97Y99, 98c, 98f, 107r obesity, stroke risk and, 28
osmotic therapy for, 97Y98 statin therapy, 21Y23, 22t, 23c
Cerebral palsy, 158, 159, 175, 177r stroke risk in children and young adults related
Cerebral perfusion pressure, 43 to, 160t
Cerebral venous sinus thrombosis (CVST), in Cholinesterase inhibitors, 246. See also Donepezil
pregnancy, 211, 212t, 228, 232 Citalopram, 248, 248c, 252r
Cerebrovascular malformations, 181Y182, CK (creatine kinase), statin myopathy and, 22Y23
192Y208, 209rY210r Clopidogrel for High Atherothrombotic Risk and
arteriovenous malformations, 192Y196, 193f, Ischemic Stabilization, Management, and
195tY197t Avoidance (CHARISMA) trial, 34
capillary telangiectasia, 206Y208, 207f Clopidogrel for stroke prevention, 34, 39r, 155r
cavernous malformations, 196Y205, 198f, in aortic arch atherosclerosis, 128, 132r
199tY201t, 203tY204t, 204f in atrial fibrillation, 116Y117, 130r
comparison of, 182t ACTIVE A, 116
developmental venous anomalies, 205Y206, 205f CAPRIE trial, 34, 39r, 155r
CES-D (Center for Epidemiological CHANCE trial, 90, 137, 155r
StudiesYDepression Scale), 106 CHARISMA trial, 34
CHA2DS2VASc score, to estimate stroke risk in in children, 172c
atrial fibrillation, 114Y115, 115c, 117t in extracranial vertebral artery atherosclerosis,
CHADS2 score, to estimate stroke risk in atrial 153c
fibrillation, 114Y115, 116t, 121 in large artery atherosclerosis, 136t, 137
CHANCE (Clopidogrel in High-risk Patients With MATCH trial, 34, 39r, 155r
Acute Non-disabling Cerebrovascular Events) in patients with mechanical and bioprosthetic
trial, 90, 137, 155r heart valves, 125t
CHARISMA (Clopidogrel for High in symptomatic intracranial arterial stenosis,
Atherothrombotic Risk and Ischemic Stabilization, 149, 150, 151c, 155r
Management, and Avoidance) trial, 34 after TIA, 89, 90, 92r, 155r
Cheyne-Stokes respiration, 105 Clopidogrel in High-risk Patients With Acute
Childhood and young adult ischemic stroke, Non-disabling Cerebrovascular Events
77rY180r, 158Y177, 162cY163c. See also (CHANCE) trial, 90, 137, 155r
Neonatal stroke Clopidogrel Versus Aspirin in Patients at Risk of
acute management of, 170Y171 Ischaemic Events (CAPRIE) trial, 34, 39r, 155r
delayed diagnosis of, 159Y160 CLOSURE I (A Prospective, Multicenter, Randomized
epidemiology of, 158Y159 Controlled Trial to Evaluate the Safety and
evaluation of, 164Y170 Efficacy of the STARFlex Septal Closure System
brain imaging, 164Y165 Versus Best Medical Therapy in Patients With a
further diagnostic testing, 169Y170 Stroke and/or Transient Ischemic Attack Due to
mitochondrial disorders, 169Y170 Presumed Paradoxical Embolism Through a
thrombophilia testing, 165Y169, 166t, 167t Patent Foramen Ovale), 126Y127
mimics of, 159Y160, 159t, 171, 178r CMS (Centers for Medicare & Medicaid Services),
moyamoya disease/syndrome and, 160t, 162, 21, 264
171, 172c, 172f, 173 Cocaine-related stroke risk, 169, 175, 179r
outcomes and long-term management of, Coding in cerebrovascular disease, 268
175Y177 Coenzyme Q10, 23
recurrence risk for, 162Y164 Coffee, stroke risk and, 26

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 Cerebrovascular Disease

Cognitive impairment for mechanical thrombectomy, 69, 70t, 72,

in CADASIL, 215, 217, 220, 234r 72cY73c, 73f
in cerebral amyloid angiopathy, 224, 226c in moyamoya disease, 223
poststroke in pediatric stroke, 164, 165t, 172c, 172f
childhood stroke and, 158, 163c, 171, in pregnancy-associated stroke, 228, 229, 229c
175Y178, 180r telestroke interpretation, 262, 265t
depression and, 105, 242 in TIA, 82, 83c, 87, 89c, 89f, 92r
exercise and, 29, 30t in wake-up stroke, 76f
falls and, 102 Computed tomography (CT) perfusion imaging,
return to driving and, 249 64, 70t, 72, 74f
return to work and, 249 in pediatric stroke, 165t
sleep-disordered breathing and, 104t in TIA, 87
after surgical clipping of aneurysm, 188 in wake-up stroke, 75, 76c, 76f
COL4A1-related cerebral small vessel disease, 170, Computed tomography (CT) venography, 165t
212t, 222Y223, 232, 234r Conscious sedation, for mechanical
Coma thrombectomy, 73Y75, 80r, 231, 236r
basilar artery occlusion and, 53, 255c Constraint-induced movement therapy, 243, 245,
CADASIL, 216, 216c 251r, 252r
vs. locked-in syndrome, 54, 55c Continuous positive airway pressure (CPAP), 32,
Computed tomography (CT) 39r, 103, 104, 105, 109r
in acute stroke evaluation, 40, 41t, 44, 45, Continuum of stroke care, 238
46cY47c, 46t, 51cY52c, 51f, 55c, 55f, 62r, 74f The Contribution of Intra-arterial Thrombectomy
Alberta Stroke Program Early CT Score, 45, in Acute Ischemic Stroke in Patients Treated
61r, 70t, 72, 72c, 72t, 74f, 80r, 97 With Intravenous Thrombolysis (THRACE) trial,
in children, 162c, 164, 165t 71t, 77, 80r
dense artery sign, 45, 46cY47c, 46t, 51cY52c, Corticosteroids
51f, 55c, 55f, 72c, 98c, 230c for cerebral amyloid angiopathyYassociated
for rtPA use, 41t, 61t, 64, 67t, 68, 68c, 72, angiitis, 225
74f, 263 cortisone injection for shoulder syndrome, 248
telestroke interpretation, 261, 262, 263, 263t, for orolingual angioedema, 68, 94
265t, 266r CPAP (continuous positive airway pressure), 32,
of brain aneurysms and cerebrovascular 39r, 103, 104, 105, 109r
malformations, 182t, 183 Creatine kinase (CK), statin myopathy and, 22Y23
arteriovenous malformations, 192 Credentialing of telestroke providers, 261, 264
cavernous malformations, 197, 204c CREST (Carotid Revascularization Endarterectomy
developmental venous anomalies, 205 Versus Stenting Trial), 142Y143, 145, 146,
in cardioembolic stroke, 111, 113, 114t 147, 156r
of hemorrhages in cerebral amyloid CREST-2 (Carotid Revascularization Endarterectomy
angiopathy, 226c, 227f Versus Stenting Trial 2), 142, 143, 143c, 156r
in infective endocarditis, 126 Cryoprecipitate, for intracerebral hemorrhage, 68,
in lacunar infarct, 57 94, 96c
in large artery atherosclerosis, 134 CRYSTAL AF (Study of Continuous Cardiac
malignant cerebral edema on, 97, 98c, 98f Monitoring to Assess Atrial Fibrillation After
for mechanical thrombectomy, 69, 72, Cryptogenic Stroke), 122
72cY73c, 73f CT. See Computed tomography
mobile stroke units with, 77, 262 CTA. See Computed tomography angiography
in pregnancy-associated stroke, 228Y229, CVST (cerebral venous sinus thrombosis), in
229c, 230c pregnancy, 211, 212t, 228, 232
in TIA, 82, 83c, 84c, 86, 87, 89c, 92r Cyclophosphamide, for cerebral amyloid
in wake-up stroke, 75, 76c, 76f angiopathyYassociated angiitis, 225
Computed tomography angiography (CTA), 53c,
64, 74f
of brain aneurysms and cerebrovascular D
malformations, 182t, 183, 189c, 191, 192 Dabigatran
in cardioembolic stroke, 113, 114t for acute MI and left ventricular thrombus, 128
intracranial hemorrhage on, 96c drug interactions with, 119t
in large artery atherosclerosis, 134 to prevent stroke in atrial fibrillation, 118,
basilar artery stenosis, 152c 120t, 131r
carotid artery stenosis, 143c reversal of, 119t, 120, 120t, 131r
vertebral artery stenosis, 153c rtPA use and, 75

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DASH (Dietary Approaches to Stop Hypertension) medications for, 19
diet, 21, 28, 28c, 38r lacunar infarcts and, 57
DAWN (DWI or CTP Assessment With Clinical screening for, 24
Mismatch in the Triage of Wake-Up and Late sleep-disordered breathing and, 104t
Presenting Strokes Undergoing statins for hyperlipidemia in, 21, 22
Neurointervention) trial, 75, 77, 80r stroke recurrence risk and, 86, 88t, 89c
Decompressive Craniectomy in Malignant in elderly patients, 24
Cerebral Artery Infarcts (DECIMAL) study, 99 in young adults, 164
Decompressive hemicraniectomy, 98c, 98f, 99, stroke risk and, 15, 17, 23f, 24, 135, 138
254c, 262 in children and young adults, 160t, 161, 164
Decompressive Surgery for the Treatment of in stroke survivors, 29
Malignant Infarction of the Middle Cerebral use of rtPA in, 67t, 68, 95
Artery (DESTINY) study, 99 Diazepam, 247
Deep venous thrombosis (DVT) after stroke, Diet/nutrition, 37rY38r
99Y100, 101 Atkins diet, 28c
DEFUSE 3 (Diffusion and Perfusion Imaging DASH diet for hypertension, 21, 28, 28c,
Evaluation for Understanding Stroke Evolution 3) 36r, 38r
trial, 75, 77, 80r Mediterranean diet, 21, 26Y27, 27t, 28c, 36r,
Dejerine syndrome, 53t 38r, 136t
Dense artery sign on CT, 45, 46cY47c, 46t, 51cY52c, poststroke dysphagia and, 100Y101
51f, 55c, 55f, 72c, 98c, 230c sodium intake, 28, 28c, 38r
Depression stroke risk and, 15, 17, 26Y28
in CADASIL, 215, 216c, 217, 218 Dietary Approaches to Stop Hypertension
in Fabry disease, 213 (DASH) diet, 21, 28, 28c, 38r
poststroke, 102, 105Y106, 105cY106c, Diffusion and Perfusion Imaging Evaluation for
109rY110r, 252r Understanding Stroke Evolution 3 (DEFUSE 3)
in children and young adults, 158, 173c, 176 trial, 75, 77, 80r
impact on recovery, 106, 238, 242, 248, 248c Digital subtraction angiography (DSA), 73f
medications for, 246Y247, 248, 252r in acute stroke evaluation, 74f
prevalence of, 105, 248 for aneurysm detection, 183
risk factors for, 105 arteriovenous malformation on, 182t
screening for, 106, 250 internal carotid artery occlusion on, 73f
Desmoteplase, 77, 81r middle cerebral artery occlusion on, 76f
DESTINY (Decompressive Surgery for the Diphenhydramine, for orolingual angioedema,
Treatment of Malignant Infarction of the Middle 68, 94
Cerebral Artery) study, 99 Dipyridamole, combined with aspirin for stroke
Developmental venous anomalies, 181, 182t, prevention, 34
205Y206, 205f, 210r Dizziness, 61r, 98c, 151c, 153c. See also Vertigo
cavernous malformation and, 198Y199, 205 acute vestibular syndrome, 56, 57, 61r
clinical presentation of, 205Y206 TIA with, 84, 85, 88t
definition and radiologic appearance of, Donepezil
205, 205f in CADASIL, 220, 234r
epidemiology of, 205 in poststroke aphasia, 252r
management and treatment of, 206 Doppler ultrasound, 113t
natural history of, 206 carotid, 82, 134, 155r, 164
seizures due to, 206 transcranial, 87t, 134, 137, 141, 155r, 223, 229
Dexamethasone, for orolingual angioedema, Driving after stroke, 249Y250
68, 94 DSA. See Digital subtraction angiography
Diabetes mellitus, 36rY37r, 96c, 254c DVT (deep venous thrombosis) after stroke,
atherosclerotic occlusive disease and, 135, 99Y100, 101
136t, 137, 138 DWI or CTP Assessment With Clinical Mismatch
aortic arch atherosclerosis, 128 in the Triage of Wake-Up and Late Presenting
carotid endarterectomy or carotid artery Strokes Undergoing Neurointervention
stenting for, 147, 148c (DAWN) trial, 75, 77, 80r
endovascular vs. medical therapy to prevent Dysarthria, poststroke, 46c, 68c, 259c
recurrent stroke, 149, 151c acute vestibular syndrome and, 56, 57t
in CHADS2 risk stratification for atrial basilar artery stroke and, 48t
fibrillation, 114, 115c, 116t, 117t in cerebral amyloid angiopathy, 226c
hemoglobin A1c goal in, 24 in pontine syndromes, 54
hypertension and, 18 in Wallenberg syndrome, 53t

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 Cerebrovascular Disease

Dysarthria-clumsy hand syndrome, 57, 58t Encephalopathy. See also Leukoencephalopathy

Dyslipidemia. See Hyperlipidemia in Aicardi-Goutieres syndrome, 221
Dysphagia, poststroke, 100Y101, 108r CADASIL, 216Y217, 216c, 231r
acute vestibular syndrome and, 56, 57t differentiating aphasia from, 49, 58
aspiration pneumonia and, 101 differentiating stroke from, 42, 59t
evaluation for, 64, 101, 244 in children, 159t
sleep-disordered breathing and, 104t infectious, 59t, 245c
therapy for, 244, 251r metabolic, 59t
in Wallenberg syndrome, 53t, 54 posterior reversible encephalopathy syndrome,
211, 212t, 228, 229, 229c, 232
E toxic, 59t
ENCHANTED (Enhanced Control of Hypertension
E-cigarettes (electronic cigarettes), 15, 25Y26,
and Thrombolysis Stroke Study), 65
26c, 37r
Endocarditis, 124Y126
Early Prediction of Functional Outcome After
infective, 114t, 124Y126, 131r, 212t
Stroke (EPOS) study, 242, 251r
nonbacterial thrombotic (marantic), 126
EC-IC. See Extracranial-intracranial bypass surgery
Endovascular coiling of intracranial aneurysm,
ECG. See Electrocardiogram
188Y191, 209r
Echocardiogram, 129rY130r
Endovascular embolization of AVM, 195
appropriate use criteria for, 129r
Endovascular thrombectomy. See Mechanical
in cardioembolic stroke, 111, 112, 113t, 115c,
thrombectomy/stenting
129rY130r
Endovascular Treatment for Small Core and
in cerebral amyloid angiopathy, 226c
Anterior Circulation Proximal Occlusion With
in children, 162c, 164, 173c
Emphasis on Minimizing CT to Recanalization
to detect congenital heart lesions, 169
Times (ESCAPE) trial, 70t
in nonbacterial thrombotic endocarditis, 126
ENGAGE-AF TIMI-48 (A Phase 3, Randomized,
in TIA evaluation, 85
Double-Blind, Double-Dummy, Parallel Group,
transesophageal (TEE), 112, 113t, 129rY130r
Multi-Center, Multi-National Study for Evaluation
in aortic arch atherosclerosis, 128
of Efficacy and Safety of Edoxaban (DU-176b)
in atrial fibrillation, 123c
Versus Warfarin in Subjects With Atrial
in children, 164
Fibrillation), 118
in infective endocarditis, 125
Enhanced Control of Hypertension and
transthoracic (TTE), 112, 113t, 115c
Thrombolysis Stroke Study (ENCHANTED), 65
in aortic arch atherosclerosis, 128
Enoxaparin, prophylaxis for venous
in infective endocarditis, 125
thromboembolism, 100
in large artery atherosclerosis, 134
Epidemiology of stroke, 15Y17, 16f, 17f, 35rY36r
left ventricular thrombus identified on, 127
in children and young adults, 158Y159
Eclampsia, 228Y231, 230c, 232, 236rY237r
EPOS (Early Prediction of Functional Outcome
Economic costs of stroke, 238
After Stroke) study, 242, 251r
Edoxaban
ESCAPE (Endovascular Treatment for Small Core
to prevent stroke in atrial fibrillation, 118,
and Anterior Circulation Proximal Occlusion
120t, 131r
With Emphasis on Minimizing CT to
rtPA use and, 75
Recanalization Times) trial, 70t
EEG. See Electroencephalogram
Ehlers-Danlos syndrome type IV, 170, 184t ESICM (European Society for Intensive Care
Electrocardiogram (ECG) Medicine), 255
in acute stroke evaluation, 44, 45c ESPS-2 (European Stroke Prevention Study 2),
in children, 164 34, 39r
in atrial fibrillation, 45c, 85, 115c, 122 Estrogen therapy, 33, 168
in cardioembolic stroke, 111, 112, 113t Ethics: discussing life-sustaining therapy with
in infective endocarditis, 125 surrogate decision makers, 254Y257,
Electroencephalogram (EEG) 254cY255c, 255, 257rY258r
in CADASIL, 216c American Thoracic Society guidelines for, 255,
in cerebral amyloid angiopathy, 225 257, 257r
Electronic cigarettes (e-cigarettes), 15, 25Y26, futile care/potentially inappropriate treatment, 255
26c, 37r need for fair process, 255Y256
Electrostimulation, functional, 245, 245f, 248, palliative care, 256, 257
251rY252r steps for conflict resolution, 256
EMBRACE (30-Day Cardiac Event Monitor Belt for time pressure in decision making, 256Y257
Recording Atrial Fibrillation After a Cerebral European Society for Intensive Care Medicine
Ischemic Event) trial, 122 (ESICM), 255

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European Stroke Prevention Study 2 (ESPS-2), FLAME (Fluoxetine for Motor Recovery After Acute
34, 39r Ischemic Stroke) trial, 106, 110r, 246, 252r
Exercise. See Physical activity/exercise Fluoxetine, 105, 110r, 246, 248, 252r
Extending the Time for Thrombolysis in Emergency Fluoxetine for Motor Recovery After Acute Ischemic
Neurological DeficitsVIntra-Arterial (EXTEND-IA) Stroke (FLAME) trial, 106, 110r, 246, 252r
trial, 70t Fluvastatin, 22t
Extracranial-Intracranial (EC-IC) Bypass Study, Foville syndrome, 53t
147, 150 Fractures, poststroke, 102Y103, 108rY109r
Extracranial-intracranial (EC-IC) bypass surgery Fugl-Meyer Assessment of Sensorimotor Recovery
for intracranial stenosis, 147, 150Y151 After Stroke, 246
in moyamoya disease, 223 Functional electrostimulation, 245, 245f, 248,
Ezetimibe, 136t 251rY252r
Functional Independence Measure, 264, 265t
Futile care, 255. See also Life-sustaining therapy
F
Fabry disease, 113t, 169, 178r, 211, 212t,
213Y215, 231Y232, 232rY233r G
diagnosis of, 214 G20210A gene, 166, 166t, 167, 168, 169
enzyme replacement therapy for, 211, 215, GAL gene, 213
232rY233r !-Galactosidase deficiency, 214
genetics of, 213Y214 Gemfibrozil, 136t
MRI in, 213, 214, 214f Gender
neurologic manifestations of, 213 statin myopathy and, 22
prevalence of, 213 stroke risk and, 16Y17, 35r
Factor V, 166, 166t, 167t lipoprotein (a) elevation, 33
Factor VIII, 166, 166t, 167t metabolic syndrome, 24
Factor Xa inhibitors Genetic causes of stroke, 169Y170, 212t,
for acute MI and left ventricular thrombus, 128 213Y222, 231, 232rY234r
contraindicated for patients with mechanical or CADASIL, 169, 211, 212t, 213, 215Y220, 216c,
bioprosthetic heart valves, 124, 125t 217f, 219f, 221, 231, 232, 233rY234r
disadvantages of, 119t, 120 CARASIL, 170, 212t, 220Y221, 232, 234r
drug interactions with, 119t COL4A1-related cerebral small vessel disease,
to prevent stroke in atrial fibrillation, 118, 120t, 170, 212t, 222Y223, 232, 234r
121c, 123c, 131r Fabry disease, 113t, 169, 178r, 211, 212t,
rtPA use and, 66t, 75 213Y215, 214f, 231Y232, 232rY233r
Falls hereditary cerebral amyloid angiopathy, 213
anticoagulation for atrial fibrillation and, Marfan syndrome, 170, 212t, 213
121, 131r MELAS, 170, 213
poststroke, 102Y103, 106, 108r, 115c, 239t monogenic disorders, 213
Familial hypercholesterolemia, 33 retinal vasculopathy with cerebral leukodystrophy,
Familial Intracranial Aneurysm (FIA) study, 186 212t, 221, 232, 235r
Famotidine, effect on poststroke recovery, 247 Genome-wide association study of stroke,
Fast Assessment of Stroke and Transient Ischemic 138Y139
Attack to Prevent Early Recurrence (FASTER) Geographic disparities in stroke mortality, 16Y17,
trial, 89Y90, 92r 17f, 36r
Fatigue, poststroke, 105Y106, 110r Glycemic control, 63Y64, 152
in children and young adults, 176, 180r Gout, 136t, 138, 155r
Greater Cincinnati/Northern Kentucky Stroke
depression and, 105cY106c, 106, 248, 248c
Study, 35r
Fats, dietary, 27t, 28
Federation of State Medical Boards, 261
Fever H
in CADASIL encephalopathy, 216, 216c H2 blockers, effect on poststroke recovery, 247
in Fabry disease, 213 Hamilton Depression Rating Scale (HDRS), 106
in infection-induced encephalopathy, 246c HAMLET (Hemicraniectomy After Middle Cerebral
infective endocarditis with, 125 Artery Infarction With Life-threatening Edema
in mothers of infants with stroke, 162 Trial), 99
after stroke, 64, 102 HAS-BLED score, to estimate stroke risk in atrial
in children, 161, 161t, 162c, 169 fibrillation, 115, 115c, 118t
FIA (Familial Intracranial Aneurysm) study, 186 HDAC9 gene, 139
Fibrates, 33, 136t HDRS (Hamilton Depression Rating Scale), 106

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 Cerebrovascular Disease

Head Position in Stroke Trial (HeadPoST), 63, 78r preeclampsia/eclampsia and, 231
Headache statins for, 21Y23, 22t, 23c, 23f, 136t
in children, 159t, 172c, 173c stroke risk and, 15, 17, 21c, 36r, 135
with dipyridamole-aspirin therapy, 34 CADASIL and, 219
due to cavernous malformation, 199 in children and young adults, 160t, 161, 175
with intracerebral hemorrhage, 200 Hypertension
due to cerebral amyloid angiopathy, 225 in acute stroke, 43Y44
due to moyamoya disease, 172c, 223, 235r diabetes mellitus and, 18
due to unruptured intracranial aneurysm, 185 diet and, 28c
migraine, 59t goal blood pressure for, 18, 21c
in CADASIL, 211, 215Y216, 216c, 234r management of, 18, 36r, 136t, 138
morning, 104t lifestyle modifications, 19Y21
in pregnancy-related PRES, 229c medications, 18Y19, 19f, 20f, 21c
Health Professionals Follow-Up Study, 26 in metabolic syndrome, 24
Heart failure, 18, 62 obstructive sleep apnea and, 32
antiplatelet therapy for stroke prevention in, prevalence of, 17
128, 132r race and, 18
atrial fibrillation and, 128 stroke risk and, 15, 17Y22, 135+
cardioembolic stroke risk in, 128 CHADS2 to estimate risk in atrial
CHADS2 tool in atrial fibrillation, 114, 115c, fibrillation, 114
116t, 117t tobacco use and, 25
carotid artery stenting in, 143 Hypertonic saline, for cerebral edema, 98
hemorrhage after rtPA in, 95 Hypoglycemia, 59t, 63, 85
malignant cerebral edema and, 97 Hypothermia, 64
pediatric stroke and, 160t, 164
use of hypertonic saline in, 98
Hemicraniectomy, decompressive, 98c, 98f, 99, I
254c, 262 ICA. See Internal carotid artery
Hemicraniectomy After Middle Cerebral Artery ICARE (Interdisciplinary Comprehensive Arm
Infarction With Life-threatening Edema Trial Rehabilitation Evaluation) trial, 243
(HAMLET), 99 ICH. See Intracerebral hemorrhage
Hemoglobin A1c, 24 Idarucizumab, for dabigatran reversal, 119t, 120,
Heparin 120t, 131r
for children, 170 IDEAL (Incremental Decrease in Endpoints
prophylaxis for venous thromboembolism, Through Aggressive Lipid Lowering) trial, 22
99Y100, 101t, 108r ILAE (International League Against Epilepsy), 200
rtPA use and, 66t, 100 Incidence of stroke, 15Y16
vs. warfarin in nonbacterial thrombotic in children and young adults, 158Y159
endocarditis, 126 Incremental Decrease in Endpoints Through
Highly Effective Reperfusion Evaluated in Multiple Aggressive Lipid Lowering (IDEAL) trial, 22
Endovascular Stroke (HERMES) meta-analysis, Infections
95Y97 associated with infective endocarditis, 125
HINTS acronym, in vertigo, 56, 61r poststroke, 64, 65, 102
Hip fracture, poststroke, 102Y103, 108rY109r in children, 175
History taking, in acute stroke evaluation, 42Y43 stroke due to, 211, 212t
HIV (human immunodeficiency virus) disease, VIPS study, 160Y161, 162, 173, 178r
125, 212t Infective endocarditis, 104Y106
Homocysteine and stroke risk, 33, 138 Inferior vena cava filter, 100
in children, 166, 166t, 167, 168, 169, 179r Insulin resistance, 24, 28, 29, 38r, 136t. See also
HTRA1 gene, 220Y221, 232, 234r Diabetes mellitus
Human immunodeficiency virus (HIV) disease, Insulin Resistance Intervention After Stroke (IRIS)
125, 212t trial, 24
Hyperglycemia, 28, 63, 68, 77r, 84, 95. See also Insulin therapy, 63
Diabetes mellitus Interdisciplinary Comprehensive Arm Rehabilitation
Hyperlipidemia. See also Cholesterol Evaluation (ICARE) trial, 243
atherosclerotic occlusive disease and, 22Y23, Internal carotid artery (ICA) aneurysm, 184,
135, 138, 143c, 151c, 153c 186t, 189
aortic arch, 128 Internal carotid artery (ICA) occlusion/infarction,
diet and, 28 23c, 47Y48, 48t, 63
genetic dyslipidemia, 33 in children, 172c, 172f

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 EC-IC Bypass Study of, 150Y151 Intracranial aneurysms, unruptured, 181Y192,
endovascular treatment of, 142Y144, 148c, 148f 182t, 208rY209r
vs. medical treatment, 143c clinical presentation of, 185
in pregnancy, 230 definition and radiologic appearance of, 183
with malignant cerebral edema, 97 epidemiology of, 183Y185
measurement of, 140, 140f, 143c, 143f incidental discovery of, 181, 182t, 183, 185
mechanical thrombectomy for, 69, 70t, locations of, 183Y184
72cY73c, 73f management and treatment of, 186Y192
moyamoya disease, 222, 222f, 232 anticoagulation, 191Y192
TIA due to, 89c, 89f determining whether to treat an unruptured
carotid endarterectomy for, 89, 144, 145 aneurysm, 187Y188, 187f, 189c, 190f
extracranial-intracranial bypass for, 147 follow-up surveillance, 191
WASID study of, 149 in pregnancy, 192
International Alliance for Pediatric Stroke, 177 screening, 187
International Classification of Headache treatment of concurrent disease and lifestyle
Disorders, 200 restrictions, 191Y192
International Cooperative Study of treatment of unruptured intracranial
Extracranial-Intracranial (EC-IC) Bypass Study, aneurysm, 188Y191, 191f
147, 150Y151, 223 natural history data to predict rupture risk,
International League Against Epilepsy (ILAE), 200 185Y186, 186t
International Study of Aneurysm Treatment risk factors for growth and rupture, 186, 188t
(ISAT), 189, 191, 209r PHASES score, 181, 186, 187, 187f, 189c, 208r
International Study of Unruptured Intracranial Unruptured Intracranial Aneurysm Treatment
Aneurysms (ISUIA), 185Y186, 188, 189, 189c Score, 181, 187Y188, 190t
Intracerebral hemorrhage (ICH), 108r, 234r, 235r Intracranial atherosclerosis, 133, 147Y151,
antithrombotic therapy and, 126, 235r 151c, 157r
antiplatelet agents, 137Y138 Intravenous (IV) thrombolysis. See Recombinant
newer oral anticoagulants, 118, 119t, 121 tissue plasminogen activator
warfarin, 235r IRIS (Insulin Resistance Intervention After Stroke)
in atrial fibrillation patients who fall, 131r trial, 24
in CADASIL, 217Y218, 220, 234r ISAT (International Study of Aneurysm Treatment),
after carotid endarterectomy, 145 189, 191, 209r
in cerebral amyloid angiopathy, 212t, 224Y226, ISUIA (International Study of Unruptured
226c Intracranial Aneurysms), 185Y186, 188, 189, 189c
in COL4A1-related cerebral small vessel disease, IV (intravenous) thrombolysis. See Recombinant
221, 222, 232, 234r tissue plasminogen activator
as contraindication to rtPA, 41t, 66t
CT exclusion of, 41t, 86, 112, 113t, 115c, 228c
due to arteriovenous malformation, 192, 193, 194 K
due to capillary telangiectasias, 208 KRIT 1 gene, 199, 200t
due to cavernous malformation, 181, 196, 200,
201Y202, 201t, 212t
due to developmental venous anomalies, 206 L
early rehabilitation after, 243, 251r Labetalol, 44, 229c
heart failure and, 128 Lacunar (small vessel) stroke, 56Y57, 58t, 111, 224
hereditary, with amyloidosis, 212t basal ganglia, 248c
hypertension and, 43 blood pressure goal in, 19, 21c
infective endocarditis and, 125, 126 in CADASIL, 211, 215, 217, 232, 233r
after mechanical thrombectomy, 69, 70t, 97, 107r in CARASIL, 220
moyamoya disease and, 223 in children and young adults, 164
reversal of antithrombotics in, 79r, 107r clinically silent, 57
after rtPA, 65, 68, 79r, 94Y97, 95f in COL4A1-related cerebral small vessel disease,
hemorrhagic transformation subtypes, 94, 96t 221, 232
risk factors for, 68, 95 Large artery atherosclerosis, 133Y154, 154rY157r
treatment of, 68, 94, 96c anatomic localization of, 134
statin use after, 235r clinical presentation and workup of, 134Y135
telestroke approach to, 260cY261c, 262, 264 extracranial carotid atherosclerosis, 139Y147
unusual causes of, 212t assessment of, 139Y140, 140f
venous thromboembolism prophylaxis and, asymptomatic, 133, 141Y144, 143c
100, 101t symptomatic, 133, 144Y147, 148c

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 Cerebrovascular Disease

extracranial vertebral artery atherosclerosis, arteriovenous malformations, 192

133, 151Y154, 153c in cardioembolic stroke, 112, 114t
genome-wide association study of, 138Y139 in large artery atherosclerosis, 134
intracranial atherosclerosis, 133, 147Y151, 151c carotid stenosis, 140, 142, 148c, 148f
risk factors for, 135Y139 vertebral artery stenosis, 153c
emerging factors, 138Y139 for mechanical thrombectomy, 71t
vascular factors, 133Y134, 135Y138 in moyamoya disease, 223
TIA due to, 134 in pediatric stroke, 163f, 164, 165t, 172c,
treatment options for, 134 173c, 174f
Leukoaraiosis penumbra imaging, 63
CADASIL and, 215, 216c, 217, 219f, 233r telestroke interpretation, 265t
CARASIL and, 220 in TIA, 87
cerebral amyloid angiopathy and, 224 Magnetic resonance imaging (MRI)
COL4A1-related cerebral small vessel disease for acute stroke evaluation, 41t, 45, 47, 56, 61r
and, 221, 232 in children, 162cY163c, 164, 165t, 172c,
Fabry disease and, 213, 232 173c, 174f
as risk factor for intracerebral hemorrhage after telestroke interpretation, 265t
rtPA, 95 of aneurysms and vascular malformations, 182t,
Leukoencephalopathy 183, 209r
in CADASIL, 169, 211, 212t, 213, 215Y220, arteriovenous malformations, 192, 193, 193f
216c, 217f, 219f, 221, 231, 232, 233rY234r capillary telangiectasia, 206, 210r
in CARASIL, 170, 212t, 220Y221, 232, 234r cavernous malformations, 197Y199, 198f,
COL4A1-related cerebral small vessel disease 200, 204c, 204t, 209r
and, 221 developmental venous anomalies, 205,
Licensing of telestroke providers, 261, 264, 267t 205f, 206
Life-sustaining therapy, discussing with surrogate in CADASIL, 214, 216Y218, 216c, 217f, 219f,
decision makers, 254Y257, 254cY255c, 220, 233r
257rY258r in CARASIL, 220, 234r
American Thoracic Society guidelines for, 255, in cardioembolic stroke, 111, 112, 114t, 115c,
257, 257r 125Y126, 253c
futile care/potentially inappropriate atrial fibrillation, 123c
treatment, 255 in cerebral amyloid angiopathy, 225, 226,
need for fair process, 255Y256 226c, 227f
palliative care, 256, 257 in Fabry disease, 213, 214, 214f
steps for conflict resolution, 256 in large artery atherosclerosis, 134, 150c
time pressure in decision making, 256Y257 vertebral artery stenosis, 153c
Lifestyle modifications in malignant cerebral edema, 97
to lower stroke risk, 18.19.21c, 23c, 24, 28, 38r, in pregnancy-associated stroke, 228Y229, 229c
88Y89, 135, 136t, 138, 144, 148, 151c, 152, 153c in retinal vasculopathy with cerebral
in young adults, 175, 178r leukodystrophy, 221, 232
for patients with cavernous malformation, for rtPA, intracerebral hemorrhage due to, 94
202, 203t during stroke rehabilitation, 241f
to reduce cardiovascular risk after preeclamptic in TIA, 82, 83c, 83f, 87Y88, 92r
pregnancy, 231, 237r Magnetic resonance imaging (MRI)
to reduce risk of aneurysm rupture, 191, 192 diffusion/perfusion
Lipoprotein (a) elevation in pediatric stroke, 165t
conditions associated with, 33 penumbra imaging, 63, 72
large artery atherosclerosis and, 138 in wake-up stroke, 75, 76r
medications for, 33 Magnetic resonance venography, 165t
stroke risk and, 15, 32Y33, 39r Malcavernin, 199, 200t
in children, 166, 167, 167t Management of Atherothrombosis With
testing for, 33, 166t, 168, 169 Clopidogrel in High-Risk Patients With Recent
Locked-in syndrome, 48t, 54, 55c Transient Ischaemic Attack or Ischaemic Stroke
Lovastatin, 22t (MATCH) trial, 34, 39r, 155r
Mania, in CADASIL, 217
Mannitol, for cerebral edema, 97Y98
M Marantic endocarditis, 126
Magnetic resonance angiography (MRA) Marfan syndrome, 170, 212t, 213
of aneurysms and vascular malformations, 182t, MATCH (Management of Atherothrombosis With
183, 187, 189c, 191 Clopidogrel in High-Risk Patients With Recent

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 Transient Ischaemic Attack or Ischaemic aphasia due to, 48, 48t, 49, 72c, 105c, 115c
Stroke) trial, 34, 39r, 155r EC-IC Bypass Study of, 147, 150
MCA. See Middle cerebral artery endovascular treatment in pregnancy, 230, 230c
Mechanical and bioprosthetic heart valves, intracranial hemorrhage after rtPA for, 96c
123Y124, 124tY125t lacunar syndromes, 58t
Mechanical thrombectomy/stenting, 52c, 62, 63, with malignant cerebral edema, 97Y99, 98c, 98f,
64, 69Y75, 74f, 79rY81r, 246c 107rY108r
benefits of, 69 mechanical thrombectomy for, 69, 70t,
candidates for, 69, 72, 72cY73c, 72t, 73f, 74f 72cY73c, 73f
in children, 171 moyamoya disease, 222, 235r
conscious sedation for, 73Y75, 80r, 231, 236r nondominant (right MCA), 49Y51
future directions for, 77Y78 poststroke depression and, 105c
intracerebral hemorrhage after, 69, 70t, 97, 107r rehabilitation for, 235f, 246c
vs. IV thrombolysis for posterior circulation remote evaluation of, 259cY260c
strokes, 77 wake-up stroke due to, 76c, 76f
for large vessel atherosclerosis, 133Y154, WASID Study of, 149
155rY157r Migraine, 59t
asymptomatic extracranial carotid stenosis, in CADASIL, 211, 215Y216, 216c, 234r
133, 134, 139, 141Y144, 143c Mimics
CREST and CREST-2, 142Y143, 143c, 145, of cavernous malformation, 199t
146, 147, 156r of stroke, 40, 41, 43, 45, 57Y58, 59, 59t, 60r, 61r
extracranial vertebral artery disease, in children, 159Y160, 159t, 171, 178r
151Y154, 157r of TIA, 82, 84, 84c, 85, 86, 233
intracranial atherosclerosis, 149Y150 Mitochondrial disorders, 169, 170, 179r
SAMMPRIS trial, 90, 137Y138, 149Y150, 151c, Mitochondrial encephalomyopathy, lactic acidosis,
152, 153c, 157r and strokelike episodes (MELAS), 170, 213
SAPPHIRE trial, 141, 142, 144Y145 Mitral valve replacement, 123Y124
symptomatic extracranial carotid stenosis, Mobile stroke units, 77, 81r, 267r
144Y147, 148c Mortality from stroke, 15Y17, 35rY36r, 93, 106r,
vs. medical therapy for intracranial arterial 135, 238
stenosis, 90, 92r geography and, 16Y17, 17f, 36r
in patients taking newer anticoagulants, 75 race and, 16, 17
for posterior circulation strokes, 77 Moyamoya disease/syndrome, 179r, 211, 212t,
in pregnancy, 230Y231, 230c 222Y223, 222f, 232, 234rY235r
therapeutic window for, 74f, 77, 159 in children, 160t, 162, 171, 172c, 172f, 173
trials of, 69, 70tY71t, 75, 80r clinical features of, 223
in wake-up stroke, 76c, 76f ethnicity and, 223
Medical costs of stroke, 238 extracranial-intracranial bypass surgery in, 223
Mediterranean diet, 21, 26Y27, 27t, 28c, 36r, histopathology of, 222
38r, 136t MR CLEAN (Multicenter Randomized Clinical Trial
Medullary stroke syndromes, 53t, 54, 56, 57 of Endovascular Treatment for Acute Ischemic
MELAS (mitochondrial encephalomyopathy, lactic Stroke in the Netherlands), 70t, 73
acidosis, and strokelike episodes), 170, 213 MR WITNESS (A Phase II Safety Study of
Melodic intonation therapy, 245 Intravenous Thrombolysis With Alteplase in
Metabolic syndrome, 24 MRI-Selected Patients), 75, 77, 80r
Metformin, 24, 148c MRA. See Magnetic resonance angiography
MI. See Myocardial infarction MRI. See Magnetic resonance imaging
Middle cerebral artery (MCA) aneurysm, 184, MTHFR gene, 169
186t, 189c Multicenter Randomized Clinical Trial of
Middle cerebral artery (MCA) occlusion/infarction, Endovascular Treatment for Acute Ischemic
47, 47c, 48Y51, 48t, 52c Stroke in the Netherlands (MR CLEAN), 70t, 73
anterior cerebral artery territory infarction Multiple sclerosis, 84
and, 52 CADASIL misdiagnosed as, 211, 218, 219f, 232
atrial fibrillation and Myocardial infarction (MI), 36r, 78
anticoagulation for, 122 antiplatelet therapy for prevention of, 34,
risk stratification for recurrent stroke, 115c 39r, 128
in children, 162cY163c, 163f, 170, 171, 172c, in cerebral amyloid angiopathy, 226
172f, 173cY174c, 174f, 175, 180r blood pressure target and, 18
deciding on life-sustaining therapy for, 254c cardioembolic stroke and, 111, 127Y128
dominant (left MCA), 49 in young adults, 160t, 164, 175

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 Cerebrovascular Disease

carotid stenosis management and, 137, 147 NINDS. See National Institute of Neurological
gout and, 155r Disorders and Stroke
hormonal contraception and, 236r NOACs. See Novel oral anticoagulants
Mediterranean diet and, 26 NOMAS (Northern Manhattan Study), 33, 35r, 39r
rtPA use after, 67t Nonsteroidal anti-inflammatory drugs, 115,
TIA and, 86 118t, 136t
tobacco use and, 25, 36r North American Symptomatic Carotid
Myopathy, statin-induced, 22Y23, 23c, 36r Endarterectomy Trial (NASCET), 137Y138,
144Y145
Northern Manhattan Study (NOMAS), 33, 35r, 39r
N NOTCH3 gene, 216c, 217, 218, 234r
NASCET (North American Symptomatic Carotid Nothnagel syndrome, 53t
Endarterectomy Trial), 137Y138, 144Y145 Novel oral anticoagulants (NOACs), 120t
National Institute of Neurological Disorders and cost of, 120
Stroke (NINDS), 178r to prevent stroke in atrial fibrillation, 111, 115c,
genome-wide association study of stroke, 138Y139 118Y120
study of rtPA for acute ischemic stroke, 79r, trials of, 118, 131r
94, 107r vs. warfarin, 118Y120, 119t
National Institutes of Health (NIH) rtPA use and, 75, 120
genome-wide association study of stroke, use in cerebral amyloid angiopathy, 225Y226
138Y139 use in patients with mechanical heart valves,
POINT trial, 90 124, 125t
National Institutes of Health Stroke Scale Nurses’ Health Study, 26
(NIHSS), 40, 41t, 44, 46c, 51c, 55c, 59, 60r,
79r, 98c
biases in, 44 O
certification training, 59 Obesity/overweight, 96c
for mechanical thrombectomy, 70t, 72c, 72t, 76c dosing of novel oral anticoagulants in, 120
in remote stroke management, 259c, 261, 265t large artery atherosclerosis and, 135, 136t, 153c
for rtPA, 44, 64, 65f, 67t, 68c sleep-disordered breathing and, 104t
intracerebral hemorrhage, 94, 96c stroke risk and, 15, 17, 28Y29, 38r
in pregnancy, 230c in young adults, 160t, 175, 177
in young adults, 176 in stroke survivors, 29
Natural history of stroke, 240Y242 Obstructive sleep apnea (OSA)
Neglect, poststroke, 29, 48t, 96c atrial fibrillation and, 123c
bedside testing for extinction in, 50 continuous positive airway pressure for, 32,
fall risk and, 102 39r, 103, 104, 109r
on NIHSS, 44 CPAP for, 32, 39r, 103, 104, 105, 109r
nondominant (right) MCA stroke, 48, 48t, 49Y50 hypertension and, 32
rotigotine for, 252r large-vessel atherosclerosis and, 136t, 138, 153c
Neonatal stroke, 177rY179r. See also Childhood poststroke, 103Y105, 109r
and young adult ischemic stroke stroke risk and, 15, 32, 38rY39r
acute management of, 170 SLEEP TIGHT study, 155r
incidence of, 158, 159 in young adults, 161t
outcomes after, 175 Occupational therapy, 204c, 243, 244
recurrence risk for, 163, 167, 171 One-and-a-half syndrome, 53t
risk factors for, 162, 178r Oral hypoglycemic drugs, 24
secondary prevention of, 171Y173 Orolingual angioedema, rtPA-induced, 68,
thrombophilia and, 166, 168, 179r 93Y94, 106r
Neural regeneration, 240 OSA. See Obstructive sleep apnea
Osmotic therapy, for cerebral edema, 97Y98
Neurocritical care. See Life-sustaining therapy
O’Sullivan sign on MRI, in CADASIL, 217, 217f
Neuroplasticity and rehabilitation, 238, 240, 241f,
Oxford Vascular Study (OXVASC), 92r, 151Y152
245, 246, 247, 251r
in children, 163c
Neuroprotective agents, 63, 78 P
Niacin, 33, 136t PAIS (Paracetamol (Acetaminophen) in Stroke)
Nicardipine, 44, 96c trial, 79r
Nicotine replacement therapy, 25, 37r Palliative care, 256, 257, 258r
NIHSS. See National Institutes of Health Paracetamol (Acetaminophen) in Stroke (PAIS)
Stroke Scale trial, 79r

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Patent foramen ovale (PFO), 112, 123c POINT (Platelet-Oriented Inhibition in New TIA and
closure for cryptogenic stroke, 111, 126Y127, Minor Ischemic Stroke) trial, 90, 92r, 137, 155r
131rY132r, 179r Pollock-Flickinger score, to select AVM patients
pediatric stroke and, 160t, 169 for stereotactic radiosurgery, 194Y195, 197t
Patient Health Questionnaire (PHQ-9), 106 Polysomnography, 32, 105, 105c
PC-Trial (Randomized Clinical Trial Comparing Pontine stroke, 48t, 52, 54, 58t, 77
the Efficacy of Percutaneous Closure of Patent POSITIVE (PerfusiOn Imaging Selection of Ischemic
Foramen Ovale (PFO) With Medical Treatment STroke Patients for EndoVascular ThErapy) trial,
in Patients With Cryptogenic Embolism), 127 75, 80r
PCA. See Posterior cerebral artery Positron emission tomography (PET), 147
PDCD10 gene, 199, 200t Posterior cerebral artery (PCA)
Pediatric patients. See Childhood and young adult aneurysm, 186t
ischemic stroke occlusion/infarction, 48t, 52Y53, 53t, 54, 58t,
Penumbra 122, 123c, 254c
imaging of, 63, 72 Posterior circulation syndromes, 52Y56
maintaining viability of, 63 acute vestibular syndrome, 56, 57t
PerfusiOn Imaging Selection of Ischemic STroke brainstem syndromes, 52Y54, 53t, 55c
Patients for EndoVascular ThErapy (POSITIVE) cerebellar arteries, 56
trial, 75, 80r medullary stroke syndromes, 54
PET (positron emission tomography), 147 posterior cerebral artery, 54
PFO. See Patent foramen ovale reperfusion strategies for, 78
A Phase 3, Randomized, Double-Blind, Posterior inferior cerebellar artery (PICA) occlu-
Double-Dummy, Parallel Group, Multi-Center, sion/infarction, 48t, 53t, 54, 56
Multi-National Study for Evaluation of Efficacy Posterior reversible encephalopathy syndrome
and Safety of Edoxaban (DU-176b) Versus (PRES), in pregnancy, 211, 212t, 228, 229,
Warfarin in Subjects With Atrial Fibrillation 229c, 232
(ENGAGE-AF TIMI-48), 118 Potentially inappropriate treatment, 255. See also
A Phase II Safety Study of Intravenous Life-sustaining therapy
Thrombolysis With Alteplase in MRI-Selected Pravastatin, 22t
Patients (MR WITNESS), 75, 77, 80r PREDIMED (PrevenciFn con Dieta Mediterránea)
Phase IIIB, Double-Blind, Multicenter Study to study, 26
Evaluation the Efficacy and Safety of Alteplase Preeclampsia/eclampsia, 228Y231, 230c, 232,
in Patients With Mild Stoke: Rapidly Improving 236rY237r
Symptoms and Neurologic Deficits (PRISMS) Pregnancy
trial, 77, 80r cavernous malformation in, 201, 202, 203t
PHASES score, to predict risk of intracranial factors associated with neonatal stroke, 67t162
aneurysm rupture, 181, 186, 187, 187f, 189c, 208r stroke in, 226Y231, 232, 236rY237r
Phenobarbital, 247 causes of, 211, 212t, 228
Phenytoin, 247 highest risk time period for, 228
PHQ-9 (Patient Health Questionnaire), 106 preeclampsia/eclampsia and, 228Y231, 230c,
Physical activity/exercise, 29 232, 236rY237r
effect on insulin resistance, 29 prevalence of, 226, 228
for hypertension, 21 rtPA use for, 67t, 211, 230, 230c
for patients with unruptured intracranial treatment of, 230Y231, 230c
aneurysm, 192 unruptured intracranial aneurysm in, 192, 209r
recommendations for, 29Y31, 30tY31t, 31c, 38r, PRES (posterior reversible encephalopathy
135, 136t syndrome), in pregnancy, 211, 212t, 228, 229,
Physical inactivity and stroke risk, 15, 17, 29Y31 229c, 232
Physical therapy, 31, 31c, 243, 244 PREVAIL (PREvention of VTE after Acute Ischemic
PICA (posterior inferior cerebellar artery) Stroke With LMWH Enoxaparin) study, 99Y100
occlusion/infarction, 48t, 53t, 54, 56 Prevalence of stroke, 15Y16, 16f
Pioglitazone, 24, 37r, 136t in children and young adults, 158Y159
Pitavastatin, 22t PrevenciFn con Dieta Mediterránea (PREDIMED)
Platelet-Oriented Inhibition in New TIA and study, 26, 38r
Minor Ischemic Stroke (POINT) trial, 90, 92r, Prevention of stroke, 15, 16, 17Y35, 35rY39r
137, 155r antiplatelet therapy, 34Y35
Pneumatic compression devices to prevent risk factor management, 17Y33, 135Y138
venous thromboembolism, 100, 101t PREvention of VTE after Acute Ischemic Stroke
Pneumonia, 102, 241 With LMWH Enoxaparin (PREVAIL) study,
aspiration, 101, 102, 242 99Y100

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 Cerebrovascular Disease

PRISMS (Phase IIIB, Double-Blind, Multicenter Rankin Scale score, 27, 65f, 69, 70t, 79r, 99, 176,
Study to Evaluation the Efficacy and Safety of 197t, 243, 249, 265, 266t
Alteplase in Patients With Mild Stoke: Rapidly RCVS (reversible cerebral vasoconstriction
Improving Symptoms and Neurologic Deficits) syndrome), in pregnancy, 211, 212t, 228, 229,
trial, 77, 80r 229c, 232
PROactive (Prospective Pioglitazone Clinical Trial RE-LY (Randomized Evaluation of Long-Term
in Macrovascular Events), 24, 37r Anticoagulant Therapy With Dabigatran
A Prospective, Multicenter, Randomized Etexilate) trial, 118, 131r
Controlled Trial to Evaluate the Safety and REasons for Geographic and Racial Differences in
Efficacy of the STARFlex Septal Closure System Stroke (REGARDS) study, 16, 27, 35r
Versus Best Medical Therapy in Patients With Recanalization, 62, 63. See also Mechanical
a Stroke and/or Transient Ischemic Attack Due thrombectomy/stenting; Recombinant tissue
to Presumed Paradoxical Embolism Through a plasminogen activator
Patent Foramen Ovale (CLOSURE I), 126Y127 for basilar artery occlusion, 77, 81r
Prospective Pioglitazone Clinical Trial in in children, 171
Macrovascular Events (PROactive), 24, 37r malignant cerebral edema after, 98c
Protein C deficiency, 166, 166t, 167, 167t, 168, 169 reperfusion injury after, 64, 68, 111
Protein S deficiency, 166, 166t, 167t, 168, 169 in wake-up stroke, 75, 76c, 76f
Prothrombin G20210A mutation, 166, 166t, 167, Recombinant tissue plasminogen activator (rtPA),
168, 169 62, 64Y69, 68c, 79rY81r
Proton pump inhibitors, 247 in CADASIL, 220
Pseudobulbar affect, in CADASIL, 217 contraindications to, 43, 64, 66tY67t
Pulmonary embolism CT evaluation for, 41t, 61t, 64, 67t, 68, 68c,
after stroke, 86, 99, 100, 108r 74f, 263
unruptured aneurysm and anticoagulation for, decision to use, 52c
191Y192 determining eligibility for, 43, 64
CT findings, 47c
laboratory data, 44
Q NIHSS and, 44, 64, 65f, 67t, 68c, 75, 77
Quality monitoring for telestroke, 264, 265t dose and administration of, 65
guidelines for use of, 41tY42t
indications for, 64, 66t
R intracerebral hemorrhage after, 65, 68, 79r, 94,
R506Q gene, 166, 166t, 167t, 168, 169 94Y97, 95f
Race/ethnicity hemorrhagic transformation subtypes, 94, 96t
hypertension and, 18 risk factors for, 68, 95
moyamoya disease and, 223 treatment of, 68, 94, 96c
stroke risk and, 16, 17, 35rY36r limitations of, 68Y69
lipoprotein (a) elevation, 33 mechanical thrombectomy and, 72cY73c
Randomized Clinical Trial Comparing the Efficacy meta-analysis of trials of, 65f
of Percutaneous Closure of Patent Foramen orolingual angioedema after, 68, 93Y94, 106r
Ovale (PFO) With Medical Treatment in Patients for patients with minor and rapidly improving
With Cryptogenic Embolism (PC-Trial), 127 deficits, 75, 77
Randomized Evaluation of Long-Term Anticoagulant for posterior circulation strokes, 77
Therapy With Dabigatran Etexilate (RE-LY) trial, premixing of, 41t, 47c
118, 131r rapid access to and administration of, 41t, 47c
Randomized Evaluation of Recurrent Stroke sudden neurologic decline during infusion of, 68
Comparing PFO Closure to Established Current telestroke administration, in mobile stroke
Standard of Care Treatment (RESPECT), 127 unit, 77
Randomized Trial of Revascularization With telestroke decision to use, 260, 260c, 263Y264
Solitaire FR Device Versus Best Medical therapeutic window for, 64Y65, 68c, 74f, 77
Therapy in the Treatment of Acute Stroke Due use in children, 64, 171
to Anterior Circulation Large Vessel Occlusion use in older adults, 64, 65
Presenting Within 8 Hours of Symptom Onset use in patients taking anticoagulants, 75
(REVASCAT), 71t use in pregnancy, 67t, 211, 230, 230c
A Randomized Trial of Unruptured Brain for wake-up stroke, 75
Arteriovenous Malformations (ARUBA), 195Y196 Recurrent artery of Heubner, 52
Ranitidine Recurrent stroke. See Stroke recurrence
effect on poststroke recovery, 247 REGARDS (REasons for Geographic and Racial
for orolingual angioedema, 68, 94 Differences in Stroke) study, 16, 27, 35r

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Rehabilitation. See Stroke rehabilitation SAPPHIRE (Stenting and Angioplasty With
Remote evaluation of stroke. See Telestroke Protection in Patients at High Risk for
Rendu-Osler-Weber syndrome, 207 Endarterectomy trial, 141, 142, 144Y145
Reperfusion injury, 64, 68, 111 SCCM (Society of Critical Care Medicine), 255, 257r
Reperfusion treatments, 62Y63, 64Y75 Seizures, 109r
complications of, 93Y97 antiepileptic drugs for
orolingual angioedema after rtPA, 68, in cerebral amyloid angiopathy, 225, 225c
93Y94, 106r for children, 170
symptomatic intracranial hemorrhage, effect on poststroke recovery, 247
94Y97, 95f, 96c, 96t for patients with cavernous malformation,
IV thrombolysis with rtPA, 64Y69, 65f, 202, 203t
66tY67t, 68c in pregnancy, 203t
mechanical thrombectomy, 69Y75, 70tY72t, prophylaxis, 103
72cY73c, 73f, 74f in CADASIL, 215, 216, 216c
RESPECT (Randomized Evaluation of Recurrent cardioembolic stroke and, 111
Stroke Comparing PFO Closure to Established in cerebral amyloid angiopathy, 225
Current Standard of Care Treatment), 127 in children, 159, 159t
Retinal vasculopathy with cerebral leukodystrophy, cognitive outcomes of, 176
212t, 221, 232, 235r neonates, 170
Return to driving after stroke, 249Y250 differentiation from stroke, 59t
Return to work after stroke, 249, 253r driving and, 249Y250
REVASCAT (Randomized Trial of Revascularization due to brain tumor, 59t
With Solitaire FR Device Versus Best Medical due to subdural hematoma, 84c
Therapy in the Treatment of Acute Stroke Due to in eclampsia, 228, 229, 229c
Anterior Circulation Large Vessel Occlusion poststroke, 102, 103, 106, 109r
Presenting Within 8 Hours of Symptom rtPa use and, 51cY52c, 67t
Onset), 71t vascular malformations and, 182t, 208
Reversible cerebral vasoconstriction syndrome arteriovenous malformations, 192, 193,
(RCVS), in pregnancy, 211, 212t, 228, 229, 194, 196
229c, 232 capillary telangiectasias, 207
Rhabdomyolysis, statin-induced, 22, 136t cavernous malformations, 196, 199Y200,
Rivaroxaban 202, 203t
for acute MI and left ventricular thrombus, 128 developmental venous anomalies, 206
to prevent stroke in atrial fibrillation, 118, 120t, Selective serotonin reuptake inhibitors (SSRIs),
123c, 131r 106, 238, 246, 248, 248c
rtPA use and, 75 Sertraline, 248, 252r
Rivaroxaban Once-daily Oral Direct Factor Xa SHINE (Stroke Hyperglycemia Insulin Network
Inhibition Compared With Vitamin K Antagonism Effort) trial, 63Y64, 78r
for Prevention of Stroke and Embolism Trial in Shoulder syndrome, 247Y248
Atrial Fibrillation (ROCKET-AF), 118, 131r Sickle cell anemia, 161t, 168, 170, 171, 173, 179r,
RNF213 gene, 223 180r, 212t, 222
Robert J. Waters Center for Telehealth & e-Health SiGN (Stroke Genetics Network), 139
Law, 261 Silent infarction, 15, 25, 57
ROCKET-AF (Rivaroxaban Once-daily Oral Direct Simvastatin, 22, 22t, 89c, 204t
Factor Xa Inhibition Compared With Vitamin K Single-photon emission computed tomography
Antagonism for Prevention of Stroke and (SPECT) perfusion scan, 165t, 172c
Embolism Trial in Atrial Fibrillation), 118, 131r Sleep apnea
Rosuvastatin, 22t, 23c, 151c, 153c atrial fibrillation and, 123c
Rotterdam Study, 86Y87 CPAP for, 32, 39r, 103, 104, 105, 109r
rtPA. See Recombinant tissue plasminogen activator hypertension and, 32
large-vessel atherosclerosis and, 136t, 138, 153c
poststroke, 32, 103Y105, 109r
S stroke risk and, 15, 32, 38rY39r
Saccular aneurysms, 183. See also Intracranial SLEEP TIGHT study, 155r
aneurysms, unruptured in young adults, 161t
SAH. See Subarachnoid hemorrhage Smoking. See Tobacco use/smoking
SAMMPRIS (Stenting vs. Aggressive Medical Society of Critical Care Medicine (SCCM),
Management for Preventing Recurrent Stroke 255, 257r
in Intracranial Stenosis) trial, 90, 137Y138, Soda consumption, stroke risk and, 26
149Y150, 151c, 152, 153c, 157r Sodium, dietary, 28, 28c, 38r

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 Cerebrovascular Disease

Solitaire With the Intention for Thrombectomy as antiplatelet therapy, 34Y35

Primary Endovascular Treatment (SWIFT-PRIME) risk factor management, 17Y33, 135Y138
trial, 71t silent infarction, 15, 25, 57
Spasticity, poststroke, 248Y249, 251rY252r TIA and, 82Y91, 91rY92r
in cerebral palsy, 158, 159 Stroke clinical evaluation, 40Y59, 59rY61r
exercise and, 29 AHA/ASA guidelines for, 40, 41tY42t
in shoulder syndrome, 247, 248 defining stroke syndromes, 45Y57
spinal shock and, 57 anterior circulation syndromes, 47Y52
treatment of, 249 lacunar (small vessel) syndromes, 56Y57
SPECT (single-photon emission computed posterior circulation syndromes, 52Y56
tomography) perfusion scan, 165t, 172c spinal vascular syndromes, 57
Speech and language therapy, 244Y245 establishing last known well time, 42, 46c, 64
Spetzler-Martin AVM grading system to assess initial brain imaging, 45, 46cY47c, 46t
surgical risk, 194, 195t, 196t initial examination, 43Y44
Spinal vascular syndromes/spinal shock, 57 initial history, 42Y43
Spondylosis deformans, in CARASIL, 220, 232 laboratory data, 44Y45
SPRINT (Systolic Blood Pressure Intervention NIHSS, 40, 41t, 44
Trial), 138 telestroke, 61r, 250, 259Y265, 259cY260c,
SSRIs (selective serotonin reuptake inhibitors), 265rY267t
106, 238, 246, 248, 248c Stroke complications, 93Y106, 106rY110r
Statin therapy, 15, 16, 35. See also specific drugs early, 93Y102
for aortic arch atherosclerosis, 128Y129 associated with acute reperfusion therapy,
in CADASIL, 220, 234r 93Y97, 95f, 96c, 96t
effect on intracerebral hemorrhage risk, 234r dysphagia and nutritional issues, 100Y101
in cerebral amyloid angiopathy, 226, 226c, 232 falls, 102
in Fabry disease, 215 infection, 102
for hyperlipidemia, 21Y23, 22t, 23c malignant cerebral edema, 97Y99, 98c, 98f
to lower lipoprotein (a), 33 venous thromboembolism, 99Y100, 101t
myopathy induced by, 22Y23, 23c, 36r late, 102Y106
for patients with cavernous malformation, 204t depression, 105Y106, 105cY106c
for patients with vascular risk factors, 136t, 138 falls and fractures, 102Y103
carotid stenosis, 143c, 145 seizures, 103
extracranial vertebral artery atherosclerosis, sleep-disordered breathing, 103Y105, 104t
152, 153c Stroke Genetics Network (SiGN), 139
intracranial atherosclerosis, 150, 151c Stroke Hyperglycemia Insulin Network Effort
after TIA, 88, 89c, 234r (SHINE) trial, 63Y64, 78r
use in young adults, 175 Stroke mimics, 40, 41, 43, 45, 57Y58, 59, 59t, 60r, 61r
Stem cell therapy, 240, 250 in children, 159Y160, 159t, 171, 178r
Stenting. See Mechanical thrombectomy/stenting remote evaluation of, 260, 265t
Stenting and Angioplasty With Protection in Stroke recurrence, 35r
Patients at High Risk for Endarterectomy acute stroke treatment to reduce risk of, 64
(SAPPHIRE) trial, 141, 142, 144Y145 antiplatelet therapy to reduce risk of, 34Y35,
Stenting vs. Aggressive Medical Management for 89Y90, 155r
Preventing Recurrent Stroke in Intracranial aortic arch atherosclerosis and, 128
Stenosis (SAMMPRIS) trial, 90, 137Y138, atrial fibrillation and, 115c
149Y150, 151c, 152, 153c, 157r in children and young adults, 158, 162Y164,
Stroke 169, 178rY179r
acute ischemic, treatment of, 62Y78, 78rY81r prevalence of, 175
cardioembolic, 111Y129, 129rY132r secondary prevention of, 171Y175,
in children and young adults, 158Y177, 177rY180r 173cY174c, 177
continuum of care for, 238 thrombophilia and, 166, 167Y168, 167t
epidemiology of, 15Y17, 16f, 17f, 35rY36r VIPS study, 173
incidence of, 15Y16 diabetes mellitus and risk of, 24
inherited and uncommon causes of, 212Y232, due to uncommon causes, 211, 232
232rY237r cerebral amyloid angiopathy, 224
medical costs of, 238 Fabry disease, 215
mortality from, 15Y17, 93, 106r, 135, 238 moyamoya disease, 223
natural history of, 240Y242 exercise effect on risk of, 29
prevalence of, 15Y16, 16f extracranial vertebral artery atherosclerosis
prevention of, 15, 16, 17Y35, 35rY39r and, 152, 153

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 intracranial atherosclerosis and, 149, 157r middle cerebral artery, 48Y51
SAMMPRIS trial, 90, 137Y138, 149Y150, 151c, lacunar (small vessel) syndromes, 56Y57
152, 153c, 157r posterior circulation syndromes, 52Y56
lipoprotein (a) and, 33 acute vestibular syndrome, 56, 57t
obstructive sleep apnea and, 32, 104 brainstem syndromes, 52Y54, 53t, 55c
patent foramen ovale closure and, 126Y127, cerebellar arteries, 56
169 medullary stroke syndromes, 54
in patients with motor and speech symptoms, 84 posterior cerebral artery, 54
rate of, 15, 16 spinal vascular syndromes, 57
after TIA, 82, 83, 87 Study of Continuous Cardiac Monitoring to Assess
carotid artery stenosis and, 89, 89c Atrial Fibrillation After Cryptogenic Stroke
clinical and imaging findings predictive of, (CRYSTAL AF), 122
87Y88, 88t, 92r Subarachnoid hemorrhage (SAH)
risk factors for, 86Y87, 91r arteriovenous malformation and, 193
risk stratification tools for, 86 cavernous malformation and, 200, 226c, 227f
Stroke rehabilitation, 238Y250, 250rY253r cerebral amyloid angiopathy and, 225
definition of, 239 as contraindication to rtPA, 66t
emerging techniques in, 250 hypertension and, 43
natural history of stroke, 240Y242 incidence of, 185
pharmacologic approaches to, 246Y247 as risk factor for intracranial aneurysm rupture,
settings for, 244, 245Y246, 246c 181, 182t, 186tY188t, 189c
specific issues in, 247Y250 unruptured intracranial aneurysm in persons
depression, 248, 248c with family history of, 183, 184t, 187, 208r
return to driving, 249Y250 Subdural hematoma, 84c, 86, 121
return to work, 249 Surgical clipping of intracranial aneurysm,
shoulder syndrome, 247Y248 188Y191, 209r
spasticity, 248Y249 Surrogate decision makers, 52c
vs. stroke recovery, 239Y240 discussing life-sustaining therapy with,
telerehabilitation, 250 254Y257, 254cY255c, 257rY258r
therapy approaches and goals for SWIFT-PRIME (Solitaire With the Intention for
constraint-induced movement therapy, Thrombectomy as Primary Endovascular
243, 245 Treatment) trial, 71t
functional electrostimulation, 245, 245f Systolic Blood Pressure Intervention Trial
melodic intonation therapy, 245 (SPRINT), 138
team-based approach, 244Y245
therapy approaches and goals of, 239t, 244Y246
timing and intensity of, 238, 242Y244 T
Stroke risk factors, 15Y16, 17Y33 TCD (transcranial Doppler), 87t, 134, 137, 141,
age, 16, 17f 155r, 223, 229
in children and young adults, 160Y162, TEE. See Echocardiogram, transesophageal
160tY161t Telerehabilitation, 250
diabetes mellitus and metabolic syndrome, 24 Telestroke, 61r, 250, 259Y265, 259cY260c,
diet/nutrition, 26Y28 265rY267t
emerging factors, 31Y33 CT/MRI interpretation, 261, 262Y263, 263t,
elevated lipoprotein (a), 32Y33 265t, 266r
obstructive sleep apnea, 32 decision to use rtPA, 77, 260, 260c, 263Y264
gender, 16, 17 documentation and coding for, 264
hyperlipidemia, 15, 17, 22Y23, 23f guidelines and recommendations for practice
hypertension, 15, 17Y22 of, 261, 262t
obesity, 28Y29 licensing, credentialing, and privileging of
physical inactivity, 29Y31 providers of, 261, 264
race, 16, 17 metrics of, 263Y264
scoring systems in atrial fibrillation, 114Y115, time points for documentation, 263, 263t
115c, 116tY118t monitoring quality of, 264, 265t
tobacco use, 25Y26 network models for, 260Y261
vascular factors, 133Y134, 135Y138 NIHSS in, 259c, 261, 265t
Stroke syndromes, 45Y57, 48t stroke systems of care and, 261Y263
anterior circulation syndromes, 47Y52 30-Day Cardiac Event Monitor Belt for Recording
anterior cerebral artery, 51Y52 Atrial Fibrillation After a Cerebral Ischemic
internal carotid artery, 47Y48 Event (EMBRACE) trial, 122

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 Cerebrovascular Disease

THRACE (The Contribution of Intra-arterial United Kingdom Transient Ischemic Attack

Thrombectomy in Acute Ischemic Stroke in trial, 19, 19f
Patients Treated With Intravenous Thrombolysis) mimics of, 82, 84, 84c, 85, 86, 233
trial, 71t, 77, 80r moyamoya disease and, 223, 231
Thrombocytopenia, 95, 229 MRI in, 82, 83c, 83f, 87Y88, 92r, 134
Thrombophilia and childhood ischemic stroke, obstructive sleep apnea and, 32, 38r, 109r
165Y169, 166t, 167t, 178rY179r patent foramen ovale closure and, 127
TIA. See Transient ischemic attack prognosis for, 86Y88
Tissue plasminogen activator. See Recombinant clinical/event features and scores, 86Y87
tissue plasminogen activator imaging findings, 87Y88, 88t
Tobacco use/smoking prolonged cardiac rhythm monitoring
aortic arch atherosclerosis and, 128 after, 122
CADASIL and, 219 stuttering, 42Y43
carotid artery stenosis and, 143c, 147, 148c Treatment of acute ischemic stroke, 62Y78,
cessation of, 25, 26, 26c, 37r, 89, 135, 136t, 231 78rY81r
e-cigarettes, 25Y26, 26c, 37r acute reperfusion treatments, 64Y75, 74f
intracranial aneurysm and, 183, 184t, 185, 186, complications of, 93Y97, 95f, 96c, 96t
188t, 192 mechanical thrombectomy, 69Y75, 70tY72t,
intracranial atherosclerosis and, 151c, 153c 72cY73c, 73f, 74f
preeclampsia/eclampsia and, 231 rtPA, 64Y69, 65f, 66tY67t, 68c
secondhand smoke exposure, 25, 26c, 37r in children and young adults, 170Y171
smokeless tobacco products, 25, 37r future directions for, 77Y78
stroke risk and, 15, 17, 23f, 25Y26, 37r principles of, 63Y64
in young adults, 160t, 161, 175, 177 remote (See Telestroke)
TIA and, 89c in special situations, 75Y77
Topiramate, 172c, 173c IV thrombolysis in patients taking newer
tPA. See Recombinant tissue plasminogen activator anticoagulants, 75
Tranexamic acid, for intracerebral hemorrhage, minor and rapidly improving deficits,
68, 94 75Y77
Transcranial Doppler (TCD), 87t, 134, 137, 141, posterior circulation strokes, 77
155r, 223, 229 wake-up stroke, 75, 76c, 76f
Transient ischemic attack (TIA), 82Y91, 91rY92r therapeutic window for, 64Y65, 74f, 77
atrial fibrillation and, 86, 87, 114, 122 TREX1 gene, 170, 221, 232, 234r
CADASIL and, 215 Triglyceride levels, 24, 28, 38r, 136t, 226
cerebral amyloid angiopathy and, 225, 226c Triptans, use in CADASIL, 220
in children and young adults, 171 Troponins, 44, 112
recurrent stroke risk and, 164, 167, 173, TSPAN2 gene, 139
173c, 175 TTE. See Echocardiogram, transthoracic
clinical presentation and workup of, 134
CT in, 82, 83c, 84c, 86, 87, 89c, 92r, 134
definition and clinical diagnosis of, 82Y84, 83c U
diagnostic workup for, 134 UCAS (Unruptured Cerebral Aneurysm Study),
due to extracranial carotid artery stenosis, 185, 208r
89c, 89f UIATS (Unruptured Intracranial Aneurysm
carotid endarterectomy for, 89, 144, 145 Treatment Score), 181, 187Y188, 190t
extracranial-intracranial bypass for, 147 UK-TIA (United Kingdom Transient Ischemic
due to extracranial vertebral artery stenosis, Attack) trial, 19, 19f
151, 152 Ultrasound
due to intracranial atherosclerosis, 149, 150 carotid, 23c, 82, 87, 112, 134, 140, 142, 143c,
Fabry disease and, 215 143f, 155r, 164
laboratory investigations in, 85Y86 in pregnancy, 229
management for stroke prevention, 88Y90 transcranial Doppler, 87t, 134, 137, 141, 155r,
antiplatelet therapy, 34, 89Y90, 127, 129, 137, 223, 229
149, 151, 155r United Kingdom Transient Ischemic Attack
carotid revascularization, 89, 89c (UK-TIA) trial, 19, 19f
diabetes mellitus screening, 24 Unruptured Cerebral Aneurysm Study (UCAS),
exercise, 31 185, 208r
obesity screening, 29 Unruptured Intracranial Aneurysm Treatment
outpatient vs. inpatient assessment, 90 Score (UIATS), 181, 187Y188, 190t
statin therapy, 21, 22Y23, 88, 129 Urinary tract infection, 59t, 102, 246c

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V Vertigo, 48t, 53, 54, 56. See also Dizziness
acute vestibular syndrome, 56, 57, 61r
VADAS-cog (Vascular Dementia Assessment Scale
in Fabry disease, 213
cognitive subscale), 220
HINTS acronym for diagnosis of, 56, 61r
Valvular heart disease and stroke, 122Y126, 131r
Very Early Constraint-Induced Movement During
infective endocarditis, 124Y126
Stroke Rehabilitation (VECTORS) trial, 243, 251r
mechanical and bioprosthetic heart valves,
VIPS (Vascular Effects of Infection in Pediatric
123Y124, 124tY125t
Stroke) study, 160Y161, 162, 173, 178r
nonbacterial thrombotic endocarditis, 126
VIST (Vertebral Artery Ischaemia Stenting Trial),
Varenicline, for smoking cessation, 25, 37r
152, 157r
Vascular Dementia Assessment Scale cognitive
Vitamin D
subscale (VADAS-cog), 220
for cavernous malformations, 204t
Vascular Effects of Infection in Pediatric Stroke
for statin myopathy, 23
(VIPS) study, 160Y161, 162, 173, 178r
after stroke, 103
Vascular malformations, 181Y182, 192Y208,
Vocational rehabilitation, 249
209rY210r
arteriovenous malformations, 192Y196, 193f,
195tY197t W
capillary telangiectasia, 206Y208, 207f Wake-up stroke, 75, 76c, 80r, 155r
cavernous malformations, 196Y205, 198f, Wallenberg syndrome, 48t, 53t, 54
199tY201t, 203tY204t, 204f WARCEF (Warfarin Versus Aspirin in Reduced
comparison of, 182t Cardiac Ejection Fraction) trial, 128
developmental venous anomalies, 205Y206, 205f Warfarin
Vasopressors, 63, 77Y78, 162c in acute MI and left ventricular thrombus,
VAST (Vertebral Artery Stenting Trial), 151Y152 127Y128
VECTORS (Very Early Constraint-Induced Movement in aortic arch atherosclerosis, 128Y129, 132r
During Stroke Rehabilitation) trial, 243, 251r APOE ( variants and bleeding risk with, 235r
Venous developmental anomalies, 181, 182t, in cerebral amyloid angiopathy, 225
205Y206, 205f, 210r in heart failure, 128, 132r
cavernous malformation and, 198Y199, 205 in intracranial atherosclerosis, 149, 159r
clinical presentation of, 205Y206 laboratory testing of stroke patients on, 41t, 44, 45
definition and radiologic appearance of, in nonbacterial thrombotic endocarditis, 126
205, 205f for patients with mechanical or bioprosthetic
epidemiology of, 205 heart valves, 123Y124, 124tY125t
management and treatment of, 206 bleeding associated with, 124, 126
natural history of, 206 in pediatric stroke, 162c, 170
seizures due to, 206 rtPA use and, 67t, 75
Venous thromboembolism for stroke prevention in atrial fibrillation, 60r,
after stroke, 62, 99Y100, 101, 108r 115c, 120t, 131r
thrombophilia and, 166 vs. antiplatelet therapy, 116Y117
Vertebral artery vs. novel oral anticoagulants, 118Y120,
aneurysm, 186t 119t, 121c
dissection of, 57t Warfarin-Aspirin Symptomatic Intracranial Disease
endarterectomy, 153Y154 (WASID) study, 149, 150
Vertebral Artery Ischaemia Stenting Trial (VIST), Warfarin Versus Aspirin in Reduced Cardiac
152, 157r Ejection Fraction (WARCEF) trial, 128
Vertebral artery occlusion/infarction, 48t, 53t, 54 WASID (Warfarin-Aspirin Symptomatic Intracranial
atherosclerotic disease, 133Y134, 139 Disease) study, 149, 150
extracranial, 151Y154, 153c, 157r Weber syndrome, 48t, 53t
in children, 172c, 172f Work return after stroke, 249, 253r
prognosis for, 157r Wyburn-Mason syndrome, 207
WASID study of, 149
Vertebral Artery Stenting Trial (VAST), 151Y152
Vertebrobasilar occlusive disease, 87, 133Y134, Y
139, 151, 157r Young adults. See Childhood and young adult
in Fabry disease, 213, 214 ischemic stroke

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 Cerebrovascular Disease
List of Abbreviations
5-HT1 5-Hydroxytryptamine 1 ICARE Interdisciplinary Comprehensive Arm Rehabilitation
AACN American Association for Critical Care Nurses Evaluation [trial]
ACA Anterior cerebral artery ICD-9-CM International Classification of Diseases, Ninth Revision,
ACAS Asymptomatic Carotid Atherosclerosis Study Clinical Modification
ACCP American College of Chest Physicians ICD-10-CM International Classification of Diseases, Tenth Revision,
ACES Asymptomatic Carotid Emboli Study Clinical Modification
ACST Asymptomatic Carotid Surgery Trial ICH Intracerebral hemorrhage
ACTIVE A Atrial Fibrillation Clopidogrel Trial With Irbesartan for ICSS International Carotid Stenting Study
Prevention of Vascular Events IDEAL Incremental Decrease in Endpoints Through Aggressive Lipid
AED Antiepileptic drug Lowering [trial]
AF Atrial fibrillation IgG Immunoglobulin G
AHA American Heart Association IgM Immunoglobulin M
AICA Anterior inferior cerebellar artery ILAE International League Against Epilepsy
ARAT Action Research Arm Test IM Intramuscular
ARCH Aortic Arch Related Cerebral Hazard Trial INR International normalized ratio
ARIC Atherosclerosis Risk in Communities [registry] IQ Intelligence quotient
ARISTOTLE Apixaban for the Prevention of Stroke in Subjects With IRIS Insulin Resistance Intervention After Stroke [trial]
Atrial Fibrillation ISAT International Study of Aneurysm Treatment
ARUBA A Randomized Trial of Unruptured Brain Arteriovenous ISTH International Society on Thrombosis and Haemostasis
Malformations ISUIA International Study of Unruptured Intracranial Aneurysms
ASA American Stroke Association IV Intravenous
ASCOT-BPLA Anglo-Scandinavian Cardiac Outcomes Trial–Blood JNC 8 Eighth Joint National Committee
Pressure–Lowering Arm LDL-C Low-density lipoprotein cholesterol
ASPECTS Alberta Stroke Program Early CT Score MATCH Management of Atherothrombosis With Clopidogrel in High-Risk
AVERT A Very Early Rehabilitation Trial Patients With Recent Transient Ischaemic Attack or Ischaemic
AVM Arteriovenous malformation Stroke [trial]
BASICS Basilar Artery International Cooperation Study MCA Middle cerebral artery
BMI Body mass index MELAS Mitochondrial encephalomyopathy, lactic acidosis, and
CADASIL Cerebral autosomal dominant arteriopathy with subcortical strokelike episodes
infarcts and leukoencephalopathy MI Myocardial infarction
CAPRIE Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic MR Magnetic resonance
Events [trial] MR CLEAN Multicenter Randomized Clinical Trial of Endovascular Treatment
CARASIL cerebral autosomal recessive arteriopathy with subcortical for Acute Ischemic Stroke in the Netherlands
infarcts and leukoencephalopathy MR WITNESS A Phase IIa Safety Study of Intravenous Thrombolysis With
CAVATAS Carotid and Vertebral Artery Transluminal Angioplasty Study Alteplase in MRI-Selected Patients
CEA Carotid endarterectomy MRA Magnetic resonance angiography
CHANCE Clopidogrel in High-risk Patients With Acute Non-disabling MRI Magnetic resonance imaging
Cerebrovascular Events [trial] mRS Modified Rankin Scale
CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic NASCET North American Symptomatic Carotid Endarterectomy Trial
Stabilization, Management, and Avoidance [trial] NIH National Institutes of Health
CK Creatine kinase NIHSS National Institutes of Health Stroke Scale
CLOTS Clots in Legs or Stockings After Stroke [study] NINDS National Institute of Neurological Disorders and Strokes
CMS Centers for Medicare & Medicaid Services NOAC Novel oral anticoagulant
CNS Central nervous system NOMAS Northern Manhattan Study
CPAP Continuous positive airway pressure OSA Obstructive sleep apnea
CPT Current Procedural Terminology OXVASC Oxford Vascular Study
CREST Carotid Revascularization Endarterectomy Versus Stenting Trial PCA Posterior cerebral artery
CREST-2 Carotid Revascularization and Medical Management for PET Positron emission tomography
Asymptomatic Carotid Stenosis Study PFO Patent foramen ovale
CSF Cerebrospinal fluid PICA Posterior inferior cerebellar artery
CSP US Department of Veterans Affairs Cooperative Study Program POINT Platelet-Oriented Inhibition in New TIA and Minor Ischemic
CT Computed tomography Stroke [trial]
CTA Computed tomography angiography POSITIVE PerfusiOn Imaging Selection of Ischemic STroke Patents for
DASH Dietary Approaches to Stop Hyper tension EndoVascular ThErapy
DAWN DWI or CTP Assessment With Clinical Mismatch in the Triage of PREDIMED Prevención con Dieta Mediterránea
Wake-Up and Late Presenting Strokes Undergoing Neurointervention PRES Posterior reversible encephalopathy syndrome
DECIMAL Decompressive Craniectomy in Malignant Middle Cerebral PREVAIL PREvention of VTE After Acute Ischemic Stroke With LMWH
Artery Infarcts [trial] Enoxaparin [study]
DEFUSE 3 Diffusion and Perfusion Imaging Evaluation for Understanding PRISMS A Phase IIIB, Double-Blind, Multicenter Study to Evaluate the
Stroke Evolution Efficacy and Safety of Alteplase in Patients With
DESTINY Decompressive Surgery for the Treatment of Malignant Infarction Mild Stroke: Rapidly Improving Symptoms
of the Middle Cerebral Artery [trial] and Neurologic Deficits
DICOM Digital imaging and communications in medicine PROactive Prospective Pioglitazone Clinical Trial in Macrovascular Events
DNA Deoxyribonucleic acid PT Prothrombin time
DSA Digital subtraction angiography PTAS Percutaneous transluminal angioplasty and stenting
DVT Deep venous thrombosis REGARDS REasons for Geographic And Racial Differences in Stroke [trial]
DWI Diffusion-weighted imaging RE-LY Randomized Evaluation of Long-Term Anticoagulant Therapy
ECASS European Cooperative Acute Stroke Study With Dabigatran Etexilate
ECG Electrocardiogram ROCKET-AF Once-daily Oral Direct Factor Xa Inhibition Compared With
EC-IC Extracranial-intracranial Vitamin K Antagonism for Prevention of Stroke and Embolism
ECST European Carotid Surgery Trial Trial in Atrial Fibrillation [trial]
ED Emergency department rtPA Recombinant tissue plasminogen activator
EEG Electroencephalogram SAH Subarachnoid hemorrhage
EGFR Epidermal growth factor repeat SAMMPRIS Stenting vs. Aggressive Medical Management for Preventing
E/M Evaluation and Management Recurrent Stroke in Intracranial Stenosis
EMBRACE 30-Day Cardiac Event Monitor Belt for Recording Atrial SAPPHIRE Stenting and Angioplasty With Protection in Patients at High
Fibrillation After a Cerebral Ischemic Event Risk for Endarterectomy [trial]
EMG Electromyography SCCM Society of Critical Care Medicine
EMS Emergency medical services SHINE Stroke Hyperglycemia Insulin Network Effort [trial]
ENCHANTED Enhanced Control of Hypertension and Thrombolysis sICH Symptomatic intracerebral hemorrhage
Stroke Study SiGN Stroke Genetics Network
EPOS Early Prediction of Functional Outcome After Stroke [study] SPACE Stent-Supported Percutaneous Angioplasty of the Carotid Artery
ESICM European Society for Intensive Care Medicine Versus Endarterectomy [study]
ESPS-2 European Stroke Prevention Study 2 SPECT Single-photon emission computed tomography
EVA-3S Endarterectomy Versus Angioplasty in Patients with Symptomatic SPRINT Systolic Blood Pressure Intervention Trial
Severe Carotid Stenosis [study] SSRI Selective serotonin reuptake inhibitor
FASTER Fast Assessment of Stroke and Transient Ischemic Attack to SWI Susceptibility-weighted imaging
Prevent Early Recurrence TCD Transcranial Doppler
FDA US Food and Drug Administration TEE Transesophageal echocardiography
FIA Familial Intracranial Aneurysm [study] THRACE The Contribution of Intra-arterial Thrombectomy in Acute
FLAIR Fluid-attenuated inversion recovery Ischemic Stroke in Patients Treated With Intravenous Thrombolysis
FLAME Fluoxetine for Motor Recovery After Acute Ischaemic TIA Transient ischemic attack
Stroke [trial] TTE Transthoracic echocardiography
GRE Gradient recalled echo UCAS Unruptured Cerebral Aneurysm Study
HAMLET Hemicraniectomy After Middle Cerebral Artery Infarction With UIATS Unruptured Intracranial Aneurysm Treatment Score
Life-threatening Edema Trial UK-TIA United Kingdom Transient Ischemic Attack [aspirin trial]
HCPCS Healthcare Common Procedure Coding System VADAS-cog Vascular Dementia Assessment Scale cognitive subscale
HDL-C High-density lipoprotein cholesterol VAST Vertebral Artery Stenting Trial
HeadPoST Head Position in Stroke Trial VIST Vertebral Artery Ischaemia Stenting Trial
HERMES Highly Effective Reperfusion Evaluated in Multiple VECTORS Very Early Constraint-Induced Movement During Stroke
Endovascular Stroke [study] Rehabilitation [trial]
HERNS Hereditary endotheliopathy, retinopathy, nephropathy, and stroke VIPS Vascular Effects of Infection in Pediatric Stroke [study]
HIV Human immunodeficiency virus WARCEF Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction
ICA Internal carotid artery WASID Warfarin-Aspirin Symptomatic Intracranial Disease [study]

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