Continuum 2023 Vol 29.2

APRIL 2023
VOL. 29 NO. 2 Cerebrovascular Disease

Guest Editor: Hooman Kamel, MD, MS
410 Editor’s Preface

Editor-in-Chief: Lyell K. Jones Jr, MD, FAAN
REVIEW ARTICLES
412 Diagnostic Evaluation of Stroke Etiology

James F. Meschia, MD, FAAN
425 Intravenous Thrombolysis for Acute Ischemic Stroke

James C. Grotta, MD, FAAN
443 Mechanical Thrombectomy for Acute Ischemic Stroke

Sunil A. Sheth, MD
462 Diagnosis and Management of Cardioembolic Stroke

Shadi Yaghi, MD, FAHA
486 Diagnosis and Management of Large Artery Atherosclerosis

Seemant Chaturvedi, MD, FAAN, FAHA
501 Diagnosis And Management of Cerebral Small Vessel Disease

Anjail Sharrief, MD, MPH, FAHA
519 Diagnosis and Treatment of Cerebral Venous Thrombosis

Ava L. Liberman, MD
540 Cervical Artery Dissection

Setareh Salehi Omran, MD
DENOTES CONTINUUM
AUDIO INTERVIEW
566 Pediatric Ischemic Stroke
Christine Fox, MD, MAS
584 Management of Unruptured Intracranial Aneurysms and Brain

Arteriovenous Malformations
Thanh Ngoc Nguyen, MD, FRCPc, FSVIN, FAHA
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

605 Stroke Rehabilitation and Motor Recovery
Michael W. O’Dell, MD
PRACTICE ISSUES
628 The Transformation of Documenting and Coding for Neurologic

Hospital Inpatient and Observation Services
Raissa Villanueva, MD, MPH, FAAN; Neil A. Busis, MD, FAAN;
Bruce H. Cohen, MD, FAAN; Luana Ciccarelli, CPC, CRC
SELF-ASSESSMENT AND CME
402 Learning Objectives and Core Competencies
641 Instructions for Completing Postreading Self-Assessment and CME

Test and Tally Sheet
643 Postreading Self-Assessment and CME Test
655 Postreading Self-Assessment and CME Test—Preferred Responses
666 Index
List of Abbreviations (Back Cover)

CONTRIBUTORS a
Hooman Kamel, MD, MS Seemant Chaturvedi, MD,

Guest Editor FAAN, FAHA
Vice Chair for Research, Stewart J. Greenebaum
Department of Neurology, Endowed Professor of Stroke
Weill Cornell Medicine, Neurology, University of
New York, New York Maryland School of Medicine,
Baltimore, Maryland
Relationship Disclosure: Dr Kamel has
received personal compensation in the Relationship Disclosure: Dr Chaturvedi
range of $10,000 to $49,999 for serving as an has received personal compensation in
editor, associate editor, or editorial advisory the range of $500 to $4999 for serving
board member for the Journal of the as a consultant for AstraZeneca and on a
American Medical Association Neurology, scientific advisory or data safety monitoring
and in the range of $50,000 to $99,999 board for the University of Calgary, and in
for serving on an endpoint adjudication the range of $10,000 to $49,999 for serving
committee for Boehringer-Ingelheim. as an editor, associate editor, or editorial
advisory board member for the American
Unlabeled Use of Products/Investigational Heart Association and as an expert witness
Use Disclosure: Dr Kamel reports no for Ramar & Paradiso (Troy, MI) and Cole,
disclosure. Scott, & Kissane (Palm Beach, FL). The
institution of Dr Chaturvedi has received
research support from the National Institute
of Neurological Disorders and Stroke.
Neil A. Busis, MD, FAAN
Associate Chair, Technology Unlabeled Use of Products/Investigational
Use Disclosure: Dr Chaturvedi reports no
and Innovation, Department of disclosure.
Neurology, NYU Langone Health,
New York, New York
Relationship Disclosure: Dr Busis has Luana Ciccarelli, CPC, CRC
received personal compensation in the Associate Director,
range of $0 to $499 for serving as an editor,
associate editor, or editorial advisory board Medical Economics and
member for Neurology Today from the Practice, American Academy
American Academy of Neurology (AAN) and of Neurology, Minneapolis,
in the range of $500 to $4999 for serving
as a speaker for the AAN and as the AAN’s Minnesota
primary advisor to the American Medical
Association’s CPT Editorial Panel. Relationship Disclosure: Ms Ciccarelli
reports no disclosure.
Unlabeled Use of Products/Investigational
Use Disclosure: Dr Busis reports no Unlabeled Use of Products/Investigational
disclosure. Use Disclosure: Ms Ciccarelli reports no
disclosure.
a
All relevant financial relationships have been mitigated.
404 APRIL 2023

Bruce H. Cohen, MD, FAAN Christine Fox, MD
Director, The Associate Professor of
NeuroDevelopmental Science Neurology and Pediatrics,
Center, Akron Children’s University of California San
Hospital, Akron, Ohio Francisco, San Francisco,
California
Relationship Disclosure: Dr Cohen has
received personal compensation in the range
Relationship Disclosure: The institution of
of $500 to $4999 for serving as a speaker
Dr Fox has received personal compensation
for the American Academy of Neurology
in the range of $500 to $4999 for serving as a
(AAN) and as an AAN advisor to the American
consultant for Competitive Drug Development
Medical Association’s CPT Editorial Panel.
International Ltd, research support from
Dr Cohen has received personal
the American Heart Association/Bugher
compensation in the range of $0 to $499 for
Foundation, and from the National Institutes
serving as a consultant for CoA Therapeutics/
of Health/National Institute of Neurological
BridgeBio and Neuroene Therapeutics; in
Disorders and Stroke, and has received
the range of $500 to $4999 for serving as a
publishing royalties from a publication relating
consultant for Abliva AB, Astellas Pharma
to health care.
Inc, Modis/Zogenix, PTC Therapeutics, and
Reneo Pharmaceuticals, Inc. The institution
of Dr Cohen has received research support
Use Disclosure: Dr Fox discusses the use
from Abliva, BioElectron Technologies/
of thrombolysis and thrombectomy for the
PTC Therapeutics, Astellas Pharma Inc,
treatment of stroke in children.
Reneo Pharmaceuticals, Inc., and Stealth
BioTherapeutics, Inc. Dr Cohen has received
publishing royalties from a publication relating
to health care and has noncompensated
relationships as the president of the board of
directors of the Child Neurology Society and
as a member of the board of directors of the Director of Stroke Research
Child Neurology Foundation that are relevant and Mobile Stroke Unit at the
to the American Academy of Neurology
interests or activities. Memorial Hermann Hospital,
Texas Medical Center in
Unlabeled Use of Products/Investigational Houston, Texas
Use Disclosure: Dr Cohen reports no
disclosure. Relationship Disclosure: Dr Grotta has
received personal compensation in the range
of $5000 to $9999 for serving on a scientific
advisory or data safety monitoring board for
Haemonetics and Prolong Pharmaceuticals
and in the range of $10,000 to $49,999 for
serving as a consultant for Frazer Ltd and on a
scientific advisory or data safety monitoring
board for Acticor Biotech. The institution of
Dr Grotta has received research support from
Chiesi, CSL Behring, and Genentech.
Dr Grotta has received publishing royalties
from publications relating to health care.

Use Disclosure: Dr Grotta reports no
disclosure.
C O N T I N U U M J O U R N A L .C O M 405

CONTRIBUTORS a (CONTINUED)
Ava L. Liberman, MD Thanh Ngoc Nguyen, MD

Assistant Professor, Director of Interventional
Weill Cornell Medicine, Neurology and Neuroradiology,
New York, New York Boston Medical Center;
Professor of Neurology,
Dr Liberman has received research support Neurosurgery, and Radiology,
from the National Institutes of Health. Boston University Chobanian
and Avedisian School
Use Disclosure: Dr Liberman reports no of Medicine, Boston,
disclosure. Massachusetts
Relationship Disclosure: Dr Nguyen has

received personal compensation in the
James F. Meschia, MD, FAAN range of $0 to $499 for serving on a scientific
Professor of Neurology; advisory or data safety monitoring board
Frances Bartlett Kinne Professor, for the National Institutes of Health, and in
the range of $500 to $4999 for serving on a
Mayo Clinic, Jacksonville, Florida scientific advisory or data safety monitoring
board for Avania, Idorsia Pharmaceuticals,
and Vesalio, and as an editor, associate
Dr Meschia has received research support
editor, or editorial advisory board member
from the National Institute of Neurological
for the American Heart Association. The
Disorders and Stroke.
institution of Dr Nguyen has received
research support from Medtronic and
the Society of Vascular and Interventional
Use Disclosure: Dr Meschia reports no
Neurology.
disclosure.
Use Disclosure: Dr Nguyen reports no
disclosure.
Professor Emeritus of
Rehabilitation Medicine,
Department of Rehabilitation
Medicine, Weill Cornell
Medicine, New York, New York
Relationship Disclosure: Dr O’Dell has
range of $0 to $499 for serving as an officer
or member of the board of directors for
Franklin College of Indiana, and in the range
of $500 to $4999 for serving on a scientific
advisory or data safety monitoring board for
Merz Pharmaceuticals, LLC.

Use Disclosure: Dr O’Dell discusses
several clinical trials involving the use of
investigational drugs, none of which are
US Food and Drug Administration (FDA)
approved for use in people with stroke.
a
406 APRIL 2023

Setareh Salehi Omran, MD Sunil Sheth, MD
Assistant Professor of Associate Professor,
Neurology, University of Department of Neurology;
Colorado School of Medicine, Director, Division of Vascular
Aurora, Colorado and Interventional Neurology,
University of Texas Health
Relationship Disclosure: Dr Salehi Omran
reports no disclosure. Sciences Center, Houston,
Texas
Use Disclosure: Dr Salehi Omran reports no
Relationship Disclosure: Dr Sheth has
disclosure.
range of $500 to $4999 for serving as a
consultant for CERENOVUS and Imperative
Care, and in the range of $100,000 to
Anjail Sharrief, MD, MPH, FAHA $499,999 for serving as a consultant for
Associate Professor of Penumbra Inc.
Neurology, McGovern Medical
School, University of Texas Use Disclosure: Dr Sheth reports no
Health Sciences Center, disclosure.
Houston, Texas
Dr Sharrief has received research support Raissa Villanueva MD, MPH,
from the National Institutes of Health and FAAN
from the University of Houston. Dr Sharrief
Division Chief, General
has a non-compensated relationship as a
consultant with Abbot Laboratories that Neurology Division, University
is relevant to the American Academy of of Rochester Medical Center,
Neurology interests or activities.
Rochester, New York
Use Disclosure: Dr Sharrief reports no Relationship Disclosure: Dr Villanueva
disclosure. has received personal compensation in
the range of $500 to $4999 for serving
as a speaker for the American Academy
of Neurology (AAN) and as the AAN’s
alternate advisor to the American Medical
Association’s CPT Editorial Panel.
Dr Villanueva has a noncompensated
relationship as a practice management
committee member with the American
Headache Society that is relevant to the
American Academy of Neurology interests
or activities.

Use Disclosure: Dr Villanueva reports no
disclosure.

CONTRIBUTORS a (CONTINUED)
Shadi Yaghi, MD
Associate Professor of
Neurology, Brown University,
Providence, Rhode Island
Relationship Disclosure: Dr Yaghi reports no

disclosure.

Use Disclosure: Dr Yaghi reports no
disclosure.
Self-Assessment and CME Test Writers
Allyson R. Zazulia, MD Douglas J. Gelb, MD, PhD,

Professor of Neurology and FAAN
Radiology; Associate Dean for Professor of Neurology,
Continuing Medical Education, University of Michigan,
Washington University, Ann Arbor, Michigan
St. Louis, Missouri
Relationship Disclosure: Dr Gelb has
Relationship Disclosure: Dr Zazulia reports received personal compensation in the
no disclosure. range of $500 to $4999 for serving as
a multiple-choice question writer for
Unlabeled Use of Products/Investigational Continuum with the American Academy of
Use Disclosure: Dr Zazulia reports no Neurology. Dr Gelb has received publishing
disclosure. royalties from a publication relating to health
care.

Use Disclosure: Dr Gelb reports no
disclosure.
a
408 APRIL 2023

EDITOR’S PREFACE
Progress and Promise in Stroke

Neurology
To study stroke is to understand loss. The sudden focal
disappearances that characterize cerebrovascular disease can
immediately change a person’s life. Lingering stroke deficits may tip
over dominoes that include jobs, hobbies, mobility, social
engagement, and personal independence. We collectively lose lives,
loved ones, and leaders to stroke.
Against these abrupt personal losses, our field has stroke: a review of the state of the art of intravenous
gradually built an array of offsetting gains. In the past thrombolysis by Dr James C. Grotta, and of
2 decades, improvements in stroke care have steadily mechanical thrombectomy by Dr Sunil A. Sheth.
demoted stroke from the third to now the fifth The next three articles provide a detailed
leading cause of death in the United States. discussion of the three most common mechanisms of
Breathtaking developments in diagnostic, acute ischemic stroke. Dr Shadi Yaghi outlines the
therapeutic, and systems technologies have reshaped latest in cardioembolic stroke, Dr Seemant
the management of acute ischemic stroke. We have Chaturvedi covers all things related to large artery
transformed the problem of “not enough to do” for atherosclerotic disease, and cerebral small vessel
stroke patients into “not enough people, time, and disease receives a comprehensive review from
resources” to do all the things that can be done. An Dr Anjail Sharrief. As neurologists, we must also be
avalanche of stroke clinical trials and observational familiar with uncommon cerebrovascular disorders,
studies has created a real risk that we will run out of and the next few articles in the issue provide
acronyms to name them all. To study stroke is to beautifully written summaries of these less frequent
understand innovation, hope, and progress. scenarios. Dr Ava L. Liberman unravels the mysteries
In the pages of this issue of Continuum you will of cerebral venous thrombosis, and Dr Setareh Salehi
find ample evidence of just how much stroke care has Omran covers the identification and management of
changed. Our guest editor for this issue, Dr Hooman cervical artery dissection. Dr Christine Fox outlines
Kamel, has selected essential topics and an the clinical management and systems challenges in
extraordinary group of expert authors, covering the the care of ischemic stroke in children, and Dr Thanh
full span of cerebrovascular disease (with the Ngoc Nguyen discusses advances in the management
acknowledgment that many hemorrhagic of unruptured intracranial aneurysms and CNS
cerebrovascular disorders are comprehensively arteriovenous malformations. Dr Michael W. O’Dell
reviewed in our neurocritical care issues). Dr James rounds out the clinical reviews with a summary of
F. Meschia leads off the issue with a pragmatic, modern approaches to motor recovery in stroke
thoughtful, and evidence-based discussion of how to rehabilitation care.
identify culprit mechanisms in ischemic stroke More than many facets of our specialty, optimal
patients. Two articles are dedicated to developments, stroke care relies on our ability as clinicians to
many of which are very recent, in acute reperfusion navigate (and improve) systems of health care. The
strategies for patients presenting with acute ischemic clinical review articles in this issue contain excellent
410 APRIL 2023

discussions of prehospital and posthospital systems Royal College of Physicians and Surgeons of Canada
necessary for the care of patients with stroke. Also in with our posttest, written by Drs Douglas J. Gelb and
this issue, Drs Raissa Villanueva, Neil A. Busis, Bruce Allyson R. Zazulia.
H. Cohen, and Ms. Luana Ciccarelli have written an Our audiophile subscribers have additional
approachable and thorough Practice Issues article opportunities to enjoy Continuum. Interviews with
summarizing recent meaningful changes to inpatient our expert authors are posted on the Continuum
documentation and coding requirements. As always, Audio online platform and mobile app, with separate
after reading or listening to the content in this issue, self-assessment CME credits available. Verbatim
subscribers can obtain up to 20 AMA PRA Category 1 audio recordings of each article are available to
CreditsTM toward self-assessment CME or, for subscribers through our Continuum Read Aloud
Canadian participants, a maximum of 20 hours program found at the article level at
toward the Self-Assessment Program [Section 3] of ContinuumJournal.com and in the AAN’s Online
the Maintenance of Certification Program of the Learning Center at continpub.com/CME.
Cerebrovascular neurology exemplifies the
therapeutic posture of our specialty. The first issue of
Continuum dedicated to vascular neurology was
published in 1996. Diagnostic tools that were
described then as novel are now routine and widely
available. In that issue, reperfusion was only
“Our guest editor for this issue, discussed as a future trend. Much has changed in
stroke care, and here’s to the next issue on
Dr Hooman Kamel, has selected cerebrovascular disease rendering this one obsolete.
essential topics and an extraordinary
—LYELL K. JONES JR, MD, FAAN
group of expert authors, covering EDITOR-IN-CHIEF
the full span of cerebrovascular
disease…” © 2023 American Academy of Neurology.
CONTINUUMJOURNAL.COM 411

REVIEW ARTICLE

Diagnostic Evaluation of
C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Stroke Etiology
By James F. Meschia, MD, FAAN
ABSTRACT
OBJECTIVE: Precise therapies require precise diagnoses. This article provides
an evidence-based approach to confirming the diagnosis of ischemic
stroke, characterizing comorbidities that provide insights into the
pathophysiologic mechanisms of stroke, and identifying targets for
treatment to optimize the prevention of recurrent stroke.
LATEST DEVELOPMENTS: Identifying the presence of patent foramen ovale,

intermittent atrial fibrillation, and unstable plaque is now routinely
included in an increasingly nuanced workup in patients with stroke, even as
ongoing trials seek to clarify the best approaches for treating these and
other comorbidities. Multicenter trials have demonstrated the therapeutic
utility of patent foramen ovale closure in select patients younger than age
60 years. Insertable cardiac monitors detect atrial fibrillation lasting more
than 30 seconds in about one in ten patients monitored for 12 months
following a stroke. MRI of carotid plaque can detect unstable plaque at
risk of being a source of cerebral embolism.
ESSENTIAL POINTS: To
optimize the prevention of recurrent stroke, it is
CITE AS:
CONTINUUM (MINNEAP MINN)
important to consider pathologies of intracranial and extracranial blood
2023;29(2, CEREBROVASCULAR vessels and of cardiac structure and rhythm as well as other inherited or
DISEASE):412–424. systemic causes of stroke. Some aspects of the stroke workup should be
done routinely, while other components will depend on the clinical
Address correspondence to
Dr James F. Meschia, Division of circumstances and preliminary testing results.
Cerebrovascular Disease,
Department of Neurology, Mayo
Clinic, Jacksonville, FL 32224,
meschia.james@mayo.edu.
INTRODUCTION
W
RELATIONSHIP DISCLOSURE: ith the advent of evidence-based mechanical thrombectomy, it
The institution of Dr Meschia has is tempting to view all ischemic strokes as falling into two
received research support from
the National Institute of
broad categories: strokes caused by an accessible clot (large
Neurological Disorders and vessel occlusion) and everything else. This perspective, while
Stroke. pragmatic when presented in the emergency department with
UNLABELED USE OF a patient with acute stroke, is woefully inadequate when attempting to optimize
PRODUCTS/INVESTIGATIONAL prevention of recurrent stroke. To optimize prevention, a more nuanced
USE DISCLOSURE:
characterization of stroke is required. While trying to identify stroke etiology is
Dr Meschia reports no
disclosure. customary, usually etiology can only be inferred through identifying, or not
identifying, various comorbidities. Often we cannot be certain that a specific
comorbidity truly was on the causal pathway to the presenting stroke, in part
© 2023 American Academy because multiple comorbidities frequently coexist in the same patient. For some
of Neurology. comorbidities, such as carotid atherosclerotic stenosis, whether a specific
412 APRIL 2023

treatment (eg, endarterectomy) is indicated depends on whether the KEY POINTS
comorbidity is believed to be mechanistically related to stroke by perfusion zone
● The stroke workup is the
(eg, symptomatic versus asymptomatic stenosis). For other comorbidities, set of diagnostic tests
such as atrial fibrillation, the indicated treatment is influenced by the increased performed to gain insight
risk associated with a history of stroke. For example, stroke increases the into modifiable risk factors
CHA2DS2-VASc risk estimation score (consisting of congestive heart failure, and stroke mechanism. The
stroke workup has fixed and
hypertension, age 75 years or older, diabetes mellitus, previous stroke, vascular
variable components, the
disease, age 65 to 74 years, and sex category) by two points.1 Reference to a latter being contingent on
“stroke workup” (ie, a set of diagnostic tests performed because a patient has had clinical circumstances,
a recent stroke) can be found in the medical literature since at least the early initial testing, and
therapeutic objectives.
1980s.2 The stroke workup has advanced in parallel with progress in diagnostic
technologies and medical and interventional therapies. While some elements of ● Recent American Heart
the stroke workup should be done routinely in nearly all cases, other elements are Association guidelines on
contingent on clinical circumstances. Recently, the American Heart Association/ secondary stroke
American Stroke Association (AHA/ASA) published evidence-based guidelines prevention include an
algorithm for performing an
on stroke prevention in patients with recent stroke or transient ischemic attack evidence-based diagnostic
(TIA).3 These guidelines have a section on the diagnostic evaluation of patients evaluation.
that includes an algorithm for ordering diagnostic tests annotated with class of
recommendation and level of evidence for each decision (FIGURE 1-1). This article ● Three or more transient
ischemic attacks in a 2-week
explains the AHA/ASA guidelines, puts them in clinical context, and highlights
period in the same arterial
recent substantial advances. Hemorrhagic stroke will be addressed only insofar as distribution suggest an
it can mimic ischemic stroke at presentation. unstable atherosclerotic
plaque as a mechanism.
CLINICAL ASSESSMENT
● A stroke evaluation
Before launching into a diagnostic workup, a focused but detailed clinical should include examining
assessment of the patient experiencing stroke should be performed.4 The history the patient for preceding
of the present illness will include stroke symptoms and time last known to be at strokes or transient ischemic
neurologic baseline. Patients should be questioned about recent prior transient attacks, atherosclerotic risk
factors, head or neck trauma
neurologic deficits consistent with TIAs. Often these events will not be or radiation therapy,
volunteered spontaneously because the patient is overwhelmed with concern migraines, and a family
over their presenting symptoms. If multiple TIAs have occurred, the physician history of stroke or
should determine whether they all conform to dysfunction in the same area of dementia.
perfusion (eg, left anterior circulation), which would suggest upstream
atherosclerotic stenosis, and how many attacks occurred within 2 weeks of
presentation (three or more attacks suggests unstable plaque).5 The physician
should ask about head or neck trauma or high-velocity chiropractic neck
manipulation, as these may cause arterial dissection.6 The physician should also
inquire about the use of drugs that can precipitate stroke such as amphetamines
and cocaine.7 Although understudied, routine use of cannabis appears to
significantly increase risk of stroke.8 Head or neck external beam radiotherapy
should also be queried, as this can cause a vasculopathy. Vascular risk factors
need to be surveyed, including the status of atrial fibrillation and all the
components of CHA2DS2-VASc. A history of migraine should also be discussed,
as migraine can be a stroke mimic or chameleon9 as well as a risk factor or cause
of stroke.10 Migraine with or without aura is also an important component of the
cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) phenotype. Head, neck, and chest pain can
point to various stroke-relevant conditions, such as cervicocephalic arterial
dissection, aortic dissection, or myocardial infarction.11 A family history of
dementia, migraines, venous thrombosis, and premature atherosclerosis, not

DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
FIGURE 1-1
Algorithm for evaluating patients with a clinical diagnosis of stroke to optimize prevention of
recurrent stroke.
CT = computed tomography; CTA = computed tomography angiography; ECG = electrocardiography;
MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; SOE = source of embolism;
TEE = transesophageal echocardiography.
a
When a patient has a transient neurologic deficit clinically characteristic of transient ischemic attack, the
patient should be evaluated in the same manner as a patient who has an ischemic stroke with a
corresponding cerebral infarct on imaging.
b
Basic laboratory tests include complete blood count, troponin, prothrombin time, partial thromboplastin
time, glucose, hemoglobin A1c, creatinine, and fasting or nonfasting lipid profile.
Reprinted with permission from Kleindorfer DO, et al, Stroke.3
merely stroke, must be obtained to properly assess potential heritable risk

factors.
Cursory screening examinations miss strokes. Emergency medical services
miss about one-fourth of strokes using screening examinations like FAST (facial
drooping, arm weakness, speech difficulties, and time of onset).12 The most
common symptoms among false-negative stroke cases are speech disturbance,
nausea and vomiting, dizziness, changes in mental status, and visual complaints.
414 APRIL 2023

Every patient should have a National Institutes of Health Stroke Scale (NIHSS) KEY POINTS
assessment performed by a certified examiner. The acute NIHSS score, which
● Nearly 5% of strokes,
is an excellent predictor of outcomes, also moderately correlates with acute most of which are lacunar
diffusion-weighted imaging (DWI) and perfusion-weighted imaging lesion and infratentorial, have a
volumes.13 However, an NIHSS score of 0 does not mean that the patient has not National Institutes of Health
had a stroke. Nearly 5% of strokes, most of which are lacunar and infratentorial, Stroke Scale (NIHSS) score
of 0. Although these strokes
will score a 0 on the NIHSS.14 These 0-point strokes are not benign and have
are usually not treated with
similar stroke recurrence rates as other stroke types. All potential acute stroke thrombolytics, they are
patients deserve a thorough neurologic examination; however, given the time nonetheless important to
constraints of decision making in the emergency department, a thorough recognize because the
stroke recurrence rates for
neurologic examination may not be appropriate at the time. Nonetheless, after
NIHSS 0 and non-0 strokes
performing an NIHSS assessment, if uncertainty about whether the patient had a are very similar.
stroke remains, a few quick bedside tests can enhance the NIHSS examination to
bring out focal deficits often poorly characterized or missed entirely by the scale. ● Nearly 7% of acute
Dysarthria testing in the NIHSS is not very sensitive. The patient can be asked to ischemic strokes do not
have a focal area of
repeat “PA-TA-KA” three or four times to elicit scanning dysarthria or other restricted diffusion on initial
impairment in forming labial, lingual, or fricative sounds. The physician can also diffusion-weighted imaging.
perform “H” testing for external ophthalmoparesis and test for clumsy hands or Patients with posterior
distal weakness by having the patient tap the thumb and index finger as fast as circulation stroke are 5 times
as likely to have diffusion-
possible (test each side separately to avoid mirror movements) and look for weighted imaging–negative
left-right asymmetry. stroke as patients with
Head CT, CT angiography, and, where appropriate, CT perfusion should be anterior circulation stroke.
obtained as soon as possible to provide information about vessel occlusion,
infarct core, ischemic penumbra, and degrees of collaterals (the so-called
“imaging is brain” paradigm).15 Because of this time pressure, performing a
thorough neurovascular clinical assessment prior to imaging is neither realistic
nor even appropriate, but after the go/no-go decisions to proceed with
thrombolysis or mechanical thrombectomy have been made, one should return
to the patient’s bedside and explore the clinical case in greater detail.
BRAIN IMAGING
The first diagnostic step after clinical assessment is to determine with CT or MRI
of the head whether a patient who presents with signs and symptoms of an acute
stroke has had an acute ischemic stroke (AHA/ASA class 1 recommendation).3
National guidelines recommend initial imaging within 25 minutes of arrival
at a stroke center to screen patients for thrombolysis with or without
thrombectomy.16 Patients routinely receive a head CT combined with CT
angiography, with or without CT perfusion, to rule out intracranial hemorrhage
and assess for large vessel occlusion and ischemic penumbra. In many instances,
this imaging is sufficient to confirm the diagnosis of acute ischemic stroke,
although small strokes are often missed. If the patient remains symptomatic and
multimodal CT imaging does not confirm the diagnosis, then MRI with DWI will
often suffice. DWI is so sensitive and specific for acute cerebral infarcts, even for
punctate lesions of only a few millimeters, that it is sometimes forgotten that a
negative scan does not completely rule out a stroke (CASE 1-1). Nearly 7% of
patients with acute ischemic stroke will have DWI-negative stroke.17 Patients
with posterior circulation stroke are 5 times as likely to have DWI-negative stroke
as patients with anterior circulation stroke.17
A head CT can reasonably be avoided in favor of MRI in neurologically stable
patients who present late or with minor, nondisabling deficits. For patients who

present late, the brain MRI should include DWI sequences. In a consecutive
series of 300 patients presenting 3 or more days after TIA or minor stroke, DWI
showed a high-signal lesion in 70% of cases of stroke and 13% of cases of TIA and
provided clinically meaningful information (eg, confirming the diagnosis or
vascular territory of the lesion) in 36% of cases.18 Patients with minor (NIHSS
score ≤3), nondisabling (modified Rankin scale, 0 or 1) stroke do not clearly
benefit from thrombolytic therapy and rarely have a large vessel occlusion that
requires immediate thrombectomy, so the timeliness of multimodal CT can be
traded for the diagnostic yield of MRI. The diagnostic yield of DWI falls with
lower NIHSS scores17 but remains clinically meaningful, even for patients with
resolved deficits (TIAs).19 MRI with DWI can detect acute ischemic stroke in
about 20% of patients presenting with acute dizziness and vertigo, whereas the
sensitivity of CT for diagnosing acute ischemic stroke (typically posterior
inferior cerebellar artery infarcts) in this patient population is under 10%.20
CASE 1-1 A 93-year-old man with hypertension presented to the emergency

department with sudden generalized weakness, which had begun the
previous day. The morning of presentation he could barely get out of bed
and fell while trying to get to the bathroom. His son had to help him get
off the floor. He did not hit his head, and the patient denied trouble with
balance, vision, facial droop, speech, or language. On repeated
questioning, he endorsed that his weakness may have been worse on his
left side. He denied prior strokes, other neurologic illnesses, cancer,
fevers, chills, shortness of breath, angina pectoris, or recent change in
medications. He was taking lisinopril and hydrochlorothiazide. His
temperature was 36.6°C (97.8°F), and his blood pressure was
162/95 mm Hg. His general physical examination was unremarkable. His
National Institutes of Health Stroke Scale score was 6 (his left arm had
some effort against gravity; right arm and both legs drifted; and there was
ataxia on left-sided finger-to-nose testing). Complete blood count, basic
metabolic panel, and thyroid-stimulating hormone (TSH) were normal,
and chest x-ray showed clear lungs. Urinalysis showed no signs of
infection. Head CT showed no acute intracranial abnormality. Brain MRI
revealed an acute subcortical infarction in the right paracentral lobule
and old small infarcts in the right frontal corona radiata and right
thalamus as well as extensive small vessel ischemic disease seen on
T2 fluid-attenuated inversion recovery (FLAIR). (FIGURE 1-2) CT angiography
revealed highly calcified stenosis (<50%) of the right internal carotid
artery. Transthoracic echocardiogram detected concentric left
ventricular hypertrophy and a left ventricular ejection fraction of 71%.
In-patient cardiac monitoring showed no atrial fibrillation.
416 APRIL 2023

Patients with nonlacunar stroke can present with a classic lacunar syndrome:
ataxic hemiparesis, dysarthria–clumsy hand syndrome, pure hemiparesis, pure
hemisensory loss, or sensorimotor stroke. Almost one in six patients presenting
with a classic lacunar syndrome has multiple infarctions demonstrated on DWI.21
MRI is usually required to detect acute infarcts in multiple cerebral circulations.
This pattern of lesions can be found in about 10% of patients with acute
infarction and is attributable to cardioembolism half of the time and less
frequently to a hematologic or vasculitic mechanism.22
CERVICOCEPHALIC ARTERIAL IMAGING

The AHA/ASA regards noninvasive imaging by ultrasonography, CT
angiography, or magnetic resonance angiography (MRA) of the cervical anterior
circulation (both carotid arteries) as a class 1 recommendation in patients with
symptomatic infarction in the zone perfused by the anterior circulation.3 The
FIGURE 1-2
Imaging of the patient in CASE 1-1. Axial diffusion-weighted (A) and T2 fluid-attenuated
inversion recovery (FLAIR) (B) sequences of brain MRI showing an acute ischemic stroke
and severe cerebral small-vessel ischemic disease. If the patient’s MRI had been delayed
it might have been impossible to appreciate that there had been an acute focal area of
ischemia given the preexisting severe white matter ischemic changes.
This patient presented with vague symptoms of generalized weakness, but COMMENT
the abrupt onset and slight asymmetry to the motor examination favored
diagnosis of an acute stroke. The head CT was only helpful in excluding an
intraparenchymal or subdural hemorrhage that could present similarly.
Although suspicion was high for an acute ischemic stroke after the CT, the
brain MRI was helpful in securing a positive diagnosis. Knowing the size and
location of the acute infarct and the presence of comorbid small vessel
disease also helps with prognostication and planning of rehabilitation.

CASE 1-2 A 75-year-old right-handed man noted the sudden onset of numbness and
clumsiness in his left hand. He chose to go to bed and see if his symptoms
would pass; when they did not, he presented for medical attention at the
emergency department. He had a history of hyperlipidemia, but no prior
neurologic history. He quit cigarette smoking more than two decades
prior. He denied chest pain or palpitations. Vital signs were unremarkable.
His National Institutes of Health Stroke Scale score was 7 (aphasia and
left-sided numbness and weakness). Initial head CT showed an old right
frontal infarction, but no acute changes. CT angiography showed no large
vessel occlusion but did show an estimated 50% to 70% stenosis of the
cervical right internal carotid artery. The next day a brain MRI showed
scattered infarcts in the right frontal parietal lobes on DWI and a right
frontal gliotic infarct on T2 fluid-attenuated inversion recovery (FLAIR). MR
angiography estimated the right internal carotid artery stenosis to be 50%.
MR plaque imaging (FIGURE 1-3) showed hemorrhagic plaque with a lipid core
in the right carotid bifurcation extending 18 mm into the internal carotid
artery. The patient was referred for revascularization.
FIGURE 1-3
Imaging of the patient in CASE 1-2. Two-dimensional spin echo T1-weighted double inversion
recovery images in two consecutive axial sections (A, B) of the neck at the C3 to C4 levels of
the cervical spine show hemorrhagic plaque in the right internal carotid artery. Arrows
indicate hyperintensities in the carotid plaque corresponding to plaque hemorrhage. MRI
can be protocoled to highlight several features of plaque composition that indicate a
so-called unstable or vulnerable plaque. There is an increased risk of stroke recurrence in
the territory of brain supplied by an artery with vulnerable plaque.
COMMENT This patient presented outside of a time window to allow for safe
thrombolysis and did not have a large vessel occlusion to treat with
mechanical thrombectomy. However, MRI was useful in ensuring that his
stroke involved the right anterior circulation. CT angiography and MR
angiography supported a moderate-to-severe carotid stenosis of the right
internal carotid artery. Plaque characteristics were those seen in so-called
vulnerable or unstable plaque and represented high-risk features. Most
studies support early revascularization (within 2 weeks, and preferably
within 2 days).
418 APRIL 2023

AHA/ASA regards noninvasive imaging using CT angiography or MRA of the KEY POINTS
posterior circulation (vertebrobasilar arteries) and intracranial arteries as a
● CT angiography in the
class 2a recommendation.3 The difference in recommendation level can be oblique and axial planes is
explained by the proven effectiveness of revascularization of a highly stenotic the imaging modality of
symptomatic cervical carotid artery, whereas there is no compelling evidence for choice for identifying
angioplasty, stenting, or surgery of symptomatic vertebrobasilar or intracranial carotid webs.
arteries. The distinction between imaging anterior versus posterior and
● Long-term cardiac
intracranial arteries is moot for most patients as those with suspected ischemic rhythm monitoring detects
stroke are now routinely submitted to emergent CT angiography of head and severalfold more cases of
neck to screen for large vessel occlusion warranting attempted mechanical atrial fibrillation than routine
thrombectomy. CT angiography is particularly good for detecting carotid webs, inpatient monitoring
following a stroke (12.1%
which appear as a thin intraluminal filling defect along the posterior wall of the versus 1.8%), although the
carotid bulb just distal to the bifurcation on oblique sections and as a septum on minimum burden of
axial sections.23 If protocoled appropriately, vessel-wall imaging using MRI intermittent atrial fibrillation
technology can identify several features associated with plaque vulnerability: to justify anticoagulation
remains uncertain.
intraplaque hemorrhage, a lipid-rich necrotic core, and thinning of the fibrous
cap (CASE 1-2).24
CARDIAC RHYTHM ASSESSMENT

Every patient with stroke should have an ECG to screen for atrial fibrillation or
flutter and, even if there is a well-documented history of atrial fibrillation, to
screen for cardiac comorbidities like acute or chronic myocardial infarction and
left ventricular hypertrophy (AHA/ASA class 1 recommendation).3 Long-term
rhythm monitoring is an AHA/ASA class 2a recommendation for patients with
cryptogenic stroke and no contraindication to anticoagulation.3 This monitoring
can be done in various ways, including mobile cardiac outpatient telemetry or an
insertable loop recorder. The longer the rhythm is monitored the more likely
atrial fibrillation is to be detected. For example, in the STROKE-AF (Rate of
Atrial Fibrillation Through 12 Months in Patients With Recent Ischemic Stroke
of Presumed Known Origin) trial, 12 months of insertable cardiac monitoring
detected severalfold more cases of atrial fibrillation than routine care in patients
with recent ischemic stroke (12.1% versus 1.8%).25 Currently, oral anticoagulation
is an AHA/ASA class 1 (level of evidence B-R) recommendation for atrial
fibrillation, whether paroxysmal, persistent, or permanent.3 However, uncertainty
remains around the optimal duration of monitoring and the minimum burden
of atrial fibrillation detection necessary to justify long-term oral anticoagulation.
As noted in a recent editorial,26 trials have shown that many patients have
subclinical atrial fibrillation after non–atrial-fibrillation-related ischemic stroke;
the longer the monitoring, the more subclinical atrial fibrillation will be detected.
Furthermore, there appears to be a dose relationship between duration of
atrial fibrillation and stroke risk.27 Future trials are underway to clarify the
threshold of subclinical atrial fibrillation that justifies long-term anticoagulation.
STRUCTURAL CARDIAC IMAGING

Echocardiography with or without contrast is an AHA/ASA class 2a
recommendation for patients with cryptogenic stroke. Transesophageal
echocardiography (TEE), cardiac CT, or cardiac MRI of patients with embolic
stroke of undetermined significance is an AHA/ASA class 2b recommendation.3
Echocardiography can detect a host of pathologies that predispose a patient to
cardioembolism; some are common, such as patent foramen ovale, and many are

rare, such as atrial myxoma, papillary fibroelastoma, and valvular vegetations.

Many echocardiographically detected abnormalities are likely etiologically
related but are not likely to change management. For example, patients with
known atrial fibrillation and a moderate to high CHA2DS2-VASc score need
long-term oral anticoagulation regardless of whether a thrombus is identified by
echocardiography in the left atrium, left atrial appendage, or aorta. TEE is
generally considered more sensitive and specific than transthoracic
echocardiogram (TTE) for detecting sources of cardioembolism, but the
discovery of pathologies that should alter management occurs in less than 5% of
cases.28 TEE, the more invasive test, may be less effective in detecting patent
foramen ovale than TTE with contrast and the Valsalva maneuver.29
EMBOLIC STROKE OF UNDETERMINED SOURCE

Embolic stroke of undetermined source (ESUS) is a diagnostic subset of ischemic
stroke. ESUS is a diagnosis made by negation (ie, that the stroke is not lacunar in
size and is not associated with large vessel high-grade stenosis or obvious cardiac
source of embolism).30 ESUS is a subset of cryptogenic stroke. A stroke may be
cryptogenic because a cursory workup failed to identify an etiology. However,
ESUS requires a certain diagnostic intensity, with a proposed workup including
brain imaging, ECG, transthoracic echocardiography, cardiac monitoring for at
least 24 hours, and imaging of both intracranial and extracranial arteries.30 Only
when and if clinical trials clearly establish that patients with ESUS require
treatment different from patients without ESUS will the concept truly be
proven useful.
TESTING FOR INHERITED STROKE SYNDROMES

Testing for single-gene disorders that cause stroke is of vanishingly low yield in
most stroke patients and should not be done routinely. However, certain clinical
scenarios should push the neurologist to perform targeted testing. This author
has found the yield to be much higher when patients have a positive family
history or a plethora of recurrent strokes and a paucity of conventional risk
factors, particularly if the strokes appear to be related to small vessel disease
(<15-mm infarcts with unremarkable MRA or CT angiography). There are
many well-characterized monogenic cerebral small vessel diseases: CADASIL;
cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL); pontine autosomal dominant microangiopathy
and leukoencephalopathy (PADMAL); Fabry disease; mitochondrial
encephalopathy, lactic acidosis, and strokelike episodes (MELAS); and type IV
collagen–related diseases (COL4A1/COL4A2 mutations).31,32 At present, none
of these conditions are curable, but that should not dissuade the neurologist
from securing a definitive diagnosis with gene testing. A definitive diagnosis can
avoid mistreatment for conditions that the patient does not have (eg, multiple
sclerosis or central nervous system [CNS] vasculitis). Family history taking
has evolved in the postgenomic era; some patients may present as at-risk because
they were contacted by a relative about the results of a direct-to-consumer
genomic test that found a mutation in NOTCH3. Ultimately, if a patient is
diagnosed with a monogenic stroke syndrome, the physician should refer the
patient to genetic counseling to properly review who may or may not be at risk in a
family and what the medical, occupational, and social implications are for
presymptomatic testing.
420 APRIL 2023

HEMATOLOGIC DISORDERS AND HYPERCOAGULABLE STATES KEY POINTS
It is vital to diagnose sickle cell disease or be aware of the diagnosis in patients
● Transesophageal
who present with stroke because proven, highly effective therapies exist, echocardiography may be
including hydroxycarbamide, blood transfusions, and hematopoietic stem cell less sensitive in detecting
transplantation.33 Sickle cell disease causes ischemic stroke, hemorrhagic stroke, patent foramen ovale than
and moyamoya vasculopathy. In children and adolescents, transcranial Doppler contrasted transthoracic
echocardiography.
screening for elevated blood flow velocities in the middle cerebral artery can
detect signs of an emerging vasculopathy for which exchange transfusions ● To diagnose embolic
dramatically reduce the risk of stroke. stroke of undetermined
Indiscriminate screening for thrombophilia is low yield in patients with source, patients should have
ischemic stroke. Testing patterns vary greatly, and testing results in a treatment a stroke workup that
includes, at a minimum,
change only about 1% to 8% of the time.34 Among young patients with ischemic brain imaging, ECG,
stroke, rates of positive thrombophilia screening are higher but management transthoracic
changes in only 8% of patients.35 Screening for hypercoagulable states like echocardiography, cardiac
protein C, protein S, and antithrombin III deficiencies, and factor V Leiden monitoring for at least
24 hours, and imaging of
and prothrombin 20210 mutations seems justifiable in patients with cerebral both intracranial and
venous thrombosis.36 extracranial arteries.
Antiphospholipid antibody syndrome is an acquired hypercoagulable state
in which the main manifestations are recurrent thromboses (thrombotic ● The yield of testing for
genetic stroke syndromes is
antiphospholipid syndrome) and pregnancy complications (obstetric
much higher when patients
antiphospholipid syndrome). Current diagnostic criteria require persistently have a positive family history
(12 or more weeks) positive lupus anticoagulant, anti–β2 glycoprotein I, or or a plethora of recurrent
anticardiolipin antibodies.37 Routine screening for antiphospholipid antibodies strokes and a paucity of
conventional risk factors,
is hard to justify. APASS (Antiphospholipid Antibody and Stroke Study)
particularly if the strokes are
was a prospective, observational study nested within a multicenter randomized due to small vessel disease.
trial of warfarin versus aspirin for the prevention of stroke recurrence.
This study of more than 1700 patients did not find the presence of ● Patients with aseptic
antiphospholipid antibodies to predict increased stroke risk or a differential cerebral venous thrombosis
should be screened for
response to treatment.38 Diagnostic nihilism is not appropriate either. Some thrombophilia.
patients can have a severe variant of the syndrome known as catastrophic
antiphospholipid syndrome, a life-threatening syndrome requiring immediate ● A C-reactive protein level
treatment.39 higher than 10 mg/L should
raise suspicion for stroke
caused by endocarditis.
INFECTIOUS CAUSES OF STROKE
Being vigilant for an infectious etiology is crucial, not because it is common, but
because delay in diagnosis can have devastating consequences. Embolism from
infective endocarditis occurs in less than 2% of all patients hospitalized with
stroke.40 Both native and prosthetic valves can become infected. Although
transcatheter aortic valve replacement generally has lower overall risk than open
surgical aortic valve replacement, the risk of subsequent endocarditis appears
to be comparable with both valve procedures.41 In an administrative data review
of nonfederal acute care hospitals in California, the absolute increase in risk of
stroke was 9.1% in the month after diagnosis of infectious endocarditis.42
Interestingly, the risk of stroke was significantly elevated in the 4 months preceding
the diagnosis of infectious endocarditis. While this increased risk might be the result
of a systemic inflammatory state, some of the increase might be due to delayed
diagnosis of infective endocarditis. Suspicion for infective endocarditis should be
raised if C-reactive protein levels are higher than 10 mg/L.40 In most patients with
known or suspected infective endocarditis, acute ischemic lesions and cerebral
microbleeds are seen on brain MRI, with other hemorrhagic lesions seen in about

one-fourth of patients and intracranial mycotic aneurysms occurring in less than

10% of patients.43 DWI may help differentiate acute cardioembolism from infective
endocarditis from nonbacterial thrombotic endocarditis. One large, single-center
study found that all patients (14/14) with nonbacterial thrombotic endocarditis
had numerous <10 mm, 10 mm to 30 mm, and >30 mm lesions in multiple
territories, whereas patients with infective endocarditis showed different patterns,
including having a single lesion, a territorial infarction, or disseminated punctate
lesions.44 When clinical suspicion for infective endocarditis is high, it may be
necessary to repeat echocardiography, optimally TEE, to secure a diagnosis.45
In addition to infections causing endocarditis and, secondarily,
cardioembolism, infections can cause stroke through cerebral vasculitis.46 The
microbiological differential diagnosis is quite different; common conditions and
organisms associated with infectious cerebral vasculitis include syphilis, Lyme
disease, invasive fungi, and herpes zoster. Headache, seizures, and
encephalopathy are commonly associated with stroke due to infectious cerebral
vasculitis. Diagnosis of an infectious cerebral vasculitis typically requires
angiography (CT angiography, MRA, or digital-subtraction catheter angiography)
as well as appropriate microbiological studies of blood and CSF. Sometimes brain
biopsy is required.
AUTOINFLAMMATORY CENTRAL NERVOUS SYSTEM VASCULITIS

Stroke is rarely caused by noninfectious vasculitis, so vigilance is required for
early diagnosis. Several rheumatologic conditions can cause CNS vasculitis:
giant cell arteritis, Takayasu disease, eosinophilic granulomatosis with
polyangiitis, granulomatosis with polyangiitis, polyarteritis nodosa, and
Buerger disease. Clues found during the neurologic evaluation that lead to
the diagnosis of an underlying systemic vasculitis causing CNS vasculitis
include mononeuritis multiplex, visual loss, seizures, muscle disease, and
encephalopathy.47 Primary CNS vasculitis is particularly challenging to
diagnose. Suspicion for the condition may be raised in an individual who is
40 to 60 years old who has headache, encephalopathy, and ischemic or
hemorrhagic strokes. A normal brain MRI practically excludes the diagnosis, while
an abnormal CSF is seen in 80% to 90% of affected individuals.48 Brain biopsy
is the only way of securing a definitive premortem diagnosis, but sensitivity is
poor. If the cerebral angiogram is consistent with CNS vasculitis, there may be
reluctance to pursue a tissue diagnosis. However, brain biopsy may identify a
lymphoproliferative disease or an infectious vasculitis in more than 30% of cases.49
CONCLUSION
The stroke workup has evolved and expanded with advances in diagnostic
testing and refinement in clinical trials of stroke prevention. Some tests are
fundamental to nearly every patient, while others should be performed only in
response to positive or negative results of first-round testing or in the context
of specific clinical situations (eg, strongly positive family history of stroke).
Because the stroke evaluation has fixed and variable elements, the workup
may be at risk of cognitive biases like anchoring, premature closure, and
availability of testing.50 It is important to revisit presumptions of etiology,
particularly when patients have recurrent stroke despite good medical
compliance.
422 APRIL 2023

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and genetic risk factors for adult cerebral venous 20(1):102714. doi:10.1016/j.autrev.2020.102714
thrombosis. Thromb Res 2018;169:15-22. doi:10.
50 Croskerry P. The rational diagnostician and
1016/j.thromres.2018.07.005
achieving diagnostic excellence. JAMA 2022;
37 Linnemann B. Antiphospholipid syndrome - an 327(4):317-318. doi:10.1001/jama.2021.24988
update. Vasa 2018;47(6):451-464. doi:10.1024/
0301-1526/a000723
424 APRIL 2023

Intravenous REVIEW ARTICLE

Thrombolysis for Acute CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
Ischemic Stroke
By James C. Grotta, MD, FAAN
ABSTRACT
OBJECTIVE: This article reviews the history of IV thrombolysis, its current
indications and implementation, the duality of the “time is brain” versus
“tissue clock” approaches, the impact of endovascular thrombectomy on
IV thrombolysis, the emergence of tenecteplase, and future research
directions.
CITE AS:
LATEST DEVELOPMENTS: The growing use of factor Xa inhibitors has increasingly CONTINUUM (MINNEAP MINN)
caused patients with stroke to be excluded from treatment with IV 2023;29(2, CEREBROVASCULAR
DISEASE):425–442.
thrombolysis. Important geographic, socioeconomic, sex, race, and ethnic
disparities have been identified in the implementation of IV thrombolysis Address correspondence to
and need to be overcome. IV thrombolysis substantially improves Dr James Grotta, Memorial
Hermann Hospital - Life Flight,
outcomes when provided within the first golden hour after stroke onset in 18th Floor Sarofim—18.300.2,
patients treated in mobile stroke units, supporting the “time is brain” 6411 Fannin St, Houston, TX
concept and encouraging the possible value of more widespread 77030, james.grotta@
memorialhermann.org.
implementation of the mobile stroke unit approach. At the same time,
other studies have shown that IV thrombolysis can be successful in RELATIONSHIP DISCLOSURE:
patients whose “tissue clock” is still ticking up to 9 hours after stroke onset Dr Grotta has received personal
compensation in the range of
or in patients who awaken with their stroke, as demonstrated by favorable $5000 to $9999 for serving on a
imaging profiles. These considerations, along with the emergence of scientific advisory or data
safety monitoring board for
endovascular thrombectomy, have fostered examination of our care
Haemonetics and Prolong
systems, including the “drip and ship” versus direct to comprehensive or Pharmaceuticals and in the
endovascular thrombectomy stroke center approaches, as well as the range of $10,000 to $49,999 for
serving as a consultant for
possibility of skipping IV thrombolysis in certain patients treated with Frazer Ltd and on a scientific
endovascular thrombectomy. Data suggesting that tenecteplase is at least advisory or data safety
noninferior to alteplase, as well as its more convenient dosing, has led to monitoring board for Acticor
Biotech. The institution of
its increased use. Ongoing studies are evaluating newer thrombolytics and Dr Grotta has received research
adding antithrombotic therapy to IV thrombolysis. support from Chiesi, CSL
Behring, and Genentech.
Dr Grotta has received
IV thrombolysis remains the most common acute stroke
ESSENTIAL POINTS: publishing royalties from
treatment. Advances in acting faster to treat stroke have increased its publications relating to
health care.
efficacy, and advances in imaging have expanded its use. However,
implementing these advances and overcoming disparities in IV UNLABELED USE OF
thrombolysis use remain major challenges. PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Grotta reports no disclosure.
© 2023 American Academy

of Neurology.

INTRAVENOUS THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE
INTRODUCTION
T
he benefits of IV thrombolysis for the treatment of acute ischemic
stroke are well established. First, this article will briefly review the
development and approval of recombinant tissue plasminogen
activator (rtPA) followed by the exclusion criteria that have evolved
since the drug’s approval. The increasing use of rtPA is described,
along with the sober reality of substantial disparities in its use. This article
explores the duality of the “time is brain” versus “tissue clock” concepts, which
are more complementary than conflicting, and then summarizes the recent
positive results with ultra-fast treatment on mobile stroke units and with imaging
selection of patients with wake-up stroke or strokes of unknown onset.
Tissue plasminogen activator is a naturally occurring protease that attaches to
fibrin on the surface of a clot and activates plasminogen attached to the fibrin.
Activated plasminogen produces plasmin, the primary enzyme for clot lysis.
Recombinant technology has allowed the manufacturing of several modifications
of tissue plasminogen activator, namely alteplase, reteplase, and tenecteplase,
which vary slightly in their fibrin specificity and half-life. Alteplase was the
first and only recombinant tissue plasminogen activator that was studied
and proven effective for stroke for over 25 years, and so by default has been
equated with the term tissue plasminogen activator or rtPA. Thus, the two terms,
rtPA and alteplase, have been used interchangeably in the literature and in this
review. The emerging use of tenecteplase will be discussed, along with the
current and future effects of endovascular thrombectomy on IV thrombolysis
and future research directions. The terms rtPA and IV thrombolysis will also be
used interchangeably, but for the most part, rtPA will be used when referring
specifically to studies with rtPA, and IV thrombolysis will be used when
referring to the general therapeutic approach of IV thrombolysis.
HISTORY
Prompted by earlier success in animal models, National Institute of Neurological
Disorders and Stroke (NINDS) rtPA pilot studies1,2 were aimed at determining
the upper limit of safety and, although based on relatively small numbers of
patients in each dosing group, chose 0.9 mg/kg with 10% given as a bolus and the
remainder infused over 1 hour. This was 63% to 90% of the cardiac dose
depending on patient weight. Equally important, the pilot studies demonstrated
the feasibility of administering rtPA within 90 minutes of symptom onset, which
was much earlier than in any previous clinical trial. This led to the pivotal NINDS
stroke study,3 which was really two sequential randomized controlled trials of IV
rtPA 0.9 mg/kg versus placebo, with half of patients enrolled within 90 minutes
and half between 90 to 180 minutes of postsymptom onset. The first of these
studies, part 1, was a phase 2b study whose primary outcome was a 4-point
improvement in the 24-hour National Institutes of Health Stroke Scale (NIHSS)
score. While it failed on that primary outcome, all secondary outcomes were
positive, including more substantial improvement at 24 hours and the 90-day
modified Rankin Scale (mRS), Glasgow Outcome Scale, and Barthel Index. Part 2
then confirmed the results of part 1, with the primary outcome being a composite
of all four scales. In the meantime, Mori and colleagues4 conducted a small
randomized trial of a lower dose of rtPA in Japan, and Hacke, Kaste, and Fieschi5
and their European colleagues began ECASS (European Cooperative Acute
Stroke Study),6 a study of a higher dose of rtPA with a 6-hour time window.
426 APRIL 2023

ECASS I was published in 1995 before the NINDS studies and failed on its KEY POINTS
primary outcome but was positive in a target population without substantial
● Extensive clinical trial
early ischemic changes on CT. This was followed in 1998 by ECASS II,6 which data and “real world”
included both European and Australian centers and used the 0.9 mg/kg dose of experience support the
rtPA. This study, which included very few patients in the 0- to 3-hour time efficacy and safety of
window, was also negative on its primary outcome (mRS score of 0 or 1 at 90 days) recombinant tissue
plasminogen activator (rtPA)
but was positive on its secondary outcomes (mRS score of 0 to 2). Importantly,
as the primary treatment for
all these studies confirmed the relative safety of rtPA, with symptomatic acute ischemic stroke.
hemorrhage rates of 6% to 9%, depending on the definition. Taken together,
these studies supported the use of rtPA 0.9 mg/kg within 3 hours of symptom ● An improving deficit or
onset, which became the guideline-approved therapy until 2008 when ECASS III low National Institutes of
Health Stroke Scale score
demonstrated better outcomes with rtPA treatment in the 3- to 4.5-hour time does not exclude a patient
window.7 Subsequent meta-analyses and pooled analyses in thousands of from receiving rtPA if, after a
randomly assigned patients confirmed the effectiveness and safety of rtPA8,9 as careful neurologic history
well as a clear relation between time elapsed from symptom onset to treatment and examination, the
stroke-related deficit would
and decay of efficacy.10,11 In the 0- to 90-minute time window, the number be disabling if it persisted
needed to treat for one patient to benefit from rtPA treatment was 3.6, and the without treatment.
number needed to harm was 65; in the time windows of 90 to 180 minutes and
181 to 270 minutes, these numbers were 4.3 and 38, and 5.9 and 30, respectively.12 ● While rtPA is approved by
the US Food and Drug
Administration (FDA) for
INDICATIONS AND CONTRAINDICATIONS FOR INTRAVENOUS only up to 3 hours after
THROMBOLYSIS symptom onset, data and
The initial US Food and Drug Administration (FDA)-approved rtPA package guidelines support its use for
up to 4.5 hours after
insert essentially repeated the same inclusion and exclusion criteria that were used
symptom onset.
in the NINDS rtPA study. In practice, however, as clinicians became more
comfortable using rtPA, these criteria have evolved. TABLE 2-113-16 lists the most ● The use of factor Xa
current inclusion and exclusion criteria in the guidelines and package insert. For inhibitors is an increasing
instance, many patients had treatment delayed or not administered because of the cause of exclusion from
treatment with IV
initial exclusion of “rapidly improving neurologic deficit.”17 This exclusion is no thrombolysis.
longer listed, and the patient should be treated as soon as possible as long as the
deficit would be considered “disabling” if it persisted. What is disabling, of course,
can be a matter of judgment. While there is no lower NIHSS score cutoff, data
suggest that patients with an NIHSS score of less than 5 whose deficit is not
disabling will usually recover without rtPA treatment, and a study in such patients
was stopped early without showing a trend for better outcome with treatment.18
However, clinicians should complete a thorough examination to detect disabling
signs. For instance, an isolated mild aphasia might disable a person whose work or
social life involves substantial speaking or conversation. Weakness in the hand and
truncal ataxia are not measured on the NIHSS but may be disabling (CASE 2-1).
The biggest change in the inclusion criteria for intravenous thrombolysis occurred
after ECASS III, in which benefits were demonstrated from rtPA treatment up to
4.5 hours after symptom onset. While the FDA package insert still lists 3 hours as
the cutoff, American Heart Association guidelines accept rtPA treatment up to
4.5 hours after symptom onset, and this is the practice for most clinicians.19 While
there was an initial warning about treatment in patients older than 80 years, this has
been removed from the guidelines based on data demonstrating the benefit of
treatment in older adults, assuming no other contraindications.
On the other hand, clinical experience has led to additional contraindications
(eg, aortic arch dissection) in the guidelines that were not in the initial list. An
emerging common reason for exclusion is use of a factor Xa inhibitor. Since there

is no point-of-care test available to determine if patients are anticoagulated,

current practice is to withhold rtPA treatment within 48 hours of the last dose
unless a coagulation assay confirms normal coagulation.
CURRENT USE OF INTRAVENOUS THROMBOLYSIS

The most recent data suggest that rtPA is administered to approximately 12% of
patients with acute ischemic stroke in the United States.20 The most common
reason for exclusion is that patients often arrive too late to the emergency
department for treatment to occur within 4.5 hours of symptom onset. Several
factors have led to increased use of rtPA among patients who do present within
4.5 hours of symptom onset: the development and certification of designated
stroke centers with preferential emergency medical services (EMS) triage to
their emergency departments, increased training and availability of vascular
neurologists, education of nonstroke specialty clinicians about rtPA use, and
the use of telemedicine to extend rtPA treatment expertise to nonstroke
centers. This last development, also referred to as “telestroke,” has made a
TABLE 2-1 Indications and Contraindications for IV Recombinant Tissue Plasminogen

Activatora
American Heart Association Guideline 201914 US Food and Drug Administration (FDA) Package Insert 201515
Indicationsb
Diagnosis of ischemic stroke with disabling neurologic Same

deficit (regardless of severity)
Symptom onsetc within 4.5 hours Within 3 hours
Wake-up stroke with diffusion-weighted imaging FLAIR Not contemplated

mismatch on MRId
Age ≥18 years Warning for age >77 years with risk factors for intracranial
hemorrhage
Contraindications
Severe head trauma within 3 months Same
Ischemic stroke within 3 months Removede
Previous intracranial hemorrhage Warning for recent intracranial hemorrhage (contraindicated if

active intracranial hemorrhage)
Suspected subarachnoid hemorrhage Same
Suspected infective endocarditis Not listed
Suspected aortic arch dissection Not listed
Recent intracranial or intraspinal surgery (within 3 months) Same
Intracranial intraaxial neoplasm Not listed
Gastrointestinal malignancy or gastrointestinal bleeding Warning

within previous 21 days
CONTINUED ON PAGE 429
428 APRIL 2023

particular impact,21 and it has been estimated that as many patients in the United
States are currently treated by telestroke as by primary treatment by the emergency
department staff. Despite these advances, the fact that only 12% of patients with
acute ischemic stroke receive rtPA indicates opportunities for improvement.
One solution is community education emphasizing the recognition of stroke
symptoms and the need to call 911 when they occur.22 Community education has
been only modestly successful. Going forward, such education programs need to
be complemented by efforts to remove financial and other disincentives to
activating 911 and to alter our emergency systems of care, which might include
wider use of mobile stroke units that can provide treatment at the home and have
been shown to increase the rate of rtPA treatment.23,24 In the future, home
telemedicine may quickly and accurately identify acute stroke symptoms, and
early warning devices used in the home may detect physiologic changes and
encourage the patient or bystander to call for help.
The last several years have seen increased focus on disparities in the use of IV
thrombolysis between the sexes and among various geographic regions,
CONTINUED FROM PAGE 428
American Heart Association Guideline 201914 US Food and Drug Administration (FDA) Package Insert 201515
Active internal bleeding Same
Systolic blood pressure (BP) >185 mm Hg or diastolic BP Contraindicated for severe uncontrolled hypertension (BP
>110 mm Hg that cannot be lowered safely values removede); warning for BP >175/110 mm Hg
Bleeding diathesis Same (laboratory values removede)
International normalized ratio (INR) >1.7
Heparin within 48 hours with abnormal activated partial

thromboplastin time
Low-molecular-weight heparin full treatment dose within

previous 24 hours
Platelets <100,000/mm3
Current use of direct thrombin inhibitor or factor Xa

inhibitor with abnormal coagulation testsf
CT showing acute hemorrhage Same
CT showing extensive hypodensity (eg, >1/3 of the cerebral Removede

hemisphere)
CT = computed tomography; FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging.
a
Reprinted with permission from Rabinstein AA, Continuum.13 © 2020 American Academy of Neurology.
b
In other situations listed in the guideline, the risk and benefit need to be individually assessed. Some of these situations include major extracranial
trauma or major surgery within the previous 14 days, intradural arterial dissection, untreated giant intracranial aneurysm, intracranial arteriovenous
malformation, multiple cerebral microbleeds on MRI (count >10), recent but not concomitant anterior wall ST-elevation myocardial infarction,
pregnancy, and early puerperium.
c
Last known well.
d
Evidence also exists that perfusion imaging can be used to select candidates with stroke presenting upon wake up or between 4.5 and 9 hours of
last known well,16 but these studies were published after the evidence review for the 2019 American Heart Association guidelines.
e
The term removed is used to denote a change compared with the previous version of the package insert (2009).
f
Activated partial thromboplastin time, INR, platelet count, ecarin clotting time, thrombin time, factor Xa activity assays.

socioeconomic groups, ethnicities, and races.20 Clearly, IV thrombolysis is rarely

implemented in developing regions of the world where the drug is prohibitively
expensive and appropriate emergency diagnostic and medical care is not
available. Even in the developed world, IV thrombolysis is less frequent in rural
areas, and among women and Black and Hispanic people, although no evidence
suggests that the benefit of IV thrombolysis differs among these groups
(FIGURE 2-125). Continued efforts are needed to address and overcome these
disparities in access to IV thrombolysis.
TIME WINDOWS FOR INTRAVENOUS THROMBOLYSIS

Because of the aforementioned relationship between shorter time to rtPA bolus
from symptom onset (or time last known well) and reduced disability at 90 days,
“time is brain” has been the mantra for acute stroke treatment with rtPA
(FIGURE 2-2). Ample preclinical and clinical data support this notion; a seminal
study in primates demonstrated that the middle cerebral artery can be occluded
for up to an hour without causing infarction.26 This is because residual cerebral
blood flow provided by collateral circulation can maintain the ischemic region in
a penumbral state where tissue is threatened and will eventually die if flow is not
restored.27 Over the next minutes to hours, if the artery remains occluded,
penumbral tissue will become infarcted and a “core” of irreversible damage
grows to incorporate the entire threatened territory. Based on rodent models that
showed that infarction becomes complete after 3 hours,26,28 and the 3-hour time
window of the successful NINDS stroke study,3 the “time window” for
FDA-approved rtPA treatment was established at 3 hours between symptom
onset or last time known well, with better results seen with earlier treatment.10,11
CASE 2-1 A 65-year-old man, employed as a construction worker, was evaluated

by a mobile stroke unit at his job after experiencing symptoms of a
stroke. During his 9:30 AM coffee break that morning, his colleagues
noticed that he was having difficulty speaking. His coworkers had
reported having a normal conversation with him when he arrived at work
at 8:00 AM. The patient was evaluated on scene by the mobile stroke unit
team at 9:55 AM. His National Institutes of Health Stroke Scale score was
4 (for answering one question erroneously), and he presented with mild
aphasia, facial asymmetry, and slight pronator drift of his right arm. After
obtaining a normal CT scan on the mobile stroke unit and discussing risks
and benefits with the patient, recombinant tissue plasminogen activator
(rtPA) IV bolus was administered at 10:10 AM, followed by the 1-hour
infusion. He was transported to the emergency department, where his CT
angiography was found to be normal. Over the next 2 hours, the patient’s
aphasia improved, and he was back to normal after 24 hours. Subsequent
MRI showed no acute infarct.
COMMENT This case shows that IV thrombolysis can be beneficial in patients with
relatively mild but disabling deficits, and that such treatment can
completely avert the stroke.
430 APRIL 2023

FIGURE 2-1
Racial and geographic disparities in the use of IV thrombolysis. IV thrombolysis use in
Black (A), Hispanic (C), and Asian/Pacific Islander (PI) (E) patients compared with White
patients, stratified by geographic region, and corresponding color-coded US maps
(B, D, and F, respectively).
CI = confidence interval; NIS = National Inpatient Sample; OR = odds ratio.
Reprinted with permission from Suolang D, et al, Stroke.25 © 2021, Wolters Kluwer Health.

FIGURE 2-2
Time window versus tissue window. A, Relation between time from symptom onset and
treatment with recombinant tissue plasminogen activator (rtPA) and odds ratio of excellent
outcome. Efforts such as stroke teams, telemedicine, and mobile stroke units are used to
treat patients faster in the first hours after onset (left side of plot), whereas imaging of
ischemic core (B, purple) and hypoperfusion (B, green) can guide treatment in the later time
window (right side of plot).
mRS = modified Rankin Scale; NIHSS = National Institutes of Health Stroke Scale.
The “time is brain” concept has been further demonstrated in studies of mobile
stroke units, which deliver rtPA treatment on scene and increase the proportion
of patients treated in the first “golden hour” after last time known well.23,24
Treatment in this time frame is rare with usual care in the emergency
department,11 but is 10 times more likely with a mobile stroke unit.29 Faster
treatment, coupled with higher rates of treatment than in the emergency
department, results in significantly better clinical outcome with mobile stroke
unit treatment compared with standard management by EMS.29,30 With
treatment in the first hour, approximately 60% of patients will recover to an mRS
score of 0 or 1 (eg, no disability) by 90 days compared with approximately 40%
with treatment at 3 hours (FIGURES 2-3A and 2-3B29) (CASE 2-2). The better
results occurring within the first hour of treatment are probably not only because
of the absence of an irreversibly damaged “core,” but also because fresher clots
are more porous with a higher ratio of red blood cells to platelets, and thereby are
more easily lysed by rtPA compared with more mature clots.31
While time is of unquestionable importance in delivering rtPA, the
development of penumbral imaging using positron emission tomography (PET),
MRI, and CT perfusion32-34 has shown that some patients are slow progressors (ie,
their collateral flow or other less obvious cytoprotective features delay the
incorporation of penumbral regions into infarcted core). Hence, the positive
results of ECASS III, the third International Stroke Trial, and a pooled analysis of
all randomized data showed the benefit of rtPA treatment up to 4.5 hours if
extensive ischemic changes are not already present on CT scanning.7,8,35 More
dramatically, studies in patients who awaken from their stroke or who have
uncertain time of onset up to 9 hours from last time known well have
432 APRIL 2023

demonstrated as much benefit as KEY POINTS
earlier treatment, provided
● Use of emergency
substantial irreversible ischemic department telestroke,
damage is not present on bringing stroke treatment
imaging.36,37 This has fostered to the patient’s home
the concept of the “tissue clock” via mobile stroke
units, improved
that is unique to each patient
telecommunication, and
and becomes more important other devices will help
with time elapsed from last time increase the use of IV
known well. The tissue clock can thrombolysis.
be read on each patient using
● There are many
MRI or CT perfusion techniques disparities in the availability
demonstrating a favorable ratio and use of IV thrombolysis,
of penumbral tissue volume and overcoming them is an
compared with irreversibly important priority for
improving stroke outcomes.
damaged ischemic core volume.
The tissue clock concept opens ● The sooner IV
the window of treatment to thrombolysis is delivered
substantially more patients after symptom onset, the
better the outcome; if
(CASE 2-3).
treatment can be given in
the first golden hour via
INTERACTION WITH mobile stroke units or by
ENDOVASCULAR expedited emergency
department care, two-thirds
THROMBECTOMY
of patients will recover with
While not the subject of this no disability.
article, endovascular
thrombectomy has transformed ● Advanced imaging reveals
the field of acute stroke treatment that the temporal
progression of stroke is
FIGURE 2-3 because of its powerful benefit on different in each patient;
Increased frequency of “golden hour” treatment outcomes in patients with large outcomes with treatment
by mobile stroke units results in better outcome.
vessel occlusions.38 While patients out to 9 hours after symptom
A, Distribution of time from symptom onset to onset in imaging-selected
recombinant tissue plasminogen activator (rtPA) with large vessel occlusions are a
patients may result in
bolus in patients treated by a mobile stroke unit critical population to identify and comparable benefit to
versus standard management by emergency transport to endovascular earlier treatment.
medical services. B, Relation of time from
thrombectomy centers because of
symptom onset and recovery to modified Rankin
Scale score of 0 or 1 at 90 days in patients treated the substantial benefits they
with rtPA in the BEST-MSU (BEnefits of Stroke receive from endovascular
Treatment Delivered Using a Mobile Stroke Unit) thrombectomy, most patients with
study showing increasing benefit with treatment acute stroke who qualify for rtPA
in the first hour.
Reprinted from Grotta JC, et al, N Engl J Med.29 do not have large vessel occlusions
© 2021 Massachusetts Medical Society. that are accessible by endovascular
thrombectomy.39 Therefore, IV
thrombolysis with rtPA or any
other systemic lytic that may replace it will not disappear from the acute stroke
treatment armamentarium and will remain the most frequent treatment for the
largest proportion of patients with stroke.
For the foreseeable future, there will be more primary stroke centers able to
carry out IV thrombolysis than comprehensive or thrombectomy-capable centers
able to deliver endovascular thrombectomy. Therefore, in managing patients
with acute stroke, systems of care need to balance the need to administer IV

thrombolysis as soon as possible to those who qualify, and at the same time,
identify patients with large vessel occlusion and expedite their triage to the
nearest endovascular thrombectomy center. This has led to the “drip and ship”
concept, where patients stop first at the nearest primary stroke center for IV
thrombolysis, get screened for large vessel occlusions, and if one is found, they
are sent to the endovascular thrombectomy center. The alternative approach is to
use various prehospital screening tools to identify potential patients with large
vessel occlusions and deliver them directly to the endovascular thrombectomy
center for both IV thrombolysis and endovascular thrombectomy. A recent study
carried out in Catalonia, Spain, where relatively long distances separate the
primary and endovascular thrombectomy centers, showed that these approaches
are equivalent.40 It is likely that the optimal solution will depend on local
distribution of available resources. Mobile stroke units are also a logical solution
since they are essentially a primary stroke center on wheels that can deliver IV
thrombolysis and screen the patient for large vessel occlusions, thereby obviating
the need to choose between a drip and ship or direct to endovascular
thrombectomy center approach.
CASE 2-2 A 65-year-old man with a history of treated hypertension was noted by
his wife to suddenly stop speaking and slump over to the right at 10:35 AM
as they were sitting having coffee. She immediately called 911, which
dispatched an emergency medical services (EMS) first responder and
medic and the mobile stroke unit. EMS arrived on scene at 10:50 AM and,
recognizing a severe stroke (Los Angeles Motor Scale = 5), began
transport to the nearest comprehensive stroke center and inserted two
IV lines. The mobile stroke unit rendezvoused with the EMS part way
between the scene and the nearest stroke center at 11:12 AM.
The patient was awake and attentive with a blood pressure of 175/80 mm
Hg and a regular rate and rhythm, but had global aphasia, gaze to the left,
no response to threat in the right visual field, right facial weakness, right
hemiplegia, no response to pain on the right, and a National Institutes of
Health Stroke Scale (NIHSS) score of 25 measured by the mobile stroke unit
nurse in concert with the telemedicine-based vascular neurologist. The
patient was transferred into the mobile stroke unit where a CT scan was
performed, and images were uploaded to a web-based picture archiving
and communications system and immediately read by the telemedicine-
based vascular neurologist. Based on an estimated weight of 113 kg (250 lb),
the patient was administered an IV recombinant tissue plasminogen
activator (rtPA) bolus of 9 mg at 11:22 AM (47 minutes after symptom onset)
followed immediately by an rtPA infusion of 81 mg over 60 minutes. While
still in the mobile stroke unit, CT angiography was then carried out using the
second IV line for the contrast (FIGURE 2-4). The CT angiography images were
read by the vascular neurologist and showed a lack of opacification of the
left distal internal carotid artery and middle cerebral artery at 11:27 AM.
The endovascular physician on call was called by the vascular
neurologist, and the mobile stroke unit began transport and arrived at the
emergency department at 11:46 AM. The patient was taken directly to the
434 APRIL 2023

Some patients may qualify for endovascular thrombectomy but not for IV
thrombolysis, or IV thrombolysis may be relatively ineffective in some
candidates for thrombectomy. For instance, patients taking factor Xa inhibitors
are excluded from IV thrombolysis according to current guidelines41 but may be
safely treated with endovascular thrombectomy. The more common situation
where IV thrombolysis may be skipped is when the patient directly presents to
the endovascular thrombectomy center. Several studies have examined outcomes
in patients with large vessel occlusions presenting directly to the endovascular
center emergency department who were randomly assigned to receive rtPA or not,
prior to endovascular thrombectomy, with conflicting results.42-44 While rtPA is
relatively ineffective in dissolving a large vessel occlusion, it can do so in 10% to 30%
of cases,45 particularly if administered in the first hour after last time known well
and given 30 to 60 minutes to work. A recent meta-analysis of patients presenting to
nonendovascular thrombectomy centers with large vessel occlusions showed that
outcomes were better if rtPA was given prior to transfer to the endovascular center
than if it was skipped.46 Therefore, current practice is not to skip rtPA unless the
patient presents directly to the endovascular thrombectomy center, has an
endovascular suite; skin puncture occurred at 11:56 AM, and reperfusion with
thrombolysis in cerebral infarction grade 3 flow was established at 12:26 PM.
At 24 hours after symptom onset, the NIHSS score was 3 for mild right
facial weakness, right arm pronator drift, and speech hesitancy.
FIGURE 2-4
Imaging of the patient in CASE 2-2. A, CT angiography from the mobile stroke unit showing
occluded distal left internal carotid artery. B, Arteriogram showing the distal internal
carotid artery occlusion.
This case illustrates how a mobile stroke unit can achieve treatment within COMMENT
the first hour after symptom onset by beginning rtPA treatment on the
scene and identify and triage an appropriate thrombectomy candidate to
the appropriate stroke center.

CASE 2-3 A 71-year-old woman presented to the emergency department after

waking up at 9:30 AM with left-sided weakness. She had a history of
hypertension and hypothyroidism, and was last known well at 1:30 AM
when she got up to use the bathroom. The patient’s National Institutes of
Health Stroke Scale (NIHSS) score was 14, and her examination
demonstrated left hemiparesis and sensory loss, right gaze preference,
and visual neglect. Head CT was negative for acute hemorrhage or signs
of early ischemic change. CT angiography showed a subocclusive right
middle cerebral artery clot, and CT perfusion showed a 79 mL area of
decreased perfusion with no infarction “core” (FIGURE 2-5).
After obtaining informed consent, the patient was given a recombinant
tissue plasminogen activator (rtPA) bolus at 10:37 AM per the “wake-up”
protocol. The patient rapidly improved and thus did not receive
thrombectomy, and by 24 hours after symptom onset her NIHSS score was 4
and MRI showed a small area of infarction in the right corona radiata.
FIGURE 2-5
Imaging of the patient in CASE 2-3. CT perfusion study showing decreased tissue perfusion
in the right middle cerebral artery territory (green) but no area where flow was reduced
to a level predicting irreversible damage (infarct). Please refer to the legend of
FIGURE 2-2 for a depiction of a region with decreased perfusion (green) versus a region
with irreversible damage (purple). For the software used in these images, the area of
decreased perfusion is defined as the volume of brain tissue having a greater than
6-second delay in the arrival of the maximal dye bolus, whereas the area of irreversible
damage (“infarct core”) is defined as the volume of brain tissue with a calculated cerebral
blood flow of less than 30%, both compared to the homologous region of the contralateral
hemisphere. Note the absence of any purple infarct core in this figure.
COMMENT This case illustrates the use of perfusion imaging to identify a patient who
could be safely and effectively treated with IV thrombolysis beyond
4.5 hours from the time they were last known well.
436 APRIL 2023

approachable clot, and the thrombectomy team is immediately available. Even in KEY POINTS
those circumstances, it is possible that endovascular thrombectomy will not be
● Regional systems of care
successful, and the patient would be deprived of any treatment if IV thrombolysis must balance the need to
were skipped. administer IV thrombolysis
as soon as possible to those
TENECTEPLASE AND OTHER APPROACHES who qualify while also
identifying and expediting
Tenecteplase is under evaluation as an alternative to rtPA for acute stroke
triage of patients with large
treatment and has a class 2b recommendation in patients with acute stroke due to vessel occlusion to the
large vessel occlusion.14,47-50 Tenecteplase has a longer half-life and is given as an nearest endovascular
IV bolus without infusion.51 This provides important logistic advantages; thrombectomy center.
specifically, it is not necessary to insert a dedicated IV line for the infusion. This
● IV thrombolysis can
may lead to faster time between entering the emergency department to needle dissolve 20% to 30% of large
time but, more importantly, provides a therapeutic blood level after the bolus vessel occlusion clots and
without requiring the continuous 1-hour infusion needed with rtPA. In our should not be withheld in
experience, when rtPA bolus and infusion are started by the mobile stroke unit patients meeting treatment
criteria except in rare
and the patient is then handed off to the emergency department stroke team for circumstances.
completion of the infusion, the rtPA infusion is delayed or interrupted 8% of the
time, usually because of technical difficulties with the IV or suspicion of bleeding ● Compared with rtPA,
or other adverse effects. Such delays will reduce the blood level of rtPA below the tenecteplase is more
convenient, delivers the full
therapeutic range without rebolusing.52 Finally, EMS agencies may be reluctant to
dose faster, and produces
transfer patients from a primary stroke center to an endovascular thrombectomy comparable outcomes, but
center with a rtPA infusion running in the drip and ship scenario. Tenecteplase is not yet approved by the
may have advantages over rtPA beyond logistics. It is more fibrin specific and FDA for IV thrombolysis.
therefore may achieve superior clot lysis, as was demonstrated in at least one study
of large vessel occlusions,51 and may also be associated with fewer bleeding
complications. Several studies of tenecteplase versus rtPA are ongoing and should
provide a definitive answer about best dose and relative efficacy. However, the
best evidence to date, based on two large, randomized comparisons53,54 and three
different meta-analyses of studies,55-57 shows that tenecteplase is “noninferior” to
rtPA, meaning their outcomes and safety are similar. Other thrombolytics are also
under evaluation.58
Other investigational approaches focus on achieving more complete lysis
than intravenous thrombolysis alone by adding an antithrombotic agent during
the thrombolytic infusion. Concomitant heparin has been associated with
increased bleeding, but GP2b3a receptor antagonists and thrombin inhibitors
have proven safe in phase 2 studies59,60 and are under evaluation in an ongoing
phase 3 study.61
THE FUTURE OF IV THROMBOLYSIS

The “time is brain” and “tissue clock” concepts will continue to be the focus of IV
thrombolysis. Regarding the former concept, this will include efforts to
streamline our emergency department pathways and prehospital triage systems.
Mobile stroke units have the potential to provide an important quantum leap in
speeding care if financial and logistic issues can be solved. These include
appropriate reimbursement so that mobile stroke unit programs can be fiscally
sustainable. Models of the best method of deploying mobile stroke units in
regions with sparse or concentrated stroke centers need to be developed. Also, we
need to reduce patient disincentives for calling 911, and use artificial intelligence
and other technology to screen 911 calls to make mobile stroke unit dispatch more
efficient. More research on devices to help with early detection of stroke might

increase the number of patients who call for help immediately after symptom
onset. Regarding the tissue clock, more widespread dissemination of imaging to
community hospitals where most patients with stroke seek care may detect more
patients who may benefit from IV thrombolysis in the late time window.
However, this improved imaging access should be combined with efforts to
simplify the required imaging protocol. In addition, studies should refine the
risks versus benefits of extending the time window even further and in certain
subpopulations, such as those with significant preexisting disability. It will be
important to develop public health messaging that alerts patients with stroke and
their caregivers to the potential of late treatment without diluting the imperative
to call 911 immediately after symptoms occur.
Another focus of IV thrombolysis research will be how to improve clot lysis
and reperfusion beyond what we now achieve with rtPA and tenecteplase. There
are two targets: increasing immediate recanalization and reversing “no reflow” in
the microcirculation. Studies using continuous transcranial Doppler insonation
of middle cerebral artery clots after rtPA show that the clots may start to dissolve
and fragment but then the artery may reocclude (FIGURE 2-6).62 The newer
FIGURE 2-6
Recanalization and reocclusion after IV thrombolysis in a representative case of a middle
cerebral artery occlusion. The top panel shows the transcranial Doppler signal with signal
loss at the time of occlusion, reappearance of signal with clot fragmentation, and signal
dampening with reocclusion (white arrow). This is associated with clinical improvement
(decrease) and then deterioration (increase) on the National Institutes of Health Stroke Scale
(middle panel). The lower panel shows the pre–recombinant tissue plasminogen activator
(rtPA) noncontrast CT scan, the timetable of events, the post-rtPA noncontrast CT scan
done after the patient had clinical deterioration, and the digital subtraction angiogram
showing persistent occlusion of the right middle cerebral artery as predicted by the
transcranial Doppler.
CT = computed tomography; DSA = digital subtraction angiography; TPA = tissue plasminogen activator.
Reprinted from Alexandrov and Grotta, Neurology.62 © 2002, American Academy of Neurology.
438 APRIL 2023

thrombolytics and linking thrombolytics with antithrombotic agents, as already KEY POINT
mentioned, may prevent such reocclusion and could be the next step in achieving
● Research is ongoing to
improved recanalization. In addition, inadequate reperfusion due to distal study the wider
embolization and impaired microcirculatory flow may exist despite excellent implementation of mobile
recanalization of the proximal occlusion. A recent study showed that infusing stroke units in speeding up
rtPA intraarterially distal to the site of occlusion after successful endovascular the delivery of IV
thrombolysis to patients
thrombectomy results in improved clinical oucome63 and supports the
with stroke.
importance of “no reflow.” Longer-lasting thrombolytics or linking IV
thrombolysis with antithrombotic drugs may be effective for improving
reperfusion as well as increasing recanalization.
CONCLUSION
IV thrombolysis will remain the most common acute stroke treatment. Exciting
advances in speeding up treatment have increased its efficacy, and advances in
imaging have expanded its use. Newer thrombolytics and antithrombotic agents
may improve recanalization and reperfusion after IV thrombolysis. However,
developing the systems of care to implement these advances and overcoming
disparities in IV thrombolysis utilization remain major challenges.
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442 APRIL 2023

Mechanical REVIEW ARTICLE

Thrombectomy for Acute C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Ischemic Stroke
By Sunil A. Sheth, MD
ABSTRACT
OBJECTIVE: Endovascular stroke therapy has greatly improved the ability to
treat the deadliest and most disabling form of acute ischemic stroke. This
article summarizes some of the recent innovations in this field and
discusses likely future developments.
LATEST DEVELOPMENTS: At present, there is robust activity to improve all

facets of care for patients with large vessel occlusion stroke, including
better prehospital routing, more efficient in-hospital screening, expanding
indications for thrombectomy eligibility, innovating novel thrombectomy
devices, and improving the effects of recanalization on clinical outcomes.
In addition, the integration of endovascular stroke therapy (EVT)—an
emergent and frequently off-hours procedure that requires a specialized
team of nurses, technologists, and physicians—into acute stroke care has
transformed referral patterns, hospital accreditation pathways, and
physician practices. The eligibility for the procedure will potentially CITE AS:
continue to grow to include patients screened without advanced imaging, CONTINUUM (MINNEAP MINN)
2023;29(2, CEREBROVASCULAR
larger core infarcts, and more distal occlusions. DISEASE):443–461.
ESSENTIAL POINTS:In this review, we discuss the current state of EVT and its Address correspondence to
Dr Sunil Sheth, Department of
implications for practice, and present three cases that highlight some of
Neurology, McGovern Medical
the directions in which the field is moving. School at UTHealth Houston,
6431 Fannin St, MSB 7.220,
Houston, TX 77030,
ssheth@post.harvard.edu.
INTRODUCTION
T
RELATIONSHIP DISCLOSURE:
he rapidly advancing field of endovascular stroke therapy (EVT) is Dr Sheth has received personal
accruing new findings that change clinical practice, and since the 2015 compensation in the range of
randomized clinical trials the pace seems to be accelerating.1 $500 to $4999 for serving as a
consultant for CERENOVUS and
Endovascular stroke therapy has become the consensus approach for Imperative Care, and in the
appropriately selected patients and can produce dramatic range of $100,000 to $499,999
for serving as a consultant for
improvements in clinical outcomes for patients with the deadliest and most
Penumbra, Inc.
disabling form of acute ischemic stroke: large vessel occlusion. Beyond its effect
on patient outcomes, the procedure and its implications have necessitated UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
changes in acute ischemic stroke systems of care, neurointerventional practices, USE DISCLOSURE:
and hospital accreditation structures. This article reviews the current state of Dr Sheth reports no disclosure.
EVT, discusses its impact on acute ischemic stroke care delivery, and outlines
ongoing investigations. In addition, three cases are presented, all of which © 2023 American Academy
concern relatively young patients who presented with signs, symptoms, and of Neurology.

MECHANICAL THROMBECTOMY FOR ACUTE ISCHEMIC STROKE
imaging evidence of left middle cerebral artery (MCA) occlusions in the M1

segment; however, the evaluation, decision making, and treatment of these
patients differed substantially in ways that illustrate the current and future
directions of EVT for large vessel occlusion acute ischemic stroke.
CURRENT STATE OF ENDOVASCULAR STROKE THERAPY

Only 2 years after the neutral trials of 2013, the positive EVT trials of 2015 ushered
in a new era of acute ischemic stroke care.1,2 These studies established EVT as
clearly beneficial compared to medical management. In these later trials, the
number needed to treat (a measure of the effect size of the intervention) to
change a patient’s clinical course from moderate-or-severe disability to
functional independence ranged from 3 to 5.3,4 As a comparison and point of
reference, the number needed to treat for percutaneous coronary intervention in
the setting of ST-segment elevation myocardial infarction is 45 to prevent short-
term mortality and 22 to prevent short-term reinfarction.5 As such, the
demonstration of EVT’s effect on outcomes, particularly in the large vessel
occlusion acute ischemic stroke population, which is known to have the worst
clinical outcomes of all acute ischemic strokes, has changed the consensus
approach to the management of these patients.6 Because neurologists are
frequently the frontline evaluators of patients with large vessel occlusion acute
ischemic stroke and serve as the gatekeepers for the procedure, and because
training pathways beginning in neurology residency are rapidly becoming the
most popular routes to attain neurointerventional subspecializations, all
neurologists need to have a basic understanding of the risks, benefits, and
technical aspects of EVT. At present, guideline-based treatment
recommendations include administering intravenous thrombolysis (ie, IV
recombinant tissue plasminogen activator [rtPA]) in eligible patients and
pursuing endovascular therapy in patients with proximal large vessel occlusions
that present without evidence of large territory infarct (defined by noncontrast
head CT with an Alberta Stroke Program Early CT Score [ASPECTS] greater
than 6 in the 0- to 6-hour time window, and by CT perfusion or MRI in the 6- to
24-hour time window).7 An illustrative case of modern EVT is given in CASE 3-1.
Since 2015, the numbers of EVT procedures, EVT proceduralists, and
EVT-capable hospitals have grown. In an administrative database analysis, an
estimated 188 new hospitals across the United States started performing EVT
annually from 2012 to 2016.8 Many of these hospitals were relatively low-volume
centers, which is particularly relevant because, as with almost all procedures,
clinical outcomes after EVT improve with increased experience. In a study using
claims data, every ten additional cases a physician performed led to a 4%
decreased likelihood of inpatient mortality.9 In large, real-world observational
cohorts, rates of good neurologic outcomes are very similar to those of the
randomized clinical trials (approximately 55% functional independence at
90 days), relative to the control populations of the clinical trials who did not
receive EVT (26.5%).1,10,11 Rates of symptomatic intracerebral hemorrhage
(approximately 2% to 6%) remain low, and comparable with those of IV
rtPA alone.10-12
Despite this growth in EVT performance, a large proportion of patients
receive their acute ischemic stroke care at hospitals not capable of performing
EVT. For patients in rural areas, fewer than 30% received their initial care at an
EVT-capable hospital, and these patients are less likely to ultimately receive the
444 APRIL 2023

treatment, even if transfer to an EVT center is an option.13 The demand for KEY POINTS
procedures has led to a rapid increase in the number of proceduralists, and
● Endovascular therapy has
neurointerventional groups have had to grow. For many of these practices become the consensus
prior to the advent of EVT, most of their work could have been confined to approach for appropriately
regular office hours, but now, the call burden has increased substantially and selected patients and can
shifted the case mix of neurointerventional proceduralists considerably. For produce dramatic
improvements in clinical
many physicians, EVT is now the most commonly performed intervention as a
outcomes for patients with
result of the fixed number of aneurysms and AVMs split among the larger large vessel occlusion.
neurointerventional physician pool. Even with the rapid increase in the number
of proceduralists, additional demand for EVT availability remains. The challenge ● Several endovascular
of how to balance the availability of sufficient daytime elective work with the therapy trials published in
2015 established the
need for additional physicians to sustainably cover the call burden remains treatment as clearly
unsolved.14 This challenge is of particular relevance in neurology, as the fastest beneficial compared to
growing interest in the neurointerventional subspeciality is from neurology medical management.
trainees. Multiple proposals, ranging from training vascular neurologists to
● Because neurologists are
serve as EVT-only neurointerventionalists to including pathways for other frequently the frontline
specialties such as cardiology or interventional radiology to perform EVT, have evaluators of patients with
been proposed.15,16 One of the lingering obstacles remains the absence of a large vessel occlusion acute
uniformly accepted neurointerventional accreditation system for training ischemic stroke and serve as
the gatekeepers for the
and certification.
procedure, they must have a
basic understanding of the
ONGOING INVESTIGATIONS risks, benefits, and
There has been and continues to be robust exploration at every phase of care for technical aspects of
endovascular stroke
patients with large vessel occlusion acute ischemic stroke. In the sections below,
therapy.
some of the key advances from the past few years are highlighted.
● Despite this growth in
Prehospital Bypass for Large Vessel Occlusion Acute Ischemic Stroke endovascular stroke therapy
The efficacy of EVT for large vessel occlusion acute ischemic stroke is highly time performance, a large
proportion of patients
sensitive and bringing appropriate patients directly to EVT-performing centers receive their acute ischemic
could accelerate treatment times and possibly improve clinical outcomes. Many stroke care at hospitals not
prehospital agencies in the United States have routing rules whereby patients capable of performing
who screen positive for large vessel occlusion on prehospital stroke scales can endovascular stroke
therapy.
bypass centers that do not perform EVT and be transported directly to EVT
centers, as recommended by the Mission: Lifeline algorithm.17 The allowable ● The challenge of how to
additional distance to the EVT center can vary, but many localities have adopted balance the availability of
a rule that an additional 15 minutes of transport time is allowable. If travel time to sufficient daytime
neurointerventional elective
the EVT center exceeds that amount, the ambulance would go to the center that
work with the need for
does not perform EVT so that thrombolysis would not be delayed. additional physicians to
This question of prehospital bypass was studied in a small region of Spain in sustainably cover the call
the RACECAT (Rapid Arterial oCclusion Evaluation - Catalonia) trial.18 In this burden remains unsolved.
study, patients were screened with the prehospital Rapid Arterial oCclusion
● One of the lingering
Evaluation (RACE) score, and those who screened positive were enrolled and obstacles to endovascular
randomized to either transport to the closest primary stroke center for treatment access remains
thrombolysis, or direct transfer to an EVT-performing referral center. Patients the absence of a
who were routed to the primary stroke center were more likely to receive IV uniformly accepted
neurointerventional
thrombolysis but less likely to undergo EVT, and nearly 65% of patients routed to accreditation system for
the primary stroke center were ultimately transferred to an EVT-performing training and certification.
hospital.18 The primary analysis of the study demonstrated no significant
difference in 90-day disability outcomes between the primary stroke center–first
versus EVT-performing center–first approaches.18

While this study is the first to provide randomized data on this topic, its results
may not be immediately applicable to many localities in the United States. The
primary stroke centers in RACECAT functioned very well, with door-in to
door-out times of close to 70 minutes on average, with subsequent transport to
the EVT centers that were likely much shorter than can happen outside of major
urban centers in the United States.19 It is also worth noting that robust efforts are
being made for automated large vessel occlusion detection in the field, using
ultrasound, electrical impedance, and other technologies, which may justify
longer transport times to bring patients to EVT-performing hospitals.20 Given
the known adverse effects on clinical outcomes with delays in IV thrombolysis,
accurate large vessel occlusion detection in the field to ensure that patients with
non–large vessel occlusion do not experience delays in IV rtPA is now of
CASE 3-1 A 64-year-old man presented with symptoms of right hemiparesis, left
gaze deviation, and global aphasia. He was last known well
approximately 3 hours prior to presentation, had a history of atrial
fibrillation, and was not on anticoagulation treatment. Initial imaging with
noncontrast head CT demonstrated early infarct signs in the left
lentiform nuclei but otherwise preserved left hemispheric parenchyma
(Alberta Stroke Program Early CT Score = 8) (FIGURE 3-1A). Vascular imaging
with CT angiogram confirmed occlusion of the left middle cerebral artery
(MCA) in the proximal M1 segment (FIGURE 3-1B). The patient was treated
with IV thrombolysis. All the features of the presentation were consistent
with guidelines-based evidence for endovascular stroke therapy (EVT),
and the patient was taken for treatment. Digital subtraction angiography
images in the anterior-posterior (FIGURE 3-1C) and lateral projections
(FIGURE 3-1D) confirmed the M1 MCA occlusion, which was successfully
treated with complete reperfusion after a single pass of aspiration
(FIGURE 3-1E). Follow-up imaging demonstrated the infarct that had been
visualized on preprocedure imaging, without additional areas of injury
(FIGURE 3-1F). The patient’s clinical examination improved substantially
after the EVT procedure.
COMMENT This case exemplifies how rapid reperfusion with EVT, in a patient treated
soon after symptom onset and without rapid progression of the ischemic
infarct, can frequently result in a nearly complete reversal of severely
disabling deficits.
446 APRIL 2023

heightened importance. Mobile stroke units, which allow for transport as well as
concurrent treatment, are another option for offsetting delay.21
Simplify and Minimize Preprocedural Imaging

In the most recent iteration of the American Heart Association/American Stroke
Association guidelines, the recommended imaging screening for patients who
present within 6 hours of last known well is noncontrast head CT and CT
angiogram (CTA) to detect the presence or absence of large vessel occlusion, as
well as CT perfusion (CTP) (or MRI) for patients who present after 6 hours.22
CTA is commonly used as the imaging modality of choice for its high sensitivity
for large vessel occlusion, rapid acquisition, and widespread availability. As
clinical experience with EVT has grown, the need for CTP to screen patients has
FIGURE 3-1
Imaging of the patient in CASE 3-1 showing a modern workflow for a patient with left middle
cerebral artery (MCA) occlusion. Noncontrast head CT reveals preservation of the left
hemispheric parenchyma with minimal early ischemic change (A, arrow). CT angiogram
confirms the proximal left MCA occlusion (B, arrow), and the patient is brought in for
emergent angiography. Initial digital subtraction angiography images in anterior-posterior
(C) and lateral (D) projections show the occlusion with a meniscuslike shape typical of
thromboembolic occlusions (C, D, arrows). Complete reperfusion following the endovascular
stroke therapy procedure occurs (E, digital subtraction angiography), which results in minimal
final infarct on subsequent diffusion-weighted MRI 24 hours later (F, arrow).

been called into question for several reasons. First, the availability of CTP is
limited. In a study examining Medicare claims data, nearly 70% of patients
diagnosed with acute ischemic stroke presented to hospitals that did not perform
CTP.23 As such, if all late-window EVT screening required CTP, an
overwhelming and unfeasible number of patients would need to be transferred to
CTP-performing centers. A simpler screening methodology that uses the widely
available noncontrast head CT would be preferable.
Apart from availability, several other challenges with CTP exist. First, in a
series from a high-volume and well-performing stroke center, up to 25% of CTP
studies were unusable because of head movement during acquisition.24
Moreover, the inclusion of this additional imaging study has been shown to delay
care.25 Even more striking, routine use of CTP has been associated with a reduced
likelihood of offering EVT, potentially leading to undertreatment of large vessel
occlusion acute ischemic stroke.26 Another driver of undertreatment is the
inherent inaccuracy of the technique at identifying both the ischemic core and
penumbra. Cerebral blood flow and blood volume are known to fluctuate in
patients suffering from acute large vessel occlusion acute ischemic stroke. CTP
snapshots of these parameters may underestimate or overestimate regions of
infarct and penumbra.27 In a study using data from the MR CLEAN (Multicenter
Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke
in the Netherlands) trial, essentially no correlation between CTP predictions of
tissue “at risk” and ultimate infarct was found.28
Several publications have also demonstrated no difference in clinical outcomes
between patients in the 6- to 24-hour time window treated with EVT identified
using a noncontrast CT-only approach versus CTP.25,29 In the CLEAR (CT for
Late Endovascular Reperfusion) study, which included 15 sites and over 1600
patients, 90-day functional independence was similar between the cohorts
screened for treatment using noncontrast CT alone versus CTP (41% and 44%),
which was also nearly identical to the rates of good outcome from the
late-window randomized clinical trials (see section Endovascular Stroke Therapy
for Late-Window Patients).25 After adjustment for relevant covariables, no
significant difference between those two groups (adjusted odds ratio 0.9 [0.7 to
1.2]) was found. Importantly, patients treated in the noncontrast CT-only group
were treated nearly 20 minutes faster. Nevertheless, given the required use of
MRI or CTP in the major late-window trials of EVT, class 1 recommendations in
major guidelines support the use of advanced imaging to identify candidates in
the late time window at present.22 The results of the MR CLEAN LATE (MR
CLEAN for late arrivals) trial were recently presented and confirmed the benefit
of EVT in patients arriving in the late time window without CTP compared with
medical management.29 Another ongoing randomized clinical trial, RESILIENT
Extend (Randomization of Endovascular Treatment with Stent-retriever and/or
Thromboaspiration versus Best Medical Therapy in Acute Ischemic Stroke due
to Large VEssel OcclusioN Trial in the Extended Time Window), will add
high-quality data to this discussion.
Withholding IV Thrombolysis in Patients with Planned Endovascular

Stroke Therapy
A series of trials were conducted and published in 2020 and 2021 examining
whether IV thrombolysis is beneficial in patients undergoing EVT for large
vessel occlusion acute ischemic stroke. Six trials, all performed outside the
448 APRIL 2023

United States, had similar noninferiority study designs, although the structures KEY POINTS
of the trials varied. The Japanese SKIP (Direct Mechanical Thrombectomy in
● The efficacy of
Acute LVO Stroke) trial studied thrombolysis at the lower alteplase dosage endovascular stroke therapy
(0.6 mg/kg) used in Japan and failed to show noninferiority of an EVT-only for large vessel occlusion
approach.30 This same result, using the US-standard 0.9 mg/kg dose, was seen acute ischemic stroke is
in the Dutch MR CLEAN NO-IV, European/Canadian SWIFT-DIRECT, and highly time sensitive and
bringing appropriate
Australian DIRECT-SAFE studies.31-33 On the other hand, the Chinese DEVT
patients directly to
trial was stopped early for meeting its primary endpoint after reaching less endovascular stroke
than one-quarter of its planned enrollment, and similarly, the Chinese therapy–performing centers
DIRECT-MT trial also showed noninferiority of an EVT-only approach may accelerate treatment
times and possibly improve
compared to combination therapy.34,35 A recently published meta-analysis of
clinical outcomes.
these six studies, however, failed to demonstrate noninferiority of an EVT-only
approach with a weak trend toward the superiority of a combination approach.36 ● Given the known adverse
As such, the consensus remains to treat with IV rtPA in all eligible patients, effects on clinical outcomes
including those with large vessel occlusion acute ischemic stroke for whom EVT with delays in IV
thrombolysis, accurate large
may be needed. vessel occlusion detection
in the field to ensure that
TREATMENT SELECTION AND INDICATION EXPANSIONS non–large vessel occlusion
In the near future, treatment eligibility criteria for EVT may be different. patients do not suffer from
delays in IV recombinant
The following sections summarize some of the ongoing investigations to study tissue plasminogen activator
potential new indications. (rtPA) is now of heightened
importance.
Endovascular Stroke Therapy for Basilar Occlusions
● As clinical experience
Evidence in support of EVT for basilar occlusions was surprisingly difficult to
with endovascular stroke
obtain. Despite tremendous success for anterior circulation EVT and good rates therapy has grown, the need
of recanalization for posterior circulation occlusions, multiple initial trials for for CTP to screen patients
basilar artery EVT were neutral.37,38 In retrospect, limitations in both the trial has been called into
design and execution of those previous studies can be seen, including high question.
crossover rates between the medical and interventional arms. ● Two ongoing randomized
Many of these limitations were addressed by the BAOCHE (Basilar Artery clinical trials—MR CLEAN
Occlusion Chinese Endovascular) and ATTENTION (Endovascular Treatment LATE and RESILIENT Extend
for Acute Basilar Artery Occlusion) trials.39,40 These two studies, both performed —are evaluating the efficacy
of endovascular stroke
in China, demonstrated the superiority of EVT over medical management therapy in late-window
alone in patients with basilar artery large vessel occlusion acute ischemic stroke, patients without relying
in both the early time period (<12 hours from last known well in ATTENTION) on CTP.
and late time window (6 to 24 hours from last known well in BAOCHE).
● The consensus remains to
Both used a modified Rankin Scale (mRS) score of 0 to 3 at 90 days as their
treat with IV rtPA in all
primary outcome and replicated the effect sizes that were seen in anterior- eligible patients, including
circulation EVT trials (number needed to treat of 4 in ATTENTION and 4.5 in those with large vessel
BAOCHE). Rates of good outcomes in the control group were expectedly poor occlusion acute ischemic
(approximately 22%), whereas rates of good outcomes in the EVT group were stroke for whom
endovascular stroke therapy
comparable to those in the anterior circulation large vessel occlusion studies may be needed.
(approximately 45%).
Endovascular Stroke Therapy for Low National Institutes of Health Stroke

Scale Scores
Nearly all the EVT trials to date set a lower limit on the National Institutes of
Health Stroke Scale (NIHSS) of 6 as a cutoff for inclusion, leaving open the
question of whether patients with low-NIHSS large vessel occlusion acute
ischemic stroke benefit from treatment. Natural history studies have shown that

up to 25% of patients with a low NIHSS score may have a large vessel occlusion
and, although patients with low-NIHSS large vessel occlusion likely have better
outcomes than those with higher NIHSS scores, their outcomes can still be quite
poor.41 Observational studies have shown rates of death or dependency ranging
from 23% to 38% at the time of hospital discharge, and outcomes are particularly
poor in patients with neurologic deterioration from their initial mild presentation.41
Retrospective studies have shown mixed results on outcomes in patients treated
with EVT relative to medical management, and part of this variability may be
related to heterogeneous pathophysiology. Patients who are treated up front with
EVT, as opposed to those who are treated only after experiencing further decline,
will likely have different outcomes. To address this topic with increased rigor,
multiple randomized clinical trials are currently enrolling patients, including
ENDOLOW (Endovascular Therapy for Low NIHSS Ischemic Strokes) in North
America and MOSTE (Minor Stroke Therapy Evaluation) in Europe.
Endovascular Stroke Therapy for Late-Window Patients

Treatment of patients with large vessel occlusion acute ischemic stroke up to
24 hours from last known well has now been firmly established, following the
release of DAWN (Diffusion Weighted Imaging or Computerized Tomography
Perfusion Assessment With Clinical Mismatch in the Triage of Wake Up and Late
Presenting Strokes Undergoing Neurointervention) and DEFUSE 3
(Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3)
data in 2018.42,43 More recently, the AURORA (Analysis of Pooled Data From
Randomized Studies of Thrombectomy More Than 6 Hours After Last Known
Well) collaboration published a meta-analysis of six studies that included
patients with late-window EVT and demonstrated benefit for patients across the
entire range of mRS outcomes, most notably 46% versus 19% for an mRS score of
0 to 2 at 90 days (EVT versus control).44 The poor outcomes in the control arm
are a striking feature of this subset of patients. These trials were not large infarct
core studies, and as such the patients in the control group had relatively small
infarct cores despite presenting during later time windows. While this finding
may imply that their collateral circulation was sustaining tissue viability, the
natural history for these patients with large vessel occlusion acute ischemic
stroke is poor, with over 80% having substantial disability. The benefit of
late-window EVT was sustained in all the relevant subgroups including those
with wake-up symptoms, witnessed onset, aged 80 years or older, and severe
stroke severity (NIHSS score ≥18). Attention in this cohort has now shifted
toward simplifying pretreatment imaging screening (as discussed in the section
Simplify and Minimize Preprocedural Imaging) and, in a related topic, whether
patients with large established infarct at the time of presentation still benefit
from treatment.
One interpretation of the large effect sizes seen in these trials is a need to shift
from time-based selection paradigms to an imaging-based one. The concepts of
“early” and “late” windows were based on assumptions that infarcts grow at a
certain rate, and that earlier treatment is more likely to result in good outcomes
because the infarct size will be smaller. While time to treatment remains a
powerful predictor of patient outcomes, with the current ability to more
accurately determine the infarct core it no longer needs to be an exclusion
criterion. The 24-hour time limit set by the DAWN trial was only chosen because
such a limit was required. With imaging-based selection, this time limit may be
450 APRIL 2023

extended, with some studies reporting signals of effectiveness in patients treated KEY POINTS
on average 44 hours after onset when clinical and imaging parameters remained
● Two studies, both
within the DAWN and DEFUSE 3 bounds.45 performed in China,
demonstrated superiority of
Endovascular Stroke Therapy for Distal Occlusions endovascular stroke therapy
Given the success of EVT for proximal large vessel occlusion, one natural over medical management
alone in patients with basilar
subsequent question is whether it is effective in smaller, more distal vessels. In
artery large vessel occlusion
some estimations, distal vessel occlusions, termed medium vessel occlusions, acute ischemic stroke, in
account for up to 40% of all acute ischemic strokes.46 These occlusions can arise both the early time window
as either initial occlusions or as a consequence of clot fragmentation in the course (<12 hours from last known
well in ATTENTION) and late
of treatment of a proximal large vessel occlusion. Endovascular stroke therapy for
time window (6 to 24 hours
both of these lesions, however, can be substantially more complicated than that of from last known well in
a proximal large vessel occlusion for several reasons. First, distal vessels are far BAOCHE).
smaller, more fragile, and mobile, particularly in the sylvian fissure, and thus more
prone to injury and rupture. In addition, the margin for error is much smaller, as ● The natural history for
patients with large vessel
the clinical deficit attributable to a distal occlusion is likely less than that of a occlusion acute ischemic
proximal occlusion, so the risk-to-benefit profile is narrower. stroke presenting in the late
As EVT technology has improved, the willingness of neurointerventionalists treatment window is poor,
to target medium vessel occlusions has grown. Multiple published series with over 80% having
substantial disability.
including a subset of patients from the HERMES (Highly Effective Reperfusion
evaluated in Multiple Endovascular Stroke) Collaboration have looked at M2 ● One of the interpretations
occlusions.47 One of the challenges of pooling these data is that the first branch of of the large effect sizes
the MCA (M1 segment) has multiple definitions, and the M2 segment has even seen in DAWN and DEFUSE 3
is a need to shift from
more. More classifications continue to be proposed. As a result, combining
time-based selection
multiple studies with varying definitions can be challenging. At least one clinical paradigms to an
trial, DISTAL (EnDovascular Therapy Plus Best Medical Treatment [BMT] imaging-based one.
Versus BMT Alone for MedIum VeSsel Occlusion sTroke - a prAgmatic,
International, Multicentre, Randomized triaL), is studying whether EVT
provides benefit compared to medical management alone in patients with
medium vessel occlusion. While the field does not appear to be converging on a
single nomenclature, the design and completion of clinical trials for medium
vessel occlusion may produce, as an unintended consequence, some uniformity
on the matter.
Endovascular Stroke Therapy for Patients with Large Core Infarcts

One of the most common reasons for not offering EVT to a patient with large
vessel occlusion acute ischemic stroke is concern that the infarct core is already
too large at presentation. Current guidelines define this “large core” population
as patients who present with an ASPECTS less than 6, and as patients who
present in the late time window (6 hours after last known well) with
CTP-defined infarct volumes of greater than 70 mL (based on the DEFUSE 3 trial
results).22 Note that current guidelines do not recommend CTP in patients
presenting in the early time window without evidence of large core infarct, as
discussed earlier in this article. Nonrandomized data, however, have suggested
that patients with large core infarcts in both the early and late windows may
still benefit from EVT.48 In an individual patient-level HERMES meta-analysis,
178 patients were identified with an ASPECTS of 3 to 5, of whom 98 had
undergone EVT and 80 had undergone medical management. In this subgroup,
the adjusted common odds ratios remained in favor of treatment with EVT
(common odds ratio 2.0, 1.16 to 3.46). A clinical case outlining the unique

considerations in the decision making and care of a patient with a large core
infarct is described in CASE 3-2.
Given the poor natural history of this disease, multiple clinical trials are
evaluating the potential benefit of EVT in the large core population. The first of
these trials to be published was RESCUE-Japan LIMIT (Randomized Controlled
Trial of Endovascular Therapy for Acute Large Vessel Occlusion With Large
Ischemic Core).49 This study was largely MRI-based, included patients up to
24 hours from last known well, and used an mRS score of 0 to 3 at 90 days as the
primary outcome. The trial succeeded in enrolling patients with true large cores,
with a mean diffusion-weighted imaging infarct volume at the time of
presentation of 94 mL in the endovascular group and 110 mL in the medical
approximately 7 hours prior to presentation and had a history of
cardiomyopathy with left ventricular systolic ejection fraction of 30% to
35%. Initial imaging with noncontrast head CT (FIGURES 3-2A and 3-2B)
demonstrated established infarction of the left hemisphere lentiform
nuclei, insula, and substantial portions of the temporal and frontal lobes.
His Alberta Stroke Program Early CT Score was determined to be 3 or 4.
Concurrently acquired CT perfusion (FIGURE 3-2C) demonstrated large
regions of collapsed cerebral blood flow (not shown) and cerebral blood
volume. All these findings were consistent with a large, established
infarct core. However, given the possible preservation of some of the
cortical regions involved in motor control, endovascular stroke therapy
(EVT) was offered and ultimately performed. Digital subtraction
angiography images (FIGURE 3-2D) confirmed occlusion of the left middle
cerebral artery (MCA) in the mid-M1 segment. Thrombectomy was
successful with complete reperfusion after two passes of a stent
retriever (FIGURE 3-2E). Subsequent follow-up imaging (FIGURE 3-2F)
demonstrated a large-territory left MCA infarct with mild hemorrhagic
transformation. During hospitalization, the patient did not develop
malignant edema and did not require hemicraniectomy. Over time he
improved, and at 90 days post-treatment he had recovered motor
function of his right arm and leg nearly completely. Receptive language
function had also improved.
COMMENT This case exemplifies how patients with established large core infarcts on
presentation imaging may be candidates for EVT reperfusion.
452 APRIL 2023

management group. A significantly greater proportion of patients achieved the
primary outcome with EVT (31% versus 13%, P = .002), without increased rates of
symptomatic intracranial hemorrhage, mortality, or need for
decompressive craniectomy.
Two additional trials have now also been presented and published:
ANGEL-ASPECT (Trial of Endovascular Therapy for Acute Ischemic Stroke with
Large Infarct) and SELECT 2 (Trial of Endovascular Thrombectomy for Large
Ischemic Strokes).50,51 ANGEL-ASPECT followed the guideline definitions for
large cores, using an ASPECTS of 3 to 5 for the early time window and a CTP core
volume of 70 mL to 100 mL in the late time window. SELECT 2 differed,
including patients with an ASPECTS greater than or equal to 6 and a CTP core
FIGURE 3-2
Imaging of the patient in CASE 3-2 showing large core thrombectomy. The patient presents with
symptoms consistent with left middle cerebral artery (MCA) syndrome and on initial imaging
with noncontrast head CT is found to have established infarction of the left hemisphere
lentiform nuclei, insula, and substantial portions of the temporal and frontal lobes (Alberta
Stroke Program Early CT Score of 3 or 4) (A, B, arrows). The extent of the relative cerebral
blood volume decrement is confirmed on CT perfusion (C). Subsequent angiography images
confirm occlusion of the left middle cerebral artery (MCA) in the mid-M1 segment (D, arrow).
Thrombectomy is successful with complete reperfusion after two passes of a stent retriever
(E). Subsequent follow-up imaging with noncontrast head CT demonstrates a large territory
left MCA infarct with mild hemorrhagic transformation (F, arrow).

volume greater than or equal to 50 mL. Both studies showed benefits for EVT
relative to medical management. While the three published trials differed in their
designs and studied populations, several consistent lessons emerged from these
data. The rate of good outcomes with EVT is lower in these large core populations
(14% in RESCUE-Japan LIMIT, 30% in ANGEL-ASPECT, and 20% in SELECT 2)
relative to small core patients (46% in the early window HERMES consortium
and 46% in the late window AURORA consortium). Further, symptomatic
hemorrhage rates post-EVT in this population may be higher (9% in RESCUE-
Japan LIMIT and 6.1% in ANGEL-ASPECT).
Three additional ongoing large core trials are expected to be completed and
released in 2023. These trials use MRI or noncontrast CT ASPECTS for selection
criteria, including TENSION (Efficacy and Safety of Thrombectomy in Stroke
With Extended Lesion and Extended Time Window), LASTE (Large Stroke
Therapy Evaluation), and TESLA (Thrombectomy for Emergent Salvage of
Large Anterior Circulation Ischemic Stroke). Some of the key questions to
ask regarding the results of large core trials, however, will be the extent of
clinical improvement and the proportion of patients who achieve good quality
of life, rather than slightly less but still severe disability. Another area of interest
will be to determine which large core subgroups (ie, ASPECTS = 0 to 2 versus 3 to
5) experience substantial benefit and whether rates of hemorrhage differ
between them. A wealth of data on this topic should be available in the
near future.
ENDOVASCULAR STROKE THERAPY PROCEDURE AND TECHNIQUE

ADVANCES
Continuous improvements in EVT devices and techniques have led to faster,
safer, and more effective reperfusion. These advances have translated into better
clinical outcomes, and newer generations of devices and approaches may be close
to reality.
More Effective Devices

Improvement in device technology was likely an important factor in the success
of the 2015 thrombectomy trials. Many of the initial trials relied on small, poorly
trackable aspiration catheters and first-generation clot retrieval devices.
Procedures could take hours, with multiple passes, and were often fraught with
complications. The advent of the stent retriever improved the procedure into one
that could be done quickly, effectively, and safely. Since then, technology has
continued to improve.
The goal of EVT procedures has become achieving complete reperfusion
(thrombolysis in cerebral infarction grade 3) with a single pass, termed the first
pass effect. This bar has become the new standard by which device performance
can be measured.52 First pass effect reperfusion is associated with improved
clinical outcomes and decreased procedural time. The devices commonly used in
procedures now, even relative to the highly effective ones of the 2015 trial, are
more navigable, visible, and efficacious. In addition, as neurointerventionalists
have gained experience with these devices, they have improved deployment
and capture techniques. Several recent clinical registries have been published for
both stent-retriever-like devices, as well as new generations of very large bore
aspiration catheters, demonstrating rates of over 50% for first pass effect complete
reperfusion, and over 90% for final complete reperfusion (after all passes).10,11
454 APRIL 2023

Resurrection of Intracranial Stenting KEY POINTS
While our ability to recanalize acutely occluded large cerebral arteries with
● Some of the key
endovascular techniques has improved dramatically, several acute stroke questions to ask regarding
etiologies continue to pose a challenge. One of the most common is intracranial the results of large core
atherosclerotic disease. Intracranial atherosclerotic disease can lead to large trials will be the extent of
vessel occlusion acute ischemic stroke through several different mechanisms, clinical improvement and
the proportion of patients
including artery-to-artery distal embolization, in situ parent vessel occlusion,
who achieve good quality of
occlusion of a perforator branch adjacent to the intracranial atherosclerotic life, rather than slightly less
disease plaque, or hypoperfusion related to high-grade stenosis. The clinical but still severe disability.
course of the disease can also vary, with patients presenting with recurrent minor
stroke or a transient ischemic attack, or also with acute severe disability. It is this ● Improvement in device
technology was likely an
latter type, when patients present with acute severe disability, which can important factor in the
frequently result in the diagnosis being encountered during an EVT procedure, success of the 2015
that can lead to the most challenging scenario. Given this article’s focus on EVT, thrombectomy trials.
the discussion will be limited to this situation.
● The goal of endovascular
First, the natural history of intracranial atherosclerotic disease is quite poor. stroke therapy procedures
One-year rates of recurrent stroke or death were 25% in the WASID (Warfarin- has become achieving
Aspirin Symptomatic Intracranial Disease) trial and 13% in the SAMMPRIS complete reperfusion
(Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in (thrombolysis in cerebral
infarction grade 3) with a
Intracranial Stenosis) trial, which included very aggressive medical management
single pass, termed the first
and supervision for lifestyle modification.53 Clinical trials to date have focused on pass effect. This bar has
secondary prevention indications and have failed to show benefit for intracranial become the new standard
stenting. However, when intracranial atherosclerotic disease lesions are by which device
performance can be
encountered during EVT, decision-making strategies for both medical and
measured.
procedural management can be difficult. Recognizing that a large vessel occlusion
may be secondary to intracranial atherosclerotic disease prior to EVT can be ● Intracranial
helpful. Some clues include evidence of intracranial atherosclerotic disease in other atherosclerotic disease can
vessels on preprocedural vascular imaging such as CT angiography, and also a lead to large vessel
occlusion acute ischemic
clinical examination that appears better than expected. To elaborate on this point stroke through several
further, if a patient presents with an NIHSS score that is relatively low compared different mechanisms,
to the nature of their occlusion and their comorbidities (ie, a patient with an including artery-to-artery
extensive history of smoking and poorly controlled diabetes with an M1 MCA distal embolization, in situ
parent vessel occlusion,
occlusion but minimal symptoms), the large vessel occlusion may not be acute, but occlusion of a perforator
rather acute-on-chronic, which enables the development of collateral vessels. branch adjacent to the
These are scenarios where intracranial atherosclerotic disease, as the etiology of the intracranial atherosclerotic
acute-on-chronic occlusion, should be considered. Several findings can also appear disease plaque, or
hypoperfusion related to
during the EVT procedure that serve as clues and are further discussed in CASE 3-3.
high-grade stenosis.
Management of patients with intracranial atherosclerotic disease during the
EVT procedure and afterward requires concerted medical and possibly
procedural interventions. Because these occlusions are likely secondary to in situ
thrombus superimposed on intracranial atherosclerotic disease plaque, they are
highly likely to reocclude. Antithrombotic agents, in particular antiplatelet
medications, may help prevent reocclusion, but this need must be considered
against the risk of intracranial hemorrhage. Blood pressure management is also
crucial. On the procedural side, there is reinvigorated interest in intracranial
angioplasty and stenting, particularly with balloon-mounted stents, drug-eluting
stents, or both. These devices are borrowed from the interventional cardiologists’
armamentarium, but they demonstrate high rates of technical success with fewer
complications relative to the procedures performed in SAMMPRIS and VISSIT
(Vitesse Intracranial Stent Study for Ischemic Stroke Therapy). Once one of

these stents is deployed, the antithrombotic regimen and postprocedural care

become even more critical; an example of one management strategy is given in
CASE 3-3. It is also worth noting that nonstenting approaches, including medical
management with additional antithrombotic therapy, or balloon angioplasty
alone, are other viable options. At present, given the lack of trial data or even
expert consensus on the optimal management technique, practice patterns
vary widely.
approximately 5 hours prior to presentation and had a history of
uncontrolled diabetes and hypertension. He also had a long history of
cigarette smoking. Initial imaging with noncontrast head CT (FIGURE 3-3A)
showed preservation of the left hemisphere parenchyma. Vascular
imaging with CT angiogram demonstrated a left middle cerebral artery
(MCA) occlusion in the mid-M1 segment. Notable stenoses of the other
intracranial vessels were present and were concerning for intracranial
atherosclerosis. Initial digital subtraction angiography images in the
anterior-posterior (FIGURE 3-3B) and lateral (FIGURE 3-3C) projections
demonstrated the left MCA occlusion, as well as multifocal segmental
stenoses of the left anterior cerebral artery that were concerning for
intracranial atherosclerosis. Two thrombectomy attempts were made for
the left M1 occlusion. After both attempts, transient patency of the left
MCA occurred; however, after several minutes the vessel would
reocclude. This behavior, in addition to the beak-shaped appearance of
the left M1 segment on subsequent digital subtraction angiography
(FIGURE 3-3D) and the findings seen on the anterior cerebral artery, raised
concern that the etiology of the occlusion was likely atherosclerosis. A
plan was then made for possible intracranial stenting. When considering
acute intracranial stenting, one of the principal challenges is
antithrombotic medication management. In this case, the patient had not
been treated with thrombolysis, which can at times complicate matters
further. However, given the fact that multiple thrombectomy attempts
had been made, a flat panel CT was performed on the angiography table,
which demonstrated the absence of any intracranial hemorrhage up to
that point. The patient was given a bolus of IV heparin and eptifibatide. A
drug-eluting balloon-mounted stent was navigated and positioned over
the area of occlusion and deployed. Subsequent digital subtraction
angiography demonstrated restored patency of the left MCA in
anterior-posterior views (FIGURE 3-3E) and restored but delayed perfusion
to the left MCA territory in lateral views (FIGURE 3-3F). Immediate
postoperative noncontrast head CT (FIGURE 3-3G) showed stent positioning
and absence of intracranial hemorrhage. The patient was subsequently
loaded with aspirin and clopidogrel and monitored closely in the
intensive care unit for strict blood pressure control. Follow-up MRI
(FIGURE 3-3H) showed a relatively small final infarct, without hemorrhage,
and the patient’s symptoms improved substantially.
456 APRIL 2023

OPTIMIZING THE BENEFITS OF RECANALIZATION AND FUTURE
DIRECTIONS
Despite the greater than 90% substantial recanalization rates that can be achieved
with modern EVT, about 50% of patients still do not achieve functional
independence after treatment. This finding is the same in nearly all EVT studies,
including the early window and late window randomized control trials and
observational registries.1,10,44 While some of this gap between recanalization
FIGURE 3-3
Imaging of the patient in CASE 3-3, showing a case of severe intracranial atherosclerosis
presenting as middle cerebral artery (MCA) occlusion. The patient presents with acute onset
of symptoms consistent with left MCA syndrome, and initial noncontrast head CT
(A) shows preservation of the left hemisphere parenchyma. Angiographic images in the
anterior-posterior (B) and lateral (C) projections show the MCA occlusion (B, arrow) and also
evidence of diffuse atherosclerosis affecting the anterior cerebral artery branches.
Subsequent thrombectomy attempts result in a beak-like appearance (D, arrow), raising
concern that the etiology of the occlusion is likely atherosclerosis. Intracranial stenting
restores patency of the left MCA in anterior-posterior views (E) with restored but
delayed perfusion to the left MCA territory in lateral views (F). Immediate postoperative
noncontrast head CT shows stent positioning (G, arrow) and the absence of intracranial
hemorrhage. Follow-up MRI (H) shows a relatively small final infarct, without hemorrhage.
This case demonstrates how not all MCA occlusions are due to embolic COMMENT
mechanisms and how considering alternative strategies when
atherosclerosis is revealed to be the etiology is vital when performing
endovascular stroke therapy.

KEY POINTS rates and good clinical outcomes is related to patient comorbidities (ie, the
patients who did poorly were in relatively poor health), it cannot explain the
● Despite the greater than
90% substantial
disparity entirely, as all of the randomized clinical trials excluded patients with
recanalization rates that can conditions that would substantially adversely affect 90-day disability outcomes.
be achieved with modern In preclinical models a considerable difference between recanalization and
endovascular stroke reperfusion exists, implying that recanalization alone may not freeze infarct
therapy, about 50% of
growth. Ischemia and reperfusion can lead to continued injury and dysfunction
patients still do not achieve
functional independence at the arteriolar and capillary levels even after recanalization. Continued infarct
after treatment. growth has been attributed to several mechanisms including microthrombus
formation related to the activation of von Willebrand factor with collagen and
● While its results will need glycoprotein I, along with many other inflammatory pathways. These
to be replicated, the
CHOICE trial provides one of phenomena, however, remain poorly characterized in human disease.54,55
the first treatment The recently published CHOICE (Chemical Optimization of Cerebral
approaches for Embolectomy) trial demonstrated that in patients who underwent EVT for large
microvascular dysfunction. vessel occlusion acute ischemic stroke and had successful revascularization,
additional treatment with intra-arterial alteplase improved clinical outcomes
relative to placebo.56 No hemorrhages occurred in the alteplase group, suggesting
that lysis of distal microthrombi might result in improved perfusion and reduced
reperfusion-related injury. While its results will need to be replicated, CHOICE
provides one of the first treatment approaches for microvascular dysfunction.
In addition to intraarterial thrombolysis, blood pressure goals postreperfusion
likely play a large role in outcomes. Multiple studies have shown correlations
between hypotension and hypertension and outcomes, and the variability in
optimal blood pressure is likely related to microcirculatory differences between
patients. Given the growing evidence of a population of patients who may
require additional measures beyond recanalization alone, neuroprotection
strategies targeted at these patients may emerge in the coming years.
CONCLUSION
How we screen, treat, and build systems of care for patients with large vessel
occlusion acute ischemic stroke has changed dramatically since the publication of
the EVT trials in 2015. Given the breadth and rapid pace of ongoing
investigations, more change is certainly on the way. The overall safety of the
procedure has led to the exploration of expanding indications. Crucial to this
process will be organization around prehospital routing, hospital accreditation,
physician training and certification, and sustainable financial structures. As the
area within the field of neurointervention that is currently receiving the most
research investment from academic and industry sources, as well as the fastest
growth in terms of procedural volume, EVT’s future is undoubtedly one of rapid
evolution and progress.
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0000000000012805

REVIEW ARTICLE

Diagnosis and
ONLINE
Management of
Cardioembolic Stroke
By Shadi Yaghi, MD, FAHA
ABSTRACT
OBJECTIVE: Cardioembolic stroke accounts for nearly 30% of ischemic
strokes. Prompt diagnosis of the underlying mechanism may improve
secondary prevention strategies. This article reviews recent randomized
trials, observational studies, case reports, and guidelines on the diagnosis
and treatment of cardioembolic stroke.
LATEST DEVELOPMENTS: Several pathologies can lead to cardioembolic stroke,

including atrial fibrillation, aortic arch atheroma, patent foramen ovale,
left ventricular dysfunction, and many others. Secondary stroke
prevention strategies differ across these heterogeneous mechanisms. In
addition to medical treatment advances such as the use of direct oral
anticoagulants in patients with atrial fibrillation, surgical treatments such
as closure of patent foramen ovale have been shown to reduce the risk of
recurrent stroke in select patients. Furthermore, left atrial appendage
occlusion is a promising strategy for patients with atrial fibrillation who are
candidates for short-term oral anticoagulation therapy but not long-term
oral anticoagulation therapy.
ESSENTIAL POINTS:A thorough diagnostic evaluation is essential to determine

cardioembolic causes of stroke. In addition to risk factor management and
lifestyle modifications, identification and targeting of the underlying
CITE AS:
cardioembolic stroke mechanisms will lead to improved stroke prevention
CONTINUUM (MINNEAP MINN) strategies in patients with cardioembolic stroke.
DISEASE):462–485.
Address correspondence to INTRODUCTION
C
Dr Shadi Yaghi, 593 Eddy St, APC ardioembolic stroke accounts for nearly 30% of ischemic strokes
527, Providence, RI 02903,
shadiyaghi@yahoo.com. and is associated with increased morbidity and mortality.1,2 Several
cardiac pathologies can lead to ischemic stroke, and these include
high-risk cardiac sources such as atrial fibrillation, endocarditis,
Dr Yaghi reports no disclosure.
and left ventricular thrombus, as well as lower-risk cardiac sources
UNLABELED USE OF such as patent foramen ovale.1,2 While secondary prevention strategies in
USE DISCLOSURE:
cardioembolic stroke have improved over the past decades, gaps in knowledge
Dr Yaghi reports no disclosure. remain. In addition to risk factor control, which is the basis of secondary stroke
prevention, identifying and targeting the stroke mechanism is a key element of
© 2023 American Academy secondary prevention. This is particularly important in patients with acute
of Neurology. cardioembolic stroke given the wide range of potential mechanisms. This article
462 APRIL 2023

provides an overview of specific cardioembolic sources and discusses secondary KEY POINT
prevention strategies in these patients.
● Direct oral anticoagulants
are at least as effective as
EVALUATION OF PATIENTS WITH SUSPECTED CARDIOEMBOLIC STROKE warfarin in stroke
In patients with suspected cardioembolic stroke (ie, embolic-appearing infarct prevention in atrial
on imaging but no cardiac source identified on initial diagnostic evaluation), fibrillation and have lower
risk of intracranial
a transesophageal echocardiogram and prolonged outpatient cardiac rhythm
hemorrhage.
monitoring may be considered to identify cardiac sources, which may lead to a
change in clinical management. For instance, identifying paroxysmal occult atrial
fibrillation on outpatient cardiac monitoring leads to anticoagulation therapy,
and identification of a patent foramen ovale may lead to consideration of closure.
A transesophageal echocardiogram can also identify less common cardioembolic
sources such as cardiac myxoma or fibroelastoma that may require surgery. This
topic is discussed in more detail in the article “Diagnostic Evaluation of Stroke
Etiology,” by James F. Meschia, MD, FAAN, in this issue of Continuum.3
ATRIAL FIBRILLATION
Atrial fibrillation is the most common heart arrhythmia, affecting nearly 2% of
the general population in a European study, with increased incidence in older
adults.4 Atrial fibrillation is divided into two categories: valvular atrial fibrillation
(defined as atrial fibrillation in the setting of moderate to severe mitral valve
stenosis or mechanical valve replacement) and nonvalvular atrial fibrillation.5
The incidence of atrial fibrillation is increasing with the aging population and
improved detection tools. In one study incidence rates by year increased from a
minimum of 4.74 per 1000 person-years in 2008 to 6.82 per 1000 person-years in
2018.5 Studies have shown an association between atrial fibrillation and ischemic
stroke and cardiovascular death.6 In patients with atrial fibrillation, clinical
variables associated with increased stroke risk include age, female sex,
hypertension, diabetes, congestive heart failure, history of stroke or transient
ischemic attack (TIA), and evidence of atherosclerotic disease.6 Furthermore,
using these clinical variables, the CHADS2 score (congestive heart failure,
hypertension, age 75 years or older, diabetes mellitus, and previous stroke or
TIA) and CHA2DS2VASc score (CHADS2 plus vascular disease, age 65 to
74 years, and sex category [female]) can aid in risk-stratifying patients and
selecting those who may benefit from anticoagulation therapy. In addition to
clinical variables, laboratory variables (eg, N-terminal pro b-type natriuretic
peptide or high-sensitivity cardiac troponin) and cardiac biomarkers (eg, atrial
fibrillation burden, fibrosis, atrial enlargement, or left atrial appendage
morphology) have been identified as predictors of stroke risk in atrial fibrillation
but are not currently widely utilized to risk-stratify patients.6
Secondary stroke prevention in patients with atrial fibrillation encompasses
medical and surgical treatment options and is somewhat different from other
subtypes. While risk factor management and lifestyle changes are of importance,
studies have shown the superiority of warfarin over aspirin therapy for primary
and secondary stroke prevention in patients with atrial fibrillation.7,8 Over the
past decade, randomized trials showed that direct oral anticoagulants are at least
as effective as warfarin in stroke prevention in atrial fibrillation and have lower
risk of intracranial hemorrhage (TABLE 4-19).10-12 Furthermore, the AVERROES
(Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation
Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment)

DIAGNOSIS AND MANAGEMENT OF CARDIOEMBOLIC STROKE
trial13 compared apixaban to aspirin in patients deemed unsuitable for warfarin and
was stopped early due to a significant reduction in stroke risk with apixaban without
increased risk of intracranial hemorrhage (TABLE 4-1).
On the other hand, in patients with valvular atrial fibrillation, warfarin is the
preferred treatment since the above-mentioned trials were limited to nonvalvular
atrial fibrillation and the RE-ALIGN (Dabigatran Etexilate in Patients With
Mechanical Heart Valves) randomized trial14 comparing dabigatran to warfarin in
TABLE 4-1 Major Recent Stroke Prevention Trials in Atrial Fibrillationa
Patient Comparator
Study population groups Stroke or systemic embolism Major hemorrhage
RE-LY Mean age: 71 years Dabigatran Dabigatran 150 mg versus Dabigatran 150 mg versus
(open label) 150 mg warfarin: risk ratio 0.66; 95% warfarin: risk ratio 0.93; 95%
Mean CHADS2
confidence interval, 0.53 to 0.82 confidence interval, 0.81 to 1.07
score: 2.1
Dabigatran Dabigatran 110 mg versus Dabigatran 110 mg versus
Mean TTR: 64%
110 mg warfarin: risk ratio 0.91; 95% warfarin: risk ratio 0.80; 95%
History of stroke confidence interval, 0.74 to 1.11 confidence interval, 0.69 to 0.93
or TIA: 20% Warfarin
ROCKET-AF Mean age: Rivaroxaban Rivaroxaban versus warfarin: Rivaroxaban versus warfarin:
(randomized 73 years 20 mg hazard ratio 0.88; 95% hazard ratio 0.69; 95%
controlled) confidence interval, 0.75 to 1.03 confidence interval, 0.90 to 1.20
Mean CHADS2
score: 3.5 Warfarin
Mean TTR: 55%
History of stroke,
systemic
embolism, or TIA:
55%
ARISTOTLE Mean age: Apixaban 5 mg Apixaban versus warfarin: Apixaban versus warfarin: hazard
(randomized 70 years hazard ratio 0.79; 95% ratio 0.69; 95% confidence
controlled) confidence interval, 0.66 to 0.95 interval, 0.60 to 0.80
Mean CHADS2
score: 2.1 Warfarin
Mean TTR: 62%
History of stroke,
systematic
embolism, or TIA
19.4%
ENGAGE Median age: Edoxaban Edoxaban 60 mg versus warfarin: Edoxaban 60 mg versus

(randomized 72 years 60 mg hazard ratio 0.79; 95% warfarin: hazard ratio 0.80;
controlled) confidence interval, 0.63 to 0.99 95% confidence interval, 0.71 to
Mean CHADS2
0.91
score: 2.8
Edoxaban Edoxaban 30 mg versus warfarin: Edoxaban 30 mg versus
Median TTR: 68%
30 mg hazard ratio 1.07; 95% confidence warfarin: hazard ratio 0.47; 95%
History of stroke interval, 0.87 to 1.31 confidence interval, 0.41 to 0.55
or TIA: 28% Warfarin
464 APRIL 2023

patients with mechanical heart valves showed increased thromboembolic and
bleeding complications in the dabigatran group.
In patients with nonvalvular atrial fibrillation, the left atrial appendage is the
site of thrombus formation in at least 95% of patients.15 Growing evidence
supports left atrial appendage occlusion as an alternative to oral anticoagulation
in patients with atrial fibrillation. Data from the PREVAIL (Evaluation of the
WATCHMAN Left Atrial Appendage [LAA] Closure Device in Patients With
Patient Comparator
Study population groups Stroke or systemic embolism Major hemorrhage
AVERROES Mean age: Apixaban 5 mg Apixaban versus aspirin: hazard Apixaban versus aspirin: hazard
(randomized 70 years ratio 0.45; 95% confidence ratio 1.13; 95% confidence
Aspirin 81 mg
controlled) interval, 032 to 0.62 interval, 0.74 to 1.75
Mean CHADS2 to 324 mg
score: 2.0
History of stroke
or TIA: 14%
PREVAIL-AF and Mean age: WATCHMAN WATCHMAN versus warfarin: WATCHMAN versus warfarin
PROTECT AF: 73 years hazard ratio 0.96; 95% (including procedural bleeding):
Warfarin
5-year follow-up confidence interval, 0.60 to 1.54 hazard ratio 0.91; 95%
Mean CHADS2
confidence interval, 0.64 to 1.29
score: 2.3
WATCHMAN versus warfarin
Mean TTR: 62%
(excluding procedural bleeding):
History of stroke hazard ratio 0.48; 95%
or TIA: 23% confidence interval, 0.32 to 0.71
PRAGUE-17 Mean age: WATCHMAN WATCHMAN versus DOACs: All WATCHMAN versus DOACs:
73 years stroke or TIA, WATCHMAN versus Major and nonmajor bleeding,
DOACs
DOACs: hazard ratio 1.00; 95% WATCHMAN versus DOACs:
Mean CHA2DS2-
confidence interval, 0.40 to 2.51 hazard ratio 0.53; 95%
VASc score: 4.7
confidence interval, 0.26 to 1.06
History of stroke:
32.1%
AMULET-IDE Mean age: Amulet Amulet versus WATCHMAN: Amulet versus WATCHMAN:
75 years All stroke, Amulet versus hazard ratio 1.07; 95%
WATCHMAN
WATCHMAN: hazard ratio confidence interval, 0.80 to 1.43
Mean CHA2DS2-
0.81; 95% confidence interval,
VASc score: 4.6
0.47 to 1.39
History of stroke:
19.0%
a
Reprinted with permission from Mac Grory B, et al, Circulation Research.8 © 2022, Wolters Kluwer Health.
CHADS2 = congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, and previous stroke/TIA; CHA2DS2VASc = CHADS2 plus
vascular disease, age 65 to 74 years, and sex category (female); DOACs = direct oral anticoagulants; TIA = transient ischemic attack; TTR = time in
therapeutic range.

Atrial Fibrillation Versus Long Term Warfarin Therapy) and PROTECT AF

(WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients
With Atrial Fibrillation) trials demonstrated that left atrial appendage occlusion
may provide stroke prevention and lead to a lower risk of major hemorrhage and
death (TABLE 4-1).16 Furthermore, the PRAGUE-17 (Interventional Left Atrial
Appendage Closure vs. Novel Anticoagulation Agents in High-risk Patients With
Atrial Fibrillation) trial demonstrated that left atrial appendage occlusion is
noninferior to direct oral anticoagulant treatment in terms of a broad composite
endpoint in patients with nonvalvular atrial fibrillation (TABLE 4-1).17
Furthermore, data from AMULET-IDE (Amplatzer Amulet Left Atrial
Appendage Occluder Randomized Controlled Trial) suggest that the Amulet
left atrial appendage occlusion device is noninferior to WATCHMAN
(TABLE 4-1).18 However, no trials have assessed the noninferiority of left atrial
occlusion versus anticoagulation for the endpoint of stroke. Therefore, at this
time, left atrial appendage occlusion is reserved for patients who are deemed
to be at high risk for long-term oral anticoagulation therapy but are candidates
for 45 days of anticoagulation therapy.19 The ongoing CHAMPION-AF
(WATCHMAN FLX Versus NOAC for Embolic ProtectION in the Management
of Patients With Non-Valvular Atrial Fibrillation) and CATALYST (Clinical Trial
of Atrial Fibrillation Patients Comparing Left Atrial Appendage Occlusion
Therapy to Non-vitamin K Antagonist Oral Anticoagulants) trials are comparing
WATCHMAN FLEX (a newer version of WATCHMAN) and Amulet,
respectively, to direct oral anticoagulants in patients with nonvalvular atrial
fibrillation. These trials will be essential to determine if the use of left atrial
appendage occlusion is a viable initial treatment in patients with nonvalvular
atrial fibrillation.
In patients with acute cardioembolic stroke in the setting of atrial fibrillation,
studies have shown that parenteral anticoagulation with heparin or low-
molecular-weight heparin is associated with increased risk of intracranial
hemorrhage, without a reduction in the risk of ischemic recurrence.20,21 Therefore,
in most patients with acute cardioembolic stroke, oral anticoagulation, preferably
with direct oral anticoagulants,21 is generally started without bridging with heparin
or low-molecular-weight heparin.
The RAF (Early Recurrence and Cerebral Bleeding in Patients With Acute
Ischemic Stroke and Atrial Fibrillation) study showed that it is reasonable to start
warfarin 4 to 14 days after a cardioembolic stroke, but more recent observational
studies suggest that starting a direct oral anticoagulant 0 to 3 days after an ischemic
stroke does not carry increased risk of hemorrhage when compared with
starting after 3 days.22-24 Current American Heart Association/American Stroke
Association guidelines suggest initiating anticoagulation after 2 to 14 days in
patients at low risk for hemorrhagic conversion and beyond 14 days for those at
high risk.19 Ongoing clinical trials will help determine the optimal timing of
anticoagulation initiation in patients with atrial fibrillation–associated acute
ischemic stroke.
One challenging scenario clinicians face is when patients have an ischemic
stroke despite anticoagulation (CASE 4-1). While anticoagulation is associated
with reduced risk of stroke in patients with atrial fibrillation, certain patients
have an ischemic stroke despite oral anticoagulation therapy. Studies have shown
that one-fourth to one-third of ischemic strokes in patients with atrial fibrillation
occur in patients on anticoagulation therapy; these patients have increased stroke
466 APRIL 2023

recurrence rates and switching oral anticoagulation does not seem to reduce this KEY POINTS
risk.25,26 The management of these patients is challenging (FIGURE 4-2). A
● There is growing evidence
detailed history regarding compliance with anticoagulation and drug interactions to support left atrial
with other medications is essential. Furthermore, drug levels, coagulation appendage occlusion as an
markers, or both can help determine the adequacy of anticoagulation at the time alternative to oral
of presentation. Studies suggest performing a comprehensive diagnostic anticoagulation in patients
with atrial fibrillation.
evaluation to identify competing mechanisms such as large artery
atherosclerosis, small vessel disease, and cancer-associated hypercoagulability. In ● In patients with acute
patients who develop a breakthrough atrial fibrillation–associated ischemic cardioembolic stroke
stroke despite anticoagulation therapy, further research is needed to determine treated with oral
secondary prevention strategies such as the addition of antiplatelet therapy or the anticoagulants, treatment is
generally started without
combination of left atrial appendage occlusion and oral anticoagulation.27 bridging with heparin or low-
The management of patients with atrial fibrillation and high bleeding risk can molecular-weight heparin.
be challenging. In patients with atrial fibrillation, studies have shown that
patients at increased risk for thrombotic events are also at higher risk for bleeding ● In patients with atrial
fibrillation and ischemic
complications,28 but in most patients the benefit of oral anticoagulation for stroke despite
stroke prevention outweighs the hemorrhage risk. In patients for whom anticoagulation a full
anticoagulation is contraindicated, small observational studies suggest that left diagnostic evaluation is
atrial appendage occlusion may be safe29; in particular, recent studies suggest important to rule out
alternative mechanisms
that periprocedural dual antiplatelet therapy is equivalent to oral
such as small vessel disease
anticoagulation.30 In patients with a history of intracerebral hemorrhage, or large artery
particularly deep hemorrhages31 thought to be related to hypertension, atherosclerosis that are not
observational studies suggest that anticoagulation resumption may be safe and necessarily related to the
atrial fibrillation and thus do
effective.32,33 The ongoing randomized trials ASPIRE (Anticoagulation in ICH
not signify anticoagulation
Survivors for Stroke Prevention and Recovery) and ENRICH-AF (EdoxabaN foR failure.
IntraCranial Hemorrhage Survivors With Atrial Fibrillation) are comparing the
efficacies of direct oral anticoagulants and aspirin in these patients. In patients
with a history of extracranial hemorrhage, studies have shown an increased risk
of ischemic stroke. Thus, in these patients, anticoagulation should generally be
resumed after the bleeding source is successfully treated.34 On the other hand,
left atrial appendage occlusion can be considered in patients with recurrent major
extracranial hemorrhage or those whose bleeding source cannot be successfully
treated such as those with multiple gastrointestinal arteriovenous malformations.
ATRIAL CARDIOPATHY
Atrial dysfunction or cardiopathy has been proposed as a mechanism of
cardioembolic stroke, even in the absence of atrial fibrillation.35 This is supported
by studies showing no temporal relationship between atrial fibrillation and
ischemic stroke,36 suggesting that atrial fibrillation may not be the direct cause of
ischemic stroke in all patients with this arrhythmia and that atrial cardiopathy
may instead be the pathomechanistic substrate for thrombus formation.37
In epidemiological studies, atrial cardiopathy biomarkers such as left atrial
enlargement,38-40 increased p-wave terminal force in lead V1,41-43 and increased
N-terminal pro b-type natriuretic peptide44,45 have been shown to be associated
with increased ischemic stroke risk as well as brain infarcts, particularly those
related to embolism. Furthermore, studies have linked atrial fibrosis to ischemic
stroke risk in patients with atrial fibrillation46 and to the embolic stroke of
undetermined source (ESUS) stroke subtype.47,48 While associations with atrial
biomarkers and ischemic stroke risk are well established, these were based on
studies performed in cohorts where prolonged cardiac monitoring was not

performed and thus it remains uncertain whether these associations are truly
independent of concomitant atrial fibrillation which can be brief, paroxysmal,
and asymptomatic. Furthermore, cutoff values for these biomarkers that can
help risk-stratify patients have not been well established, limiting the clinical
utility of such biomarkers.
In addition to atrial biomarkers, certain left atrial appendage biomarkers may
indicate an increased risk of atrial thromboembolism. These include high-risk left
atrial appendage morphology, reduced left atrial appendage flow velocity, as well
as left atrial appendage fibrosis.15,49,50 Although some reports suggest that left
atrial appendage thrombi may form in patients with atrial or left atrial appendage
dysfunction but without known atrial fibrillation,51 most studies of left atrial
appendage biomarkers have involved patients with known atrial fibrillation and
more studies are needed to investigate these biomarkers as evidence of a direct
cause of ischemic stroke in patients without known atrial fibrillation.
Post-hoc analyses of clinical trials suggest that patients with ischemic stroke in
the setting of atrial cardiopathy may benefit from oral anticoagulation. For
instance, WARSS (Warfarin-Aspirin Recurrent Stroke Study) randomized
patients with noncardioembolic stroke to warfarin versus aspirin. The primary
outcome of stroke or death at 2 years was similar between the two groups.52 In
a post-hoc analysis of WARSS patients with N-terminal pro b-type natriuretic
CASE 4-1 A 75-year-old man with a history of hypertension and atrial fibrillation
presented with a 2-day history of dysarthria. He was taking lisinopril
10 mg once daily and rivaroxaban 20 mg once daily. He reported
compliance with his medications and took rivaroxaban daily with dinner.
On physical examination, he had a blood pressure of 176/97 mm Hg and a
heart rate of 86 beats/min. His general examination was remarkable for
an irregularly irregular rhythm and his neurologic examination was
pertinent for mild dysarthria and mild right lower facial droop. Upon
further history, the patient reported that while at home his blood
pressure ranged between 140/70 mm Hg and 160/90 mm Hg. His
low-density lipoprotein cholesterol level was 135 mg/dL and his
glycosylated hemoglobin level was 5.0%. He underwent a diagnostic
evaluation, which revealed a punctate acute infarct in the corona radiata
on diffusion-weighted imaging (FIGURE 4-1A) and no significant intracranial
or extracranial stenosis on MR angiography (MRA) (FIGURE 4-1B and
FIGURE 4-1C). His ECG showed atrial fibrillation and his transthoracic
echocardiogram showed normal ejection fraction, moderate left atrial
dilation, and moderate left ventricular hypertrophy. His infarct was
attributed to small vessel disease in the setting of uncontrolled
hypertension. His lisinopril dosage was increased to 40 mg daily with
ambulatory blood pressure monitoring and a goal of less than 130/80 mm
Hg. He was also started on high-intensity statin therapy for a target
low-density lipoprotein cholesterol level of less than 70 mg/dL and
recommended for healthy lifestyle measures including diet and regular
exercise.
468 APRIL 2023

peptide levels greater than 750 pg/mL, warfarin was superior to aspirin in
reducing the risk of recurrent stroke or death (hazard ratio 0.30; 95% confidence
interval 0.12 to 0.84, P = .021).53 Similarly, the NAVIGATE-ESUS (Rivaroxaban
Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic
Embolism in Patients With Recent Embolic Stroke of Undetermined Source) trial
randomized patients with ESUS to rivaroxaban versus aspirin and showed no
difference in recurrent stroke risk between the two groups but significantly
higher risk of major hemorrhage in patients randomized to rivaroxaban.54 A
post-hoc analysis of NAVIGATE-ESUS showed that in patients with a left atrial
diameter on transthoracic echocardiogram of greater than 4.6 cm, rivaroxaban
was superior to aspirin in reducing the risk of recurrence stroke (hazard ratio
0.26; 95% confidence interval 0.07 to 0.94).55 These markers are also predictors
of atrial fibrillation detection after ESUS,56,57 and since routine cardiac
monitoring was not performed in these trials it remains unclear whether the
observed benefit of anticoagulation is only in the subset of patients with
paroxysmal atrial fibrillation. Furthermore, findings from post-hoc analyses are
only hypothesis generating and should be interpreted with caution.
The ATTICUS (Apixaban for Treatment of Embolic Stroke of Undetermined
Source) trial compared apixaban to aspirin in patients with ESUS and evidence of
risk for cardiac thromboembolism such as a left atrial size greater than 45 mm,
FIGURE 4-1
Imaging of the patient in CASE 4-1. A, Diffusion-weighted imaging sequence with punctate
infarct in left corona radiata (arrow). B, MR angiogram (MRA) of the intracranial arteries
showing no significant stenosis. C, MRA of the extracranial arteries showing no significant
stenosis.
This case highlights that in patients with atrial fibrillation and ischemic COMMENT
stroke despite anticoagulation therapy, a full diagnostic evaluation is
important to rule out alternative mechanisms such as small vessel disease
or large artery atherosclerosis that are not necessarily related to the atrial
fibrillation and thus do not signify anticoagulation failure.

FIGURE 4-2
Approach to patients with atrial fibrillation and ischemic stroke on anticoagulation therapy. A
careful history to assess for medication adherence and dosing and rule out underdosing or
poor adherence (left column), followed by a noncardiac workup (middle column) to look for
competing noncardioembolic mechanisms as well as a cardiac workup to look for competing
cardioembolic causes (right column), are all important steps in managing patients with
ischemic stroke who are prescribed anticoagulation therapy.
CSF = cerebrospinal fluid; DOAC = direct oral anticoagulant; DWI = diffusion-weighted imaging;
FLAIR = fluid-attenuated inversion recovery; MRI = magnetic resonance imaging, TEE = transesophageal
echocardiography.
Reprinted with permission from Stretz C, et al, J Neurol Neurosurg Psychiatry.27 © 2021, BMJ Publishing
Group Ltd.
spontaneous echocardiographic contrast in the left atrial appendage, left atrial

appendage flow velocity less than or equal to 0.2 cm/s, atrial high-rate episodes,
a CHA2DS2VASc score greater than or equal to 4, or patent foramen ovale, and
was stopped early after an interim analysis due to futility.58 The rate of recurrent
stroke during follow-up was 6.8% and the atrial fibrillation detection rate in the
ATTICUS cohort was reported as 23%.58 Publication of the full trial results is
underway. Since this study was not restricted to atrial cardiopathy, it remains
unclear whether empiric anticoagulation is superior to aspirin in patients with
atrial cardiopathy and ESUS. The ongoing ARCADIA (AtRial Cardiopathy and
Antithrombotic Drugs In Prevention After Cryptogenic Stroke) trial is
randomizing patients with cryptogenic stroke and evidence of one or more atrial
cardiopathy biomarkers (ie, left atrial index ≥3 cm/m2, N-terminal pro b-type
natriuretic peptide >250 pg/mL, or P-wave terminal force in lead V1 on ECG
≥5000 μV ms) to apixaban versus aspirin and will shed light on whether oral
anticoagulation is safe and effective in patients with cryptogenic stroke and
atrial cardiopathy.59
PATENT FORAMEN OVALE

Patent foramen ovale (PFO) is a congenital septal defect that is present in nearly
25% of the population60 and may be associated with a right-to-left shunt, which is
more prominent during Valsalva maneuvers. The diagnosis of a PFO is suspected
based on the presence of a right-to-left shunt, which highly suggests the presence
of a PFO in patients aged 18 years or older. The diagnosis is made based on a
positive bubble study (indicative of a right-to-left shunt) on a transthoracic
echocardiogram, transesophageal echocardiogram, or transcranial Doppler.61
The bubble study is enhanced by the Valsalva maneuver and evidence suggests
470 APRIL 2023

that transcranial Doppler is superior to transthoracic echocardiography in KEY POINTS
diagnosing a right-to-left shunt.62 Transesophageal echocardiography provides
● In addition to atrial
the best views of the septum and thus is best at visualizing the PFO and biomarkers, certain left
associated abnormalities such as atrial septal aneurysm. The limitations of atrial appendage biomarkers
transesophageal echocardiography are that it is semi-invasive and requires may indicate an increased
sedation which may limit the patient’s ability to perform a Valsalva maneuver, risk of atrial
thromboembolism.
leading to a suboptimal bubble study.63 When diagnosing a PFO in the setting of
an ischemic stroke, it is important to determine whether high-risk features are ● Patent foramen ovale
present which include the degree of shunting (classified as a small shunt [3 to 10 (PFO) is a congenital septal
bubbles], medium shunt [10 to 20 bubbles], or large shunt [>20 bubbles])64 and defect that is present in
whether an associated atrial septal aneurysm was present. nearly 25% of the population
and is associated with a
Studies have shown an association between PFO and ischemic stroke risk, right-to-left shunt, which is
particularly cryptogenic stroke.65 One postulated pathomechanism of ischemic more prominent during
stroke in patients with PFO is paradoxical embolism from deep venous thrombosis. Valsalva maneuvers.
This theory is supported by the increased prevalence of pelvic deep venous
● Evidence suggests that
thrombi in patients with cryptogenic stroke,66 particularly when a PFO is transcranial doppler is
present.67 Another postulated pathomechanism is in situ thrombosis at the superior to transthoracic
PFO site.61 echocardiography in
Due to the substantial prevalence of PFOs in the general population and the diagnosing a right-to-left
cardiac shunt.
low risk of ischemic stroke due to a PFO, it is very important to determine in a
patient with ischemic stroke whether the PFO is pathogenic or incidental. The ● Transesophageal
first step is to perform diagnostic testing which includes laboratory tests, brain echocardiography provides
imaging, intracranial and extracranial vascular imaging, ECG, and cardiac the best views of the septum
telemetry and at least 30 days of outpatient cardiac rhythm monitoring and thus is best at visualizing
the PFO and associated
(in patients aged 40 years or older) to exclude high-risk ischemic stroke abnormalities such as atrial
mechanisms.68 In the absence of a competing mechanism, researchers have septal aneurysm.
suggested using the Risk of Paradoxical Embolism (RoPE) score to help
determine whether a PFO is pathogenic or incidental (TABLE 4-269).69 For ● In patients with
cryptogenic stroke in the
instance, in patients whose RoPE score is 9 to 10, where the PFO is very likely setting of a PFO, medical
to be pathogenic, the risk of recurrent stroke at 2 years was 2%.69 This is contrary and in certain cases surgical
to patients with a RoPE score of 0 to 2, indicating that the PFO is likely incidental, management are
in whom the risk of recurrent stroke was 20% at 2 years.69 recommended for
secondary stroke
In 2021 investigators introduced the PFO-Associated Stroke Causal Likelihood
prevention.
(PASCAL) classification system, which adds high-risk PFO characteristics (the
presence of a substantial shunt and the presence of an atrial septal aneurysm) to
the RoPE score.70 This score classifies the pathogenicity of the PFO as unlikely,
possible, or probable and provides added benefit when selecting patients for PFO
closure (TABLE 4-3). Both scores will be discussed in the PFO Closure section.
As illustrated in CASE 4-2, the management of patients with ischemic stroke
and PFO includes antithrombotic therapy and PFO closure in certain patients. In
the presence of deep venous thrombosis, anticoagulation is generally the
antithrombotic treatment of choice. The duration depends on whether the deep
venous thrombus is provoked or unprovoked. In patients without an indication
for anticoagulation use, several studies have compared anticoagulation to
antiplatelet therapy in patients with ischemic stroke and PFO.
PICSS (Patent Foramen Ovale in Cryptogenic Stroke Study) was a substudy of
WARSS that compared warfarin to aspirin in patients with ischemic stroke and
PFO. PICSS showed no benefit from warfarin over aspirin in the risk of stroke or
death at 2 years in ischemic stroke patients with PFO (hazard ratio 0.96; 95%
confidence interval 0.62 to 1.48, P = .84) and in cryptogenic stroke patients with

TABLE 4-2 Risk of Paradoxical Embolism (RoPE) Scorea
RoPE score components Score
No history of hypertension 1
No history of diabetes 1
No history of stroke or TIA 1
Nonsmoker 1
Cortical infarct on imaging 1
Age in years
18-29 5
30-39 4
40-49 3
50-59 2
60-69 1
≥70 0
Total RoPE score. For patients with stroke and PFO, points are added with higher
scores indicating a higher likelihood of stroke due to PFO.
a
Modified from Kent DM, et al, Neurology.69 © 2013 American Academy of Neurology.
PFO = patent foramen ovale; TIA = transient ischemic attack.
TABLE 4-3 PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System
Likelihood that the

PFO is causative of the
ischemic stroke
RoPE RoPE
score ≥7 score <7
PFO with straddling thrombus Definite Definite
Venous thromboembolism (DVT or PE) preceding Highly probable Probable

the index infarct AND PFO with atrial septal
aneurysm OR large shunt
PFO with atrial septal aneurysm or large shunt Probable Possible
PFO with small shunt and without an atrial Possible Unlikely

septal aneurysm
DVT = deep vein thrombosis; PE = pulmonary embolism; PFO = patent foramen ovale; RoPE = Risk of
Paradoxical Embolism.
472 APRIL 2023

PFO (hazard ratio 1.17; 95% confidence interval 0.60 to 2.37, P = .65). These
differences remained nonsignificant regardless of the PFO shunt size and
whether an atrial septal aneurysm was present.
The NAVIGATE-ESUS and RESPECT-ESUS (Dabigatran Etexilate for
Secondary Stroke Prevention in Patients With Embolic Stroke of
Undetermined Source) trials included patients with PFO. Secondary analysis
of NAVIGATE-ESUS showed that in patients with PFO, when compared with
aspirin, rivaroxaban was associated with a similar risk of recurrent ischemic
stroke (hazard ratio 0.54; 95% confidence interval 0.22 to 1.36) and major
bleeding (hazard ratio 2.05; 95% confidence interval 0.51 to 8.18).71
Furthermore, secondary analysis of the RESPECT-ESUS trial showed that
when compared to aspirin, dabigatran was associated with a similar risk of
recurrent ischemic stroke (hazard ratio 0.88; 95% confidence interval 0.45 to
1.71) and major bleeding (hazard ratio 0.65; 95% confidence interval 0.15 to
2.74) in patients with PFO.72
A 42-year-old woman with no known medical history was brought to the CASE 4-2
emergency department by ambulance after she developed left-sided
weakness that occurred during sexual activity. Upon arrival, her blood
pressure was 125/85 mm Hg and her blood glucose level was 128 mg/dL.
Her general physical examination was within normal limits, and her
neurologic examination was pertinent for left facial droop, mild
dysarthria, mild left hemiparesis with 4/5 strength in her left arm and left
leg, and sensory extinction on the left side.
She underwent a head CT that showed no hemorrhage and CT
angiography of the head and neck that showed a right M1 segment
occlusion. She was treated with IV alteplase and was taken for mechanical
thrombectomy with successful reperfusion and full resolution of her
deficits except for mildly reduced dexterity in her left hand and foot. She
underwent a diagnostic evaluation including an MRI showing an acute
infarction in the right middle cerebral artery territory. MR angiography
(MRA) of the head and neck with fat-suppressed images showed no
evidence of acute dissection. Laboratory testing for antiphospholipid
antibodies was negative at two time points 12 weeks apart. An ECG
showed normal sinus rhythm and cardiac telemetry showed no evidence
of atrial fibrillation. A 30-day cardiac monitor showed no evidence of
atrial fibrillation. A transthoracic echocardiogram showed a large right-to-
left shunt and a patent foramen ovale was visualized by transesophageal
echocardiogram. She was started on aspirin 81 mg once daily and
underwent successful patent foramen ovale closure without
complications and has been stroke free for 3 years.
This case illustrates that in patients with cryptogenic stroke in the setting of COMMENT
a patent foramen ovale, medical and in certain cases surgical management
are recommended for secondary stroke prevention.

TABLE 4-4 Summarized Data From the Six Major Randomized Controlled Trials
Looking at PFO Closure Versus Medical Therapy in Patients With
Cryptogenic Stroke and PFOa
GORE
CLOSURE 174 PC75 RESPECT76 CLOSE77 REDUCE78 DEFENSE PFO79
Year of 2012 2013 2013 2017 2017 2018
publication
Study population 909 414 980 663 664 120

(N)
Inclusion criteria
Age (years) 18-60 <60 18-60 16-60 18-59 18-60
Large shunt NA 20% 50% 90% 40% NA

(% of patients)
Atrial septal 35% 25% 35% 35% 20% 11%

aneurysm
(% of patients)
Vascular risk
factors
Hypertension 30% 25% 30% 10% 25% 24%
Diabetes NA 5% 5% 5% 5% 12%
Active tobacco 20% 25% 15% 30% 15% 22%

use
Treatments
Closure device STARFlex AMPLATZER AMPLATZER Multiple Helex or AMPLATZER

options CARDIOFORM
Medical therapy Antiplatelet or Antiplatelet or Antiplatelet or Antiplatelet Antiplatelet Antiplatelet or

anticoagulation anticoagulation anticoagulation onlyb only anticoagulation
Outcomes
Median length 2 years 4 years 2.5 years 5.5 years 3 years 2.8 years
of follow-up
Hazard ratio for 0.9 (0.4-2) 0.2 (0-1.7) NA 0.1 (0-0.3) 0.2 (0.1-0.6) 0% versus 12.9%,
stroke (95% P = .013
confidence
interval)
Rate of atrial 5.7% versus 2.9% versus 1% NA 4.6% versus 6.6% versus 1.7% versus 0%
fibrillation 0.7% 0.9% 0.4%
(closure versus
medical arm)
a
Modified from Thaler A, et al, Curr Cardiol Rep.73 © 2021 Thaler A, et al, under exclusive license to Springer Science Business Media, LLC, part of
Springer Nature.
b
One randomized arm took anticoagulation, but no comparison of PFO closure versus anticoagulation was reported.
NA = not available; PFO = patent foramen ovale.
474 APRIL 2023

A meta-analysis of four randomized trials showed that antiplatelet and KEY POINT
anticoagulant medications led to similar rates of recurrent ischemic stroke in the
● In the absence of
setting of a PFO (odds ratio 0.70; 95% confidence interval 0.43 to 1.14).72 another indication for
Therefore, in the absence of another indication for anticoagulation, antiplatelet anticoagulation, antiplatelet
therapy may be reasonable for secondary stroke prevention in patients with therapy may be reasonable
ischemic stroke in the setting of a PFO. for secondary stroke
prevention in patients with
ischemic stroke in the
PFO Closure setting of a PFO.
Several randomized controlled trials tested PFO closure against medical
treatment for stroke prevention. These trials are summarized in TABLE 4-4.73 The
initial randomized controlled trials (CLOSURE [Evaluation of the STARFlex®
Septal Closure System in Patients With a Stroke or TIA Due to the Possible
Passage of a Clot of Unknown Origin Through a Patent Foramen Ovale], PC
[Patent Foramen Ovale and Cryptogenic Embolism], and RESPECT [Randomized
Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current
Standard of Care Treatment]) showed no benefit from PFO closure compared to
medical treatment (TABLE 4-4). There were several limitations of these trials. For
instance, CLOSURE74 randomized patients with TIA and included TIA as an
endpoint, and PC75 included patients with peripheral arterial embolism.
RESPECT76 was the most selective despite including patients with small right-to-
left shunts and without an associated atrial septal aneurysm. While RESPECT
showed no significant benefit of PFO closure over medical treatment, patients
randomized to PFO closure had fewer events (hazard ratio 0.49; 95% confidence
interval 0.22 to 1.11, P = .08) and the difference between the two groups was
statistically significant in the per-protocol analysis ( P = .03) and as-treated
analysis ( P = .007).76 Furthermore, individual patient-level data meta-analysis
of the three trials demonstrated a significant benefit in patients with a RoPE
score greater than or equal to 7 (hazard ratio 0.31; 95% confidence interval 0.11 to
0.85, P = .03) as opposed to those with a RoPE score less than 7 (hazard ratio 0.82;
95% confidence interval 0.42 to 1.59, P = .56).
These trials were followed by three further randomized controlled trials
with more tailored protocols and inclusion criteria. These are summarized in
TABLE 4-4. All three trials (CLOSE [Patent Foramen Ovale Closure or
Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence],77
GORE REDUCE [GORE Septal Occluder Device for Patent Foramen Ovale
Closure in Stroke Patients],78 and DEFENSE PFO [Device Closure Versus
Medical Therapy for Cryptogenic Stroke Patients With High-Risk Patent
Foramen Ovale]79) showed a benefit from PFO closure with higher rates of atrial
fibrillation in patients randomized to PFO closure versus medical treatment
(TABLE 4-4).
A meta-analysis of the six trials utilizing the RoPE score and the PASCAL
classification system showed significant treatment effect heterogeneity across
RoPE score and PASCAL classification categories. For instance, the benefit from
PFO closure was more pronounced in patients with a RoPE score greater than or
equal to 7 (hazard ratio 0.21; 95% confidence interval 0.11 to 0.42) as opposed to
those with a RoPE score less than 7 (hazard ratio 0.61; 95% confidence interval
0.37 to 1.00) ( Pinteraction = .02).70 Similarly, the benefit from PFO closure was
only seen in patients classified as PASCAL possible (hazard ratio 0.38; 95%
confidence interval 0.22 to 0.65) and PASCAL probable (hazard ratio 0.10; 95%
confidence interval 0.03 to 0.35), but not PASCAL unlikely (hazard ratio 1.14;

Pinteraction = .003).70 Device-associated complications varied based on the

PASCAL classification categories: atrial fibrillation beyond day 45 after
randomization with a device was 4.41%, 1.53%, and 0.65% in the unlikely,
possible, and probable PASCAL categories, respectively.70
Given that the trials showing a benefit from PFO closure focused on
pathogenic and high-risk PFOs, the inclusion and exclusion criteria of positive
trials should be carefully reviewed when considering PFO closure in patients
with cryptogenic stroke in the setting of PFO.
A challenging scenario is patients with cryptogenic stroke and PFO who are
more than 60 years old, particularly those without vascular risk factors. This is
the case since closure trials showing a benefit from PFO closure were limited to
patients 60 years or younger, and thus there is no proven benefit from PFO
closure in patients who are over 60 years old. That said, PFO closure might still be
considered in a very small subgroup of patients over 60 years old with (1) a PFO
with high-risk features (substantial shunt, atrial septal aneurysm, or both), (2)
no other mechanism is identified despite at least 30 days of cardiac rhythm
monitoring, (3) minimal or no vascular risk factors, and (4) PASCAL
classification as possible or probable.
ISCHEMIC STROKE IN THE SETTING OF AORTIC DISEASE

Atheromas of the aortic arch, particularly when large or mobile, have been
suggested to cause ischemic stroke by artery-to-artery embolism.68 Studies
have shown an association between aortic arch atheromas greater than 4 mm
in size with ischemic stroke risk80,81 as well as recurrent ischemic stroke.82
This association was more likely to be seen in patients with ascending80 and
mobile or ulcerated aortic atheromas81 and more so with cryptogenic strokes,81
suggesting a potentially causal association between the two. While some studies
suggest that aortic arch atheromas can be frequently detected by transthoracic
echocardiography,68 transesophageal echocardiography is superior in the
diagnosis and grading of atheromas of the aortic arch.83 Transesophageal
echocardiography, however, is semi-invasive and there is accumulating data that
noninvasive tests such as CT angiography84 or cardiac MRI may be used as
screening tools.85
The secondary prevention of ischemic stroke in the setting of aortic arch
atherosclerosis consists of risk factor modification, high-intensity statin therapy,
as well as antiplatelet therapy. ARCH (Aortic Arch Related Cerebral Hazard
Trial) was the only secondary prevention trial in patients with high-risk aortic
arch atheromas.86 ARCH randomized patients to warfarin versus aspirin and
clopidogrel and showed numerically higher ischemic events and major bleeding
in patients randomized to warfarin. Furthermore, the rate of vascular death was
higher in patients treated with warfarin versus dual antiplatelet therapy (3.4%
versus 0%, P = .013).86 Therefore, antiplatelet therapy is preferred in patients
with ischemic stroke in the setting of aortic arch atheroma and no indication for
anticoagulation. Furthermore, dual antiplatelet therapy for up to 30 days may be
considered in low-bleeding-risk patients, particularly those who meet criteria for
the CHANCE (Clopidogrel in High-risk Patients With Acute Non-disabling
Cerebrovascular Events),87 POINT (Platelet-Oriented Inhibition in New TIA and
Minor Ischemic Stroke),88 or THALES (Acute STroke or Transient IscHaemic
Attack Treated With TicAgreLor and ASA for PrEvention of Stroke and Death)89
trials. In very rare cases of high-risk aortic atheromas causing recurrent
476 APRIL 2023

ischemic stroke despite aggressive medical therapy, surgical treatment may KEY POINTS
be considered.
● Atheromas of the aortic
Another aortic pathology that can cause ischemic stroke is ascending aortic arch, particularly when large
dissection. Ascending aortic dissection is an extremely rare cause of ischemic or mobile, have been
stroke associated with high mortality. Spontaneous aortic dissections can be seen suggested to cause ischemic
in patients with Marfan syndrome, familial thoracic aortic aneurysm or stroke by artery-to-artery
embolism.
dissection, bicuspid aortic valve, Loeys-Dietz aneurysm syndrome, and vascular
Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV).90 In addition to ● The secondary prevention
symptoms attributable to cerebral ischemia, most (but not all) patients have of ischemic stroke in the
chest pain, and some have symptoms attributable to other end-organ ischemia. setting of aortic arch
In patients with acute stroke, ascending aortic dissections can be visualized on atherosclerosis consists of
risk factor modification,
vascular imaging with CT angiography of the head and neck (generally high-intensity statin
performed to rule out an emergent large vessel occlusion). CT angiography of the therapy, and antiplatelet
aorta is the preferred test to detect aortic arch dissection in hemodynamically therapy.
stable patients. In hemodynamically unstable patients, echocardiography may
● Spontaneous aortic
help identify aortic valve disruption, hemorrhagic pericardial effusion or dissections can be seen in
tamponade, and regional wall abnormalities that can be seen in patients with patients with Marfan
aortic dissections. syndrome, familial thoracic
The management of ischemic stroke in the setting of an aortic dissection aortic aneurysm or
dissection, bicuspid aortic
is challenging and measures to stabilize the dissection can worsen the degree
valve, Loeys-Dietz aneurysm
of brain injury. For instance, tight blood pressure control can potentially lead syndrome, and vascular
to worsened cerebral perfusion of the ischemic territory and extension of Ehlers-Danlos syndrome
the infarction. Furthermore, the risk of hemorrhagic transformation of the (Ehlers-Danlos syndrome
type IV).
ischemic bed may be further increased in the setting of aortic surgery. Given
the high mortality (approximately 60%) of medically treated patients with ● In patients with systolic
ascending aortic dissection,91 emergent surgical repair is generally performed heart failure, studies have
on patients with ascending aortic dissection with or without cerebral shown an increased
ischemia.90 ischemic stroke risk with low
left ventricular ejection
fraction.
ISCHEMIC STROKE IN THE SETTING OF LEFT VENTRICULAR
DYSFUNCTION ● In patients with ischemic
In patients with systolic heart failure, studies have shown an increased ischemic stroke and low ejection
fraction, prolonged cardiac
stroke risk with low left ventricular ejection fraction.92-94 This risk was shown to
rhythm monitoring is
be particularly higher with an ejection fraction of less than 15% (adjusted hazard important to look for atrial
ratio 2.13; 95% confidence interval 1.18 to 3.82, P = .012) or in patients with prior fibrillation which would lead
history of stroke (adjusted risk ratio 2.66; 95% confidence interval 1.59 to 4.45, to anticoagulation therapy.
P < .001).93,95 The pathophysiology of ischemic stroke in patients with low
● In the setting of a low
ejection fraction is presumably due to the formation of left ventricular thrombus ejection fraction and
which may be detected by a transthoracic echocardiogram with perflutren evidence of a left ventricular
contrast.96 Cardiac MRI85 may be superior to a transthoracic echocardiogram in thrombus with or without
these patients.97 Another potential etiology is paroxysmal atrial fibrillation, ischemic stroke, patients
should receive at least
particularly given that left ventricular systolic dysfunction is associated with 3 months of anticoagulation
atrial fibrillation.98 Thus, in patients with ischemic stroke and low ejection with warfarin and until
fraction, prolonged cardiac rhythm monitoring is important to look for atrial repeat cardiac imaging
fibrillation which would lead to anticoagulation therapy. shows resolution of the
thrombus.
In the setting of a low ejection fraction and evidence of a left ventricular
thrombus with or without ischemic stroke, patients should receive at least
3 months of anticoagulation with warfarin and until repeat cardiac imaging
shows resolution of the thrombus. There are limited data to support using direct
oral anticoagulants in such patients.

The WARCEF (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction)

trial randomized patients with an ejection fraction less than or equal to 35% and
sinus rhythm to warfarin (international normalized ratio [INR] 2.0 to 3.5) versus
aspirin (325 mg daily). WARCEF showed that when compared to aspirin, warfarin
was associated with significantly lower risk of ischemic stroke (hazard ratio 0.52;
95% confidence interval 0.33 to 0.82) but a nonsignificantly higher rate of
intracerebral hemorrhage (hazard ratio 2.22; 95% confidence interval 0.43 to 11.66).
However, the composite primary outcome of stroke or death was not different
between the two (hazard ratio 0.93; 95% confidence interval 0.79 to 1.10).95
Results were similar in patients with an ejection fraction less than 35% and a
history of stroke. Warfarin can still be considered in a subset of patients with low
ejection fraction, particularly those with ischemic stroke and an ejection fraction
less than 30% who have a reasonable life expectancy. In patients who are started
on anticoagulation, a repeat transthoracic echocardiogram is helpful to look for
improvement in the ejection fraction after targeted congestive heart
failure therapy.
Since direct oral anticoagulants are associated with a lower risk of
intracerebral hemorrhage compared to warfarin, it is possible that direct oral
anticoagulants will have a net benefit in patients with low ejection fraction. In
fact, a post-hoc analysis of the NAVIGATE-ESUS trial investigated the effect of
rivaroxaban versus aspirin in patients with ESUS and evidence of moderate to
severe left ventricular dysfunction (7.1% of patients enrolled in NAVIGATE-
ESUS), which was defined as moderate to severe global impairment in left
ventricular contractility, regional wall motion abnormalities, or both. In this
analysis, those with left ventricular dysfunction assigned to rivaroxaban versus
aspirin had a lower risk of recurrent stroke or systemic embolism (hazard ratio 0.
36; 95% confidence interval, 0.14 to 0.93), but those without left ventricular
dysfunction did not (hazard ratio 1.16; 95% confidence interval, 0.93 to 1.46)
( Pinteraction = .03).99
Given this analysis and the findings from the WARCEF trial, clinical trials are
needed to test the safety and efficacy of direct oral anticoagulants when
compared to aspirin in patients with left ventricular dysfunction, particularly
those with low ejection fraction and with an ischemic stroke.
ISCHEMIC STROKE IN THE SETTING OF MYOCARDIAL INFARCTION

There is an increased ischemic stroke risk in patients with an acute myocardial
infarction,100 and this risk is particularly high in the first 12 weeks after myocardial
infarction.101 The elevated stroke risk appears to be similar in patients with non-
ST-elevation myocardial infarction and ST-elevation myocardial infarction, likely
due to advances in revascularization strategies.100,101 Furthermore, analysis from
the Cardiovascular Health Study demonstrated that silent myocardial infarction is
associated with increased ischemic stroke risk (hazard ratio 1.51; 95% confidence
interval 1.03 to 2.21) and this association was limited to nonlacunar ischemic stroke
(hazard ratio 2.40; 95% confidence interval 1.36 to 4.22).102
In patients with ischemic stroke in the setting of an anterior ST-segment-
elevation myocardial infarction, experts recommend consideration of oral
anticoagulation with warfarin if deemed safe for 3 months,103 but this approach
lacks high-quality supporting evidence. In patients with myocardial infarction
and left ventricular thrombus with or without ischemic stroke, anticoagulation
treatment should be initiated for at least 3 months pending resolution of the
478 APRIL 2023

thrombus on follow-up cardiac imaging.19 In all other patients, cardiac KEY POINTS
monitoring may be beneficial to rule out paroxysmal occult atrial fibrillation
● Clinical trials are needed
and in the absence of atrial fibrillation, antiplatelet therapy is preferred. Given to test the safety and
the heightened risk of ischemic stroke in patients with acute myocardial efficacy of direct oral
infarction, clinical trials are needed to test the safety of direct oral anticoagulants anticoagulants when
as an alternative to antiplatelet agents in patients with an acute myocardial compared to aspirin in
patients with left ventricular
infarction but without one of the above-mentioned indications for short-term
dysfunction, particularly
anticoagulation. those with low ejection
fraction and with an
VALVULAR HEART DISEASE ischemic stroke.
Valvular pathologies that are associated with increased stroke risk are prosthetic
● There is an increased
heart valves, rheumatic heart disease, and both infective and noninfective ischemic stroke risk in
endocarditis. patients with an acute
In patients with an ischemic stroke in the setting of a bioprosthetic valve, a myocardial infarction, and
diagnostic evaluation is needed to exclude valve failure, thrombosis, or infection this risk is particularly high in
the first 12 weeks after
as an etiology. In addition, it is important to exclude noncardioembolic non- myocardial infarction.
valve-related ischemic stroke mechanisms such as larger artery atherosclerosis
and small vessel disease. In patients with ischemic stroke in the setting of a ● In patients with
mechanical heart valve, current guidelines recommend anticoagulation with myocardial infarction and
left ventricular thrombus
warfarin with a goal INR of 2.0 to 3.0 for a mechanical aortic valve and 2.5 to 3.5
with or without ischemic
for a mechanical mitral valve.102 The addition of low-dose aspirin may be stroke, anticoagulation
considered, particularly in patients with low bleeding risk, underlying treatment should be
atherosclerotic cardiovascular disease, or both.104 Furthermore, the RE-ALIGN initiated for at least
3 months pending resolution
trial randomized 252 patients with mechanical aortic or mitral valves to
of the thrombus on
dabigatran versus warfarin. This trial was stopped early due to increased rates of follow-up cardiac imaging.
thromboembolic and bleeding complications with dabigatran versus warfarin.14
Therefore, direct oral anticoagulants are not recommended in patients with ● Valvular pathologies that
mechanical heart valves. In patients with bioprosthetic heart valves without are associated with
increased stroke risk are
evidence of atrial fibrillation, guidelines recommend oral anticoagulation for prosthetic heart valves,
3 months to 6 months followed by antiplatelet therapy.19 In those who have an rheumatic heart disease,
ischemic stroke while on antiplatelet therapy, the benefit of switching to oral and both infective and
anticoagulation remains uncertain.19 In these patients, long-term cardiac noninfective endocarditis.
monitoring is important to exclude concomitant atrial fibrillation which would
● In patients with an
warrant oral anticoagulation. ischemic stroke in the
Ischemic stroke risk in patients with rheumatic mitral disease has been setting of a bioprosthetic
suggested to be linked to atrial fibrillation,105 particularly since studies valve, a diagnostic
evaluation is needed to
demonstrating such associations did not involve cardiac monitoring.106 In
exclude valve failure,
patients with ischemic stroke in the setting of rheumatic valve disease, a thrombosis, or infection as
diagnostic evaluation may help exclude other ischemic stroke mechanisms. In the an etiology.
absence of an indication for anticoagulation, workup may include long-term
cardiac monitoring to look for atrial fibrillation. In patients with ischemic stroke ● Direct oral anticoagulants
are not recommended in
and rheumatic mitral disease without atrial fibrillation, there is no evidence to patients with mechanical
support oral anticoagulation therapy. In those with atrial fibrillation and heart valves.
moderate to severe mitral stenosis, warfarin is preferred, whereas in those with
atrial fibrillation but without moderate to severe mitral stenosis, direct oral
anticoagulants or warfarin could be used.19
Ischemic stroke is an established complication of infective or noninfective
aortic or mitral valve endocarditis and in patients with infective endocarditis,
data suggest that ischemic stroke risk is heightened between 4 months before the
endocarditis diagnosis is made and 5 months after diagnosis.107 In patients with

KEY POINTS ischemic stroke, infective endocarditis is typically suspected in those who have
clinical or laboratory concern for bacteremia (modified Duke criteria),108
● Ischemic stroke risk in
patients with rheumatic
whereas noninfective endocarditis is typically seen in patients with systematic
mitral disease has been lupus erythematosus (Libman-Sacks endocarditis) or malignancy (marantic
suggested to be linked to endocarditis). The diagnosis is confirmed by visualization of a valvular
atrial fibrillation, particularly vegetation on echocardiography, particularly transesophageal
since studies demonstrating
echocardiography.109 Infarct patterns may differ between infective and
such associations did not
involve cardiac monitoring. noninfective endocarditis, with one study suggesting that any infarct pattern can
be seen with infective endocarditis, whereas disseminated punctate lesions are
● In patients with marantic the dominant infarct pattern in noninfective endocarditis.110 For patients with
endocarditis in the setting of ischemic stroke and infective endocarditis, noninvasive intracranial vascular
cancer, treatment entails
management of the imaging to screen for mycotic aneurysms with or without a diagnostic angiogram
underlying malignancy as should be considered.109 The treatment of endocarditis depends on the etiology.
well as antithrombotic For infective endocarditis, treatment entails IV antimicrobial treatment for at
therapy. least 6 weeks as well as consideration for surgery in a subgroup of patients.
● In patients with ischemic
Surgery is typically considered in those with valvular dysfunction causing heart
stroke in the setting of failure, complications (eg, paravalvular extension), or poor response to
Libman-Sacks endocarditis, antimicrobial therapy. Antithrombotics are generally contraindicated in the
guidelines suggest acute setting.109 In patients with marantic endocarditis in the setting of cancer,
anticoagulation with heparin
treatment entails treating the underlying malignancy as well as antithrombotic
or low-molecular-weight
heparin instead of oral therapy. In these patients, some experts suggest direct oral anticoagulants or
anticoagulation if deemed parenteral anticoagulation with heparin or low-molecular-weight heparin and
safe, but these suggestions others only suggest parenteral anticoagulation with heparin or low-molecular-
lack high-level supporting
weight heparin,104 but a high level of evidence supporting those treatments is
evidence.
lacking.111 In patients with ischemic stroke in the setting of Libman-Sacks
● Left-sided cardiac tumors endocarditis, guidelines suggest anticoagulation with heparin or low-molecular-
such as atrial myxomas and weight heparin instead of oral anticoagulation if deemed safe,104 but these
fibroelastomas are very rare suggestions lack high levels of supporting evidence.19 Moreover, in patients with
causes of ischemic stroke.
systemic lupus erythematosus, the occurrence of valve lesions is independent
● While the optimal stroke of disease activity and may occur at any time;112 thus, it is unclear whether
prevention strategy for control of disease activity is effective in stroke prevention in such patients and
patients with ischemic antithrombotic therapy is usually recommended regardless of the disease
stroke and left sided cardiac
activity. In certain patients with noninfectious endocarditis, valve replacement
tumors is unknown, in
addition to antithrombotic surgery may be considered.
treatment, surgical tumor
resection is a reasonable ISCHEMIC STROKE IN THE SETTING OF LEFT HEART TUMORS
approach.
Left-sided cardiac tumors such as atrial myxomas and fibroelastomas are very
rare causes of ischemic stroke.113,114 Left atrial myxomas can lead to ischemic
stroke via embolization of thrombus, tumor, or both,115 whereas aortic valve
papillary fibroelastomas, particularly those that are mobile, are thrombogenic,
increasing the risk of thromboembolism.113,116
While the optimal stroke prevention strategy for patients with ischemic stroke
and left-sided cardiac tumors is unknown, in addition to antithrombotic
treatment, surgical tumor resection is a reasonable approach.19,117
CONCLUSION
Several pathologies can lead to cardioembolic stroke, including atrial fibrillation,
aortic arch atheroma, patent foramen ovale, left ventricular dysfunction, and
many others. Secondary stroke prevention strategies differ across these
480 APRIL 2023

heterogeneous mechanisms. Therefore, a thorough diagnostic evaluation is
essential to determine cardioembolic causes of stroke. In addition to risk factor
management and lifestyle modifications, identification and targeting of the
underlying cardioembolic stroke mechanisms will lead to improved stroke
prevention strategies in these patients.
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REVIEW ARTICLE

Diagnosis and
ONLINE
Management of Large
Artery Atherosclerosis
By Seemant Chaturvedi, MD, FAAN, FAHA
ABSTRACT
OBJECTIVE: Ischemic stroke due to large vessel atherosclerosis is a
significant cause of stroke globally. With the aging population, the number
CITE AS:
of people with atherosclerotic stroke will increase in the coming decades.
CONTINUUM (MINNEAP MINN) This article reviews the recent developments in the assessment and
2023;29(2, CEREBROVASCULAR treatment of extracranial and intracranial atherosclerotic disease.
DISEASE):486–500.
Address correspondence to LATEST DEVELOPMENTS: More intensive dual antiplatelet therapy can now be
Dr Seemant Chaturvedi, recommended for patients with transient ischemic attack or stroke. More
Department of Neurology and stringent blood pressure and lipid control is also advised. The need for
Stroke Program, University of
Maryland School of Medicine, carotid revascularization will likely decrease in the coming decades
110 S Paca St, 3rd Fl, Baltimore, because of advances in multimodal medical therapy; in particular, the role
MD 21201, SChaturvedi@som.
umaryland.edu.
of revascularization for treating asymptomatic carotid stenosis is
controversial. Patients with symptomatic intracranial stenosis should
RELATIONSHIP DISCLOSURE: receive intensive medical therapy. Interest in high-resolution carotid
Dr Chaturvedi has received
personal compensation in the
plaque imaging is growing.
range of $500 to $4999 for
serving as a consultant for ESSENTIAL POINTS: Theprevention of stroke due to large vessel
AstraZeneca and on a scientific
advisory or data safety atherosclerosis has improved owing to advances in medical therapies.
monitoring board for the The role of carotid revascularization is unclear for many patient
University of Calgary, and in the
subgroups.
range of $10,000 to $49,999 for
serving as an editor, associate
editor, or editorial advisory
board member for the American
Heart Association and as an INTRODUCTION
expert witness for Ramar &
I
Paradiso (Troy, MI) and Cole, n many parts of the world, the prevalence of significant vascular risk factors
Scott, & Kissane (Palm Beach, such as diabetes, uncontrolled hypertension, and cigarette smoking is
FL). The institution of
Dr Chaturvedi has received
increasing.1 The constellation of these risk factors, along with the aging of the
research support from the population, will lead to an increasing number of strokes due to large vessel
National Institute of atherosclerosis. This article reviews the relevant advances for the optimal
Neurological Disorders
and Stroke.
evaluation and treatment of stroke due to extracranial or intracranial
atherosclerosis.
UNLABELED USE OF
USE DISCLOSURE:
Dr Chaturvedi reports no
EXTRACRANIAL CAROTID ARTERY ATHEROSCLEROSIS
disclosure. Extracranial internal carotid artery (ICA) stenosis or occlusion represents about
10% of ischemic stroke cases.2 The likelihood of ICA stenosis increases with
© 2023 American Academy well-known risk factors such as age, hypertension, diabetes, and smoking. In the
of Neurology. general adult population, 2% to 5% may have evidence of ICA stenosis, defined as
486 APRIL 2023

more than 50% stenosis of the ICA.3 The prevalence of more than 70% stenosis of
the ICA is lower but is more common in men and in those with diabetes.
Traditionally, patients with ICA stenosis have been classified as symptomatic
or asymptomatic. Asymptomatic means that the patient either has never had
ischemic symptoms in the territory of the stenotic vessel or the symptoms
occurred more than 6 months ago. Also, it is important to recognize that
nonspecific or nonlocalizing symptoms such as lightheadedness or dizziness are
not considered ICA symptoms. Similarly, syncope is not considered a symptom
of unilateral carotid stenosis.
Several questions can arise when assessing a patient with a transient ischemic
attack (TIA) or ischemic stroke and ICA stenosis on the ipsilateral side. What
type of medical therapy should be provided? How intense should the medical
therapy be? Is the patient a candidate for carotid revascularization? What type of
revascularization is preferred for the patient, and what factors should influence
the choice of revascularization technique?
Type of Medical Therapy

All patients with carotid stenosis or occlusion should receive intensive medical
therapy. This translates into the use of antithrombotic therapy, blood pressure
control, cholesterol lowering with statins or additional agents, and lifestyle
change, including smoking cessation. Dietary modification and regular physical
activity are also important elements of a lifestyle program.4
Antithrombotic therapy is typically achieved with antiplatelet agents.
First-generation carotid stenosis studies, such as NASCET (North American
Symptomatic Carotid Endarterectomy Trial), used aspirin alone, but the use of
short-term dual antiplatelet therapy, followed by antiplatelet monotherapy, has
become more common.5,6
High-flow arterial vessels respond best to antiplatelet therapy, as opposed to
anticoagulants, and in several vascular beds dual antiplatelet therapy has proven
superior to single-agent antiplatelets during the acute phase of ischemia.7,8
Regarding carotid stenosis specifically, a previous study found that use of dual
antiplatelet therapy with aspirin and clopidogrel reduced microembolic signals
on transcranial Doppler (TCD) compared with aspirin alone.9 Among 100
patients with moderate to severe ICA stenosis who were awaiting a carotid
endarterectomy, none of the patients had a recurrent stroke when placed on a
dual antiplatelet therapy regimen.9
Based on recent trials that evaluated aspirin plus clopidogrel versus aspirin
alone in patients with TIA or minor stroke, aspirin plus clopidogrel for 21 days
is commonly used as initial treatment with subsequent aspirin monotherapy.6,10
These trials did not include patients who were likely candidates for carotid
revascularization, but it is reasonable to extrapolate the results of these trials to
patients with carotid stenosis, especially considering the TCD microemboli data
mentioned previously.
Another option for dual antiplatelet therapy is the use of aspirin plus
ticagrelor. Ticagrelor is a reversible P2Y12 antagonist and is approved for patients
with coronary artery disease. In the THALES (Acute STroke or Transient
IscHaemic Attack Treated With TicAgreLor and ASA for PrEvention of Stroke
and Death) trial, aspirin plus ticagrelor proved superior to aspirin alone in
patients with TIA or minor stroke.11 The overall relative risk reduction for
ischemic stroke was 21% with aspirin plus ticagrelor, with a 0.4% absolute

LARGE ARTERY ATHEROSCLEROSIS
increase in the risk of major bleeding. Amarenco and colleagues12 studied patients
with evidence of atherosclerotic disease (30% or greater stenosis) in the THALES
trial. This analysis showed a 2.8% absolute decrease in the primary endpoint of
stroke or death within 30 days, without a significant increase in major bleeding.
Thus, aspirin plus clopidogrel or aspirin plus ticagrelor are well suited for stroke
prevention in patients with evidence of large vessel atherosclerosis. Given the
increased bleeding risk with aspirin plus ticagrelor, guidelines more strongly
recommend aspirin plus clopidogrel following TIA or minor stroke.13
Additional studies have focused on patients with a genetic tendency for
reduced response to clopidogrel. In the CHANCE-2 (Clopidogrel With Aspirin in
High-risk Patients With Acute Non-disabling Cerebrovascular Events II) trial
conducted in China, individuals with reduced response to clopidogrel, evidenced
by genotyping showing CYP2C19 loss-of-function alleles, had a 23% reduction in
stroke with aspirin plus ticagrelor compared with aspirin plus clopidogrel.14
Moderate to severe bleeding was similar in the two groups, but any bleeding was
twice as high with aspirin plus ticagrelor compared with aspirin plus clopidogrel.
The extent to which this is relevant to other populations is not clear since the Han
Chinese population has a high representation of individuals with genetic
predisposition to lower clopidogrel response.14
Intensity of Medical Therapy

In addition to antithrombotic therapy, patients with atherosclerotic carotid
stenosis require cholesterol lowering plus blood pressure control. Cholesterol
lowering and blood pressure control were not key elements of first-generation
carotid stenosis trials such as NASCET and ECST (European Carotid Surgery
Trial).15
An optimal low-density lipoprotein (LDL) target has not been defined
specifically for patients with carotid stenosis, but recent data suggest that an LDL
of less than 70 mg/dL is a reasonable target. In the TST (Treat Stroke to Target)
trial, 2860 patients were randomly assigned to an LDL target of less than
70 mg/dL compared with 90 to 110 mg/dL.16 In addition to a recent stroke or TIA,
patients were required to have evidence of atherosclerotic disease in an
TABLE 5-1 Evolution of Medical Therapy for Carotid Stenosis
Treatment in first-generation
Condition carotid stenosis trials Modern treatment
Antithrombotic therapy Aspirin alone Aspirin plus clopidogrel
Lipids Little statin use High-potency statins plus other options

(eg, ezetimibe, PCSK9 inhibitors)
Blood pressure No specific target Systolic blood pressure <130 mm Hg
Smoking cessation No pharmacologic therapy New pharmacologic treatments
Physical activity No specific target Benefits understood for regular physical activity
(3-5 sessions of aerobic exercise per week)
Diabetes No specific medications for Pharmacologic treatments that reduce

cardiovascular risk cardiovascular risk, hemoglobin A1C target of <7
488 APRIL 2023

extracranial or intracranial vessel either ipsilateral or contralateral to the cerebral KEY POINT
ischemic event. In addition, qualifying conditions included aortic plaques
● Clinical trials that
measuring 4 mm or more in thickness or the presence of coronary artery disease. compared carotid
Patients without functional independence were excluded from the trial. The endarterectomy versus
mean achieved LDL was 65 mg/dL in the lower target group, compared with medical therapy for the
96 mg/dL in the conventional target group. The overall rate of major vascular treatment of patients with
carotid stenosis are more
events was lower (22% relative risk reduction) in the group with an LDL of less
than 25 years old and some
than 70 mg/dL compared with the group with 90 to 110 mg/dL, without an consider these data to be
increase in hemorrhagic events or newly diagnosed diabetes. obsolete.
Is there a rationale for an even lower LDL target? Injectable agents (PCSK9
inhibitors) are now being used for patients with coronary artery disease and those
with familial hypercholesterolemia. These medications are very potent and have
lowered LDL levels to 30 mg/dL in clinical trials.17 In one study of patients with
coronary artery disease, lowering LDL to 30 mg/dL with evolocumab was
associated with a 15% reduction of major vascular events. The secondary endpoint
of stroke, myocardial infarction (MI), or vascular death was reduced by 20%.
A recent meta-analysis found that the benefit of robust LDL lowering in patients
with TIA or stroke is magnified in patients with evidence of atherosclerosis.18
Based on recent guidelines,19 this author employs a target of less than
70 mg/dL for most patients, but if the patient has carotid stenosis plus diabetes
or carotid stenosis plus evidence of atherosclerotic disease in another vascular
bed (polyvascular disease), one should aim for a target of less than 55 mg/dL.
A recent guideline also comments that patients at very high risk may merit an
LDL target of less than 40 mg/dL.19 Clearly, this is an area with a shifting
landscape, and clinicians should monitor the most recent guideline
recommendations.
Regarding blood pressure, during the acute stage of a stroke, excess blood
pressure lowering is discouraged. For patients who have not received
thrombolytic medication, permissive hypertension is frequently recommended.
Previously, a systolic blood pressure target of less than 140/90 mm Hg was
recommended for long-term stroke prevention. However, based on SPRINT
(Systolic Blood Pressure Intervention Trial) and other data, the American Heart
Association (AHA) now recommends a systolic blood pressure target of less than
130/80 mm Hg.20,21 Achieving this level of blood pressure control will typically
require more than one antihypertensive agent. Employing moderate doses of two
or three medications is preferred to a high dose of a single antihypertensive
medication.22 Useful algorithms for blood pressure titration are available, and
readers are encouraged to review the algorithms for blood pressure and lipid
management that are part of CREST-2 (Carotid Revascularization and Medical
Management for Asymptomatic Carotid Stenosis Trial).4
Carotid Revascularization
Carotid endarterectomy has been shown to reduce the stroke rate in select
patients with symptomatic ICA stenosis of 50% to 99%. However, the landmark
trials (NASCET, ECST) that demonstrated benefit from carotid endarterectomy
are more than 25 years old. As described in TABLE 5-1, there have been significant
developments in medical stroke prevention since the time of the first-generation
trials. Intensive medical therapy now includes high-potency statins and,
frequently, dual antiplatelet therapy. These elements were not included in
first-generation studies such as NASCET.

Although statins, antiplatelet therapy, and targeted blood pressure reduction

substantially reduce the rate of major vascular events and are in routine,
widespread use, a randomized controlled trial to compare modern medical
therapy alone to modern medical therapy plus carotid endarterectomy has not
yet occurred. This gap was noted in the 2021 AHA/American Stroke Association
(ASA) guidelines for stroke prevention in patients with stroke and TIA. The
guidelines specify that “previous CEA trials were initiated >30 years ago, and
clinicians need comparisons of CEA with currently available intensive medical
therapy options.”13
The recommendations from the first-generation carotid stenosis trials for
symptomatic patients are familiar to most clinicians. Carotid endarterectomy
had significant benefit for patients with recent symptoms plus 70% to 99%
stenosis (16% absolute risk reduction over 5 years). For individuals with 50% to
69% stenosis, a modest benefit of 4.6% occurred over 5 years (0.9% per year). No
clear benefit was found in patients with a “near occlusion,” and no benefit
occurred for patients with less than 50% stenosis.1,4
In addition to the degree of stenosis, additional analyses have identified
patients with an increased or decreased likelihood of benefit from carotid
endarterectomy (CASE 5-1). Clinical factors include patient sex, type of
symptoms (hemispheric event versus retinal ischemic event), and timing of
carotid revascularization (within 2 weeks or delayed). The extent of systemic
disease and overall patient life expectancy is an important element to consider.
Radiologic factors such as ongoing TCD microemboli or the presence of
CASE 5-1 A 75-year-old woman presented to the outpatient clinic after referral
from ophthalmology. She noticed monocular blurred vision in her left eye
1 month prior and was diagnosed with a branch retinal artery occlusion.
Evaluation included a carotid duplex ultrasound that showed a peak
systolic velocity of 240 cm/second, which was interpreted as being
consistent with 70% to 80% internal carotid artery stenosis. The patient
was on aspirin 81 mg once daily and atorvastatin 20 mg once daily. Two
months previously, her low-density lipoprotein was 132 mg/dL, and she
was not on a statin. The patient was recommended to have intensive
medical therapy based on the nature of her symptoms, sex, and timing of
her last event.
COMMENT Based on first-generation carotid stenosis trials, a clinician might refer the
patient for revascularization. However, several characteristics (including
female sex, presentation with a retinal event, and last ischemic symptom
more than 2 weeks ago) suggest she would have received reduced benefit
from carotid endarterectomy. Therefore, intensive medical therapy was
perfectly reasonable. Enrollment in ongoing studies evaluating medical
therapy for carotid stenosis should have been considered. Given the
patient's age and the associated higher complication rate with carotid artery
stenting, if revascularization were chosen, carotid endarterectomy would
have been the preferred procedure.
490 APRIL 2023

intraplaque hemorrhage on high-resolution carotid imaging can also be
considered. A schema to incorporate these factors is provided in TABLE 5-2.
Until further trial data are available, revascularization is still recommended for
symptomatic patients who meet defined stenosis and clinical criteria.13
Choice of Revascularization Procedure

Carotid endarterectomy is one of the most common operations in the United
States. Use of carotid endarterectomy for stroke prevention dates back to the
1950s, and between 50,000 and 100,000 procedures take place each year. Carotid
artery stenting was proposed in the 1990s as an alternative technique as no neck
incision was preferable.
Several trials have compared carotid endarterectomy to carotid artery
stenting. Most studies have included a combination of symptomatic and
asymptomatic patients, whereas a few have been limited to asymptomatic
patients only.23-25 In CREST (Carotid Revascularization Endarterectomy Versus
Stenting Trial),23 one of the larger trials, symptomatic patients with 50% to 99%
stenosis or asymptomatic patients with 60% to 99% stenosis were randomly
assigned to carotid endarterectomy or carotid artery stenting. The primary
outcome of the trial was periprocedural stroke or MI plus ipsilateral stroke
beyond the periprocedural period. A statistically significant difference did not
exist between the two procedures (carotid endarterectomy 5.4% versus carotid
artery stenting 6.8%). However, examination of the complications found that
carotid artery stenting was associated with an increase in periprocedural stroke
(carotid endarterectomy 2.3% versus carotid artery stenting 4.4%), whereas
carotid endarterectomy had a higher rate of periprocedural MI (carotid
endarterectomy 2.3% versus carotid artery stenting 1.1%). Beyond the
perioperative period, both carotid endarterectomy and carotid artery stenting
provide similar effectiveness. CREST found that perioperative stroke had greater
patient impact than perioperative MI. At present, large national analyses have
found that more than 80% of carotid revascularization procedures in the United
States are carotid endarterectomy operations, so one can say that carotid
endarterectomy has yet to be “dethroned.”26
Factors in Consideration of Carotid Revascularization TABLE 5-2
Favors medical Favors

Factors therapy revascularization
Type of ischemic symptom Retinal Hemispheric
Patient sex Female Male
Timing of most recent ischemic More than 2 weeks Less than 2 weeks
symptom
Severe comorbidity Present Absent
Transcranial Doppler microemboli Absent Present
Intraplaque hemorrhage on MRI Absent Present
MRI = magnetic resonance imaging.

Two other factors that should influence choice of procedure are timing of
revascularization and patient age. For patients who undergo revascularization
within 7 days of a stroke, an analysis of four trials found that carotid
endarterectomy was associated with a significantly lower rate of complications
(carotid endarterectomy 1.3% versus carotid artery stenting 8.3%).27 In addition,
carotid endarterectomy is preferred for patients older than 70 years.28
A newer revascularization technique is transcarotid artery revascularization.
With this novel form of revascularization, direct access is achieved in the
common carotid artery and “flow reversal” to a lower-pressure femoral vein is
accomplished. The goal of this reversal of flow is to reduce the risk of cerebral
embolization during the ensuing stenting procedure. A national registry found a
lower stroke or death rate with transcarotid artery revascularization compared
with transfemoral carotid artery stenting.29 In the single-arm ROADSTER 2
(Post-approval Study Of Transcarotid Artery Revascularization In Patients With
Significant Carotid Artery Disease) registry, the 30-day stroke or death rate was
5.0% in symptomatic patients and 1.4% in asymptomatic patients.30 At present,
controlled comparative trials evaluating transcarotid artery revascularization
with either carotid endarterectomy or carotid artery stenting are lacking. Despite
growing enthusiasm for transcarotid artery revascularization, the 2021 AHA/
CASE 5-2 A 68-year-old man with a history of coronary artery disease,

hyperlipidemia, and a previous habit of cigarette smoking was referred to
a neurology clinic by his primary care physician after a carotid bruit was
identified. A subsequent carotid duplex ultrasound revealed a peak
systolic velocity of 400 cm/second and was interpreted as being
consistent with an 80% to 99% stenosis. He had never had a stroke or
transient ischemic attack. The patient was taking aspirin 81 mg once daily
and rosuvastatin 20 mg once daily. His most recent low-density
lipoprotein value was 72 mg/dL. A head CT done 6 months ago after a
minor head trauma showed small vessel disease but no cortical infarcts.
The patient was recommended to enroll in CREST-2.
COMMENT It is unclear if this patient would benefit from carotid revascularization.

Because of the advances in intensive medical therapy over the past
25 years, the annual stroke risk with asymptomatic stenosis is now very low.
Assessment for transcranial Doppler microemboli would be useful in risk
stratification. For medical therapy, a target low-density lipoprotein of less
than 55 mg/dL would be reasonable considering his polyvascular disease.
If revascularization is considered, it would be important to discuss life
expectancy with his primary care physician; shared decision making is
critical. The patient should understand that the stroke risk with
asymptomatic stenosis is low and that if he opts for revascularization,
having carotid endarterectomy or carotid artery stenting at a high-volume
center with a track record of low complications is desirable.
492 APRIL 2023

ASA secondary prevention guidelines comment that the efficacy of transcarotid KEY POINTS
artery revascularization for symptomatic patients is not well established.13
● In previous trials, several
subgroups of symptomatic
Asymptomatic Carotid Stenosis patients had enhanced
The proper treatment for asymptomatic carotid stenosis has been controversial benefit from carotid
for several decades. For asymptomatic patients, the following are three endarterectomy.
important facts when deciding on the proper treatment:
● Beyond the
periprocedural period,
1 The risk of an ischemic stroke with asymptomatic stenosis is low and significantly lower long-term rates of stroke
than the risk of a recurrent ischemic stroke in a patient with symptomatic carotid appear similar between
stenosis. patients treated with carotid
endarterectomy and carotid
2 Because of the low stroke risk, if revascularization is recommended, the periprocedural artery stenting.
rate of stroke or death should be very low (preferably <2%).
3 If revascularization is being considered, the patient should have at least a 5-year life ● Timing of
expectancy. revascularization and
patient age should be
considered in selecting
Just as in the case of symptomatic carotid stenosis, the randomized controlled between carotid
trials that have evaluated medical therapy versus revascularization are quite endarterectomy and carotid
dated and of unknown relevance. In the first-generation carotid stenosis trials, artery stenting.
the annual rate of ipsilateral stroke for asymptomatic patients with 60% to 99%
● Transcarotid artery
stenosis was 2.0% to 2.5%. In more recent studies, the stroke rate has been 1% or
revascularization is an
less.31,32 It is likely that the stroke rate is higher in the 80% to 99% stenosis emerging revascularization
category compared with the range of less than 80%, as suggested by a recent technique, but randomized
analysis of a population-based study.33 studies are lacking.
With the major advances in intensive medical therapy, it is not clear if
● It is unclear if carotid
asymptomatic patients with 60% to 99% stenosis benefit from carotid revascularization is useful
revascularization. CREST-2 is comparing revascularization with either carotid for asymptomatic carotid
endarterectomy or carotid artery stenting versus intensive medical therapy.34 stenosis.
While we wait for the results of this trial, some practical tools can be used for
● For asymptomatic
risk stratification (CASE 5-2). First, men appear to benefit more from carotid carotid stenosis, men derive
endarterectomy than women. This could be related to the observation that greater benefit from
women have less macrophage infiltration and more collagen in surgical revascularization compared
specimens, providing for a less inflammatory and more stable phenotype.35 with women.
Second, assessment with TCD for ongoing microemboli can identify a higher risk
● Microemboli detection
group. Using this technique, studies have found that about 1 out of 6 patients using transcranial Doppler
with asymptomatic stenosis are at higher stroke risk.36 Third, other radiologic can be useful for risk
findings could indicate a higher stroke risk, such as identification of silent cortical stratification in patients with
infarcts in the territory of the stenotic vessel. European surgical guidelines have asymptomatic carotid
stenosis.
also identified other putative markers of potential increased stroke risk.7 A
diagram providing a high-level approach to symptomatic and asymptomatic
carotid stenosis treatment is provided in FIGURE 5-1.
EXTRACRANIAL VERTEBRAL ARTERY ATHEROSCLEROSIS

Stenosis at the origin of the vertebral artery is estimated to be linked with 5%
to 10% of posterior circulation strokes. As with carotid stenosis, intensive
medical therapy is recommended. Attempts have been made to perform
vertebral artery stenting for long-term stroke prevention. Markus and
colleagues37 conducted an analysis of three trials that evaluated vertebral artery
stenting relative to medical therapy. The periprocedural stroke or death rate was
higher for intracranial vertebral artery stenting (15.6%) compared with

FIGURE 5-1
Algorithm for approach to symptomatic and asymptomatic carotid stenosis.
Reprinted with permission from Chaturvedi S, et al, J Am Coll Cardiol.2 © 2015 American College of
Cardiology Foundation.
extracranial vertebral artery stenting (0.8%). However, relative to medical

therapy, no clear benefit was seen for vertebral artery stenting. An additional
problem regarding vertebral artery stenosis evaluation is the unreliable
noninvasive imaging owing to the angulation and tortuosity of the proximal
vertebral artery. In a previous clinical trial, about one-fourth of intended
vertebral artery stent procedures were not performed because the stenosis was
TABLE 5-3 Elements of Intensive Medical Therapy in the SAMMPRIS Trial
Condition Treatment or target

Antiplatelet therapy Aspirin plus clopidogrel for 90 days, followed by aspirin
monotherapy
Blood pressure Systolic blood pressure target <140 mm Hg for patients

without diabetes, <130 mm Hg for patients with diabetes
Lipids Low-density lipoprotein cholesterol target of <70 mg/dL
Diabetes Goal hemoglobin A1C <7%
Smoking Smoking cessation
Physical activity PACE score 4-8
PACE = Physician-based Assessment and Counseling for Exercise; SAMMPRIS = Stenting and Aggressive
Medical Management for Preventing recurrent stroke in Intracranial Stenosis.
494 APRIL 2023

found to be less than 50% on angiography.38 Therefore, proximal vertebral artery KEY POINTS
stenting is not recommended as a routine procedure at present.
● There is not an
established role for
INTRACRANIAL ATHEROSCLEROSIS proximal vertebral artery
Intracranial atherosclerotic disease is one of the leading causes of stroke stenosis stenting.
worldwide. Intracranial atherosclerotic disease occurs in all populations but is
● From a global
more common in individuals of African or East Asian descent.10 Traditionally,
perspective, intracranial
intracranial atherosclerotic disease has referred to areas of narrowing in the distal atherosclerosis is a leading
ICA, middle cerebral artery, intracranial vertebral artery, and basilar artery. cause of stroke.
However, other vessels such as the anterior cerebral artery and posterior cerebral
artery may be affected. ● Intracranial
atherosclerosis needs to be
Atherosclerotic disease must be distinguished from nonatherosclerotic distinguished from
vasculopathies, which include intracranial arterial dissection, partially recanalized emboli and
recanalized emboli, inflammatory arterial diseases, and conditions related to vasculopathies.
vasospasm. Clinicians can be assisted in making the diagnosis of intracranial
● Intensive medical
atherosclerotic disease by characteristics such as patient age, predisposing
therapy is essential in the
factors, and pattern of arterial narrowing. For example, if only one vessel is management of patients
affected, a partially recanalized embolic obstruction should be considered. In with intracranial
these instances, searching for sources of cardiac emboli is warranted. In younger atherosclerosis.
patients and in those with factors such as thunderclap headaches, serotonergic
● Intracranial stenosis has a
medication use, or recent childbirth, conditions such as reversible cerebral high stroke recurrence rate.
vasoconstriction must be considered.39
If the clinician is confident that intracranial stenosis is due to intracranial
atherosclerotic disease, decisions need to be made regarding the type and intensity
of medical therapy and the potential role for interventional therapies. The main
clinical trial that has established the role of intensive medical therapy is the
SAMMPRIS (Stenting and Aggressive Medical Management for Preventing
recurrent stroke in Intracranial Stenosis) trial.40 A previous study identified
elevated cholesterol and blood pressure as factors associated with a high rate of
recurrent stroke in the setting of intracranial atherosclerotic disease.41 Therefore,
a multimodal approach was instituted for all patients in SAMMPRIS (TABLE 5-3).
Patients with symptomatic intracranial atherosclerotic disease of 70% to 99%
have a high rate of recurrent stroke relative to other stroke etiologies. In
SAMMPRIS, the 1-year rate of any stroke was 14.9%. In the population-based
OxVasc (Oxford Vascular Study), the prevalence of symptomatic 50% to 99%
intracranial stenosis increased from 4.9% in patients aged younger than 70 years
to 19.6% in individuals aged 90 years and older.42 In the Oxford study population,
the 2-year risk of same-territory recurrent stroke was lower than in SAMMPRIS
(5.6% versus 14.1%). These differences could be due to the stenosis in
SAMMPRIS being angiographically defined, the significantly higher number of
African American patients in SAMMPRIS, or the population-based sample of
OxVasc versus selected clinical trial patients in SAMMPRIS.
In SAMMPRIS, endovascular stenting proved inferior to intensive medical
therapy. The 30-day primary endpoint of any stroke was 5.8% in the medical
therapy group compared with 14.7% in the stenting group (CASE 5-3). However,
interventional specialists are still trying to determine if there is a group of
patients who might benefit from stenting. A moderate-size registry that excluded
patients with “hot” (recently symptomatic) lesions and only performed
stenting after at least 8 days poststroke found a 2.6% major complication
rate with stenting.43 A randomized trial from China found a lower rate of

in-stent restenosis with drug-eluting stents versus bare metal stents (9.5%
versus 30.2%).44 In addition, beyond 30 days, the stroke rate was lower with
drug-eluting stents relative to bare metal stents (0.8% versus 6.9%). Although
these efforts to define a cohort of patients who might benefit from stenting are of
interest, given the results of SAMMPRIS, stenting for 70% to 99% intracranial
atherosclerotic disease is currently not recommended as a routine treatment, and
intensive medical therapy should be the first-line treatment.
TRENDS
For extracranial carotid stenosis, interest in carotid plaque imaging is increasing.
With high-resolution cross-sectional MRI, the characteristics of the lipid core and
thickness of the fibrous cap can be delineated. Intraplaque hemorrhage can also
be detected (FIGURES 5-2 and 5-3). In one study, the presence of intraplaque
hemorrhage had a significant influence on stroke recurrence rates in patients
with 50% to 99% symptomatic stenosis. In the presence of intraplaque
hemorrhage, the 1-year risk of recurrent stroke was 23.2% compared with only
0.6% in the absence of intraplaque hemorrhage.45 A meta-analysis of individual
patient data also found that intraplaque hemorrhage was a predictor of ipsilateral
stroke for both symptomatic and asymptomatic patients.46
CASE 5-3 A 64-year-old woman presented to the emergency department after a

20-minute episode of dizziness, slurred speech, and horizontal diplopia.
Blood pressure on arrival was 170/90 mm Hg. Her head CT was
unremarkable except for small vessel disease. She had a history of
hypertension, diabetes, hyperlipidemia, and a 40 pack-year smoking
history. On a recent visit with her primary care physician, her low-density
lipoprotein was 142 mg/dL and hemoglobin A1C was 8.9. CT angiography
performed in the emergency department showed severe midbasilar artery
stenosis. After admission, a brain MRI showed no acute infarct, and
magnetic resonance angiography confirmed severe basilar artery stenosis.
The patient received intensive medical therapy and was stroke-free for
the ensuing 12 months.
COMMENT This patient had evidence of severe, symptomatic intracranial

atherosclerotic disease. Based on the results of the SAMMPRIS trial, she
should have received intensive medical therapy. This would include aspirin
plus clopidogrel (or ticagrelor) for 90 days, blood pressure control,
high-intensity statin treatment, improved diabetes control, and lifestyle
management. Given the severe vascular disease plus diabetes, a target
low-density lipoprotein of less than 55 mg/dL would be reasonable. In her
case, there was considerable scope for improved risk factor control given
her active smoking and recent lipid and hemoglobin A1C values. Lifestyle
modification would have included smoking cessation, regular physical
activity, and adoption of a healthy diet. Stenting would not have been
recommended as a first-line treatment.
496 APRIL 2023

CT angiography is KEY POINTS
increasingly being performed as
● Stenting is not
part of the stroke evaluation. recommended as a first-line
Detection of complicated plaques treatment for patients with
on CT angiography is more intracranial atherosclerotic
common ipsilateral to an embolic disease.
stroke of unknown source than
● Nonstenotic plaques with
in the contralateral vessel. In a complex features are
multicenter observational study, potentially linked with
complicated plaques (AHA otherwise cryptogenic
type VI) were seen in 31% of strokes.
cases ipsilateral to the infarct,

compared with 12% in the
contralateral carotid artery.47 In
FIGURE 5-2 patients with less than 50%
Intraplaque hemorrhage. A, Time-of-flight MR stenosis, if a nonstenotic plaque
angiography (MRA) showing an approximately 70% with complicated features is
stenosis due to a plaque with intraplaque
hemorrhage near the carotid bifurcation (line).
linked to hemispheric stroke, up
B, An intraplaque hemorrhage is seen as an area to 21% of strokes classified as
of high signal intensity (yellow arrow) on the cryptogenic could be shifted to
noncontrast T1-weighted double inversion the carotid artery as the causative
recovery image, obtained at a resolution of
0.35 × 0.35 × 2 mm. A low-signal-intensity area of
factor.48 Currently, medical
peripheral calcification is also present, with the therapy is recommended for
lumen depicted above the intraplaque hemorrhage. nonstenotic plaques with
Images courtesy of Bruce Wasserman, MD.
FIGURE 5-3
Features of complex plaque on MRI. A, Two-dimensional time-of-flight MR angiography (MRA)
shows an approximately 50% stenosis of the carotid bulb. B, Contrast-enhanced long-axis
T1-weighted two-dimensional double inversion recovery image, obtained with a resolution
of 0.35 × 0.35 × 2 mm, showing complex plaque (arrows). C, Axial contrast-enhanced
fat-suppressed T1-weighted double inversion recovery image obtained with a resolution of
0.35 × 0.35 × 2 mm through the plaque reveals an enhancing fibrous cap (FC), a low-intensity
nonenhancing lipid-rich necrotic core (LRNC), and a dark area of calcification.
Images courtesy of Bruce Wasserman, MD.

complicated features, but future trials could examine the potential role of
carotid endarterectomy.
CONCLUSION
All patients with extracranial or intracranial atherosclerotic stenosis should
receive intensive medical therapy. Medical therapy has evolved considerably in
the last 2 decades, with the trend for more stringent risk factor control. As a
result, the stroke rate related to large vessel atherosclerosis is decreasing, and the
benefit of carotid endarterectomy or carotid artery stenting is now being
reexamined. Select patients with symptomatic carotid stenosis will benefit from
revascularization, but the benefit of revascularization for asymptomatic stenosis
is uncertain, pending the results of ongoing trials. New studies will also evaluate
the role of novel imaging markers and treatment paradigms for symptomatic
intracranial stenosis.
REFERENCES
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Diabetes in Asia and the Pacific: implications for antiplatelet therapy prior to expedited carotid
the global epidemic. Diabetes Care 2016;39(3): surgery reduces recurrent events prior to surgery
472-485. doi:10.2337/dc15-1536 without significantly increasing peri-operative
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34 Howard VJ, Meschia JF, Lal BK, et al. Carotid
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25 Halliday A, Bulbulia R, Bonati LH, et al. Second asymptomatic carotid stenosis: protocol of the
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37 Markus HS, Harshfield EL, Compter A, et al. 43 Alexander MJ, Zauner A, Chaloupka JC, et al.
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44 Jia B, Zhang X, Ma N, et al. Comparison of
38 Markus HS, Larsson SC, Kuker W, et al. Stenting drug-eluting stent with bare-metal stent in
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39 Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. 45 Hosseini AA, Kandiyil N, MacSweeney STS, et al.
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40 Chimowitz MI, Lynn MJ, Derdeyn CP, et al. 46 Schindler A, Schinner R, Altaf N, et al. Prediction
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30079-X
500 APRIL 2023

Diagnosis and REVIEW ARTICLE

Management of Cerebral C O N T I N U UM A U D I O
ONLINE
Small Vessel Disease

By Anjail Sharrief, MD, MPH, FAHA
ABSTRACT
OBJECTIVE: Cerebral small vessel disease (CSVD) is a common neurologic
condition that contributes to considerable mortality and disability because
of its impact on ischemic and hemorrhagic stroke risk and dementia. While
attributes of the disease have been recognized for over two centuries,
gaps in knowledge remain related to its prevention and management. The
purpose of this review is to provide an overview of the current state of
knowledge for CSVD.
LATEST DEVELOPMENTS: CSVD can be recognized by well-defined radiographic

criteria, but the pathogenic mechanism behind the disease is unclear.
Hypertension control remains the best-known strategy for stroke
prevention in patients with CSVD, and recent guidelines provide a
long-term blood pressure target of less than 130/80 mm Hg for patients
with ischemic and hemorrhagic stroke, including those with stroke related
to CSVD. Cerebral amyloid angiopathy is the second leading cause of CITE AS:
intracerebral hemorrhage and may be increasingly recognized because of CONTINUUM (MINNEAP MINN)
newer, more sensitive imaging modalities. Transient focal neurologic DISEASE):501–518.
episodes is a relatively new term used to describe “amyloid spells.”
Guidance on distinguishing these events from seizures and transient Address correspondence to
Anjail Sharrief, 6431 Fannin St,
ischemic attacks has been published.
MSB 7.110, Houston, TX 77030,
Anjail.Z.Sharrief@uth.tmc.edu.
ESSENTIAL POINTS:CSVD is prevalent and will likely be encountered by all
neurologists in clinical practice. It is important for neurologists to be able The institution of Dr Sharrief
to recognize CSVD, both radiographically and clinically, and to counsel has received research support
patients on the prevention of disease progression. Blood pressure control from the National Institutes of
Health and the University of
is especially relevant, and strategies are needed to improve blood Houston. Dr Sharrief has a
pressure control for primary and secondary stroke prevention in patients noncompensated relationship
with CSVD. as a consultant with Abbot
Laboratories that is relevant to
the American Academy of
Neurology interests or activities.
INTRODUCTION UNLABELED USE OF
C
erebral small vessel disease (CSVD) is one of the most common PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
clinical conditions that a neurologist will encounter. CSVD is Dr Sharrief reports no
associated with an increased risk of clinical ischemic and disclosure.
hemorrhagic stroke, silent infarcts, and cognitive decline and
dementia. It has well-defined radiographic features and various © 2023 American Academy
clinical presentations. Despite its increasing prevalence with the aging of Neurology.

DIAGNOSIS AND MANAGEMENT OF CEREBRAL SMALL VESSEL DISEASE
population, few specific therapies exist to decrease its progression. This article
focuses on the epidemiology, clinical characteristics, and radiographic findings of
CSVD and presents cases to describe its various clinical presentations.
EPIDEMIOLOGY AND RISK FACTORS

CSVD contributes to significant morbidity and mortality through its impact on
stroke risk, cognitive decline, and dementia. Small vessel disease accounts for
approximately 22% of ischemic stroke, and small vessel disease burden increases
the risk of recurrent stroke following ischemic or hemorrhagic stroke.1–4 CSVD
manifests as “silent” brain infarcts as well as clinically recognized small vessel
ischemic strokes. Silent brain infarcts, which are also included in the
classification of “covert cerebral small vessel disease,” are more common than
acute ischemic stroke, with an estimated prevalence of 10% to 20% in adults.5
These lesions are often found incidentally but are associated with an increased
risk of stroke and death, as well as other neurologic, neuropsychiatric, and
cognitive symptoms, which are poorly recognized in clinical practice.6 CSVD
accounts for the overwhelming majority of intracerebral hemorrhage (ICH)
through arteriosclerosis (sometimes referred to as hypertensive arteriosclerosis)
and cerebral amyloid angiopathy (CAA). Finally, the significant contribution of
CSVD to progressive cognitive and functional decline and dementia underscores
its global impact.7,8
Age is the most common nonmodifiable risk factor for CSVD, and the aging of
the population has led to the increased global prevalence of CSVD. Almost 100%
of adults aged 90 and older have evidence of CSVD, with 36% of adults aged 80 to
90 demonstrating evidence of cerebral microbleeds. Although there are no known
sex differences in CSVD prevalence, a systematic review and meta-analysis showed
that males were more likely to present with moderate to severe CSVD and more
likely to have acute stroke presentations when found with CSVD than females.9
Some evidence exists of racial and ethnic differences in the impact of CSVD and
association with other clinical disorders. Black and Hispanic patients with
intracerebral hemorrhage have been shown to have greater global CSVD on MRI,
and the association of chronic kidney disease with enlarged perivascular spaces has
been shown to be higher in Black patients compared to other racial groups.10,11
Finally, increasing evidence suggests the impact of sociodemographic factors on
CSVD burden. One study showed that early life factors including lower education
in childhood are associated with worse small vessel disease, independent of
vascular risk factors and adult sociodemographic factors.12
Several modifiable clinical risk factors are associated with the development of
CSVD. These include hypertension, obstructive sleep apnea, diabetes mellitus,
hyperlipidemia, and tobacco use.13-15 Chronic kidney disease is associated with
increased presence of cerebral microbleeds, white matter hyperintensities, and
silent brain infarctions.16,17 The complex relationship between chronic kidney
disease, hypertension, cognitive impairment, and CSVD has been explored in a
number of studies.16,18,19
PATHOLOGIC FINDINGS
The term small vessel disease refers to the pathologic processes that involve the
small arteries, arterioles, venules, and capillaries of the brain. Pathologic changes
in these small vessels lead to chronic and progressive changes in the gray and
white matter, which contribute to the clinical and radiographic findings.20
502 APRIL 2023

The work of C. Miller Fisher was critical in helping to define CSVD. In a KEY POINTS
landmark manuscript published in 1965, he presented postmortem findings of
● Cerebral small vessel
114 patients found with pathologic evidence of lacunar infarct.21 In this disease (CSVD) contributes
manuscript, he described lacunes as typically small (1 mm to 4 mm), with only to significant morbidity and
17% measuring 10 mm or more in diameter. Microscopically, the typical lacune mortality through its impact
was described as “an irregular cavity containing a few strands of fine fibrillar on stroke risk, cognitive
decline, and dementia.
connective tissue” with “fatty macrophages” in the cavity, with “their number
diminishing with the age of the lesion.”21 ● Several modifiable
While many of the findings from Fisher’s work hold true today, it is clinical risk factors are
increasingly clear that the pathologic features are influenced by etiologic associated with the
classification of CSVD.20 The common and uncommon causes of CSVD development of CSVD,
including hypertension,
(TABLE 6-115,20) have previously been categorized according to different obstructive sleep apnea,
etiopathogenic subtypes to improve consistency of reporting; however, the diabetes mellitus,
classification remains variable.20 When associated with age, hypertension, and hyperlipidemia, and
other vascular risk factors, CSVD is characterized by loss of smooth muscle cells tobacco use.
from the tunica media, lipohyalinosis, the development of microatheroma, and ● CSVD is increasingly
segmental arterial disorganization.20,22,23 These changes contribute to subclinical recognized as a dynamic,
lacunar infarcts and clinical ischemic and hemorrhagic strokes, as well as other whole-brain disorder
radiographic changes. In CAA, the accumulation of amyloid-β protein in the characterized by
endothelial dysfunction and
walls of arteries, predominantly in the leptomeninges, leads to disruption, loss of
alterations in the function of
integrity, and fragmentation of the blood vessel walls.24,25 the neurovascular unit. A
While the aforementioned pathologic findings of CSVD are supported by better understanding of the
multiple studies, the pathomechanism underlying CSVD is not well understood. underlying mechanisms may
help to identify therapeutic
CSVD is increasingly recognized as a dynamic, whole-brain disorder
targets for treatment.
characterized by endothelial dysfunction and alterations in the function of the
neurovascular unit.26 A better understanding of the underlying mechanism may ● There are six radiographic
help to identify therapeutic targets for treatment. phenotypes of CSVD: (1)
recent small subcortical
infarct, (2) white matter
NEUROIMAGING DEFINITIONS hyperintensity, (3) lacune of
Various terms have been used to describe neuroimaging findings of CSVD. These presumed vascular origin, (4)
terms include leukoaraiosis, white matter disease, leukoencephalopathy, and widened perivascular
white matter hyperintensities, among others.20,27 In 2013, a multidisciplinary spaces, (5) cerebral
microbleed, and (6) brain
group from the Centers for Standards in Neurodegeneration published a position atrophy.
paper describing the need for consistent terminology and setting the standard for
describing CSVD.27 They described six radiographic phenotypes of CSVD: (1) ● Small vessel ischemic
recent small subcortical infarct, (2) white matter hyperintensity, (3) lacune of (lacunar) stroke is the most
commonly encountered
presumed vascular origin, (4) widened perivascular spaces, (5) cerebral
acute clinical manifestation
microbleed, and (6) brain atrophy. Findings 1 through 5 are depicted in of CSVD. It represents 20%
27
FIGURE 6-1. to 30% of ischemic stroke
cases.
SMALL VESSEL ISCHEMIC STROKE
Small vessel ischemic (lacunar) stroke is the most commonly encountered acute
clinical manifestation of CSVD. It represents 20% to 30% of ischemic stroke cases.
The use of the term lacune can be traced back to Amédée Dechambre, who in 1838
described the small cavities that developed during the process of resorption within
cerebral softenings.28 In 1843, Maxime Durand-Fardel described small cavities in
the basal ganglia, attributed to healed cerebral softenings. Pathologic descriptions
were offered by others including Jean-Baptiste Vincent Laborde, but the first
clear clinicopathologic descriptions were presented by Pierre Marie and Jean
Ferrand. Ferrand recognized a typical lacunar infarct as a healed infarct that

TABLE 6-1 Common and Uncommon Forms of Cerebrovascular Small Vessel Diseasea
Arteriolosclerosis (or age-related and vascular risk factor–related small vessel diseases)
Sporadic cerebral amyloid angiopathy
Genetic conditions
◆ Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
◆ Cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL)
◆ Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS)
◆ Fabry disease
◆ Collagen type IV mutation–related cerebrovascular small vessel disease (COL4A1/A2)
◆ Frameshift mutation in TREX1 gene: retinal vasculopathy with cerebral
leukoencephalopathy
◆ Hereditary cerebral hemorrhage with amyloidosis
Immune-mediated conditions
◆ Primary CNS vasculitis
◆ Secondary CNS vasculitis
◇ Antineutrophil cytoplasmic antibody–associated vasculitis
◇ Hypersensitivity or cutaneous leukocytoclastic vasculitis
◇ Systemic lupus erythematosus–associated vasculitis
◇ Sjögren syndrome–associated vasculitis
◇ Rheumatoid vasculitis
◇ Mixed connective tissue disease–associated vasculitis
◇ Behçet vasculitis
Infection-mediated conditions
◆ Bacterial: meningovascular neurosyphilis
◆ Viral: varicella-zoster; cytomegalovirus; hepatitis B; hepatitis C; human immunodeficiency
virus (HIV)
◆ Fungal
◆ Protozoal: cerebral malaria
◆ Parasitic: schistosomiasis
Other causes
◆ Postradiation vasculopathy
CNS = central nervous system.

a
Data from Cannistraro RJ, et al, Neurology15; Pantoni L, Lancet Neurol.20
504 APRIL 2023

FIGURE 6-1
Neuroimaging characteristics of cerebral small vessel disease from STRIVE (Standards for
ReportIng Vascular changes on nEuroimaging).
Data from Wardlaw JM, Lancet Neurol.27

resulted from “rupture or obliteration” of a perforating artery or branches from

arteriosclerosis. He also described classic locations including the pons, internal
capsule, thalamus, and white matter.28
In a landmark article, Fisher described over 20 “lacunar syndromes,” five of
which are typically ascribed to small vessel disease (TABLE 6-2).29 The patient
described in CASE 6-1 presented with a sensorimotor stroke in a thalamic
location.29 The most common location of lacunar infarcts, in descending order of
frequency, include the putamen, caudate, thalamus, pons, internal capsule, and
subcortical white matter.
Hypertension, diabetes mellitus, and tobacco use are important risk factors for
small vessel ischemic stroke, and hyperlipidemia may also contribute to risk.30-32
While risk of mortality is lower for small vessel disease than for other stroke
subtypes, recurrent risk varies between 4% and 11% per year.33,34 The risk factor
profile of patients with lacunar stroke modifies recurrence risk. Although
lowering blood pressure (BP) reduces the risk of recurrent stroke for ischemic
stroke overall, the optimal BP goal for patients with small vessel stroke remains
unknown. The SPS3 (Secondary Prevention of Small Subcortical Stroke) study
compared intensive BP reduction (systolic BP [SBP] <130 mm Hg) to standard
BP reduction (SBP <150 mm Hg).35 In this study, intensive BP reduction did not
result in a significant difference in the primary outcome of all strokes and fatal
and disabling strokes. However, a significant decrease was seen in the risk of
intracerebral hemorrhage with SBP reduction to less than 130 mm Hg. Based in
part on a meta-analysis that included SPS3 data, the American Heart Association/
American Stroke Association (AHA/ASA) Guideline for the Prevention of Stroke
in Patients with Stroke and Transient Ischemic Attack includes a class 1 (level of
evidence B-R) recommendation for a target BP of less than 130/80 mm Hg for
patients with ischemic stroke.36
Available data suggest that the majority of stroke patients do not achieve
any reasonable target of BP control. Data from the SPS3 study showed that,
TABLE 6-2 Common Lacunar Syndromesa
Syndrome Symptoms Radiographic findings

Pure motor Weakness of the face, arm, and leg on one side Infarct in posterior limb of internal
hemiparesis capsule, lower basis pontis,
putamen, caudate nucleus
Pure sensory stroke Numbness of the face, arm, and leg on one side with or without Infarct in posteroventral nucleus of
corresponding sensory deficit thalamus
Ataxic hemiparesis Pure motor hemiparesis associated with cerebellar dysmetria on Infarct in basis pontis
the same side
Dysarthria–clumsy Facial weakness, dysarthria, and dysphagia combined with slight Basis pontis or genu of internal
hand weakness and clumsiness in the hand capsule
Sensorimotor Numbness and weakness of the face, arm, and leg on one side Thalamus and internal capsule
stroke
a
Data from Fisher CM, Neurology.29
506 APRIL 2023

A 56-year-old right-handed woman developed acute onset of right-sided CASE 6-1
numbness while at a party. Her family called 911 and she was emergently
transferred to the hospital. She had a history of pregnancy-related
hypertension in her thirties and untreated hypertension. Her National
Institutes of Health Stroke Scale score was 7 for right facial weakness (2);
right face, arm, and leg hemianesthesia (2); and right arm and leg
hemiparesis (3). Her head CT showed no evidence of hemorrhage and she
was treated with IV recombinant tissue plasminogen activator (rtPA). Her
CT angiogram showed no evidence of large vessel occlusion or
intracranial or extracranial atherosclerosis. Her lab work showed a
low-density lipoprotein cholesterol concentration of 131 mg/dL and a
hemoglobin A1c percent of 5.8. Her MRI showed an acute left thalamic
infarct (FIGURE 6-2). She was initiated on aspirin and atorvastatin, and her
blood pressure was controlled over the next several days. She was
counseled on medication adherence and lifestyle approaches to
cardiovascular risk reduction. She was discharged home with outpatient
therapy.
FIGURE 6-2
Imaging of an acute infarct in the patient in CASE 6-1. Axial diffusion-weighted (A),
apparent diffusion coefficient (B), and fluid-attenuated inversion recovery (FLAIR) (C)
images of acute left thalamic infarct in a patient with chronic hypertension.
This case represents a common presentation of a classic sensorimotor COMMENT

lacunar syndrome with an infarct in the thalamus. The patient has a history
of pregnancy-related hypertension which increases her risk for chronic
hypertension and future vascular events. She demonstrates the common
risk factors, clinical presentation, and approach to secondary stroke
prevention in patients presenting with a small vessel ischemic stroke.
Blood pressure control and medication adherence are critical for
secondary stroke prevention in this case.

at baseline, more than 50% of enrolled patients had uncontrolled BP

(>140/90 mm Hg) approximately 3 months following stroke.37 Additional data
from other studies showed poor rates of BP control in adults living with stroke, as
well as racial disparities in BP control.38,39 Given the relationship between
uncontrolled BP and recurrent stroke risk, cognitive decline, and dementia after
stroke, interventions to improve BP control in all stroke survivors, including
those with small vessel stroke, are urgently needed.40-43
Other medical comorbidities are known to increase the risk of recurrent stroke
in patients with small vessel stroke. Patients with diabetes mellitus, metabolic
syndrome, or both have higher risk for recurrent stroke following small vessel
stroke. Diabetes also increases the risk of myocardial infarction and death in
patients with lacunar stroke.31,44 While no current evidence supports a different
approach to diabetes or metabolic syndrome in patients with small vessel stroke,
closer monitoring of these patients may be warranted given the excess risk.
CEREBRAL AMYLOID ANGIOPATHY

CAA is a common pathologic finding in aging brains (CASE 6-2). Autopsy studies
among elderly patients with and without dementia show a CAA prevalence of
CASE 6-2 A 70-year-old man with hypertension was referred for evaluation of
memory loss and abnormal findings on his MRI. His wife started to notice
changes in his cognition approximately 3 years prior to presentation. He
would leave his wallet at home and had difficulty managing accounts at
work, forgetting his passwords, and he decided that it was time to retire.
The family attributed these changes to age and did not seek help initially.
However, when he began to get lost while driving, his wife mentioned it to
his primary care provider, who ordered lab work including serum thyroid
testing, rapid plasma reagin (RPR), and vitamin B12 levels. These studies
were normal, and she ordered a brain MRI (FIGURE 6-3) which showed
numerous microhemorrhages. The primary care provider referred him to a
neurologist for further evaluation.
The patient’s wife reported a continued decline in cognition. She
prepared all their meals and managed household finances. The patient
remained independent for self-care. His overall mood was good,
although he reported some depression and his wife described occasional
irritability. His paternal grandfather and uncle had a history of dementia.
Regarding vascular risk factors, his blood pressure at home was
controlled (<130/80 mm Hg) with one medication. He did not take aspirin
or other antithrombotic therapies. His medical review of systems was
negative. His general physical examination was normal. His Montreal
Cognitive Assessment (MoCA) score was 20 for impaired fluency,
attention (serial sevens), memory (delayed recall), and abstract thinking.
The rest of his neurologic examination was normal. His MRI showed
multiple supratentorial and infratentorial cerebral microhemorrhages
and cortical siderosis on the susceptibility-weighted imaging (SWI)
sequence. The neurologist discussed a diagnosis of probable cerebral
amyloid angiopathy (CAA) with the patient and his wife.
508 APRIL 2023

50% to 60% and 20% to 40%, respectively.45 A smaller proportion of individuals
are diagnosed with cerebral amyloid angiopathy based on clinical presentation.
Patients typically present with neurologic findings attributable to acute
hemorrhage, transient neurologic episodes, and cognitive impairment or
dementia.46 The Boston criteria 2.0 (TABLE 6-3) can be used to diagnose CAA
based on radiographic features, clinical characteristics, and histopathologic
samples when available.47 These were updated in 2022 from the modified Boston
criteria to include additional details regarding clinical and radiographic findings,
adding increased sensitivity and specificity for the detection of CAA.48,49 A
definite diagnosis of CAA requires full postmortem evaluation.
Radiographic findings in CAA include cortical hemorrhage, cerebral
microbleeds, superficial siderosis, convexal subarachnoid hemorrhage (SAH),
silent infarcts, white matter hyperintensities, and MRI-visible perivascular
spaces in the centrum semiovale (FIGURES 6-3 and 6-4).46,50,51 Cerebral
microbleeds are detected on blood-sensitive MRI sequences such as
T2*-weighted gradient echo and susceptibility-weighted imaging (SWI).
Radiographic features are associated with clinical presentation and
recurrence risk.
FIGURE 6-3
Imaging of the patient in CASE 6-2. Radiographic findings in axial susceptibility-weighted
imaging (SWI) sequence in cerebral amyloid angiopathy, showing cerebral microbleeds
(A, B) and cortical siderosis (B, C).
This case exemplifies the clinical presentation with cognitive impairment as COMMENT
the primary presentation of CAA. Patients need not have a clinical
presentation with an acute intracerebral hemorrhage to be diagnosed with
probable CAA.

TABLE 6-3 Boston Criteria 2.0 for Sporadic Cerebral Amyloid Angiopathya
Definite cerebral amyloid angiopathy

◆ Full brain postmortem examination demonstrating
◇ Spontaneous intracerebral hemorrhage (ICH), transient focal neurologic episodes (TFNEs),
convexal subarachnoid hemorrhage (cSAH), or cognitive impairment or dementia
◇ Severe cerebral amyloid angiopathy (CAA) with vasculopathy
◇ And absence of other diagnostic lesions
Probable cerebral amyloid angiopathy with supporting pathology
◆ Clinical data and pathologic tissue (evacuated hematoma or cortical biopsy specimen)
demonstrating
◇ Presentation with spontaneous ICH, TFNEs, cSAH, or cognitive impairment or dementia
◇ Some degree of CAA in specimen
◇ And absence of other diagnostic lesions
Probable cerebral amyloid angiopathy
◆ For patients age 50 years or older, clinical data and MRI demonstrating
◇ Presentation with spontaneous ICH, TFNEs, cSAH, or cognitive impairment or dementia
◇ At least two of the following strictly lobar hemorrhagic lesions on T2*-weighted MRI, in any
combination: ICH, cerebral microbleeds, or foci of cortical superficial siderosis or cSAH
OR
◇ One lobar hemorrhagic lesion plus one white matter feature (severe visible perivascular
spaces in the centrum semiovale or white matter hyperintensities in a multispot pattern)
◇ Absence of any deep hemorrhagic lesions (ICH or cerebral microbleeds) on
T2*-weighted MRI
◇ Absence of other causes of hemorrhagic lesionsb
◇ Hemorrhagic lesion in cerebellum not counted as either lobar or deep hemorrhagic lesion
Possible cerebral amyloid angiopathy
◆ For patients age 50 years or older, clinical data and MRI demonstrating
◇ Presentation with spontaneous ICH, TFNEs, or cognitive impairment or dementia
◇ Absence of other cause of hemorrhage
◇ One strictly lobar hemorrhagic lesion on T2*-weighted MRI: ICH, cerebral microbleeds, or
foci of cortical superficial siderosis or cSAH
OR
◇ One white matter feature (severe visible perivascular spaces in the centrum semiovale or
white matter hyperintensities in a multispot pattern)
◇ Absence of any deep hemorrhagic lesions (ie, intracerebral hemorrhage or cerebral
microbleeds) on T2*-weighted MRI
◇ Absence of other causes of hemorrhagic lesions
◇ Hemorrhagic lesion in cerebellum not counted as either lobar or deep hemorrhagic lesion
a
Data from Charidimou A, Lancet Neurol.47
b
Other causes of hemorrhagic lesions include antecedent head trauma, hemorrhagic transformation of an
ischemic stroke, arteriovenous malformation, hemorrhagic tumor, and central nervous system vasculitis.
Other causes of cortical superficial siderosis and acute convexity subarachnoid hemorrhage should also be
excluded.
510 APRIL 2023

Symptomatic ICH in CAA KEY POINTS
preferentially impacts the
● Hypertension, diabetes
occipital lobes, followed by the mellitus, and tobacco use
frontal, temporal, and parietal are important risk factors for
lobes.50 These hemorrhages may small vessel ischemic
follow a minor head trauma and stroke, and hyperlipidemia
may also contribute to risk.
can occur as single lobar ICH or
multiple simultaneous ICHs. ● The American Heart
Episodes of ICH recurrence can Association/American
occur over weeks, months, or Stroke Association (AHA/
years, with a yearly ICH ASA) Guideline for the
Prevention of Stroke
recurrence risk of 7.4% in CAA in Patients with Stroke
compared to 1.1% per year in and Transient Ischemic
CAA-unrelated ICH.51 In Attack includes a class 1
CAA-related ICH, the number of (level of evidence B-R)
recommendation for target
cerebral microbleeds at baseline blood pressure less than
(greater than one cerebral 130/80 mm Hg for patients
microbleed) is associated with with ischemic stroke.
FIGURE 6-4 ICH recurrence risk.51
● Given the relationship
Imaging characteristics of cerebral amyloid Disseminated cortical superficial
between uncontrolled
angiopathy. A, B, Multiple microhemorrhages on siderosis and convexal SAH are blood pressure and
axial susceptibility-weighted images (SWI) in a
additional markers of increased recurrent stroke risk,
patient with progressive cognitive impairment.
C, D, Cortical microhemorrhages, a cortical risk of recurrent ICH.52 cognitive decline, and
dementia after stroke,
hemorrhage (D, arrow), and siderosis (D, Transient focal neurologic
interventions to improve
arrowheads) on gradient echo MRI in a patient episodes (TFNEs) associated blood pressure control in all
with a recent temporal hemorrhage. with CAA can present as short stroke survivors, including
(typically <30 minutes) those with small vessel
disturbances in motor, sensory, stroke, are urgently needed.
language, or visual function which may be difficult to distinguish from transient ● The Boston criteria 2.0
ischemic attack or seizure.53 These CAA-related TFNEs, which have also been can be used to diagnose
known as “amyloid spells,” can occur as positive or negative phenomena. The cerebral amyloid angiopathy
most common positive symptom involves transient paresthesias of the mouth or (CAA) based on radiographic
features, clinical
hand that can spread gradually to other body parts. Negative symptoms include characteristics, and
focal weakness or impairments in language. CAA-related TFNEs are closely histopathologic samples
related to cerebral convexity SAH and superficial siderosis. Patients presenting when available.
with CAA-associated TFNEs are at high risk for subsequent lobar ICH and death,
● Radiographic findings in
particularly with TFNEs characterized by motor symptoms and when
CAA include cortical
antithrombotics are utilized.54 Diagnostic characteristics of CAA-related TFNEs hemorrhage, cerebral
have been reported and should be considered to support an accurate diagnosis microbleeds, superficial
(TABLE 6-4).53 siderosis, convexal
Cognitive impairment in CAA has been described for many years; however, subarachnoid hemorrhage,
silent infarcts, white matter
the specifics regarding the prevalence, progression, and profile of cognitive hyperintensities, and
impairment in CAA have not been well described. Concomitant Alzheimer MRI-visible perivascular
disease and other age-related changes can make it difficult to understand the spaces in the centrum
independent impact of CAA on cognitive change. Available data suggest that semiovale.
cognitive impairment occurs independent of and prior to the development of
ICH.25 Patients who have CAA without ICH may have abnormal cognitive profiles
in the absence of self-reported cognitive deficits.55 The cognitive profile appears to
be similar to that seen with vascular cognitive impairment; that is, impairments
in executive function and processing with relatively preserved memory.25

The most important known risk factor for sporadic CAA is age. Traditional
modifiable risk factors are not known to contribute to the risk of developing
CAA; however, hypertension is known to contribute to the occurrence of
CAA-related ICH,50 and BP management decreases the risk of CAA-related
ICH.56 Aspirin and warfarin are associated with hemorrhage risk in CAA;
however, prospective studies suggesting a strong causal relationship between
antithrombotic use and hemorrhagic stroke risk in CAA are lacking.57-59
No specific management guidelines exist for reducing ICH recurrence risk in
patients with CAA; however, the most recently published AHA/ASA guideline
for the management of patients with ICH recommends reducing BP in patients
with spontaneous ICH (class 1 recommendation) and suggests a BP target of less
than 130/80 mm Hg (class 2a recommendation).60 Regarding the clinical
dilemma of managing atrial fibrillation in patients with intracerebral hemorrhage
related to CAA, the guidelines suggest that in patients with atrial fibrillation and
spontaneous ICH deemed ineligible for anticoagulation, left atrial appendage
closure may be considered to reduce the risk of thromboembolic events (class 2b
recommendation). However, the guidelines also give a class 2b recommendation
for the resumption of anticoagulation based on weighing benefit and risk, and
some observational data support the judicious use of anticoagulation even in
patients with CAA and atrial fibrillation given their high risk of ischemic stroke.
Ongoing randomized clinical trials such as ASPIRE (Anticoagulation in ICH
TABLE 6-4 Diagnostic Characteristics of Cerebral Amyloid Angiopathy–Related

Transient Focal Neurologic Episodesa
Essential features
◆ Transient focal neurologic symptoms (often unilateral motor, sensory, or both, sometimes
including other symptoms such as dysarthria or aphasia) usually resolving within 30 minutes
(and nearly always within 3 hours); often spreading from one body part to another
represented by contiguous cortex and often recurrent in a stereotyped or similar pattern
over days or weeks
◆ Neuropathologic or neuroimaging evidence of probable or possible cerebral amyloid
angiopathy (CAA) by Boston Criteria
◆ Age ≥55 years
Supportive: suggests CAA-related transient focal neurological episode (TFNE) even when
other potential causes are present
◆ Acute convexity subarachnoid hemorrhage or cortical superficial siderosis in a sulcus
adjacent to the presumed symptomatic gyrus without other identified cause
Exclusionary: suggests event was not CAA-related TFNE even in patients with
neuropathology or imaging evidence of CAA
◆ Acute infarction in a pattern consistent with thromboembolism rather than CAA; note that
some patients with CAA-related TFNEs have small diffusion-weighted imaging–positive
lesions near the symptomatic sulcus
Uncertain: features that make it unclear whether the event was a CAA-related TFNE
◆ Competing explanations for transient event (eg, atrial fibrillation) in the absence of
supportive features of CAA-related TFNE
a
Reprinted with permission from Smith EE, et al, Neurology.53 © 2021, American Academy of Neurology.
512 APRIL 2023

Survivors for Stroke Prevention and Recovery) and ENRICH-AF (EdoxabaN foR KEY POINTS
IntraCranial Hemorrhage Survivors With Atrial Fibrillation) are enrolling
● Episodes of CAA-related
patients with CAA-related ICH and randomizing them to anticoagulation intracerebral hemorrhage
versus aspirin. (ICH) can recur over weeks,
months, or years, with a
CADASIL yearly ICH recurrence risk of
7.4% in CAA compared to
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
1.1% per year in
leukoencephalopathy (CADASIL) is the most common monogenic small vessel CAA-unrelated ICH.
disease (CASE 6-3). Its prevalence is not well established and varies across
populations, but the minimum prevalence likely varies between 2 and 5 per ● Transient focal
100,000.61 Its primary clinical features include migraine with aura, recurrent neurological episodes
associated with CAA can
subcortical ischemic events, mood disturbances, progressive cognitive present as short (typically
impairment, and acute confusional episodes.61 less than 30 minutes)
Migraine is often the first manifestation of CADASIL, presenting often, but disturbances in motor,
not always, in the third decade of life.62 Although migraine with aura is typically sensory, language, or visual
function which may be
described, a history of migraine without aura may be present, as well as isolated difficult to distinguish from
aura (without headache).63 Subcortical ischemic events including ischemic transient ischemic attack or
stroke and transient ischemic attacks are a hallmark feature of the disease. These seizure.
typically present in the fifth decade as classical lacunar syndromes (TABLE 6-2).
● Patients who have CAA
Acute confusional episodes have been described in up to 10% of patients, often
without ICH may have
evolving from migraine attacks and presenting as confusion, reduced abnormal cognitive profiles
consciousness, seizures, hallucinations, focal weakness, or other cortical signs in the absence of
that resolve spontaneously.64 These may present as the initial symptoms of self-reported cognitive
deficits. The cognitive
CADASIL and can lead to inaccurate diagnosis.64 Psychiatric disturbances,
profile appears to be more
including apathy, major depression, pseudobulbar affect, and bipolar disorder, similar to that seen with
are present in 20% to 40% of patients with CADASIL.65,66 Progressive cognitive vascular cognitive
impairment in CADASIL primarily affects executive function and processing, impairment; that is,
with preservation of memory, especially early on in the disease course.61,67 impairments in executive
function and processing
CADASIL is caused by mutations in the NOTCH3 gene, which maps to the with relatively preserved
short arm of chromosome 19. The NOTCH3 gene encodes the NOTCH3 receptor memory.
protein, which is most commonly expressed in vascular smooth muscle cells and
pericytes.68 CADASIL results in a thickening of vascular walls and luminal ● There are no specific
management guidelines
stenosis.69 Degeneration of vascular smooth muscle cells, granular deposits of for reducing ICH recurrence
NOTCH3 ectodomain immunoreactivity, and positive periodic acid–Schiff risk in patients with CAA;
staining are observed in the tunica media.70 Collagen, laminin, and other fibrous however, the most recently
intracellular matrices accumulate in the tunica adventitia. Despite an increased published AHA/ASA
guideline for the
understanding of the pathologic processes and association with genetic
management of patients with
mutations, the direct pathogenic mechanism leading to infarction in CADASIL ICH recommend reducing
remains unknown.69 blood pressure for patients
CADASIL is suspected in patients with characteristic clinical symptoms and with spontaneous ICH (class 1
recommendation) and
radiographic findings. Radiographic findings in CADASIL include subcortical
suggest a blood pressure
white matter hyperintensities typically involving the external capsule and target of less than
temporal poles and clinically apparent and silent lacunar infarcts.71,72 130/80 mm Hg (class 2a
Approximately half of patients with CADASIL have cerebral microbleeds, which recommendation).
are typically located in subcortical regions.71-73 As CADASIL inheritance is
autosomal dominant, significant family history also supports the diagnosis, but
given the possibility of variable presentation within families and the possibility of
sporadic mutation, the absence of family history does not exclude CADASIL as a
potential diagnosis.74,75 The diagnosis is typically made by genetic testing for
NOTCH3 mutations. Skin biopsy is an alternative to genetic testing and is

CASE 6-3 A 48-year-old right-handed woman presented for evaluation for a recent
episode of acute left-sided weakness. She had a history of migraine with
aura since her twenties. She stated that she was writing on the
whiteboard in her classroom when she dropped the eraser out of her left
hand. She kneeled to pick it up and stumbled to the floor because of leg
weakness. One of her students called 911. She was taken to the nearest
hospital and had a head CT and CT angiography. The CT was normal and
the CT angiography showed no flow-limiting stenosis or occlusion. Her
blood pressure was normal. She started to develop her typical migraine in
the emergency department and her left-sided weakness began to
resolve. Her symptoms were attributed to migraine and she was
discharged home. She followed up 2 days later as she still experienced
mild left arm and leg weakness and used a cane to support herself during
ambulation. MRI was performed which showed an acute right thalamic
stroke as well as extensive subcortical white matter changes (FIGURE 6-5).
She reported a family history of migraine in her mother and her mother’s
sisters. Her mother died in her sixties after multiple strokes and had been
diagnosed with dementia. A maternal aunt (age 58) had major depression
and recurrent transient ischemic attacks. Genetic testing was performed
and found a mutation in the NOTCH3 gene, which confirmed the diagnosis
of cerebral autosomal dominant arteriopathy with subcortical infarcts
and leukoencephalopathy (CADASIL).
FIGURE 6-5
Imaging of the patient in CASE 6-3. Acute infarct on axial diffusion-weighted (A) and
apparent diffusion coefficient (B) MRI (arrows). Extensive subcortical white matter
changes on fluid-attenuated inversion recovery (FLAIR) image (C) are characteristic of
cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL).
COMMENT This case demonstrates the classical clinical history and features,
radiographic findings, and diagnostic studies needed for a diagnosis of
CADASIL.
514 APRIL 2023

typically performed when genetic testing is not available or when testing is KEY POINTS
negative or equivocal.76 Skin biopsy reveals granular osmiophilic material in the
● Migraine is often the first
small vessels when examined by electron microscopy. manifestation of cerebral
Cerebral autosomal recessive arteriopathy with subcortical strokes and autosomal dominant
leukoencephalopathy (CARASIL) is another inherited small vessel arteriopathy arteriopathy with
that causes stroke and early-onset dementia.77 It may be considered in the subcortical infarcts and
leukoencephalopathy
differential diagnosis of CADASIL. It differs from CADASIL in that it is
(CADASIL) presenting often,
characterized by spondylosis deformans and alopecia. It is caused by a but not always, in the third
homozygous mutation in the high-temperature requirement A serine peptidase 1 decade of life.
(HTRA1) gene.
Clinical management of CADASIL and CARASIL involves management of ● As CADASIL inheritance is
autosomal dominant,
known vascular risk factors, including hypertension and tobacco use, which have significant family history
been shown to contribute to poorer outcomes in patients with CADASIL.78,79 also supports the diagnosis,
Antiplatelet therapies are typically prescribed as for the prevention of ischemic but given the possibility of
events; however, the benefits for stroke prevention in these disorders is variable presentation within
families and the possibility
unknown.61 As cerebral microbleeds are common in CADASIL and ICH has been of sporadic mutation, the
reported, the benefits and risks of anticoagulation therapy, when otherwise absence of family history
indicated, are also unknown.80,81 does not exclude CADASIL
as a potential diagnosis.
● Clinical management of
CONCLUSION CADASIL and cerebral
Cerebrovascular small vessel disease is a common clinical condition that has been autosomal recessive
recognized for over two centuries. Clear radiographic findings are present across arteriopathy with
subcortical strokes and
etiologic subtypes. CSVD contributes to substantial global morbidity and
leukoencephalopathy
mortality through its impact on stroke, cognitive impairment, and dementia. (CARASIL) involves
Despite its high prevalence, gaps in knowledge remain regarding the management of known
pathomechanism of stroke and therapeutic targets to halt disease progression. vascular risk factors,
Hypertension contributes to the risk of developing CSVD and the risk for including hypertension and
tobacco use, which have
recurrent stroke. However, data suggest that blood pressure control remains been shown to contribute to
suboptimal in the general population and in stroke survivors. Indeed, we have poorer outcomes in patients
come a long way but have much further to go with blood pressure control. As with CADASIL.
Fisher offered in his landmark manuscript published in 1965, “From the close
relationship of hypertension and lacunes it can be predicted that the prevention
or relief of hypertension in the clinic will be an important measure in combating
lacunar strokes.”21 In addition to therapeutic strategies to prevent and treat
CSVD based on the pathomechanism of different subtypes, strategies to optimize
blood pressure control are also urgently needed.
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518 APRIL 2023

Diagnosis and Treatment REVIEW ARTICLE

of Cerebral Venous C O N T I N U UM A U D I O
ONLINE
Thrombosis
By Ava L. Liberman, MD
ABSTRACT
OBJECTIVE: Cerebral venous thrombosis (CVT), thrombosis of the dural sinus,
cerebral veins, or both, is a rare cerebrovascular disease. Although
mortality rates after CVT have declined over time, this condition can result
in devastating neurologic outcomes. This article reviews the latest
literature regarding CVT epidemiology, details new factors associated with
the development of CVT, and describes advances in CVT treatment. It also
contains a discussion of future directions in the field, including novel
diagnostic imaging modalities, and potential strategies to reduce the risks
associated with CVT.
LATEST DEVELOPMENTS: The incidence of CVT may be as high as 2 per 100,000

adults per year. It remains a difficult condition to diagnose given its
variable clinical manifestations and the necessity of neuroimaging for
confirmation. The COVID-19 pandemic has revealed a novel CVT trigger,
vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as
an association between COVID-19 infection and CVT. Although VITT is a
very rare event, timely diagnosis and treatment of CVT due to VITT likely
improves patient outcomes. Direct oral anticoagulants are currently being
used to treat CVT and emerging data suggest that these agents are as safe
CITE AS:
and effective as vitamin K antagonists. The role of endovascular therapy to CONTINUUM (MINNEAP MINN)
treat CVT, despite a recent clinical trial, remains unproven. 2023;29(2, CEREBROVASCULAR
DISEASE):519–539.
ESSENTIAL POINTS: Theincidence of CVT has increased, outcomes have Address correspondence to
improved, and the use of direct oral anticoagulants to treat CVT represents Dr Ava L. Liberman, 520 East 70th
an important advance in the clinical care of these patients. Rates of CVT as St, Starr 607, New York, NY
10021, all9188@med.cornell.edu.
a complication of COVID-19 vaccines using adenoviral vectors are very low
(<5 per million vaccine doses administered), with the benefits of COVID-19 RELATIONSHIP DISCLOSURE:
vaccination far outweighing the risks. The institution of Dr Liberman

has received research support
from the National Institutes of
Health.
C
erebral venous thrombosis (CVT) is estimated to account for less PRODUCTS/INVESTIGATIONAL
than 1% of all strokes.1,2 Unlike arterial strokes, CVT tends to affect USE DISCLOSURE:
Dr Liberman reports no
young patients with a female predominance, is often nonapoplectic disclosure.
in onset, and has a wide spectrum of clinical presentations.3 These
and other features make CVT a challenging disease to diagnose © 2023 American Academy
without an understanding of its evolving epidemiology, clinical features, of Neurology.

CEREBRAL VENOUS THROMBOSIS
associated conditions, and the neuroimaging findings typically needed to

confirm the diagnosis.
ANATOMY AND PATHOPHYSIOLOGY

The condition of CVT includes clots in both the large dural sinuses and cortical
veins.4 The most prominent superficial sinus is the superior sagittal sinus, which
drains into the transverse (lateral) sinuses and then out of the skull via the sigmoid
sinuses into the internal jugular veins on each side. The superior sagittal sinus is the
most frequent CVT location.5 The largest of the many tributary cortical veins that
drain into the superior and transverse sinuses are the bilateral veins of Trolard
(veins draped vertically over the parietal lobe, which drain into the superior
sagittal sinus) and Labbé (veins situated horizontally over the temporal lobe,
which drain into the transverse sinus). The deep venous system includes the
straight sinus, vein of Galen, inferior sagittal sinus, internal cerebral veins that
drain the thalami, and basal veins of Rosenthal (FIGURE 7-16).7 It is thought that
venous clots often originate in dural sinuses and then propagate to smaller veins
resulting in venous infarction, increased intracranial pressure, or both.4
EPIDEMIOLOGY
Recent population-based studies have shown a higher incidence of CVT than
previously reported. The latest annual CVT incidence ranges from 1.32 to 2 per
100,000 adults based primarily on data from high-income countries.1,2,8-10 Rising
CVT incidence over time is likely partially due to better disease ascertainment
with increasing availability of neuroimaging, although it is also possible that
FIGURE 7-1
Dural sinus and venous anatomy. Three-dimensional contrast-enhanced magnetic
resonance venography (MRV) using time-resolved imaging contrast kinetics shows the
sagittal view (A) and coronal view (B) of the same patient. Arrows indicate named sinuses
and veins. In this patient, the right transverse sinus is dominant. Asymmetric transverse
sinuses are a frequent finding on MRV in unselected patients with one study reporting that
61% of patients had a greater caliber right transverse sinus as compared with the left.6
520 APRIL 2023

changes in the prevalence of known, emerging, or as yet unknown CVT- KEY POINTS
predisposing conditions may be a contributing factor.11 In one of the recent
● Unlike arterial strokes,
studies using US data from two states, 0.66% of all stroke admissions from 2005 cerebral venous thrombosis
to 2016 were for CVT, with an estimated annual CVT incidence of 1.4 to 2 per (CVT) has a wide spectrum
100,000 people.1 In this study, the authors found that the proportion of stroke of clinical presentations,
admissions due to CVT had increased by 70%, from 0.47% in 2005 to 0.80% in tends to affect younger
patients with a female
2016, with the largest increases in CVT incidence noted among men and older
predominance, and is often
women. Epidemiologic data from lower- and middle-income countries are nonapoplectic in onset.
lacking and represent an important area for future CVT research.1
Rates of CVT among women of reproductive age are consistently 3 times higher ● The latest annual CVT
than those for similarly aged men.2,8,12,13 The incidence of CVT among women age incidence ranges from 1.32
to 2 per 100,000 adults
18 to 44 years in the aforementioned US study remained virtually unchanged over based primarily on data from
the study time period at 2.9 to 3.3 cases per 100,000 people.1 Higher CVT rates high-income countries.
among young women are consistent with known sex-specific factors (eg, oral
contraceptive use, pregnancy, and the puerperium) associated with CVT.12 To ● Conditions associated
with CVT can be classified
date, racial differences in CVT incidence have been underexplored. Data from a as either predisposing (eg,
2020 study suggest that the incidence of CVT may be disproportionately higher in genetic prothrombotic
Black people compared with people of other races in the United States.1 Prevalence diseases, antiphospholipid
rates of systemic venous thromboembolism, deep venous thrombosis, and syndrome, cancer) or
precipitating (eg, oral
pulmonary embolism are generally higher in African Americans compared to other
contraceptives, infections).
racial and ethnic groups, but the reasons for these differences as well as whether or
not they are similar in patients with CVT require additional study.14
ASSOCIATED CONDITIONS
Conditions associated with CVT can be classified as either predisposing
(eg, genetic prothrombotic diseases, antiphospholipid syndrome, cancer) or
precipitating (eg, oral contraceptives, infections). In 80% of patients with CVT at
least one associated condition is found, and in nearly half of patients with CVT
more than a single condition is identified.5 Thus, the identification of one
condition known to be associated with CVT should not deter clinicians from
looking for additional conditions, particularly inherited thrombophilias.15
Indeed, the American Heart Association/American Stroke Association (AHA/
ASA) CVT guidelines note that testing for prothrombotic conditions, including
protein C, protein S, or antithrombin deficiencies antiphospholipid syndrome,
and prothrombin G20210A and factor V Leiden mutations, can be beneficial for
the management of patients with a first CVT (class 2a; level of evidence B).16
The more recently published European Stroke Organization (ESO) guidelines,
however, note that good clinical practice includes performing thrombophilia
testing in patients with a high probability of carrying severe thrombophilia (eg,
those with a personal or family history of venous thrombosis, or those with CVT
without a transient or permanent risk factor) to prevent recurrence based on the
existing low-quality evidence surrounding thrombophilia testing.17 Conditions
associated with CVT have been previously detailed in a comprehensive
meta-analysis of case-control and cohort studies from 201818; TABLE 7-118-25
summarizes and expands upon these findings. In the future, genetic and lifestyle
data may identify additional conditions associated with CVT and, perhaps,
facilitate precision medicine in this space. For example, a recent genome-wide
association study using genetic data from 11 European and 1 US research center
identified a locus on chromosome 9 that was strongly associated with a nearly
threefold increased CVT susceptibility.26 The single-nucleotide polymorphisms

TABLE 7-1 Conditions Associated With Cerebral Venous Thrombosisa
Predisposing
◆ Alcohol consumption
◆ Hypercholesterolemia
◆ Hyperhomocysteinemia
◆ Antiphospholipid antibodies present and antiphospholipid syndrome
◆ Autoimmune disease
◆ Anemia
◆ Malignancy (particularly within the first year of cancer diagnosis as well as among patients
with hematologic malignancies)19
◆ Pregnancy and the puerperium (a 2019 case-control study found a nearly 11-fold adjusted
increased risk of cerebral venous thrombosis [CVT] with higher risk during the first 6 weeks
postpartum as compared to 7 to 14 weeks)20
◆ Factor V G1691A polymorphism
◆ Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism
◆ Prothrombin G20210A polymorphism
◆ Protein C deficiency
◆ Protein S deficiency
◆ Antithrombin III deficiency
◆ Obesity (in women who used oral contraceptives, being overweight or obese was
associated with an increased risk of CVT in a dose-dependent manner)21
◆ Elevated factor VIII serum levels22
◆ Behçet disease23
Precipitating
◆ Glucocorticosteroids
◆ Trauma
◆ Infection (particularly central nervous system or ear and face)
◆ Surgical procedures
◆ Combined oral contraception pill treatment
◆ Vaccine-induced immune thrombotic thrombocytopenia
◆ L-asparaginase therapy
◆ All-transretinoic acid in acute promyelocytic leukemia24
◆ Lumbar puncture25
a
Data from Green M, et al, Thromb Res18 unless noted otherwise.
522 APRIL 2023

with the largest associations were in the coding regions of the ABO blood type KEY POINTS
gene and, after determining the blood group distribution of cases and controls,
● Data from a 2021 study
these researchers found that a non-O blood group was more prevalent in suggest that a rare but
CVT cases.26 demonstrable association
between CVT and COVID-19
COVID-19 AND CEREBRAL VENOUS THROMBOSIS infection exists, although
the underlying mechanisms
The COVID-19 pandemic has led to the identification of additional conditions
of this association are
associated with CVT. uncertain.
COVID-19 Infection ● In patients with

Infection as a precipitant of CVT (pyogenic CVT) has been well described.27,28 neurologic symptoms and
COVID-19 infection, a high
Data from a 2021 study suggest that a rare but demonstrable association between index of suspicion for CVT
CVT and COVID-19 infection exists, although the underlying mechanism of this should be encouraged, and
association is uncertain.29 Several thromboembolic pathways have been treatment of CVT should be
implicated in the pathophysiology of COVID-19 infection and cerebrovascular initiated as soon as possible.
disease as well as systemic venous thromboembolism that may also play a role in
CVT formation.30,31 The true prevalence of CVT in patients with COVID-19
infection is not known. A recent systematic review of existing case reports and
retrospective cohort studies using data from 34,331 patients hospitalized with
COVID-19 estimated the frequency of CVT at 0.08%. Signs, symptoms, and
diagnosis of CVT followed the onset of respiratory or systemic COVID-19
symptoms by 1 to 8 weeks in nearly all 54 patients with CVT included in this
study.32 Patients with CVT were often noted to have altered mental status, with
thrombosis of the deep cerebral venous system or involvement of multiple
sinuses.32 Only one of the identified patients with CVT and COVID-19 had an
isolated headache which may reflect the fact that patients with CVT without
severe neurologic deficits were underdiagnosed during the pandemic (ie,
selection bias) or that, among patients with active COVID-19 infection, CVT is
clinically more severe.33 Inpatient mortality was reported in nearly half of
patients with CVT and COVID-19 infection, much higher than that of patients
with CVT without COVID-19.34 It is unclear if this high mortality rate is related to
neurologic complications, care quality, or the severity of COVID-19 infection
itself.32 Based on these limited data, in patients with neurologic symptoms and
COVID-19 infection, a high index of suspicion for CVT should be encouraged,
and treatment of CVT should be initiated as soon as possible.
COVID-19 Vaccination
Another CVT precipitant was identified during postauthorization surveillance of
people who had received COVID-19 vaccines using adenoviral vectors (human
Ad26.COV2.S and chimpanzee ChAdOx1 nCov-19) to encode the spike
glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
In February 2021, reports emerged of patients with thrombocytopenia and
venous thromboembolism in unusual locations following administration of the
ChAdOx1 nCov-19 vaccine. Within months, three independent descriptions
were published of 39 people with thrombosis, frequently CVT, and
thrombocytopenia that developed 5 to 24 days after initial vaccination with
ChAdOx1 nCov-19.35-37 Shortly thereafter, 12 women aged 18 to 60 years who
presented with CVT and thrombocytopenia 6 to 15 days postvaccination with
Ad26.COV2.S were reported.38 To date, no independent predictors for CVT
development postvaccine have been identified, although vaccine recipients with

CVT and thrombocytopenia were often younger than age 60 years and were
women who lacked prothrombotic risk factors.39 In a comprehensive study using
data from postauthorization safety reports and official data from 30 European
countries and the United Kingdom, the calculated risk of CVT with
thrombocytopenia within 28 days of the first ChAdOx1 nCov-19 dose was 4.4
(95% confidence interval, 3.9 to 4.9) per million doses and 0.7 (95% confidence
interval, 0.2 to 2.4) after Ad26.COV2.S vaccination. In this analysis, the risk of
CVT with thrombocytopenia after ChAdOx1 nCov-19 vaccination was highest
among people aged 18 to 24 years (7.3 per million first doses) and lowest in those
aged 70 years or older (0.2 per million doses).40 On a population level, these
absolute numbers are small and, although data collection is ongoing as
vaccination continues, findings continue to overwhelmingly support the safety
and efficacy of vaccination with respect to reducing COVID-19 risk and reducing
death due to COVID-19.39,41 Additionally, the prevalence of CVT among
hospitalized patients with COVID-19, as noted above, is far higher (60-fold to
230-fold) than that of people who received adenovirus-based COVID-19
vaccines.4,29,42 However, given the link between adenoviral vector–based
vaccines and CVT, mRNA vaccines (BNT162b2 and mRNA-1273) may be
preferred for certain patient subgroups (eg, younger) since the risk of CVT with
thrombocytopenia following administration of mRNA vaccines is nearly zero.40
The entity implicated in these rare but potentially devastating cases of CVT
and thrombocytopenia following adenovirus-based COVID-19 vaccine
administration is now called vaccine-induced immune thrombotic
thrombocytopenia (VITT) or thrombosis with thrombocytopenia syndrome.
VITT is one of three rare but pathophysiologically related hypercoagulable states
associated with thrombosis, low platelet counts, and disseminated intravascular
coagulation. The other two hypercoagulable states are heparin-induced
thrombocytopenia (HIT), which occurs after heparin exposure and autoimmune
heparin-induced thrombocytopenia (aHIT), which refers to a condition where
antibodies activate platelets in the absence of heparin.4 These three
hypercoagulable states (VITT, HIT, and aHIT) are all mediated by
platelet-activating antibodies to platelet factor 4 (PF4). In HIT, exposure to
unfractionated heparin, a polyanion, causes complexes of PF4 and heparin to
form, resulting in the development of IgG autoantibodies against this complex
and eventually leading to platelet activation, aggregation, and release of
procoagulant molecules. Similarly, in VITT, autoantibodies are thought to be
generated from a not-yet-identified polyanion in the adenoviral vaccines or
expressed by the cells infected by the vaccine that binds to PF4.43 Why the
cerebral veins and sinuses, as opposed to other sites, are a frequent location of
thromboses in VITT, occurring in approximately half of patients with VITT at
presentation, is not well understood44; rates of CVT in VITT differ substantially
from rates of CVT in HIT (1.6%) and aHIT (2.5%).45,46 Prior to the COVID-19
era, thrombocytopenia at CVT presentation was very uncommon.47
In a multicenter UK cohort study, patients with VITT-associated CVT had
similar presenting features to those with non–VITT-associated CVT, including
84% presenting with headache.48 Those with VITT-associated CVT had more
intracranial veins thrombosed, more frequent extracranial thromboses, and
higher rates of death or dependency as compared to other patients with CVT
despite aggressive treatment.48 Fortunately, mortality for patients with
VITT-associated CVT has significantly decreased from nearly 50% in March 2021
524 APRIL 2023

to around 22% for cases diagnosed thereafter, likely due to the beneficial effect of KEY POINTS
earlier recognition and improved treatments, especially the avoidance of heparin
● The entity implicated in
anticoagulation to treat CVT in VITT.49 Therefore, in patients with CVT with the rare but potentially
symptom onset within 4 to 42 days of having received a COVID-19 vaccine using devastating cases of CVT
adenoviral vectors, following an algorithmic approach to evaluate and treat VITT and thrombocytopenia
is advised (FIGURE 7-243,50).43,50,51 following adenovirus-
based COVID-19 vaccine
administration is now
CLINICAL PRESENTATION OF CEREBRAL VENOUS THROMBOSIS called vaccine-induced
The signs and symptoms of CVT are diverse and may mimic other neurologic immune thrombotic
disorders, complicating diagnosis. Symptoms of CVT reflect the location of the thrombocytopenia (VITT), or
thrombosis with
vein or sinus affected and, in some cases, multiple locations may be affected
thrombocytopenia
simultaneously. Presentations of CVT can be roughly divided into four syndromes: syndrome.
(1) isolated headache or increased intracranial pressure, (2) focal neurologic
presentations, (3) subacute encephalopathy, and (4) cavernous sinus syndrome ● In patients with CVT with
with multiple cranial neuropathies.5 In ISCVT (International Study on Cerebral symptom onset within 4 to
42 days after having
Vein and Dural Sinus Thrombosis), a multicenter registry, the median time from received a COVID-19 vaccine
CVT symptom onset to diagnosis was 7 days (interquartile range 3 to 16 days), using adenoviral vectors,
suggesting considerable diagnostic delay.52 More recently, a multicenter following an algorithmic
retrospective US study found that a probable CVT misdiagnosis occurred in 3.6% approach to evaluate and
treat VITT is advised.
of patients who presented emergently mostly with headache symptoms.53
Detecting CVT in patients with isolated headache presentations, particularly those ● Presentations of CVT can
with a prior headache history, remains a significant clinical challenge.54,55 be roughly divided into four
Headaches are present in approximately 90% of patients with CVT.5,28,56 syndromes: (1) isolated
headache or increased
Failure of blood to drain properly from the brain can lead to increased
intracranial pressure, (2)
intracranial pressure manifesting with headache, vomiting, and papilledema focal neurologic
presentations, (3) subacute
encephalopathy, and (4)
cavernous sinus syndrome
with multiple cranial
neuropathies.
FIGURE 7-2
Algorithm for diagnosing vaccine-induced immune thrombotic thrombocytopenia.
aPTT = activated partial thromboplastin time; CBC = complete blood cell count; ELISA = enzyme-linked
immunosorbent assay; PF4 = platelet factor 4; PT = prothrombin time ; VITT = vaccine-induced immune
thrombotic thrombocytopenia.
a
Patients with thrombosis and a normal platelet count might be in the early stage of VITT; continued
assessment for development of thrombocytopenia/VITT is required.
Data from Rizk JE, et al, JAMA Cardiol43 and the American Society of Hematology.50

with or without visual loss or sixth nerve paresis. When any combination of these
features without other neurologic signs is present, the syndrome is referred to as
isolated intracranial hypertension and is estimated to occur in nearly one-third of
patients with CVT.5,57 Up to one-quarter of patients with CVT can present with
isolated headache without any additional stigmata of raised intracranial
pressure.56,58 Headache presentations in CVT are notoriously diverse. Among
patients with new headache, obtaining a detailed neurologic examination,
assessing for features known to be associated with CVT, and including secondary
causes of headache in the differential may help to improve diagnostic accuracy in
CVT. The International Classification of Headache Disorders, 3rd Edition,
explicitly notes that headaches attributed to CVT have no specific characteristics.
Evidence of a causal relationship between CVT and headache per the
International Classification of Headache Disorders, 3rd Edition, simply requires
that the headache developed in close temporal relation to the CVT and either
headache has significantly worsened in parallel with clinical or radiological signs
of extension of the CVT or headache has significantly improved or resolved after
improvement of the CVT.59 Some key clinical features of CVT-associated
headache include being exacerbated by Valsalva maneuver and recumbency,
subacute onset of pain, and more often diffuse than unilateral headache
location.60 However, acute presentations consistent with migraine or
thunderclap headache may also occur.58 The transverse sinus is frequently a site
of thrombosis among patients with CVT and isolated headache.58,61 Interestingly,
a prospective study from 2020 where all patients with CVT were treated with
anticoagulation acutely found no significant difference in the frequency of
headache of any type or headache with features of intracranial hypertension in
patients achieving full recanalization as compared with those who did not fully
recanalize.62 The relationship between venous recanalization and
CVT-associated headache as well as the mechanism by which CVT causes
headache pain require further investigation.
Alternatively, patients with CVT may present with focal deficits, seizures, or
both. Symptoms depend on the area of the brain affected. Common focal
symptoms in CVT include hemiparesis, aphasia, and loss of vision.5 A key feature
of focal neurologic deficits due to CVT is that they are frequently progressive in
contrast with arterial strokes, which tend to be maximal at onset.63 The duration
of CVT symptoms prior to presentation was greater than 48 hours in 53% of
patients in the VENOST study,56 another large CVT registry, and, in ISCVT,
symptom onset of between 48 hours and 30 days was seen in slightly more than
half of patients.5 Another feature that may distinguish the focal deficits of CVT
from those of more commonly encountered arterial strokes is their bilateral
nature, particularly when the superior sagittal sinus is affected.28,52 Seizures, both
generalized and focal, are far more common in CVT than with arterial
cerebrovascular events, occurring in nearly 40% of patients with CVT at
initial presentation.52
Finally, patients with thrombosis of the deep venous system may develop a
subacute encephalopathy with confusion and lethargy or experience a rapid
neurologic deterioration progressing to coma due to edema of bilateral thalami,
basal ganglia, or other deep structures typically drained by these veins.64,65
Approximately 10% of patients with CVT have thrombosis of the deep cerebral
venous system.52,64 Timely neurologic imaging is an essential component of the
diagnostic evaluation for patients who present in coma to distinguish deep
526 APRIL 2023

cerebral vein thrombosis from other neurologic causes. Cortical vein thrombosis KEY POINTS
is thought to be even more rare than deep venous system thrombosis, occurring
● A key feature of focal
in only 116 patients in the published literature.66 However, since most of the neurologic deficits due to
published cases of isolated cortical vein thrombosis have associated venous CVT is that they are
infarct, underreporting and potentially underdiagnosis of nonsevere isolated frequently progressive in
cortical vein thrombosis cases may occur. nature in contrast to arterial
strokes which tend to be
maximal at onset.
RADIOGRAPHIC FINDINGS
Given the broad spectrum of presentations seen in CVT, recognizing the ● Contrast-enhanced brain
presence of CVT on clinical grounds requires a high degree of suspicion. MRI provides detailed
Radiologic studies are crucial to establish the definitive diagnosis of CVT. In the information about the brain
parenchyma and is probably
emergency setting, CT is often the imaging test of choice for patients presenting more accurate for
with acute focal neurologic symptoms. However, ruling out CVT is difficult to do diagnosing CVT than non-
using CT alone.67 Both direct visualization of a thrombus in a cerebral vein or contrast-enhanced
sinus, often called the “dense clot sign” or “cord sign,” as well as visualization of a magnetic resonance
venography sequences.
filling defect within a dural sinus after contrast administration, the “empty delta
sign,” have high specificity but low sensitivity.68 Intracerebral hemorrhage,
which is well seen on head CT, is present in approximately one-third of patients
with CVT.5 Increased suspicion for hemorrhagic venous infarcts from CVT
should occur when multiple intraparenchymal hemorrhages are present; infarcts
are ill-defined or in a nonarterial territory; or involve the bilateral thalami or
bilateral basal ganglia, or are juxtacortical (CASE 7-1).69,70
Advanced imaging is generally required to diagnose and rule out CVT with
certainty, and noninvasive imaging is typically favored over cerebral
angiography, which is the gold standard.72 CT venography, a contrast-enhanced
helical CT examination performed with a time-optimized contrast bolus, allows
direct visualization of a thrombosed cerebral vein, and is a fairly reliable
alternative to angiography with high sensitivity but low specificity.73 Magnetic
resonance venography (MRV) can also be used to detect CVT without ionizing
radiation exposure. Both CT venography and contrast-enhanced MRV are
superior to time-of-flight MRV techniques since complex flow can produce
artifacts in the latter. Contrast-enhanced MRV allows for a direct assessment of
luminal filling similar to that of CT venography, with comparable sensitivity and
specificity to CT venography.74,75 Contrast-enhanced brain MRI provides
detailed information about the brain parenchyma and is probably more accurate
for diagnosing CVT than noncontrast-enhanced MRV sequences.68 On brain
MRI, the most common finding is visualization of the thrombus in the
T1-weighted images. However, the timing of the CVT is an important
consideration for thrombosis visualization on MRI: in the acute phase (first
5 days after CVT) thrombus is isointense on T1-weighted images and
hypointense on T2*-weighted images; from 5 to 15 days the thrombus becomes
hyperintense on T1-weighted and T2*-weighted images; finally, after 15 days it
becomes homogeneous and hypointense in all image sequences. T2*-weighted
and susceptibility-weighted imaging sequences can be useful to assist in the
diagnosis of isolated cortical venous thrombosis on brain MRI.16,76
Using MRI black-blood thrombus imaging, a noncontrast-enhanced
T1-weighted imaging method that allows for direct visualization of the thrombus
itself, to detect CVT has very high sensitivity and excellent specificity compared
to combined CT and MRI modalities in small studies.77,78 Since a similar native
contrast thrombus MRI technique is highly accurate for the diagnosis of new and

CASE 7-1 A 60-year-old right-handed man with no known past medical history
presented with a mixed aphasia. Initial imaging in the emergency
department revealed a left temporal lobe intraparenchymal hemorrhage
with subarachnoid extension (FIGURE 7-3A). On arrival, he was afebrile,
tachycardic, and had a severely elevated blood pressure of 210/103 mm
Hg. The etiology of this hemorrhage was initially thought to be
hypertensive vasculopathy; evidence of dense cord sign on head CT
(FIGURE 7-3B) was not appreciated. Two days later, he had a brief transient
episode of gaze deviation to the right and unresponsiveness.
CT venography was
performed and demonstrated
thrombosis of the left
transverse sinus, sigmoid
sinus, internal jugular vein,
and the vein of Labbé
(FIGURE 7-3C). He was started
on therapeutic IV
anticoagulation as well as
antiseizure medication.
Thrombosis of the left vein of
Labbé was confirmed on
T1-weighted brain MRI
(FIGURE 7-3D).
The patient’s hospital stay
was fairly uncomplicated. He
was diagnosed with type II
hypertension and started on FIGURE 7-3
oral antihypertensive agents Imaging of the patient in CASE 7-1. A, Initial
in addition to therapeutic emergency department imaging revealing a left
temporal lobe intraparenchymal hemorrhage with
anticoagulation and
subarachnoid extension on axial noncontrast CT
antiseizure medications prior (arrow). B, Evidence of dense cord sign on axial
to discharge. Despite noncontrast CT (arrow). C, CT venography
extensive laboratory testing, demonstrating thrombosis of the left transverse
no precipitating or sinus (arrow), sigmoid sinus, internal jugular vein,
and the vein of Labbé. D, Coronal T1-weighted MRI
predisposing factors sequence confirming thrombosis of the left vein of
associated with his left-sided Labbé; the arrow indicates thrombosis of the
cerebral venous thrombosis transverse sinus extending into the vein of Labbé.
(CVT) were found.
COMMENT This case illustrates the challenges in acute CVT diagnosis as well as the
relevant vascular anatomy and imaging findings of CVT. Antiseizure
medication treatment for CVT is only recommended for patients who have
had a seizure, as in the case presented; prophylactic use of antiseizure
medication is not recommended.16,17 Patients with CVT with supratentorial
lesions have a higher risk for both presenting with and having early
seizures.71
528 APRIL 2023

recurrent lower-extremity deep venous thrombosis,79,80 black-blood thrombus KEY POINT
imaging may be of value for CVT detection if current findings are supported by
● Both the American Heart
additional data.68 An interesting radiographic finding seen on brain MRI, the Association/American
brush sign, has recently been described in CVT. This sign is an abnormal Stroke Association (AHA/
hypointensity of the subependymal and deep medullary veins in paramagnetic- ASA) and the more recently
sensitive MRI brain sequences that has been reported in patients with CVT, published European Stroke
Organization (ESO)
particularly those with thrombosis of the deep venous system (FIGURE 7-481). The
guidelines recommend
deep medullary veins are small-caliber vessels located adjacent to the atrium and initiation of parenteral
posterior body of the lateral ventricle, draining the white matter of the cerebral anticoagulation with
hemispheres to the subependymal veins of the lateral ventricles. The brush sign unfractionated or low-
molecular-weight heparin
was associated with higher thrombus load as well as ipsilateral parenchymal
prior to transitioning to oral
lesions in one small study; this sign may be a marker of CVT severity and should anticoagulants for CVT
prompt close monitoring during the acute phase.81 treatment.
TREATMENT
Medical, endovascular, and surgical treatments can be used to treat CVT.
Acute Anticoagulation
Anticoagulation remains the first-line treatment of choice for CVT in the acute
setting, even when concurrent intracerebral hemorrhage is present.16,17,82 Both
the AHA/ASA and the ESO guidelines recommend initiation of parenteral
anticoagulation with unfractionated or low-molecular-weight heparin (LMWH)
prior to transitioning to oral anticoagulants for CVT treatment.16,17 The ESO
guidelines have a weak recommendation for LMWH over unfractionated heparin
based on a meta-analysis suggesting a nonsignificant trend toward improved
functional outcomes and mortality with LMWH without a difference in rates
of bleeding.17,83 This trend is in keeping with an analysis from ISCVT that
suggested LMWH might be safer and perhaps more efficacious than
unfractionated heparin.84
FIGURE 7-4
The brush sign in cerebral venous thrombosis. Axial T2*-weighted MRI shows bilateral brush
sign (A, arrows) in a patient with acute thrombosis of the superior sagittal sinus, bilateral
transverse sinus, jugular vein, vein of Galen, straight sinus, and internal cerebral veins; this
extensive CVT is well seen on magnetic resonance venography (MRV) (B).
Reprinted with permission from Aguiar de Sousa D et al, Stroke.81 © 2019 Wolters Kluwer Health.

The clot in the venous system is the primary target of acute anticoagulation.
In a systematic review including data from 694 patients with CVT, vessel
recanalization occurred in roughly 85% at follow-up. This study found a
significant increase in the chance of favorable outcome (defined as a modified
Rankin Scale [mRS] score of 0 to 1) in patients with CVT with recanalization.85
New data suggest that vessel recanalization occurs early once anticoagulation is
initiated. In a prospective study of 68 patients with CVT all treated acutely with
anticoagulation who were imaged 0, 8, and 90 days from diagnosis, 43 (68%) had
partial recanalization and 4 (6%) had full recanalization at day 8.62 At 90 days,
41% had partial recanalization and 54% had full vessel recanalization. Patients
with early recanalization were at a lower risk of enlargement of nonhemorrhagic
lesions and showed early regression of venous infarcts. These findings support
the widely accepted hypothesis that recanalization improves regional
perfusion.62 An additional important aspect of early anticoagulation initiation in
CVT is prevention of other dangerous venous thromboembolisms in patients
with CVT, particularly pulmonary embolisms, at index hospitalization.86
Duration of Anticoagulation
The duration of anticoagulation following CVT has not been studied in any
randomized controlled trials; current recommendations are based on
extrapolation from venous thromboembolism data.16,17 This extrapolation from
venous thromboembolism to the CVT population, who are younger and likelier
to have had a provoked event, has been challenged. EXCOA-CVT (EXtending
oral antiCOAgulation treatment after acute Cerebral Vein Thrombosis) is a
cluster randomized trial designed to evaluate the efficacy and safety of
anticoagulation with vitamin K antagonists for 3 to 6 versus 12 months after CVT
to clarify the optimal duration of this therapy.87 Current AHA/ASA guidelines
note that for patients with provoked CVT (associated with a transient risk factor)
a 3- to 6-month duration of anticoagulation is reasonable but that for patients
with unprovoked CVT anticoagulation may be continued for 6 to 12 months.16
Patients who have recurrent venous thrombosis or an associated prothrombotic
condition with a high thrombotic risk may need permanent anticoagulation;
specific recommendations for the prevention of recurrent venous
thromboembolic events should be followed in those conditions.17
Use of Direct Oral Anticoagulants

Since the noninferiority of direct oral anticoagulants to prevent systemic venous
thromboembolism as compared to vitamin K antagonists has been shown,88 a
great deal of interest has been expressed in using these newer agents to reduce
the risk of venous thromboembolism after CVT. Direct oral anticoagulants have a
favorable safety profile, predictable pharmacokinetics, and are easier to
administer than vitamin K antagonists.89 Some support for the use of direct oral
anticoagulants after CVT comes from recent clinical trials. RESPECT-CVT
(Clinical Trial Comparing Efficacy and Safety of Dabigatran Etexilate with
Warfarin in Patients With Cerebral Venous and Dural Sinus Thrombosis) was a
prospective, randomized, open-label trial to evaluate the efficacy and safety of
dabigatran compared to dose-adjusted vitamin K antagonists to prevent
recurrent venous thromboembolism.90 In this trial, 120 adult patients with CVT
were randomized in a 1:1 fashion to dose-adjusted warfarin to maintain an
international normalized ratio (INR) of 2 to 3 or dabigatran 150 mg twice a day
530 APRIL 2023

for 24 weeks. Patients were eligible for inclusion if they were stable after 5 to
15 days of treatment with therapeutic heparin, able to swallow, did not have CVT
associated with either CNS infection or major trauma, and did not have any
surgical treatments planned. At the end of the study, no recurrent venous
thromboembolisms were observed in either treatment group, but three major
bleeding events occurred. These major bleeding events involved one patient with
intestinal bleeding in the dabigatran group and two patients with intracranial
(subdural) hemorrhages in the vitamin K antagonists group. The two treatment
groups had nearly identical rates of CVT recanalization on imaging. While
RESPECT-CVT could not detect a statistically significant difference between the
two treatments for recurrent venous thromboembolism, it did suggest that
dabigatran is a reasonable option to prevent recurrent venous thromboembolism
after CVT.
The safety and efficacy of rivaroxaban in CVT has also been studied.
EINSTEIN-Jr (Oral Rivaroxaban in Children With Venous Thrombosis), a
multicenter, parallel-group, open-label, randomized study, compared
rivaroxaban to dose-adjusted vitamin K antagonists in children (aged 0 to
17 years) with venous thromboembolism; a prespecified substudy of patients
enrolled with CVT was published in 2020.91 The main trial assigned patients in a
2:1 fashion to body weight–adjusted rivaroxaban in a 20 mg equivalent dose or
standard anticoagulation. Of the 114 children with confirmed CVT, symptomatic
recurrent venous thromboembolism occurred in none of the 73 children in the
rivaroxaban group versus one (2.4%) of the 41 children in the standard
anticoagulation group. Clinically relevant, nonmajor extracranial bleeding was
observed in five rivaroxaban recipients (6.8%) and one child (2.4%) in the
standard anticoagulation arm had a major bleeding event (subdural). No new
venous infarcts occurred in either group and repeat imaging demonstrated a
similar effect on clot resolution with rivaroxaban as compared to vitamin K
antagonists.91 Although it is challenging to apply the findings from a pediatric
trial (particularly one that was not powered for hypothesis testing) to an adult
population, the CVT substudy of EINSTEIN-Jr supports the overall trend that
direct oral anticoagulants are effective after CVT. Currently, SECRET (Study of
Rivaroxaban for CeREbral Venous Thrombosis), an open-label, randomized,
controlled, phase II clinical trial designed to evaluate the safety of rivaroxaban in
adults, is ongoing.92 Another trial called RWCVT (Rivaroxaban versus Warfarin
in CVT Treatment) has completed enrollment but has not yet published results.
An ongoing international observational study, DOAC-CVT (Direct Oral
Anticoagulants for the Treatment of Cerebral Venous Thrombosis,
NCT04660747), may also inform future practice.
Many practitioners have already started using direct oral anticoagulants to
treat CVT based on existing data. A systematic review of direct oral anticoagulant
use in CVT found a substantial increase in observational cohorts and case series
that included patients with CVT treated with apixaban, dabigatran, edoxaban, or
rivaroxaban since 2019. The observational cohorts included in the systematic
review reported a similar risk of death in direct oral anticoagulant versus
standard therapy arms and noted that favorable outcomes (mRS 0 to 2) were
more likely in direct oral anticoagulant–treated patients with CVT.93
ACTION-CVT (Direct Oral Anticoagulants Versus Warfarin in the Treatment of
Cerebral Venous Thrombosis), a large multicenter retrospective study, provides
additional reassurance to those who use direct oral anticoagulants after the acute

phase of CVT. The ACTION-CVT study included 845 patients with CVT across
27 centers in four countries. It found that direct oral anticoagulant treatment was
associated with a similar rate of recurrent venous thromboembolism (5.26 versus
5.87 per 100 patient years), a lower risk of major hemorrhage (2.44 versus 4.70
per 100 patient years), and similar rates of death and recanalization as with
vitamin K antagonists.94 In ACTION-CVT, two-thirds of patients on direct oral
anticoagulants were treated with apixaban. Although ACTION-CVT and other
retrospective treatment studies are prone to confounding by indication, no major
safety issues have been found with the use of direct oral anticoagulants as
opposed to vitamin K antagonists in clinical practice.95 It is important to note that
patients with antiphospholipid antibody syndrome should not be treated with
direct oral anticoagulants based on two randomized trials showing an increase in
arterial thrombotic events when these patients were treated with rivaroxaban
instead of warfarin.96,97 Additionally, pregnant patients with CVT should likely
be continued on LMWH rather than any other agent due to potential
teratogenicity.98
Endovascular Therapy
Endovascular therapy, defined as mechanical thrombectomy with or without
thrombolysis, has long been used to rapidly recanalize occluded sinuses in
patients with severe CVT who worsen despite anticoagulation or who cannot
receive anticoagulation. The results of the TO-ACT (Thrombolysis or
Anticoagulation for Cerebral Venous Thrombosis) trial were recently
published.99 This multicenter, open-label, blinded-endpoint, randomized trial
was designed to assess the safety and efficacy of endovascular therapy. Patients
with CVT were randomized 1:1 to receive either endovascular therapy with
anticoagulation or anticoagulation alone. Adult patients with radiologically
confirmed CVT who had one or more prespecified features associated with poor
outcome (mental status disorder, coma state, intracerebral hemorrhage, or
thrombosis of the deep venous system) were included in the study. TO-ACT was
halted after the first interim analysis for futility. A total of 67 patients were
randomized into TO-ACT, accounting for approximately 16% of patients with
CVT (67 of 420) seen at the sites during the study period. The number of patients
with a favorable functional outcome (mRS 0 to 2) at 12 months was very similar
between treatment groups (85% versus 82%). The mortality rates at 6 and
12 months were numerically higher in the endovascular therapy group than the
medical management group but did not reach statistical significance. Because of
the small sample size, TO-ACT is somewhat difficult to interpret. It remains
possible that improved methods of patient selection or different endovascular
techniques (in TO-ACT, more modern stent retrievers and aspiration catheters
were not used) may increase the frequency of favorable outcomes after CVT.
Indeed, symptomatic hemorrhage was higher in the medical arm (9% versus 3%)
in TO-ACT, suggesting that EVT may be effective in reducing the risk of further
bleeding. Retrospective data, however, have suggested that the role of
endovascular therapy in CVT is limited. Using data from the Nationwide
Inpatient Sample from 2004 to 2014, researchers found that 3% of identified
patients with CVT were treated with endovascular therapy. These researchers
found that endovascular therapy was independently associated with an increased
risk of death (odds ratio 1.96) after adjustment to account for measured
confounders.100 Further data as to the role of endovascular therapy in select
532 APRIL 2023

patients with CVT are likely needed before treatment recommendations can KEY POINTS
be made.
● The ACTION-CVT study
and other retrospective
Treatment of Vaccine-Induced Immune Thrombotic Thrombocytopenia– treatment studies are prone
Associated Cerebral Venous Thrombosis to confounding by
Early recognition, diagnosis, and treatment of VITT has led to favorable patient indication; nevertheless,
there do not seem to be
outcomes.101 As in HIT, therapeutic anticoagulation with nonheparin
major safety issues with
anticoagulants is the primary treatment for VITT with or without CVT. Based on the use of direct oral
data from patients with aHIT, administration of IV immunoglobulin (IVIg) as anticoagulants as opposed
soon as VITT is diagnosed or under consideration is recommended by both the to vitamin K antagonists in
clinical practice.
American Society of Hematology (ASH) and the AHA/ASA at a recommend dose
of 1 g/kg for two days.50,51 In patients with severe VITT (extensive thrombosis ● As in heparin-induced
with platelets <50 103/μL) or resistant VITT (continued thrombosis despite thrombocytopenia,
medical therapy), treatment with IVIg as a sole immunotherapy might not be therapeutic anticoagulation
enough because of the high antibody burden.43 Although the 2020 AHA/ASA with non-heparin
anticoagulants is the primary
guidelines for VITT-associated CVT do not address plasma exchange as a treatment for VITT with or
treatment modality, the ASH notes that plasma exchange can be considered if without CVT.
thrombosis continues despite nonheparin anticoagulation and IVIg.102 Aspirin
should not be used in patients with VITT. Platelet transfusions should be avoided ● Despite the low quality of
evidence, the ESO
with careful risk and benefit assessments made in patients with bleeding, who
guidelines now strongly
require surgical intervention, or both.51 Some cases of VITT-associated CVT with recommend using
extensive clot burden treated with endovascular therapy have been reported decompressive surgery for
with mostly favorable outcomes.103 Given the rarity of thrombocytopenia and patients with acute CVT and
parenchymal lesions with
CVT, all care should be individualized for each patient.
impending herniation to
prevent death as a
Decompressive Surgery randomized controlled trial
Herniation attributable to unilateral mass effect produced by large edematous is unlikely for ethical and
venous infarctions or parenchymal hemorrhages is the major cause of acute death feasibility reasons.
in CVT.104 Although the vast majority of patients with CVT have a favorable
outcome, about 4% develop cerebral edema severe enough to cause brain
herniation. In these instances, decompressive craniectomy, hematoma
evacuation, or both have been used to prevent death.5 Although a potential
disadvantage of craniectomy is that it precludes anticoagulation for the
immediate postoperative period, support for decompressive surgery exists. In
a retrospective study that included a systematic review of the literature, a total
of 69 patients with CVT were identified.105 Of those, only 12 (17%) had a poor
outcome (mRS 5 to 6) at a median of 12 months of follow-up. Nearly one-third
of patients who were comatose prior to surgery recovered completely at
follow-up.105 An updated systematic review published in 2019 identified 169
patients with CVT who were treated with decompressive surgery, mostly
from low- to middle-income countries, and similarly found a low mortality
rate of 16% at follow-up.106 Despite the low quality of evidence, the ESO
guidelines now strongly recommend using decompressive surgery for patients
with acute CVT and parenchymal lesions with impending herniation to
prevent death as a randomized controlled trial is unlikely for ethical and
feasibility reasons.17
Chemical Prophylaxis
Whether individuals with a history of CVT would benefit from targeted
prophylaxis in scenarios associated with increased venous thromboembolism risk

KEY POINT is uncertain and represents an important area for future research. Pregnant
women have been the focus of some research regarding the use of chemical
● In general, CVT has a
favorable outcome with an
prophylaxis to prevent venous thromboembolism or CVT recurrence.107 In a
in-hospital mortality rate small retrospective study of 63 women who became pregnant after their
ranging from 1% to 4% and diagnosis of CVT and were treated with LMWH for the entire gestational
from 8% to 10% during period, two (3%) had venous thromboembolisms and none had bleeding
long-term follow-up.
complications.108 In an update of a systematic review published in 2017 that
included a total of 393 patients, an analysis stratified according to antithrombotic
prophylaxis showed a trend toward lower rates of recurrent CVT and
extracerebral venous thromboembolism in patients receiving antithrombotic
prophylaxis with heparin.109,110 Although limited, based on these and other data
both AHA/ASA and the ESO recommend LMWH prophylaxis in pregnant
patients with a previous history of CVT.16,17 The optimal dose of LMWH in
pregnant women with moderate to high risk of recurrence of venous
thromboembolism is the subject of substantial debate with an ongoing open-label
randomized controlled trial comparing two different doses of LMWH in
pregnant patients with a history of venous thromboembolism.111
CLINICAL OUTCOMES
In general, CVT has a favorable outcome with an in-hospital mortality rate ranging
from 1% to 4% and from 8% to 10% during long-term follow-up.2,5,10,13,104,112,113
Mortality rates after CVT have been declining. One systematic review found an
inverse correlation between mortality and the calendar year in which patients
with CVT were recruited into a particular study.114 The frequency of presenting
with focal neurologic deficits and coma also decreased significantly over time.
Possible explanations are improvements in treatment, a shift in risk factors, and
the identification of less severe cases by improved diagnostic methods.114 Most
studies reporting outcomes after CVT have reported mRS scores at follow-up
which may not accurately capture the morbidity that follows CVT. A
single-center study of 161 patients with CVT in Finland found that even though
82% of patients had an mRS of 0 to 1 at 6 months, as many as 68% of patients
reported residual symptoms which frequently included neuropsychological
difficulties and headache.115 Older, smaller-cohort studies have identified
cognitive impairments, headaches, and seizures after CVT, frequently resulting
in unemployment.116-118 Future research detailing functional outcome after CVT
and evaluating interventions to improve patients’ ability to return to the
workforce is warranted.
CONCLUSION
The epidemiology of CVT is changing, including more frequent detection among
older patients and increased reported incidence rates. The presentation of CVT
can be subtle and usually differs from that of other cerebrovascular diseases,
making detection of CVT on advanced neuroimaging an essential component of
diagnosis. The use of direct oral anticoagulants to treat CVT is an important
advance that has recently been shown to be safe and effective, and evidence
supports a shift toward their use in clinical practice. To date, the rates of CVT as
a complication of adenovirus-based COVID-19 vaccination are very low (<5 per
million vaccine doses) and essentially zero with mRNA-based vaccines, with
the benefits of COVID-19 vaccination far outweighing the risk of VITT.
534 APRIL 2023

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Cochrane Database Syst Rev 2021;3:CD001689.
doi:10.1002/14651858.CD001689.pub4

REVIEW ARTICLE

Cervical Artery
ONLINE
Dissection
By Setareh Salehi Omran, MD
ABSTRACT
OBJECTIVE: Cervical artery dissection is a common cause of stroke in young
adults. This article reviews the pathophysiology, etiology and risk factors,
evaluation, management, and outcomes of spontaneous cervical artery
dissection.
LATEST DEVELOPMENTS: Cervical artery dissection is believed to be a

multifactorial disease, with environmental factors serving as possible
triggers in patients who have a genetic predisposition to dissection
formation. Cervical artery dissection can cause local symptoms or
ischemic events, such as ischemic stroke or transient ischemic attack.
Neuroimaging is used to confirm the diagnosis; classic findings include a
long tapered arterial stenosis or occlusion, dissecting aneurysm, intimal
flap, double lumen, or intramural hematoma. Patients with cervical artery
dissection who present with an acute ischemic stroke should be evaluated
for IV thrombolysis, endovascular therapy eligibility, or both.
Antithrombotic therapy with either anticoagulation or antiplatelet
treatment is used to prevent stroke from cervical artery dissection. The
risk of recurrent ischemia appears low and is mostly limited to the first two
weeks after symptom onset.
Cervical artery dissection is a known cause of ischemic

ESSENTIAL POINTS:
strokes. Current data show no difference between the benefits and risks of
CITE AS: anticoagulation versus antiplatelet therapy in the acute phase of
CONTINUUM (MINNEAP MINN) symptomatic extracranial cervical artery dissection, thereby supporting
the recommendation that clinicians can prescribe either treatment.
DISEASE):540–565.
Further research is warranted to better understand the pathophysiology
Address correspondence to and long-term outcomes of cervical artery dissection.
Dr Setareh Salehi Omran, 12401
East 17th Ave, MS L950, Aurora,
CO 80045, setareh.
salehiomran@cuanschutz.edu.
RELATIONSHIP DISCLOSURE: INTRODUCTION
D
Dr Salehi Omran reports no
issections are defined by blood collection and intramural hematoma
disclosure.
formation in the arterial wall layers. Cervical artery dissection is a
UNLABELED USE OF dissection in the carotid artery, vertebral artery, or both, and most
USE DISCLOSURE:
commonly involves the extracranial portions of these arteries.
Dr Salehi Omran reports no Dissections can occur spontaneously or as a direct result of
disclosure. significant trauma. About 15% to 24% of cases of ischemic stroke in young adults
© 2023 American Academy are due to cervical artery dissection, making it a common cause of stroke in
of Neurology. this population.1,2
540 APRIL 2023

This article reviews the epidemiology, pathophysiology, risk factors, clinical KEY POINTS
presentations, evaluation, management, and outcomes of cervical artery
● The overall incidence of
dissection. In particular, recent insights on risk factors and treatment, including cervical artery dissection is
acute ischemic stroke management and secondary stroke prevention, are low at 2.6 to 3.0 per 100,000
highlighted. Spontaneous cervical artery dissections are the main focus, as these people per year.
are more commonly encountered by neurologists, whereas cervical artery
● Dissections result from
dissection from major trauma is typically managed by surgeons. Purely
the separation of the arterial
intracranial dissections are not discussed and intracranial extension of wall layers causing the
extracranial cervical artery dissection is discussed briefly. formation of a false lumen
that allows blood to enter
EPIDEMIOLOGY the vessel wall.
The overall incidence of cervical artery dissection is low in the general ● Dissections can cause
population, at an estimated 2.6 to 3.0 per 100,000 people per year.3,4 Internal subintimal or subadventitial
carotid artery (ICA) dissections are more common than vertebral artery hematomas. Subintimal
dissections (1.72 per 100,000 people per year; 95% confidence interval, 1.1 to 2.3 hematomas may lead to
intraluminal stenosis or
versus 0.97 per 100,000 people per year; 95% confidence interval, 0.5 to 1.4).3 occlusion. Subadventitial
The overall incidence of cervical artery dissection is probably underestimated, as hematomas can cause
cases with few or no clinical signs are likely to remain undiagnosed or eccentric hematoma growth
misdiagnosed. and aneurysm formation.
Most epidemiologic studies on cervical artery dissection are from North
America and Europe, and it is unclear whether the findings generalize to other
populations. Based on these studies, the average age of cervical artery
dissection occurrence is 43 to 54 years.3,5,6 Data are inconsistent regarding any
sex-based differences, with North American studies showing a higher
incidence in women3,7 and European studies showing a greater occurrence
in men.5,6
ANATOMY OF CERVICAL ARTERY DISSECTION

The exact mechanism of hematoma formation in cervical artery dissection is
incompletely understood. Dissections result from separation of the arterial wall
layers causing a false lumen to form and allowing blood to enter the vessel wall
(FIGURE 8-18). These separations are thought to be from an intimal tear or direct
bleeding from ruptured vasa vasorum. Dissections can be either subintimal or
subadventitial. Subintimal dissections may cause intraluminal stenosis or
occlusion. Subadventitial dissections more commonly cause eccentric hematoma
growth, which can result in dissecting aneurysm formation.9 Intramural
hematomas can cause vessel dilatation and compression of adjacent nerves,
which can lead to local symptoms of headache and neck pain (from stimulation
of pain-sensitive receptors10), Horner syndrome, and cranial and cervical
neuropathies.
Carotid dissections occur a few centimeters above the bifurcation and
typically involve the distal two-thirds of the extracranial ICA near the skull
base.11 Spontaneous cervical artery dissections are more likely to be in the
proximal ICA whereas traumatic cervical artery dissections are typically in the
distal extracranial ICA.12 Vertebral artery dissections typically involve the V2
(cervical transverse process of C6 through C2) and V3 segments (extracranial
segment between transverse process of C2 and foramen magnum of the skull) of
the vertebral artery.13 Traumatic vertebral artery dissections more commonly
affect the V3 segment.12 Multiple simultaneous cervical artery dissections can be
seen in 13% to 22% of cases.3,5,6,14 Most cases of multiple simultaneous dissections

CERVICAL ARTERY DISSECTION
FIGURE 8-1
Manifestations of cervical artery dissection. A, During initiation of the arterial dissection
blood dissects into the subintimal space to create a false lumen. B, The formation of true and
false lumina can lead to artery-to-artery embolism. This can occur from either an intraluminal
thrombus formed at the site of intraluminal stenosis or distal embolization from the
intramural hematoma through an exit site from the dissection. C, Intramural hematoma can
lead to narrowing of the true lumen and occlusion of the dissected artery. D, Subadventitial
dissections can result in dissecting aneurysm formation.
Reprinted with permission from Bond KM, et al, J Neuroradiol.8 © 2020 Elsevier Masson SAS.
occur after minor trauma or infection,15 although some data suggest a possible
association with fibromuscular dysplasia.14
ETIOLOGY AND PREDISPOSING FACTORS

The pathophysiology of cervical artery dissection is incompletely understood.
The leading theory is that cervical artery dissection is a multifactorial disease, and
that environmental factors serve as potential triggers in patients who have a
genetic predisposition to dissections (TABLE 8-116-33).
Genetic Factors
Cervical artery dissection has been linked to a few connective tissue disorders and
vascular diseases. Fibromuscular dysplasia is perhaps the most common, with one
study identifying the presence of fibromuscular dysplasia in 40% of cervical artery
dissection cases.34 A small portion of cervical artery dissection cases (nearly 2%)
have been linked to monogenic connective tissue diseases, such as vascular
Ehlers-Danlos syndrome (also known as Ehlers-Danlos syndrome type IV).35
Although the prevalence of vascular Ehlers-Danlos syndrome among all patients
with cervical artery dissection is low, there is a strong association between the
two conditions. A study found that more than half (55%) of patients with
vascular Ehlers-Danlos syndrome had supraaortic trunk lesions, the majority
being cervical artery dissections.36 Therefore, screening patients with cervical
artery dissection for clinical signs of connective tissue diseases such as vascular
Ehlers-Danlos syndrome is important, as it may lead to further genetic
542 APRIL 2023

counseling and preventive measures. Reports of cervical artery dissection in KEY POINTS
patients with other connective tissue and vascular disorders such as Marfan
● A small portion of cervical
syndrome, osteogenesis imperfecta, and alpha-1 antitrypsin deficiency occur; artery dissection cases
however, the majority of these conditions are rare, and it is unclear whether (nearly 2%) have been linked
concomitant occurrence is higher than would be expected by chance alone.37 to monogenic connective
Apart from monogenic connective tissue diseases, which encompass a small tissue diseases, such as
vascular Ehlers-Danlos
group of cervical artery dissection cases, genetic factors may play a role in a more
syndrome.
multifactorial process leading to cervical artery dissection. The role of a genetic
predisposition is supported by familial cervical artery dissection cases,38 ● Apart from monogenic
dissections in other arterial beds in the absence of an established connective disorders, which encompass
tissue disorder,39 the presence of ultrastructural connective tissue alterations that a small group of cervical
artery dissection cases,
follow an autosomal dominant inheritance pattern,40 and the occurrence of genetic factors may play a
concomitant arterial abnormalities suggesting a more systemic arteriopathy.41-43 role in a more multifactorial
Connective tissue alterations seen in cervical artery dissection include elastic process leading to cervical
fiber fragmentation and the presence of composite fibrils within collagen artery dissection.
bundles, and suggest a defect in the biosynthesis of the extracellular matrix.44,45 ● Minor cervical trauma
In contrast to the rare co-occurrence between cervical artery dissection and precedes nearly 41% of
hereditary connective tissue diseases, nearly all patients with cervical artery identified spontaneous
dissection have clinical signs suggestive of connective tissue abnormalities.46 cervical artery dissection
cases. These minor traumas
These include skeletal, skin, and ocular abnormalities and craniofacial
can be subtle and involve
dysmorphisms.46 The presence of clinically detectable signs of connective tissue hyperextension,
anomalies in patients with cervical artery dissection in the absence of an lateroversion, or rotation of
established hereditary connective tissue disease suggests that systemic the neck.
aberrations of connective tissue may be implicated in disease pathogenesis.46
Despite the evidence suggesting a genetic predisposition, no established genetic
markers for cervical artery dissection are currently established. A systematic
review of 15 genetic association studies revealed a possible association with
polymorphisms in ICAM1 and COL3A1 and the MTHFR 677TT genotype47;
however, the findings were severely underpowered and require confirmation in
larger genetic association studies.
Environmental Factors
Environmental factors, such as significant and minor trauma, play an important
role in cervical artery dissection development. Significant trauma causing
penetrating or nonpenetrating injuries (including blunt trauma) can lead to
traumatic cervical artery dissection, while minor cervical trauma or mechanical
events are linked to spontaneous cervical artery dissection. Minor cervical
trauma precedes nearly 41% of spontaneous cervical artery dissection cases.48
These minor traumas can be subtle and involve hyperextension, lateroversion, or
rotation of the neck, which can lead to intimal injury of the cervical arteries and
result in dissection, as illustrated in CASE 8-1. Minor traumas include commonly
occurring mechanical events, such as severe coughing or sneezing, violent
vomiting, sports activities, whiplash injury, or cervical manipulative therapy
(TABLE 8-1). The observation that common minor traumatic and mechanical
events cause dissections in only select individuals further supports the hypothesis
that environmental factors may lead to cervical artery dissection development in
patients already genetically predisposed to dissections.
Epidemiologic studies suggest an association between cervical manipulative
therapy and cervical artery dissection, in particular vertebral artery dissection.21,49
While an association may exist, the absolute incidence is unknown, and causality

is difficult to establish. It is unclear whether patients with dissection-related

local symptoms seek cervical manipulative therapy before they develop a stroke,
or if trauma from cervical manipulative therapy leads to cervical artery
dissection. Therefore, the American Heart Association/American Stroke
Association (AHA/ASA) recommends professionals who perform cervical
manipulative therapy, such as chiropractors, to consider the possibility of
cervical artery dissection and inform patients of the association between cervical
artery dissection and cervical manipulative therapy prior to manipulation of the
cervical spine.32
Several other predisposing factors have been associated with spontaneous
cervical artery dissection, including pregnancy and the postpartum period,28 oral
contraceptive use,31 migraine,30 recent infection,17 and atherosclerotic vascular
risk factors. The association between recent infection and cervical artery
dissection is supported by several studies.17,50,51 In a case-control study of
43 patients with cervical artery dissection and 58 young adults with non–cervical
TABLE 8-1 Common Triggers and Risk Factors for Cervical Artery Dissection
Minor trauma and other mechanical events

◆ Cervical manipulative therapy (also referred to as chiropractic manipulation)16
◆ Severe coughing or sneezing17
◆ Sports-related injuries,18 from activities such as
◇ Combat sports (eg, taekwondo, boxing, wrestling)
◇ Dancing
◇ Extreme sports (eg, bungee jumping, skydiving)
◇ Golf
◇ Gymnastics
◇ Horse riding
◇ Scuba diving
◇ Skating
◇ Swimming
◇ Tennis
◇ Trampoline use
◇ Volleyball
◇ Weightlifting
◇ Yoga
◆ Sudden neck movements (such as on roller coaster rides)19
◆ Whiplash injury20
Connective tissue or vascular diseases, including arteriopathies21
◆ α1-antitrypsin deficiency
◆ Aortic root dilation22
544 APRIL 2023

artery dissection ischemic stroke, recent infection was associated with cervical
artery dissection–related ischemic stroke, although the mechanical factors
occurring in upper respiratory infections (ie, coughing, sneezing, vomiting) did
not seem to account for this association.17 Another case-control study of 47
patients with cervical artery dissection–related ischemic stroke showed that
nearly 32% of patients with spontaneous cervical artery dissection had an
infection within the preceding month, compared to 14% of the patients with
non–cervical artery dissection ischemic stroke.50 The association was stronger
among patients with multiple cervical artery dissections.50 Infections may
predispose individuals to cervical artery dissection via an indirect inflammatory
response or a prothrombotic mechanism. A seasonal pattern in cervical artery
dissection incidence has also been observed regardless of geographic location,
with cervical artery dissections occurring more often in autumn or winter.52 This
seasonal pattern may be due to increased occurrence of infection and
weather-related changes in blood pressure and physical activity.
◆ Autosomal dominant polycystic kidney disease

◆ Cerebral aneurysms23
◆ Cervical artery tortuosity24 and vessel redundancy
◆ Cystic medial necrosis of intracranial vessels
◆ Fibromuscular dysplasia
◆ Hereditary hemochromatosis
◆ Hyperhomocysteinemia
◆ Osteogenesis imperfecta type I
◆ Marfan syndrome
◆ Moyamoya disease
◆ Reticular fiber deficiency25
◆ Reversible cerebral vasoconstriction syndrome26
◆ Segmental mediolytic arteriopathy27
◆ Turner syndrome
◆ Vascular Ehlers-Danlos syndrome (Ehlers-Danlos syndrome type IV)
◆ Williams syndrome
Other risk factors
◆ Current use of oral contraceptives28
◆ Hypertension29
◆ Infection30
◆ Migraine31
◆ Pregnancy and postpartum period32
◆ Longer styloid process33

CASE 8-1 A 30-year-old previously healthy woman presented to the emergency

department with severe vertigo, nausea, and gait impairment causing her
to lean to the left side. Her last time known well was 12 hours prior to
presentation. Her symptoms occurred in the setting of 4 days of
left-sided neck pain that started after hyperextending her neck during a
yoga session. Her only medication was an estrogen-containing oral
contraceptive. Neurologic examination was notable for left-sided
dysmetria and gait instability with leaning to the left.
CT angiography (CTA) of the head and neck revealed a left vertebral
artery dissection in the V2 segment at the level of C3, with thrombus
filling the false lumen and causing severe stenosis of the true lumen
(FIGURES 8-2A and 8-2B). The vertebral artery regained normal caliber distal
to the dissection before fully occluding in the intracranial V4 segment
with nonopacification of the left posterior inferior cerebellar artery
(PICA). Brain MRI confirmed a large PICA-territory infarct (FIGURE 8-2C).
The patient was admitted to the neurologic intensive care unit and
closely monitored for malignant cerebellar edema. Her brain imaging
appeared stable for several days and suboccipital craniectomy was not
necessary. She was started on treatment dose anticoagulation with
apixaban 7 days after presentation. Repeat CTA 4 months after initial
presentation showed interval recanalization of the previously occluded
left PICA and intracranial vertebral artery, with no residual dissection flap
(FIGURE 8-2D). She underwent genetic testing with gene sequencing and
deletion/duplication studies that showed no known disease-causing
genetic mutations.
COMMENT This case illustrates the importance of identifying possible risk factors and
providing a tailored treatment approach. This woman was taking an
estrogen-containing oral contraceptive, which is a risk factor for cervical
artery dissection and ischemic stroke. Additionally, she most likely suffered
from minor neck trauma while hyperextending her neck during yoga. She
was advised to discontinue the estrogen-containing oral contraceptive and
avoid yoga and other sports that can cause neck trauma. This case also
highlights the importance of managing acute stroke from cervical artery
dissection with the same approach used in all patients with stroke. In this
case, the patient was monitored for malignant cerebellar edema and
started on treatment dose anticoagulation after the risk of hemorrhagic
conversion from the stroke was decreased. While direct oral
anticoagulants have not been used to treat cervical artery dissection in
randomized controlled trials, experts believe these oral agents can be
safely used in place of vitamin K antagonists.
546 APRIL 2023

FIGURE 8-2
Imaging of the patient in CASE 8-1. A, Left vertebral artery stenosis from dissection on axial CT
angiography (CTA) of the head and neck. Vessel measurements indicate that the artery is
narrowed to only 0.9 mm. B, Redemonstration on CTA of the left vertebral artery dissection
in the V2 segment at the level of C3, with severe luminal stenosis on sagittal imaging (arrow).
C, Diffusion restriction on axial diffusion-weighted brain MRI in the distribution of the left
posterior inferior cerebellar artery, distal to the left vertebral artery dissection, consistent
with an acute infarct. D, Repeat sagittal CTA performed 4 months after initial presentation
(and treatment with oral anticoagulation) showing interval resolution of the dissection with
no residual stenosis or dissection flap (arrow).

Several vascular risk factors have also been linked to cervical artery dissection.
Patients with cervical artery dissection are more likely to have hypertension,
lower body weight, and lower body mass index than matched healthy
controls.52-54 Other studies found no association or an inverse association
between hypercholesterolemia and cervical artery dissection.52,54
CLINICAL PRESENTATION
Common local signs and symptoms of cervical artery dissection include
new-onset head pain, neck pain, or both, cranial and cervical neuropathies,
Horner syndrome, and pulsatile tinnitus. Cervical artery dissection can cause
ischemic stroke, transient ischemic attack, and rarely subarachnoid hemorrhage.
Local Symptoms and Signs

Headache and neck pain are the most common local symptoms and are seen in
roughly 57% to 69% of cervical artery dissection cases.55-57 Patients with ICA
dissection are more likely to present with headache, whereas patients with
vertebral artery dissections are more likely to have cervical neck pain.56 Headaches
are typically on the ipsilateral side of the dissection, and are anterior in ICA
dissections and occipital in vertebral artery dissections.57 The characteristics of
cervical artery dissection–related headache are not specific and can mimic
migraine symptoms. A large series of patients with cervical artery dissection
showed variable headache presentations ranging from steady and pulsating to
thunderclap in nature.57 Isolated orbital pain is a rare presentation of
ICA dissections.58
ICA dissections can also cause Horner syndrome and cranial neuropathies.
Horner syndrome is seen in 25% to 39% of cases,3,59 and results from distention of
the third-order sympathetic fibers that span the external surface of an enlarged
and dissected ICA. The Horner syndrome seen in ICA dissections is partial and
consists of ptosis and miosis without anhidrosis. Cranial nerve palsies may result
from compression of the nerves adjacent to the ICA and along its cervical
trajectory.6 The hypoglossal nerve is most commonly involved, followed by the
glossopharyngeal and vagus nerves. In rare cases, vertebral artery dissection can
cause cervical nerve root injury.60 Pulsatile tinnitus can result from turbulent
blood flow at the site of dissection and is seen in roughly 8% of cervical artery
dissection cases.61
Ischemic and Hemorrhagic Events

Ischemic stroke and transient ischemic attack are the most feared complications
of cervical artery dissection. Nearly 67% of patients with cervical artery
dissection develop symptoms of cerebral ischemia, the majority being ischemic
stroke.3 Ischemic strokes from cervical artery dissection are usually due to artery-
to-artery embolism of intraluminal thrombus formed at the site of intraluminal
stenosis. Less commonly, ischemia may occur from hypoperfusion distal to a
high-grade intraluminal stenosis or occlusion.62
Ischemic events typically accompany local signs and symptoms. Stroke
symptoms from cervical artery dissection depend on the involved vascular
territory. Carotid artery dissections can result in anterior circulation syndromes
or retinal ischemia, and vertebral artery dissection may lead to posterior
circulation strokes including brainstem or cerebellar infarcts. Rarely, vertebral
artery dissections can cause spinal cord infarcts.
548 APRIL 2023

Subarachnoid hemorrhage is a less common complication seen in 1% of KEY POINTS
cervical artery dissection cases.6 Subarachnoid hemorrhage results from
● Pregnancy and the
intracranial extension of the dissection, or from an intracranial artery dissection. postpartum period, oral
Intracranial arteries lack external elastic lamina and have a thinner media and contraceptive use, migraine,
adventitia compared with extracranial arteries. These differences allow recent infection, and
intracranial dissections to be more prone to aneurysm formation and vascular risk factors have all
been associated with
subsequent rupture.63
cervical artery dissection.
Time from Local Symptom Onset to Neurologic Event ● Common local signs and
Ischemic stroke or transient ischemic attack can be the presenting symptom in symptoms of cervical artery
cervical artery dissection; however, patients may develop local symptoms dissection include
new-onset headache, neck
without associated ischemic events. The overall incidence of local symptoms pain, cranial and cervical
without ischemia may be underestimated due to delays or failures in neuropathies, Horner
presentation. Additionally, some nonspecific cervical artery dissection syndrome, and pulsatile
symptoms, such as headache and neck pain, may lead to misdiagnosis. A tinnitus.
retrospective cohort study of 7090 patients diagnosed with cervical artery ● Ischemic strokes from
dissection found that 1 in 30 patients had a probable emergency department cervical artery dissection
misdiagnosis in the 2 weeks before their eventual cervical artery dissection are usually due to artery-to-
diagnosis.64 Around 6% of cervical artery dissection cases are completely artery embolism of
intraluminal thrombus
asymptomatic and discovered only on routine examination.3
formed at the site of
Local symptoms typically precede the ischemic event; this delay can range intraluminal stenosis. Less
from minutes to weeks. The majority of ischemic events occur within the first commonly, ischemia may
week after local symptom onset.65 A large, retrospective study of nearly 2800 result from hypoperfusion
distal to a high-grade
patients with cervical artery dissection without ischemia found an increased risk
intraluminal stenosis or
of stroke only in the first 2 weeks after diagnosis.66 ICA dissections are less likely occlusion.
to present with ischemia compared to vertebral artery dissections.56 This may be
due to the proximity of cranial nerves and sympathetic fibers to the ICA, causing ● Subarachnoid
carotid artery dissections to manifest with more local signs and symptoms from hemorrhage may result from
intracranial extension of a
compression of these adjacent structures. dissection. Intracranial
arteries lack external elastic
EVALUATION AND DIAGNOSIS lamina and have a thinner
The diagnosis of cervical artery dissection should be suspected in patients with media, making them more
prone to aneurysm
acute onset of local symptoms of headache or neck pain and Horner syndrome, formation and subsequent
particularly if these are associated with an ipsilateral ischemic stroke. A history of rupture.
recent mechanical events, including minor trauma or sports-related injuries, or a
personal or family history of connective tissue or vascular diseases should also ● The majority of ischemic
events from cervical artery
increase suspicion for cervical artery dissection. Cervical artery dissection in
dissection occur within the
older adults (≥60 years) is more likely to be painless with few mechanical first 1 to 2 weeks after
triggers; in such cases, imaging should be carefully reviewed for any signs symptom onset.
of dissection.67
Neuroimaging should be used to confirm a clinical diagnosis of cervical artery ● The diagnosis of cervical
artery dissection should be
dissection. Characteristic neuroimaging findings include the presence of a suspected in patients with
long-tapered arterial stenosis or occlusion, dissecting aneurysm, intimal flap, acute onset of local
double lumen, or intramural hematoma. Tapered stenosis is the most common symptoms of headache,
neuroimaging finding (48%), followed by tapered occlusion (35%) and neck pain, Horner
syndrome, or any
dissecting aneurysm (17%).3 The presence of a long-tapered stenosis is combination of the three,
suggestive of cervical artery dissection when located at common sites of particularly if they are
dissection (more than 2 cm after the carotid bifurcation, and the V2 and V3 associated with an
segments of the vertebral artery), and in the absence of signs of large ipsilateral ischemic stroke.
artery atherosclerosis.

The most commonly used imaging modalities include head CT and CT

angiography (CTA), or MRI of the brain and magnetic resonance angiography
(MRA) of the head and neck. Ultimately, the choice of imaging modality
depends on availability and physician preference.
MRI evaluation includes the standard axial T1-weighted, T2-weighted, and
fluid-attenuated inversion recovery (FLAIR) axial MRI imaging. MRA can be
performed using two-dimensional time of flight, three-dimensional time of
flight, or phase contrast techniques. The use of contrast for MRA can yield
higher-quality images. Characteristic MRI findings supporting cervical artery
dissection include a decrease or absence of signal flow void and a crescent sign
resulting from narrowing of the vessel by an intramural hematoma.68 This
pathognomonic crescent sign is formed by an eccentric rim of hyperintensity,
corresponding to intramural hematoma, surrounding a hypointense arterial
lumen on axial cross-sectional T1-weighted sequences (FIGURE 8-3).68 The age of
the dissection can be determined based on the methemoglobin content and signal
intensity on T1-weighted and T2-weighted MR imaging. The combination of
MRA with T1-weighted axial cervical MRI imaging with fat suppression
(sometimes referred to as T1-weighted fat sat) allows for better visualization of
intramural hematomas, in particular smaller ones.68 Intimal flaps separating the
true lumen from the false lumen may be seen on T2-weighted images. Brain MRI
performed alongside MRA can help diagnose acute ischemic strokes resulting
from a dissection. Typically, the pattern of infarct is embolic, although
borderzone infarcts may also be seen in cases of hypoperfusion.62
CTA evaluation with axial source images and three-dimensional
reconstructions can detect arterial dissections, intimal tears, intramural
hematomas, and dissecting
aneurysms.68 Common CTA findings
include an irregular and asymmetric
vessel, narrowed lumen, and a
crescentic hyperdensity (intramural
hematoma) with thickened vessel
wall.68 The sensitivity (100%),
specificity (98%), positive predictive
value (95%), and negative predictive
value (100%) of CTA for the detection
of vertebral artery dissection compares
favorably with digital subtraction
angiography,69,70 although it may be
lower for ICA dissections.71 CTA is
superior to MRA in identifying
pseudoaneurysms, intimal flaps, and
high-grade stenosis.71 Vertebral artery
dissections may also be better visualized FIGURE 8-3
71 Axial T1-weighted cervical MR
on CTA than MRA. While CTA is a angiography (MRA) with fat suppression
quick and efficient tool to diagnose showing a right vertebral artery
cervical artery dissection, image dissection. MRA demonstrates intrinsic
interpretation may be limited due to T1 hyperintensity involving the right
vertebral artery with some adjacent
inaccurate contrast bolus timing or crescent-shaped T1 hyperintensity
streak artifacts from implants or within the vessel wall caused by an
beam-hardening artifacts. Additionally, intramural hematoma (arrow).
550 APRIL 2023

CTA involves exposure to radiation and iodinated contrast, which may be an issue KEY POINTS
in pregnant patients or those with contrast allergy or renal dysfunction.
● The most commonly used
Carotid ultrasound and transcranial Doppler are inexpensive and readily imaging modalities include
available tests that may be used to diagnose cervical artery dissection. Cervical CT and CT angiography
artery dissection often demonstrates a “double lumen” on B-mode ultrasound (CTA), or MRI and magnetic
imaging, consisting of the true and false lumina; however, ultrasound has several resonance angiography
(MRA) of the head and neck.
limitations, including its highly operator-dependent nature, low diagnostic
utility for detecting dissections near the skull base or within transverse foramina, ● MRI in cervical artery
and poor ability to detect carotid dissections with isolated Horner syndrome.9,72 dissection may show a
Confirmation with MRA or CTA should be done in patients with normal pathognomonic crescent
ultrasound findings but high clinical suspicion for cervical artery dissection. sign. The crescent sign is
formed by an eccentric rim
Occasionally, noninvasive neuroimaging can be negative in suspected cases of of hyperintensity,
cervical artery dissection. When using MRA, dissection involving the horizontal corresponding to intramural
course of the V3 segment of the vertebral artery may be missed due to the hematoma, surrounding a
orientation of the vessel causing difficulty in visualizing the classic crescent sign on hypointense arterial lumen
on axial cross-sectional T1-
axial images.73 Neuroimaging may also be negative if it is performed long after weighted sequences. The
symptom onset, as early recanalization can occur (16% at 1 month and 50% combination of MRA with
at 3 months).74 T1-weighted axial cervical
Digital subtraction angiography continues to be the gold standard for MRI imaging with fat
suppression allows for
identifying cervical artery dissection; however, given the accuracy (high better visualization of
sensitivity and specificity) and ability to detect intramural hematoma on intramural hematomas.
noninvasive neuroimaging, digital subtraction angiography is rarely used in the
diagnosis of cervical artery dissection, unless the clinical suspicion for a ● CTA is an efficient tool
with high sensitivity and
dissection continues to remain high despite negative noninvasive imaging.
specificity for diagnosing
Classic cervical artery dissection findings include the presence of focal stenosis cervical artery dissection.
(“string sign”), flame-shaped tapering with occlusion, pseudolumen and true However, image
lumen, intimal flap, and dissecting aneurysm.68 interpretation may be
limited due to inaccurate
contrast bolus timing or
TREATMENT streak artifacts from
Patients with cervical artery dissection who present with acute ischemic stroke or implants or beam-hardening
transient ischemic attack should be managed with the same guideline-based artifacts.
approach used in all acute stroke patients. All patients with acute ischemic stroke
● Diagnostic cerebral
should be evaluated for eligibility for IV thrombolysis, endovascular therapy, or angiography continues to be
both, as illustrated in CASE 8-2. the gold standard for
identifying cervical artery
Acute Stroke Treatment dissection. However, given
the high sensitivity and
IV thrombolysis, either with alteplase or tenecteplase, is indicated for eligible
specificity of noninvasive
patients with acute ischemic stroke, including those with extracranial cervical imaging methods, digital
artery dissection. The landmark trials of IV thrombolysis did not exclude patients subtraction angiography is
with cervical artery dissection, and subsequent observational studies have shown rarely needed, unless the
clinical suspicion for a
a similar effectiveness and safety profile compared to stroke from other causes75;
dissection continues to
however, data are limited on the safety of IV thrombolysis in patients with remain high despite negative
isolated intracranial dissections and those with intracranial extension of an noninvasive imaging.
extracranial dissection.76 In particular, concern exists for an increased risk of
subarachnoid and intracerebral hemorrhage after thrombolysis in patients with ● All patients with acute
ischemic stroke from
intracranial dissections. Further studies should examine the safety of acute cervical artery dissection
stroke treatments in such cases. Importantly, IV thrombolysis should be avoided should be evaluated to
in patients with aortic dissections. determine eligibility for IV
Endovascular therapy should be considered in select patients with cervical thrombolysis and
endovascular therapy.
artery dissection with acute ischemic stroke from a large vessel occlusion. This

includes cases of tandem occlusions (ie, extracranial carotid dissection with

proximal intracranial artery occlusion), although the optimal treatment method is
still being explored. A prospective, multicenter observational study compared the
safety and efficacy of stenting versus no stenting in 136 patients with tandem
occlusion from carotid dissection. Patients who underwent emergent carotid
artery stenting experienced higher rates of successful reperfusion (89% versus
68%) but similar rates of 90-day favorable outcome (54% versus 61%) as those
who did not undergo stenting.77 No differences in safety outcomes were seen
between the two groups. Therefore, emergent carotid artery stenting can be
considered in cases of persistent, high-grade stenosis from dissection after
intracranial reperfusion is achieved.
Antithrombotic Agents for Stroke Prevention

Strokes from cervical artery dissection are most commonly due to artery-to-
artery embolism from an intraluminal thrombus, as illustrated in CASE 8-3.
CASE 8-2 A 63-year-old man with history of hypertension and tobacco use
presented with left arm weakness that developed 35 minutes prior to
arrival at the emergency department. His examination was notable for
normal speech, left-sided homonymous hemianopia, left-sided visual
and sensory neglect, left face and arm weakness, and left-sided
hemisensory loss (a National Institutes of Health Stroke Scale score of 7).
Head CT was negative for hemorrhage and showed no signs of early
ischemic changes. Head and neck CT angiography showed complete
occlusion of the right internal carotid artery from the level of the
bifurcation to the proximal cavernous carotid with subsequent
reconstitution, and occlusion of the right midinferior M2 branch of the
middle cerebral artery, with decreased collateralization along the sylvian
fissure, right lateral temporal lobe, and right parietal lobe. He had no
known contraindications to IV alteplase and received thrombolysis within
1 hour of symptom onset. Endovascular therapy was pursued for acute
ischemic stroke, and angiography showed tapering of the internal carotid
artery with complete occlusion just distal to a dilated carotid bifurcation,
consistent with a dissection (FIGURE 8-4A). Complete recanalization of the
intracranial middle cerebral artery occlusion was achieved, after which
emergent carotid artery stenting was performed (FIGURES 8-4B and 8-4C).
The patient was started on aspirin and clopidogrel to prevent acute stent
thrombosis and further ischemic events. Subsequent MRI showed
extensive areas of restricted diffusion throughout the right cerebral
hemisphere (FIGURE 8-4D). Despite the significant radiographic stroke
burden, he had minimal remaining neurologic deficits, with only mild left
arm weakness and pronator drift at the time of discharge.
552 APRIL 2023

Antithrombotic therapy, either with anticoagulation or antiplatelet agents, is
often used to minimize the risk of embolism and prevent either a new or
recurrent stroke from cervical artery dissection.
Current data suggest that no significant difference exists between
anticoagulation and antiplatelet therapy for preventing either new or recurrent
ischemic strokes in patients with extracranial cervical artery dissection. Two
large, randomized trials compared anticoagulation to antiplatelets for cervical
artery dissection (TABLE 8-278,79).78,79
CADISS (Cervical Artery Dissection in Stroke Study) was the first randomized
controlled trial of cervical artery dissection treatment. CADISS was an open-
label, assessor-blind study of 250 patients with extracranial cervical artery
dissection between 2006 and 2013 who were randomly assigned to either
antiplatelet or anticoagulant therapy for 3 months.78 Treatment was initiated
within 7 days of symptom onset. Importantly, the specific antiplatelet or
anticoagulant drug used was left at the discretion of the treating physician; in the
FIGURE 8-4
Imaging of the patient in CASE 8-2. Panels A, B, and C are all coronal view cerebral digital
subtraction angiograms showing injection of the carotid artery. Tapering of the internal
carotid artery with complete occlusion just distal to a dilated carotid bifurcation (A, arrow),
consistent with carotid artery dissection. Post-thrombectomy angiogram demonstrating the
recanalization of the dissected internal carotid artery using a stent (B) and recanalization of
the occluded middle cerebral artery (C). Diffusion-weighted axial MRI (D) demonstrating
diffusion restriction in the right middle cerebral artery distribution indicating an acute infarct
from the dissection.
This case illustrates the importance of acute, timely intervention for an COMMENT
ischemic stroke from cervical artery dissection. The patient presented soon
after symptom onset and was able to receive IV thrombolysis within the
golden hour. Given the presence of a tandem occlusion (extracranial carotid
artery disease and intracranial occlusion), the decision was made to proceed
with endovascular therapy with intracranial revascularization followed by
emergent carotid artery stenting.

antiplatelet arm, 22% were on aspirin monotherapy, 33% on clopidogrel

monotherapy, 28% on aspirin and clopidogrel, and 16% on aspirin and
dipyridamole. In the anticoagulant arm, all patients received warfarin. At
3 months, no significant difference was found in ischemic stroke and death
between the two treatment groups. Ischemic stroke occurred in 3 out of 126
patients (2%) in the antiplatelet group and 1 out of 124 patients (1%) in the
anticoagulation group (odds ratio 0.34, 95% confidence interval, 0.01 to 4.23). No
deaths occurred in either group. The risk of recurrent stroke continued to be low
at 12 months follow-up; although twice as many strokes occurred in the
antiplatelet group versus the anticoagulant group (4 versus 2), no statistically
significant difference in outcomes was shown (odds ratio 0.56; 95% confidence
interval, 0.10 to 3.21).78 The majority of strokes occurred within the first
3 months. One major bleeding event occurred in the anticoagulation group,
in a patient who had intracranial extension of a VA dissection. No differences in
the 3-month angiographic recanalization rate were found between the two
CASE 8-3 A 43-year-old woman with no past medical history presented to the
emergency department with 5 days of left-sided neck pain and a
transient 15-minute episode of right face and arm numbness. She denied
any accompanying weakness, slurred or nonsensical speech, or gait
abnormalities. She recently suffered from an upper respiratory viral
illness that was accompanied by a significant cough. Neurologic
examination was notable for a left-sided ptosis and miosis.
Brain MRI showed no signs of acute infarct. Head and neck CT
angiography (CTA) showed 50% stenosis of the left internal carotid artery
at the level of the carotid bulb, thought to be from nonocclusive
thrombus with a possible underlying dissection (FIGURES 8-5A and 8-5B).
Magnetic resonance angiography (MRA) of the neck with and without
contrast, with T1-weighted fat saturation imaging protocol, revealed an
intraluminal clot along the posterior wall of the left proximal internal
carotid artery. The left internal carotid artery was also 50% stenotic and
displayed internal T1 hyperintensity on T1-weighted fat saturation imaging
reflecting intramural hematoma from an underlying dissection.
The presence of an intraluminal thrombus led to the decision to start
the patient on warfarin to prevent a recurrent ischemic event. Repeat
CTA of the neck performed 3 months after initial diagnosis showed near
complete resolution of the intraluminal thrombus, and full resolution of
dissection and stenosis. Given the resolution of the intraluminal
thrombus, she was switched from warfarin to lifelong aspirin for
secondary stroke prevention.
554 APRIL 2023

groups. CADISS was a landmark trial that had several noteworthy limitations.
Because of the low stroke rate and rarity of outcome events, CADISS was unable
to determine which antithrombotic treatment was superior. The results
questioned the feasibility of a randomized controlled trial based only on clinical
endpoints, as a large sample size (>10,000 participants) would have been
required to detect a meaningful result. Additionally, 20% of CADISS participants
did not have a dissection confirmed by central adjudication, either due to an
alternative cause being identified or because of low image quality; however, the
results remained unchanged in a per-protocol analysis that excluded
these participants.78
The TREAT-CAD (Biomarkers and Antithrombotic Treatment in Cervical
Artery Dissection) trial was an open-label, assessor-blind, noninferiority trial
of 194 adult patients with symptomatic cervical artery dissection within
2 weeks of enrollment who were randomly assigned to aspirin monotherapy
(300 mg daily) or anticoagulation (vitamin K antagonist with an international
FIGURE 8-5
Imaging of the patient in CASE 8-3. CT angiography
of the head and neck (A, axial; B, coronal) showing
50% stenosis of the left internal carotid artery at
the level of the carotid bulb, thought to be due to
nonocclusive thrombus from underlying
dissection (arrows). No signs of atherosclerosis
are seen in intracranial or extracranial arteries.
This case illustrates the typical time course from clinical symptom onset to COMMENT
ischemic event (in this case, a transient ischemic attack). The majority of
patients with cervical artery dissection without ischemia have an increased
risk of stroke in the first 2 weeks after symptom onset. In this patient, the
dissection caused carotid artery stenosis with an intraluminal thrombus,
and the transient ischemic attack was most likely a result of artery-to-
artery embolism from the thrombus. While equipoise exists for the best
antithrombotic therapy after cervical artery dissection, the presence of an
intraluminal thrombus put her at high risk for another ischemic event and
led to the preference for anticoagulation over antiplatelet therapy.

TABLE 8-2 Randomized Controlled Trials of Stroke Prevention in Cervical Artery

Dissection
Study design Baseline

Study name Aim and population characteristics
CADISS (Cervical Artery Compare antiplatelet and Multicenter, open-label, N = 250; 118 (47%) carotid, 132
Dissection in Stroke anticoagulant treatment for randomized controlled trial; (53%) vertebral; mean time to
Study)78 stroke prevention in extracranial cervical artery randomization, 3.7 days; 224
cervical artery dissection dissection within the prior (90%) patients presented with
7 days; randomized to stroke or transient ischemic
antiplatelet or anticoagulant, attack and 26 (10%) with only
with specific treatment local symptoms
decided by the local clinician
TREAT-CAD (Biomarkers Test the noninferiority of Multicenter, open-label, N = 194; 130 (67%) carotid, 67
and Antithrombotic aspirin to vitamin K randomized noninferiority trial; (35%) vertebral, 14 (7%)
Treatment in Cervical antagonist treatment in symptomatic, MRI-verified multivessel dissection; mean
Artery Dissection) trial79 patients with cervical artery extracranial cervical artery time to randomization,
dissection dissection within the prior 2.9 days; 138 (71%) presented
14 days, randomized to aspirin with stroke or transient
300 mg daily or vitamin K ischemic attack and 56 (29%)
antagonists; noninferiority with only local symptoms
margin: 12%
556 APRIL 2023

Primary outcome Follow-up Results Limitations
Ipsilateral stroke or death in intention- 3 months; Intention-to-treat analysis: 126 (50.4%) (1) Time to enrollment, may
to-treat population at 90 days 1 year in antiplatelet group and 124 (49.6%) in have missed outcomes early
anticoagulant group in disease course;
Primary outcome at 3 months: 3 (2.4%) (2) central imaging review
in antiplatelet group and 1 (0.8%) in failed to confirm dissection
anticoagulant group (odds ratio, in 20% of patients;
0.335; 95% confidence interval, 0.006
(3) heterogeneity of
to 4.233). All events were strokes, no
antiplatelet treatment;
deaths. No significant differences in
treatment groups (4) use of clinical endpoints
resulted in few recurrences;
Primary outcome at 1 year in intention-
study underpowered
to-treat analysis: 4 (3.2%) in
antiplatelet group and 2 (1.6%) in
anticoagulant group (odds ratio, 0.56;
95% confidence interval, 0.10-3.21)
Primary outcome at 1 year in per-
protocol analysisa: 4 (4.0%) in
antiplatelet group and 1 (1.0%) in
anticoagulant group (odds ratio, 0.32;
95% confidence interval, 0.03-3.04)
Composite of clinical (stroke, major 3 months Per-protocol analysis: 173 patients, 91 (1) Time to enrollment, may
hemorrhage, or death) or MRI outcomes (53%) in aspirin group and 82 (47%) in have missed outcomes early
(new ischemic or hemorrhagic brain vitamin K antagonist group in disease course;
lesions) in per protocol population at
Primary outcome: 21 (23%) in aspirin (2) not powered to establish
14 days (clinical and MRI outcomes) and
group and 12 (15%) in vitamin K superiority of either
90 days (clinical outcomes only) after
antagonists group (absolute treatment
treatment
difference 8% [95% confidence
interval, -4 to 21]). Noninferiority of
aspirin was not shown
Ischemic stroke: 7 (8%) in aspirin group
and 0 (0%) in vitamin K antagonists
group
Major extracranial hemorrhage: 0 (0%)
in aspirin group and 1 (1%) in vitamin K
antagonists group
No intracranial hemorrhage or deaths
in either group
MRI = magnetic resonance imaging

a
Per-protocol analysis was performed in patients meeting the inclusion criteria following central review of imaging to confirm the diagnosis of
dissection (n = 197).

normalized ratio [INR] goal of 2.0 to 3.0) for 90 days.79 Based on the low rate
of clinical events limiting the findings of the CADISS trial, the investigators
aimed to improve the feasibility of TREAT-CAD by including both clinical and
MRI outcomes, thereby reducing their sample size. The primary outcome
was a composite of clinical (ie, stroke, major hemorrhage, or death) and
MRI (ie, new ischemic or hemorrhagic brain lesions) outcomes in the per-
protocol analysis of 173 patients who completed the assessment period, with a
noninferiority margin of 12%. The composite endpoint occurred more often in the
aspirin group compared with the vitamin K antagonist group (23% versus 15%,
absolute difference 8%; 95% confidence interval, -4% to 21%). No symptomatic
intracranial hemorrhages occurred in either group, and one major extracranial
hemorrhage (a gastrointestinal bleed) occurred in a patient in the vitamin K
antagonist group. Based on the findings, aspirin failed to meet noninferiority
criteria. These findings do not indicate that aspirin is worse than vitamin K
antagonists, or that vitamin K antagonists are superior to aspirin, either; however,
all the ischemic strokes occurred in the aspirin group (n = 7), and five of the
seven strokes occurred on day 1 after treatment onset (the remaining two occurred
on day 7). The early recurrence rate further suggests that the heightened risk of
stroke is within the immediate period and supports the early initiation of
antithrombotic treatment.
Given the inconclusive evidence, the most recent 2021 AHA/ASA
guidelines on secondary stroke prevention recommend either warfarin or
aspirin in patients with recent ischemic stroke or transient ischemic attack
(TIA) from extracranial cervical artery dissection.80 Factors such as severe
stenosis, occlusion, accompanying aneurysm, the presence of intraluminal
thrombus, and infarct size may all impact a clinician’s decision on whether to
use an antiplatelet or anticoagulant agent. Antithrombotic agents should be
delayed for 24 hours after IV thrombolytic therapy. In patients considered for
antiplatelet therapy (rather than anticoagulation), aspirin monotherapy can
be considered in those with low-risk TIA or moderate to large ischemic
strokes. No consensus exists on the best dose of aspirin (TREAT-CAD used
aspirin 300 mg daily, while local physicians decided the type and dose of
antiplatelet in CADISS); treatment with aspirin 81 mg to 325 mg daily is
reasonable. A 21-day course of dual antiplatelet therapy with aspirin and
clopidogrel can be considered in patients meeting CHANCE (Clopidogrel in
High-risk Patients With Acute Non-disabling Cerebrovascular Events) or
POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke)
trial criteria (either high-risk TIA with ABCD2 [age, blood pressure, clinical
features, duration of TIA, presence of diabetes] score ≥4 or minor ischemic
stroke with a National Institutes of Health Stroke Scale [NIHSS] score ≤5, and
within 12 [POINT] or 24 hours [CHANCE] of symptom onset) before
switching to aspirin monotherapy.81 In patients considered for anticoagulant
therapy, the size of the infarct may play a role in determining the optimal time
for anticoagulation initiation. While direct oral anticoagulants were not used
in CADISS or TREAT-CAD, observational data suggests that they are safe and
effective, and experts believe direct oral anticoagulants can be used in place
of warfarin.82
No randomized controlled trials have addressed the management of
intracranial artery dissections. Antiplatelet therapy may be preferred over
anticoagulation given the increased risk of subarachnoid hemorrhage with
558 APRIL 2023

intracranial dissections; however, a single-center study of 81 patients suggested KEY POINTS
the safety and efficacy of oral anticoagulants in patients with nonaneurysmal
● Endovascular therapy
intracranial artery dissections who presented without subarachnoid should be considered in
hemorrhage.83 Further studies are needed to determine the best antithrombotic select patients with cervical
agent for such cases. artery dissection with acute
Endovascular intervention is occasionally considered in cases of extracranial ischemic stroke from a large
vessel occlusion. This
cervical artery dissection that result in recurrent thromboembolism, enlarging
includes patients with
pseudoaneurysm, and flow-limiting dissections; however, the safety and efficacy tandem occlusions,
data are mostly from small studies, and randomized trials to support the benefit although the optimal
of endovascular interventions are lacking.84 Current AHA/ASA guidelines treatment method is still
being explored.
suggest consideration of endovascular procedures in patients with extracranial
cervical artery dissection who have recurrent ischemic events despite ● The most recent
antithrombotic therapy.80 American Heart Association
The optimal duration of antithrombotic therapy is unclear. AHA recommends (AHA) guidelines
at least 3 months of antithrombotic therapy in patients with recent ischemic stroke recommend either warfarin
or aspirin in patients with
or transient ischemic attack from cervical artery dissection.80 Anticoagulants are recent ischemic stroke or
typically discontinued after the first 6 months of treatment, and patients are transient ischemic attack
usually switched to antiplatelet therapy; only 38% of patients in the anticoagulant from extracranial cervical
arm of CADISS were still on warfarin at 6 months, and the number dropped to 13% artery dissection.
at 12 months.78 Patients on antiplatelet therapy in the acute phase are generally
● The AHA recommends at
continued on long-term antiplatelet therapy, although discontinuation can be least 3 months of
considered in patients with full recanalization of the dissected vessel81; however, antithrombotic therapy in
further studies are needed to determine optimal duration of antithrombotic patients with recent stroke
or transient ischemic attack
therapy and whether follow-up imaging may be helpful to guide treatment
from cervical artery
duration. Improving the understanding of the pathophysiology of cervical artery dissection, but the optimal
dissection may help better tailor long-term secondary stroke prevention duration of treatment is
recommendations, such as the need for long-term antithrombotic agents. unclear.
● Most cases of vessel

OUTCOME recanalization after cervical
Most cases of vessel recanalization occur within the first few months after artery dissection occur
the initial event. The rate of recurrent stroke is highest within the acute period. within the first few months
This section covers the time to vessel recanalization, risk of recurrent stroke and after the initial event (16% at
1 month, 50% at 3 months,
dissection, and overall prognosis after cervical artery dissection. and 60% at 6 and 12 months).
Initial occlusion reduces the
Resolution of Arterial Abnormalities likelihood of complete
Vessel healing can result in complete recanalization or stable residual luminal recanalization, whereas the
presence of only local signs
irregularity. Occlusions may lead to residual stenosis over time, while stenotic and
and symptoms increases the
irregular arteries can undergo more thorough recanalization and healing.85 A odds of complete
prospective study of nearly 250 patients with spontaneous carotid artery dissection recanalization.
showed a rate of complete recanalization of 16% at 1 month, 50% at 3 months, and
60% at 6 and 12 months.74 Initial occlusion reduces the likelihood of complete ● Repeat neurovascular
imaging is typically done 3 to
recanalization, whereas the presence of only local signs and symptoms increases 6 months after symptom
the odds of complete recanalization.74 Vertebral artery dissections have similar onset or diagnosis with the
rates of early recanalization.86 Another population-based study showed that goal of assessing
82% of instances of vessel healing occurred within the first year.3 Dissecting recanalization status of
affected arteries and
aneurysms can develop at various time points; some aneurysms resolve within guiding ongoing
3 months of the initial event, while others are noted for the first time on follow- antithrombotic treatment in
up imaging.87 cervical artery dissection.
Repeat neurovascular imaging is typically done 3 to 6 months after symptom
onset or diagnosis with the goal of assessing the recanalization status of affected

arteries and guiding ongoing antithrombotic treatment. This is typically done

with noninvasive imaging modalities such as MRA and CTA.
Recurrent Stroke and Dissection

The rate of recurrent ischemic events after cervical artery dissection ranges from
0% to 13% at 1 year in published studies.9 The recurrence rate is probably on the
lower end of this spectrum when accounting for events that occurred only after
cervical artery dissection diagnosis was confirmed and appropriate treatment
was started. The rate of recurrent ischemic stroke after cervical artery dissection
is low at around 2% to 4% at 3 months and 2.5% at 12 months in the two large,
randomized trials (CADISS and TREAT-CAD).78,79 The greatest risk of recurrent
ischemic stroke was within the first 2 weeks of randomization, suggesting that
the risk of recurrent events beyond the acute period is low. Dissecting aneurysms
do not appear to be associated with an increased risk of recurrent stroke.87
The rate of cervical artery dissection recurrence is inconsistent among studies.
The CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) registry
showed a recurrence rate of 2% at 3 months.56 Another single-center study found
a 16% rate of recurrence at 1 year, with the majority of events (22 out of 39)
occurring within a month of the initial dissection.88 Risk factors that may be
associated with recurrent cervical artery dissection include younger age at initial
diagnosis, family history of cervical artery dissection, vascular Ehlers-Danlos
syndrome, and fibromuscular dysplasia.9 Limited data exist regarding methods
that may prevent cervical artery dissection recurrence; however, most clinicians
discuss avoiding contact sports, cervical manipulative therapy, and mechanical
events that may lead to minor trauma. Continued surveillance for recurrent
dissections may be reasonable in patients with an underlying connective tissue
disorder or fibromuscular dysplasia, as these patients may be at an increased risk
of recurrent arteriopathies.
Long-term Functional Outcome

Functional outcome and mortality after cervical artery dissection are largely
dependent on the severity of the associated ischemic stroke or subarachnoid
hemorrhage. Overall, outcome appears to be favorable (modified Rankin Scale
score of 0 or 1) in 75% to 82% of patients with cervical artery dissection, with
mortality rates of less than 5%9,13; however, nearly two out of five patients with
cervical artery dissection report impaired quality of life at 6 months despite good
functional outcome, with posttraumatic stress syndrome playing a large role in
their quality of life.89-91 A low NIHSS score at onset of symptoms and younger age
are predictors of favorable outcome,13 whereas ICA dissection and artery
occlusion predict less favorable outcome.56,91 The vast majority of patients
experience resolution of headache and pain within the first few days, although a
small subset of patients may develop prolonged residual headaches.57
CONCLUSION
Cervical artery dissection is an important cause of ischemic stroke, particularly in
young adults. Early recognition and management of cervical artery dissection
may lead to earlier initiation of antithrombotic agents, thereby reducing the risk
of ischemic events. Although the pathophysiology is incompletely understood,
cervical artery dissection is thought to be a multifactorial disease, with
560 APRIL 2023

environmental factors serving as potential triggers in patients who have genetic KEY POINTS
predispositions to dissections. Patients can develop local symptoms and signs
● The rate of recurrent
prior to or accompanying an ischemic event; sudden-onset Horner syndrome ischemic stroke after
with headache or neck pain or with an ipsilateral ischemic stroke is highly cervical artery dissection is
suggestive of cervical artery dissection and warrants further vessel imaging. low at around 2% to 4% at
Neuroimaging studies are necessary to confirm a clinical suspicion of cervical 3 months and 2.5% at
12 months. The greatest risk
artery dissection, with MRA or CTA being the most commonly performed
of recurrent ischemic stroke
noninvasive imaging modalities. Typical imaging findings include a long-tapered is within the first 2 weeks of
arterial stenosis, a tapered occlusion (“flame-shaped” occlusion), dissecting diagnosis. Dissecting
aneurysm, intimal flap, double lumen, or intramural hematoma. Equipoise exists aneurysms do not appear to
be associated with an
for the best antithrombotic agent for primary or secondary stroke prevention
increased risk of recurrent
from cervical artery dissection, with AHA/ASA guidelines recommending either stroke.
aspirin or warfarin for secondary stroke prevention. The highest risk of recurrent
ischemic events appears to be within the first 2 weeks after diagnosis, further ● The rate of cervical artery
supporting the importance of early recognition and treatment. The risk of dissection recurrence is
uncertain, ranging from 2%
recurrent dissections is low. Future studies should aim to improve our to 9.2% within the first 1 to
understanding of the influence of environmental and genetic factors on 3 months. The highest risk of
predisposing patients to cervical artery dissection and the long-term outcomes of cervical artery dissection
this disease. Ultimately, improving the understanding of the pathophysiology of recurrence is within the first
month of the initial
cervical artery dissection would help better tailor long-term secondary stroke dissection.
prevention recommendations (eg, the need for long-term antithrombotic
therapy) for patients with cervical artery dissection.
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REVIEW ARTICLE

Pediatric Ischemic Stroke
C O N T I N UU M A UD I O By Christine Fox, MD, MAS
ONLINE
ABSTRACT
OBJECTIVE: Pediatric cerebrovascular disease is one of the leading causes of
death and disability in children. Survivors of childhood stroke and their
families are often left to cope with long-lasting sequelae, such as barriers
to school reentry and long-term challenges in attaining independence as
adults. Because childhood stroke is rare and providers may not be familiar
with the disorder, this article reviews the risk factors, acute management,
and sequelae of ischemic stroke in children.
LATEST DEVELOPMENTS: High-quality evidence has resulted in an organized

approach to emergent treatment of ischemic stroke in adults, but most
front-line providers are less prepared for emergent stroke management in
CITE AS:
children. The level of evidence for reperfusion therapies in children remains
2023;29(2, CEREBROVASCULAR low but is growing. Thrombolysis and thrombectomy are sometimes
DISEASE):566–583. considered for hyperacute treatment of stroke in children. Readiness for
pediatric stroke at regional centers should include an organized approach to
Dr Christine Fox, Sandler pediatric stroke triage and management based on extrapolation from adult
Neurosciences Center, stroke trials, expert consensus, and emerging pediatric studies.
University of California San
Francisco, 675 Nelson Rising Ln,
3rd Floor, San Francisco, CA ESSENTIAL POINTS: This review provides up-to-date information about ischemic
94143, christine.fox@ucsf.edu. stroke risk factors and management in children. Preparation for rapid stroke
diagnosis and management in children may improve outcomes.
The institution of Dr Fox
has received personal
compensation in the range of
$500 to $4999 for serving as a
consultant for Competitive Drug INTRODUCTION
S
Development International Ltd, troke is uncommon in children but can be a major cause of childhood
research support from the
American Heart Association/
mortality and morbidity when it occurs. When occurring at a young
Bugher Foundation, and the age, stroke can result in long-term neurologic sequelae and disabilities
National Institutes of Health/ over many years. Both acute and chronic care for a child with stroke
National Institute of
Neurological Disorders and
are costly. The lifetime costs for care of a child who had a stroke are
Stroke, and has received generally higher than the costs of similar types of strokes in adults, and the
publishing royalties from a economic burden for society is sustained over a longer period of time.1 Adjusting
publication relating to
health care. to new disabilities from a stroke can be difficult for children and their families.
Beyond physical health, the toll on mental and emotional health is often high for
UNLABELED USE OF
children and caregivers. For these reasons, effective stroke treatments to
USE DISCLOSURE: improve neurologic outcomes for children are essential.
Dr Fox discusses the use of By convention, a stroke that occurs in children after the first 28 days of life is
thrombolysis and
thrombectomy for the
considered a childhood stroke. A stroke that occurs during the first 28 days of life
treatment of stroke in children. is considered a perinatal stroke. Perinatal arterial ischemic stroke occurs in
approximately one in 3000 live full-term births,2 which makes the weeks around
© 2023 American Academy birth one of the highest-risk time periods for stroke to occur. The term presumed
of Neurology. perinatal stroke is used when imaging demonstrates a chronic infarct in an older
566 APRIL 2023

child who begins to show focal deficits during development. Childhood and KEY POINTS
perinatal strokes are categorized as distinct entities because management,
● Perinatal arterial ischemic
workup, risk factors, and secondary stroke prevention for perinatal and stroke occurs in
childhood arterial ischemic strokes differ. This article focuses on childhood approximately 1 in 3000 live
stroke except where perinatal stroke is specifically addressed. full-term births, which
Most children with acute ischemic stroke present with focal neurologic makes the weeks around
birth one of the highest-risk
deficits, similar to adults with stroke.3 In contrast to adults, children may have a
time periods for stroke to
stuttering rather than an abrupt symptom onset and also commonly report occur.
headache or present with an acute symptomatic seizure. About one-third of
children with stroke have acute symptomatic seizures, more commonly at ● Most children with acute
younger ages. In part because of these differences, stroke signs and symptoms in ischemic stroke present
with focal neurologic
children are often initially attributed to a stroke mimic during the crucial first deficits similar to adults with
hours. Early symptoms are often mistaken for seizure, migraine, functional stroke. Unlike adults,
neurologic deficit, infection, demyelinating disease, methotrexate toxicity, or children may have a
posterior reversible encephalopathy syndrome (PRES).4,5 Accurately stuttering rather than an
abrupt symptom onset and
determining time of stroke onset and assessing neurologic deficit may be also commonly present with
particularly challenging with young, uncooperative, or frightened children. headache or seizure.
Posterior circulation strokes are particularly challenging because presenting
features such as unsteady gait and emesis are common symptoms of other health ● Although a myriad of
chronic and acute
problems in childhood, and children may have a difficult time describing vertigo
conditions can predispose a
or dizziness. Although a myriad of chronic and acute conditions can predispose a child to have a stroke, many
child to stroke, many children who present with an initial stroke have no children who present with
significant medical history and were previously considered to be healthy. When a an initial stroke have no
significant medical history
previously healthy child presents with a stroke, initial disbelief that stroke can
and were previously
occur in children may delay diagnosis. considered to be healthy.
HYPERACUTE TREATMENT FOR PEDIATRIC STROKE ● As evidence grows,

Thrombolysis and mechanical thrombectomy are generally accepted guidelines have cautiously
moved from recommending
treatments for hyperacute reperfusion after stroke in appropriately selected against IV thrombolysis or
adults.6,7 The risk-to-benefit ratio of thrombolysis and thrombectomy in children thrombectomy outside of a
may differ from adults, and evidence in children remains at the level of case research study toward a
series and meta-analyses of individual patient data.8-12 As evidence grows, discussion of selecting
children who may benefit
guidelines have cautiously moved from recommending against thrombolysis from IV thrombolysis
or thrombectomy outside of a research study toward a discussion of and endovascular
selecting children who may benefit from IV thrombolysis and endovascular thrombectomy in certain
thrombectomy in certain circumstances.13 In 2015, American Heart Association/ circumstances.
American Stroke Association (AHA/ASA) guidelines acknowledged that benefits
of endovascular therapy were not established for children aged younger than
18 years, but may be reasonable within 6 hours of symptom onset of a large vessel
occlusion.14 A 2019 pediatric-specific stroke scientific statement from the AHA/
ASA and an Australian clinical consensus practice guideline both provide
considerations in which it may be reasonable or appropriate to consider
hyperacute reperfusion treatment in children based on evidence extrapolated
from adults.13,15 FIGURE 9-115 shows the Australian clinical consensus guideline’s
quick reference pathway for diagnosis and acute management of childhood
stroke, including an assessment for eligibility for IV thrombolysis
and thrombectomy.
According to guidelines, it may be reasonable in older children to consider IV
thrombolysis within the first 4.5 hours and mechanical thrombectomy within
6 hours of when the patient was last known well, with imaging confirmation of

PEDIATRIC ISCHEMIC STROKE
FIGURE 9-1
Australian Clinical Consensus guidelines for the diagnosis and acute management of
childhood stroke.
CT = computed tomography; CTA = computed tomography angiography; ICH = intracranial hemorrhage;
ICP = intracranial pressure; IV = intravenous; MMCAI = malignant middle cerebral artery infarction;
MRI = magnetic resonance imaging; PPSC = primary pediatric stroke center; tPA = tissue plasminogen activator.
Reprinted from Medley TL, et al, Int J Stroke.15 © 2019 World Stroke Organization.
568 APRIL 2023

vessel occlusion and stroke. Although guidelines support consideration of IV KEY POINTS
thrombolysis or thrombectomy in children in specific circumstances on a case-
● Although guidelines
by-case basis, these treatments are not considered a requirement. Hyperacute support consideration of
treatment decisions should be made in conjunction with neurologists with IV thrombolysis or
expertise in the treatment of children with stroke.13 When IV thrombolysis is thrombectomy in children in
considered in children, it should be done in a system with established guidelines specific circumstances on a
case-by-case basis, these
for stroke thrombolysis, using weight-based dosing similar to that in adults.13
treatments are not
Using statistical modeling in a small series of children treated with appropriate considered a requirement.
weight-based recombinant tissue plasminogen activator (rtPA), the estimated Hyperacute treatment
risk of symptomatic intracranial hemorrhage after thrombolysis is low.16 When decisions should be made
in conjunction with
mechanical thrombectomy is considered in children, it should be performed by
neurologists with expertise
providers with expertise in stroke thrombectomy in adults and pediatric in the treatment of children
neurointerventional treatment. Cerebral arteries do not approximate adult size with stroke.
until around the age of 5 years, so the size and age of a child should be considered
for device selection.17 In systems of care without availability of providers ● MRI and MR angiography
or CT and CT angiography
experienced in pediatric stroke treatment, the priority should instead be are both reasonable options
stabilization and transfer to the appropriate centers. as initial imaging modalities
In the 6- to 24-hour window after stroke onset, adults with anterior circulation to evaluate for a suspected
large vessel occlusion are selected by a clinical-imaging mismatch to identify childhood stroke, taking
timing, circumstances, and
those most likely to benefit from mechanical thrombectomy.6 Children have an available resources into
increased tendency to form early collaterals, so the selection criteria for children account. In either case,
likely to benefit from mechanical thrombectomy during this extended time obtaining vascular imaging
window are especially uncertain.18 If durable collateral circulation is already well in addition to brain tissue
imaging is crucial to identify
established, recanalization may not improve outcomes.
a large vessel occlusion or
The National Institutes of Health Stroke Scale is a standardized neurologic an arteriopathy that
examination that is used in adults to quantify neurologic deficits from stroke and influences management.
determine eligibility for hyperacute treatment. The Pediatric National Institutes
of Health Stroke Scale (PedNIHSS) is a modification of the adult scale with
age-appropriate adaptations for performance and scoring of each item
(see Useful Websites section). The PedNIHSS has been validated for use in
children aged 2 years and older as a quantitative assessment of the severity of
neurologic deficits that can be trended over time when considering hyperacute
treatments.19,20 CASE 9-1 illustrates a child who was treated with mechanical
thrombectomy in the extended time window, but whether the perfusion imaging
techniques used in adults similarly identify core infarct and ischemic penumbra
in children remains a point of controversy. As illustrated in both CASE 9-1 and
CASE 9-2, guidelines recommend that a stroke team including a neurologist and
neurointerventional radiologist with experience in treating children and patients
with stroke make hyperacute stroke treatment decisions.
Brain MRI with magnetic resonance angiography (MRA) is the optimal study
for diagnosis of acute childhood arterial ischemic stroke because it readily
differentiates an ischemic infarct from more common childhood stroke mimics.
Head CT with CT angiography is a reasonable alternative because it is more
readily available and may be easier to obtain quickly. Head CT and CT
angiography may also be the preferred initial study in children with known heart
disease to avoid imaging delays while assessing whether cardiac hardware is
present and magnetic resonance–conditional. Whether MRI and MRA or CT and
CT angiography is the initial imaging modality for a suspected childhood stroke,
including vascular imaging is crucial to identify a large vessel occlusion or an
arteriopathy that influences management. Consensus-based guidelines for

neuroimaging of acute childhood arterial ischemic strokes are available,

including suggested rapid stroke MRI protocol with angiography that can usually
be completed in 10 to 15 minutes to avoid sedation.21,22 When sedation is required
for neuroimaging, blood pressure should be maintained to optimize brain
perfusion, particularly in the setting of arteriopathy or dependency on
collateral circulation.
EARLY MANAGEMENT
The goals of acute care following childhood arterial ischemic stroke focus on
limiting injury by rescuing penumbra, preventing stroke extension or early
recurrence, and treating complications. Type and cross for emergent blood
transfusion should be sent for children with sickle cell disease or other forms of
severe anemia. Early after stroke, transiently elevated blood pressure may be a
compensatory mechanism to maintain cerebral perfusion. Because of the
prevalence of arteriopathies in childhood stroke with subsequent cerebrovascular
narrowing or loss of normal hemodynamic compensatory mechanisms, collateral
cerebral flow should be supported by initial fluid resuscitation if needed, keeping
the head of bed flat, instituting bedrest, and avoiding hypotension. When
treatment is needed to prevent hypertensive crisis, blood pressure should be
lowered cautiously to prevent stroke extension. If vomiting is present or elevated
CASE 9-1 A right-handed 12-year-old girl was admitted for a cardiac catheterization
to evaluate worsening exercise tolerance. Her history included normal
development, but she had a history of complex congenital heart disease
treated with several prior cardiac surgeries. The catheterization was
performed in the afternoon, and she remained on a rebreather mask with
some sedation overnight. The next morning her team and family were
concerned that she appeared confused and had not recovered from the
procedure and anesthesia as expected. A code stroke was called 12 hours
after she was last known well. The intensive care unit team and
neurologist found that she was aphasic with a right hemiparesis. She was
rapidly taken to radiology for head CT, CT angiography, and CT perfusion
study. After reviewing her imaging, which suggested that she had a large
penumbra according to adult selection criteria, the neurointerventional
radiologist and neurologist agreed to proceed with thrombectomy. The
procedure was successful, with recanalization and complete reperfusion
of all distal branches. She recovered slowly during several months of
inpatient pediatric rehabilitation. One year after experiencing the stroke,
her exercise was still limited by her heart disease, but she was
participating in school and on her dance team.
COMMENT This case exemplifies the challenges of postprocedural diagnosis of a

cardioembolic stroke in children with congenital heart disease. Provider
education about childhood stroke and a code stroke plan are critical to
institutional readiness for childhood stroke thrombectomy.
570 APRIL 2023

intracranial pressure is a concern, the head of bed can be raised to 30 degrees. Early
assessment of progressive intracranial hypertension and need for urgent
decompressive hemicraniectomy may be lifesaving in children with malignant
middle cerebral artery infarction or large cerebellar infarcts.23,24 Acute
symptomatic seizures and fever should be prevented or treated to minimize
metabolic demands on the injured brain.25 Electroencephalography monitoring
may be needed to detect subclinical seizures.
Similar to acute stroke care in adults, a swallowing evaluation may be needed
to ensure safe swallowing before advancing diet. Early assessment by physical
and occupational therapists can minimize fall risks. Children with arteriopathies
should advance activity cautiously and under supervision. Deep vein
thromboprophylaxis (mechanical deep vein thrombosis prevention or
anticoagulation) may be indicated in older children, especially in those who are
obese, postpubertal, on exogenous estrogen, or who have underlying
inflammatory disease. Medications that increase clotting, such as exogenous
estrogens, should be discontinued if possible.
A 13-year-old girl presented after experiencing a brief episode of CASE 9-2

weakness and difficulty speaking after playing lacrosse. No contact with
other players or head or neck trauma occurred during the game. She
recently had a mild respiratory illness. Her weakness improved after a
few minutes, but the coach was worried and had her taken to the
emergency department from the field. In the ambulance, she suddenly
stopped speaking and became hemiparetic, with weakness affecting her
right face, arm, and leg. On arrival to the emergency department,
emergent imaging showed a patchy basal ganglia infarct, an irregular left
middle cerebral artery without dissection, and occlusion of an M2
branch. She was rapidly transferred to a nearby children’s hospital with a
pediatric stroke team and was treated with IV thrombolysis at just under
4 hours after stroke onset. She was evaluated for thrombectomy, but she
did not have a large vessel occlusion (the M2 branch was occluded
distally). She had no complications from thrombolysis, and the next day
she began to speak with some paraphasic errors. Based on typical
imaging characteristics, she was diagnosed with an inflammatory focal
cerebral arteriopathy. She was treated with a course of corticosteroids
and a daily aspirin. After her acute stay, she completed 2 months of
inpatient rehabilitation. During that time, her speech recovered, and she
regained power in her right arm and leg. Two years following the stroke,
she was able to run and was back to playing sports despite mild residual
weakness of her right arm.
This case exemplifies a stuttering stroke onset common in children and a COMMENT
basal ganglia infarct typical of that seen in focal cerebral arteriopathy. A
practiced pediatric stroke team is key to rapid childhood stroke diagnosis
and thrombolysis.

Workup for Acute Childhood Stroke

Urgent laboratory testing in patients with childhood stroke includes complete
blood count with differential, screening coagulation laboratory tests, and a
metabolic panel with renal function. Blood draws should be minimized in small
children and those with anemia. Thrombophilia screening is not urgent but may
influence choice or duration of antithrombotic treatment outside of the acute
period, as well as long-term counseling regarding recurrent stroke or thrombosis
risk. Although elevated lipoprotein(a) is associated with childhood stroke, it is
not clear that lowering lipoprotein(a) to normal levels decreases the risk of
recurrence. The traditional cardiovascular risk factors of diabetes, hypertension,
and hyperlipidemia are less frequently a concern in children than in adults, but
screening laboratory tests could be considered in older teens or when strongly
suggested by family history.
An echocardiogram should be obtained urgently to evaluate for possible cardiac
thrombus or vegetation and should include a bubble study or color flow Doppler
study to evaluate for a right-to-left shunt. When a right-to-left shunt is identified,
venous Doppler of the extremities should then be performed to evaluate for
venous thrombosis. Although arrhythmias are less common in children than in
adults, a screening electrocardiogram is recommended, and more extensive
cardiac monitoring may be indicated in children with known cardiac disease.13
PEDIATRIC STROKE RISK FACTORS

Assessment of childhood ischemic stroke risk factors can identify children at
higher risk of stroke who may benefit from primary or secondary stroke
prevention strategies. Many childhood arterial ischemic strokes are multifactorial
rather than related to a single etiology, with overlapping genetic predisposition
and acquired risk factors (FIGURE 9-2).26 For example, a child with congenital
heart disease, genetic arteriopathy, or other persistent risk may also have a
prothrombotic predisposition. Acute infections such as the common cold or
herpes viruses and associated inflammation can act as a stroke “trigger” in
children who have other persistent underlying risk factors. Approximately 20%
of children with a stroke will have a stroke recurrence, with the highest risk
during the first year after the initial stroke. Previously healthy children with no
stroke risk factors identified after an appropriate stroke assessment have a lower
risk of recurrent stroke.27 In contrast, stroke recurrence is common in children
with complex cardiac disease,28 persistent arteriopathy,29 sickle cell disease,30 or
a significant thrombophilia.31 The most prevalent childhood stroke risk factors
are reviewed in the following sections.
Complex Cardiac Disease

Congenital heart disease is the most common major congenital malformation,
affecting approximately 1% of live births worldwide. Children with cardiac
disease often have atrial or ventricular dilation and dysfunction, right to left
shunting, or alteration in blood flow patterns that increase risk for embolic
disease. Disruptions in the balance of hemostasis, alteration in blood
composition, or loss of endothelial integrity may result in thrombosis, bleeding,
or both. About one-fourth of children with congenital heart disease have a
complex form that requires surgical intervention during the first year of life to
survive.32 Many cardioembolic strokes in children are periprocedural and occur
in the setting of cardiac surgery or catheterization to manage complex congenital
572 APRIL 2023

KEY POINTS
● Because of the
prevalence of arteriopathies
in childhood stroke with
subsequent cerebrovascular
narrowing or loss of
normal hemodynamic
compensatory mechanisms,
in the setting of acute stroke
collateral cerebral flow
should be supported by
initial fluid resuscitation if
needed, keeping the head of
bed flat, instituting bedrest,
and avoiding hypotension.
● Congenital heart disease

or acquired heart disease
are major risk factors for
perinatal or childhood
stroke, together accounting
FIGURE 9-2 for almost one-third of
Children often have multifactorial risk factors for stroke with underlying predisposition and arterial ischemic strokes in
acquired exposures. children.
Reprinted with permission from Sporns PB, et al, Lancet Child Adolesc Health.26 © 2021 Elsevier Ltd.
heart disease.33,34 As surgical management has improved over decades, a larger

group of children and young adults with complex congenital heart disease
survive early childhood but remain at risk for stroke related to their underlying
cardiac dysfunction. For all these reasons, congenital heart disease or acquired
heart disease are major risk factors for perinatal or childhood stroke, together
accounting for almost one-third of arterial ischemic strokes in children.35 In the
International Pediatric Stroke Study, which enrolled more than 3000 children
with arterial ischemic stroke between 2003 and 2014, the primary etiology for
stroke in 21% of participants was cardiac disease (excluding children who only
had isolated patent foramen ovale [PFO]).36 The risk of recurrent stroke in
children with congenital heart disease is 27% by 10 years poststroke, with the
highest risk period immediately following the initial stroke.28 However, in part
because of the large number of anatomic variations in children with congenital
heart disease, no consensus exists on the optimal approach to secondary stroke
prevention. Antiplatelet therapy or anticoagulation may be recommended
depending on the specific cardiac anatomy and surgical cardiac repair.37 The
AHA/ASA suggests systemic anticoagulation for secondary stroke prevention in
patients with congenital heart disease, with the stipulation that the nature of the
specific cardiac defect, its expected management, and other factors such as the
presence of thrombophilia should be considered.13
Stroke can occur in children without complex congenital heart disease because
of paradoxical embolization across a PFO. Based on evidence extrapolated from
adult patients, some children with otherwise cryptogenic stroke may benefit
from PFO closure for secondary stroke prevention.38-40 Clinical practice
guidelines for PFO closure in adults41 are a useful starting point when
considering PFO closure in children, but are not directly applicable to children.
The Risk of Paradoxical Embolism (RoPE) score is used to select adult patients

for PFO closure after an otherwise cryptogenic stroke42 and calculates the score
using age categories starting at 18 years or older. PFO is found in approximately
one-third of the overall pediatric population and is inversely related to age, with
increasingly higher prevalence in younger children.43 In children with
cryptogenic stroke, PFO prevalence is higher than in children with a known
stroke etiology and higher than in healthy controls.44 In the presence of other
pediatric stroke risk factors, a paradoxical embolism through a PFO is less likely
to be the causative etiology. Therefore, a thorough investigation of other risk
factors has to be completed before concluding that PFO closure might be
beneficial. If an alternative stroke mechanism is identified, PFO closure should
not be routinely recommended. When a PFO is identified during a childhood
stroke assessment, venous ultrasound of the extremities and laboratory testing
for thrombophilia risk factors should be performed. Clinical features that suggest
stroke is due to a paradoxical embolus include an echocardiogram demonstrating
a large PFO, a PFO with aneurysm, significant right-to-left shunting, stroke
onset after a Valsalva maneuver, or an identified deep venous thrombosis.
Children with underlying heart conditions are vulnerable to cardioembolic
stroke resulting in a large vessel occlusion and may be candidates for mechanical
thrombectomy, as illustrated by the child with an in-hospital periprocedural
stroke in CASE 9-1. Hyperacute reperfusion treatments are a key area of ongoing
pediatric stroke research. However, stroke diagnosis is frequently delayed even
when the stroke occurs in the hospital after cardiac catheterization or
surgery.33,34 Barriers to early diagnosis are common, including sedating or
paralytic medications in critically ill children, emergence from anesthesia after a
procedure, or difficulty with neurologic examination in poorly cooperative or
young children. Systematic quality measures that preemptively identify children
for closer postprocedural neurologic monitoring after higher-risk cardiac
procedures are key to reducing time to stroke detection and increasing
opportunities for rapid treatment.
Arteriopathy
Cerebral arteriopathy is present in at least half of all children with ischemic stroke
and is a risk factor for initial stroke and stroke recurrence.45,46 The most common
cause of ischemic stroke in a previously healthy child is a cervicocephalic
dissection or a presumed inflammatory intracranial focal cerebral arteriopathy.
The definitive etiology of inflammatory type focal cerebral arteriopathy remains
unknown, although it can be related to varicella zoster virus or other herpesvirus
infections. Among children with stroke related to severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection, about one-fourth have a
presumed inflammatory arteriopathy.47 The typical appearance of an
inflammatory focal cerebral arteriopathy on vascular imaging is a unilateral
irregular or banded stenosis involving the distal carotid terminus, proximal
middle cerebral artery, proximal anterior cerebral artery, or a combination of
these (FIGURE 9-348), in conjunction with a basal ganglia infarct from affected
lenticulostriates.48 The natural history is monophasic, with progression of the
stenosis in the first days to weeks. After the acute phase, the arteriopathy
stabilizes and other vascular territories do not become involved. Up to 25% of
children with inflammatory focal cerebral arteriopathy have a recurrent stroke
after an initial stroke from progressive lenticulostriate involvement, artery-to-
artery emboli, or flow-related ischemia.27 Although the benefit and optimal
574 APRIL 2023

dosing regimen are uncertain, children KEY POINTS
with inflammatory focal cerebral
● Systematic quality
arteriopathy may be treated with measures that preemptively
corticosteroids (CASE 9-2). Based on the identify children for closer
hypothesis that the etiology of focal postprocedural neurologic
cerebral arteriopathy is inflammatory, a monitoring after higher-risk
cardiac procedures are key
network of European and Australian
to reducing time to stroke
investigators designed PASTA (Paediatric detection and increasing
Arteriopathy Steroid Aspirin Project, opportunities for rapid
EudraCT 2017-002247-15), a randomized treatment.
controlled trial of corticosteroids, that is
● Cerebral arteriopathy is
ongoing in Europe.49 The FOCAS (Focal present in up to half of all
Cerebral Arteriopathy Steroid)50 children with ischemic
FIGURE 9-3 comparative effectiveness study of early stroke and is a risk factor for
Typical banded appearance of versus late corticosteroid treatment is initial stroke as well as
inflammatory focal cerebral stroke recurrence.
anticipated to start in the United States
arteriopathy affecting the middle
in 2023.
cerebral artery on conventional
angiogram. Cervicocephalic arterial dissection
Reprinted from Wintermark M, et al, AJNR Am J accounts for approximately 10% of
Neuroradiol.48 © 2017 American Journal of childhood arterial ischemic stroke35 and
Neuroradiology.
half of posterior circulation childhood
arterial ischemic stroke,51 occurring
spontaneously or following trauma. The
radiographic appearance of an intracranial dissection may be similar to
inflammatory focal cerebral arteriopathy, with some evidence for mixed
arteriopathies with elements of inflammation and dissection. Children with
collagenopathies or elastinopathies such as Ehlers-Danlos syndrome, Marfan
syndrome, Loeys-Dietz syndrome, and arterial tortuosity syndrome are at
increased risk for cervicocephalic arterial dissection,52 as well as other associated
comorbidities of the underlying diagnosis.
Moyamoya disease, a progressive steno-occlusive arteriopathy, may be the
most prevalent risk factor for childhood stroke in Asian countries. In a Beijing
study of children with ischemic stroke, moyamoya arteriopathy was reported in
69% of participants.46 Currently, no specific medical treatments are available to
successfully halt or reverse the progressive disease. Surgical revascularization is
often recommended to increase collateral blood flow to hypoperfused brain and
thus decrease the risk of initial and recurrent ischemic stroke. Studies have
suggested that revascularization surgery is superior to medical management alone
to decrease risk of ischemic injury,53-55 although randomized studies comparing
various surgical approaches or surgical versus medical management have not been
done. Surgical revascularization is not without risk, with surgical morbidity of
about 4% per treated hemisphere,54,55 and the optimal selection of patients and
timing for surgery has not been well defined. Experts agree that careful
intraoperative anesthetic management and perioperative care to maintain cerebral
perfusion minimize surgical risk, but specific practices vary across centers.56
Sickle Cell Disease

Without intervention, about 10% of people with sickle cell disease will sustain
an ischemic stroke during childhood. In 1997, the landmark STOP (Stroke
Prevention Trial in Sickle Cell Anemia)35 clinical trial changed primary stroke

prevention for children with hemoglobin SS and hemoglobin Sß0 thalassemia.

The STOP trial showed that a protocol of screening children aged 2 to 16 years
with transcranial Doppler (TCD) ultrasound can identify children with
arteriopathy and then reduce stroke risk through prophylactic chronic blood
transfusion. In children with elevated TCD velocity in the middle cerebral
artery, regular red blood cell transfusions for at least 1 year reduced the risk of
initial stroke by 92%.57,58 The follow-up TWiTCH (TCD With Transfusions
Changing to Hydroxyurea) trial found that children without severe
arteriopathy whose TCDs had normalized after a period of transfusion
therapy could safely transition to hydroxyurea.59
The acute management of a suspected stroke in children with sickle cell
disease differs from other stroke etiologies and should focus on providing an
emergent blood transfusion. FIGURE 9-460 shows the American Society of
Hematology’s recommended algorithm for management of acute ischemic stroke
in a child with sickle cell disease.60 Transfusion goals are to reduce the percentage
of hemoglobin S to under 30% and increase the hematocrit to 30% to improve
oxygen delivery to ischemic brain tissue. While awaiting transfusion, children
with sickle cell disease should be treated with IV fluids and supplemental oxygen
to maintain oxygen saturation greater than 93%. A transfusion should be
performed for all children with sickle cell disease who present with focal
neurologic symptoms, even if symptoms are resolving or have resolved.
FIGURE 9-4
American Society of Hematology–recommended algorithm of management of acute
ischemic stroke in children with sickle cell disease.
Hb = hemoglobin; SCD = sickle cell disease.
Reprinted with permission from DeBaun MR, et al, Blood Adv.60 © 2020 The American Society of Hematology.
576 APRIL 2023

Exchange transfusion is preferred when it can be done quickly, but a simple KEY POINTS
transfusion is acceptable if exchange transfusion cannot be provided quickly.
● The acute management of
About 20% of children with sickle cell disease who have had a stroke go on to a suspected stroke in
have a recurrent stroke, even if chronic red blood cell transfusion is started. children with sickle cell
Children with hemoglobin SS or hemoglobin Sß0 thalassemia who have had an disease differs from other
ischemic stroke should be managed with regular blood transfusions for stroke etiologies and should
be focused on providing an
secondary stroke prevention if it is safe, available, and feasible.60 Sickle cell
emergent blood transfusion.
disease can lead to a moyamoya-like syndrome, with progressive steno-occlusive
arteriopathy and collateral formation, as a further risk factor for a first or ● Assessment of function
recurrent stroke.61,62 Children with moyamoya syndrome related to sickle cell by a rehabilitation specialist
disease may benefit from surgical revascularization or stem cell transplant in and consideration of
inpatient rehabilitation are
addition to regular blood transfusion. The pathophysiology of progressive recommended for children
steno-occlusive arteriopathy related to sickle cell disease may differ from other following stroke.
genetic moyamoya syndromes, and the American Society of Hematology has
identified treatment of sickle cell disease–related moyamoya syndrome as a
priority research need.60
SECONDARY STROKE PREVENTION, OUTCOMES, AND RECOVERY

In children with ischemic stroke who do not have sickle cell disease or
cardioembolic stroke, pediatric stroke guidelines from the American College
of Chest Physicians,63 the Royal College of Paediatrics and Child Health,64
and the AHA/ASA13 recommend secondary stroke prevention with aspirin
(1 mg/kg/dose to 5 mg/kg/dose orally once daily) if there are no
contraindications. Anticoagulation is typically recommended in children with
presumed cardioembolic stroke and significant thrombophilic states such as
antiphospholipid syndrome.13,63 Although anticoagulation is often used in
cervical artery dissection,63 recent AHA/ASA guidelines note that the use of
anticoagulation as opposed to antiplatelets is controversial.13 The optimal
duration of aspirin use following childhood stroke is not known, but
guidelines recommend a minimum of 2 years13,63 and it is sometimes
used indefinitely.
Assessment of function by a rehabilitation specialist and consideration of
inpatient rehabilitation are recommended for children following stroke. Many
children benefit from inpatient rehabilitation either acutely or when medically
stable. Similar to exercise recommendations for adults after stroke,65 most
survivors of childhood stroke should be encouraged to engage in fun, regular
exercise and physical activity to maintain fitness, range of motion, function, and
cardiovascular health over their lifetime. Although some children can continue to
have improvement in function over years, others develop emerging deficits with
increased academic and other cognitive demands, and ongoing evaluation
is helpful.66
Epilepsy develops during childhood in about one-third of survivors of
pediatric stroke, and prolonged or recurrent seizures in the immediate poststroke
period may increase that risk.67 Poststroke epilepsy can worsen quality of life
even in the absence of other disabilities related to stroke. Often, children and
families experience anxiety following stroke, and depression is common.68
Psychosocial support is necessary both acutely as well as following discharge,
including a low threshold for referring for behavioral health services.
Neuropsychological evaluation can guide early reintegration into school, with
full neuropsychological testing typically performed in a delayed fashion when

poststroke deficits have stabilized. Education of the family and other care
settings such as the school should include stroke recognition and need for urgent
evaluation for new or recurrent, even transient, neurologic deficit. Education
should also include strategies to maintain vascular health throughout the
patient’s lifetime, including a healthy weight, normal blood pressure, and
aggressive treatment of patient-specific risk factors.
PERINATAL STROKE
Risk factors for perinatal ischemic stroke include chorioamnionitis or other
systemic or central nervous system infections, inherited thrombophilia, and
complex congenital heart disease.69 In infancy, focal motor seizures and
encephalopathy are the most common presenting symptoms of ischemic
stroke.70,71 Some newborns may not present with any clinical signs of stroke
initially, but during development they may have early handedness or fail to meet
developmental milestones.
When diagnosed acutely, supportive care measures focus on seizure control,
treatment of underlying conditions such as infection or dehydration,
optimization of oxygenation, and cerebral perfusion with normalization of
systemic blood pressure.13 Neonatal seizures due to a stroke may require multiple
loads of antiseizure medicines to end status epilepticus. Recanalization
therapy with thrombolytic agents and mechanical thrombectomy for perinatal
stroke lack safety and efficacy data and are not recommended. Decompressive
neurosurgery is uncommon because open cranial sutures expand with
increased intracranial pressure. Antiplatelet or anticoagulation treatment for
secondary stroke prevention after a perinatal stroke is not typically
recommended because of the low risk of stroke recurrence, except in infants
with complex congenital heart disease.28,72 If complex congenital heart disease
is present, it confers a persistent risk of recurrent stroke during the newborn
period and later in life.
BARRIERS TO RAPID CARE FOR CHILDREN WITH ACUTE

ISCHEMIC STROKE
Broad public health campaigns and a robust system of prehospital triage, in-field
care, and designated primary and comprehensive stroke centers for adults have
decreased stroke mortality and morbidity.73 Children benefit from early
recognition of stroke and should be transferred to a hospital that can provide
definitive care as soon as safely possible, but systems of care for children with
stroke lag behind those for adults. Most hospitals do not have guidelines to
administer IV thrombolysis for children aged younger than 18 years. In some
countries, a regional hospital may have guidelines and expertise to provide
thrombectomy74 but little prehospital infrastructure or few systems of triage to
identify pediatric stroke-ready hospitals and abet rapid transfer. The TIPS
(Thrombolysis in Pediatric Stroke) trial was funded in 2010 as the first prospective
treatment trial for acute pediatric stroke, and preparation for rapid enrollment into
the multicenter study sparked the emergence of pediatric stroke centers.4,75 Since
that time, the need for greater pediatric stroke infrastructure has increasingly been
recognized.76 Individual institutions have reported that implementation of
pediatric stroke guidelines and protocols have altered care by increasing the
proportion of children receiving antithrombotic treatment within the first
24 hours.77
578 APRIL 2023

HEALTH DISPARITIES KEY POINTS
Structured and organized health systems that improve the speed of triage,
● Children benefit from
transport, and treatment of children in medical centers with established early recognition of stroke
pediatric stroke guidelines are still lacking in many geographic areas. Globally, and should be transferred to
the burden of childhood stroke differs in countries with higher resources from a hospital that can provide
lower resourced regions. While fewer population-based estimates of stroke definitive care as soon as
safely possible, but systems
incidence and mortality are available from low- and middle-income countries,
of care for children with
the prevalence rates of childhood stroke appear to be significantly higher stroke lag behind those for
compared with countries with greater resources.78 Estimates of death rates adults.
and disability-adjusted life years after childhood stroke are also higher in low-
and middle-income countries.78 In the VIPS (Vascular Effects of Infection in ● Structured and organized
health systems that improve
Pediatric Stroke) study, a large multinational observational cohort study of the speed of triage,
pediatric stroke, very low income (<$10,000 per year) was associated with transport, and treatment of
worse neurologic outcomes compared with higher income levels.79 The children in medical centers
authors postulated that these health disparities may be related to racial, with established pediatric
stroke guidelines are still
ethnic, or socioeconomic factors that result in fewer resources for stroke lacking in many geographic
prevention and differences in stroke outcomes, and called for future research areas.
in this area.
Since the STOP trial and implementation of TCD screening in children with
sickle cell disease, the excess risk of death from ischemic stroke in Black children
in the United States has dropped.80 The STOP study transformed stroke
prevention for some children with sickle cell disease, but implementation of
stroke prevention guidelines for many children with sickle cell disease remains
challenging. Even in high-resource settings, chronic blood transfusion can be a
major challenge because of red blood cell alloimmunization and the social
interruption of frequent medical appointments. In low-resource settings, where
global prevalence of sickle cell disease is highest, TCD ultrasound and safe blood
supplies may not be available or affordable.81 In regions where TCD screening
and regular blood transfusion are not widely feasible, guidelines suggest that
hydroxyurea treatment should be used rather than no treatment for preventing
stroke in high-risk children with sickle cell disease.60 The SPRING (Primary
Prevention of Stroke in Children With Sickle Cell Disease in Sub-Saharan Africa
II) trial in Nigeria demonstrated that children with sickle cell disease and
abnormal TCD velocities treated with low-dose hydroxyurea have equivalent
stroke rates compared with children treated with moderate-dose hydroxyurea.
These results have changed practice in three Nigerian states to provide free
low-dose hydroxyurea to children with abnormal TCD assessments.82 More
research for stroke prevention strategies that can be feasibly implemented in
low-resource and high-resource settings is critically needed.
CONCLUSION
Similar to adults, children benefit when a stroke is recognized early after onset.
There is increasing recognition of the potential role of hyperacute recanalization
therapies and neuroprotective care to decrease lifelong morbidity following
childhood stroke. Most stroke clinical trials exclude children, so evidence for
effective therapeutics that reduce disability and improve outcomes are still
needed. Although pediatric acute stroke care does not benefit from the level of
evidence available for adult stroke, an organized approach to care can be
extrapolated from adult stroke and pediatric critical care experience, expert

consensus, and emerging pediatric stroke data. Public health measures that help
people recognize stroke in children are critical.
USEFUL WEBSITES
PEDIATRIC NATIONAL INSTITUTES OF HEALTH STROKE PRACTICE ADVISORY UPDATE: PATENT FORAMEN OVALE
SCALE (PedNIHSS) AND SECONDARY STROKE PREVENTION21
Online calculator for the PedNIHSS. aan.com/Guidelines/home/GuidelineDetail/991
mdcalc.com/calc/10270/pediatric-nih-stroke-
scale-nihss EXPANSION OF THE TIME WINDOW FOR TREATMENT OF
ACUTE ISCHEMIC STROKE WITH INTRAVENOUS TISSUE
INTERNATIONAL PEDIATRIC STROKE PLASMINOGEN ACTIVATOR: A SCIENCE ADVISORY FROM
ORGANIZATION (IPSO) THE AMERICAN HEART ASSOCIATION/AMERICAN STROKE
The IPSO website provides links to pediatric stroke ASSOCIATION43
resources for patients and families, bulletins with aan.com/Guidelines/Home/GuidelineDetail/369
recent literature reviews, research opportunities,
and information about training programs in 2015 AHA/ASA FOCUSED UPDATE OF THE 2013 GUIDELINES
pediatric stroke. FOR THE EARLY MANAGEMENT OF PATIENTS WITH ACUTE
internationalpediatricstroke.org ISCHEMIC STROKE REGARDING ENDOVASCULAR
TREATMENT50
MANAGEMENT OF STROKE IN NEONATES AND CHILDREN: aan.com/Guidelines/home/GuidelineDetail/700
A SCIENTIFIC STATEMENT FROM THE AMERICAN HEART
ASSOCIATION/AMERICAN STROKE ASSOCIATION17 PHYSICAL ACTIVITY AND EXERCISE RECOMMENDATIONS
aan.com/Guidelines/Home/GuidelineDetail/956 FOR STROKE SURVIVORS70
aan.com/Guidelines/Home/GuidelineDetail/661
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3026(21)00368-9

REVIEW ARTICLE

Management of
ONLINE
Unruptured Intracranial
Aneurysms and Brain
Arteriovenous
Malformations
By Thanh Ngoc Nguyen, MD, FRCPc, FSVIN, FAHA
ABSTRACT
OBJECTIVE: Managing a patient with an unruptured brain aneurysm or brain
arteriovenous malformation (AVM) can lead to uncertainty about
CITE AS:
CONTINUUM (MINNEAP MINN) preventive treatment. While the bleeding risks are low, the morbidity or
2023;29(2, CEREBROVASCULAR mortality associated with a hemorrhagic event is not insignificant. The
DISEASE):584–604.
objective of this article is to review the natural history of these vascular
entities, the risk factors for hemorrhage, preventive treatment options,
Dr Thanh N. Nguyen, Boston and the risks of treatment.
Medical Center, 85 E Concord
St, Boston, MA 02118, thanh.
nguyen@bmc.org. LATEST DEVELOPMENTS: Randomized trials to inform preventive treatment
strategies for unruptured intracranial aneurysms and brain AVMs are
ongoing. Higher angiographic obliteration rates of unruptured intracranial
Dr Nguyen has received
personal compensation in the aneurysms have been reported with the flow-diversion technique
range of $0 to $499 for serving compared with alternative standard techniques. One randomized trial for
on a scientific advisory or data
safety monitoring board for the
unruptured brain AVMs showed a higher rate of morbidity and mortality in
National Institutes of Health, patients who underwent interventional treatment compared with
and in the range of $500 to observation.
$4999 for serving on a scientific
advisory or data safety
monitoring board for Avania, ESSENTIAL POINTS: Thedecision to treat a patient with a brain aneurysm
Idorsia Pharmaceuticals, and should consider patient factors, the patient’s life expectancy, aneurysm
Vesalio, and as an editor,
associate editor, or editorial anatomical factors, and treatment risks. Patients with unruptured brain
advisory board member for the AVMs should be observed in light of recent clinical trial data or enrolled in
American Heart Association.
The institution of Dr Nguyen has
an ongoing clinical trial.
received research support from
Medtronic and the Society of
Vascular and Interventional
Neurology.
INTRODUCTION
C
UNLABELED USE OF erebral aneurysms and arteriovenous malformations (AVMs) are
PRODUCTS/INVESTIGATIONAL commonly detected incidentally by neuroimaging. Rarely, these
USE DISCLOSURE:
Dr Nguyen reports no
vascular abnormalities can rupture and lead to life-threatening
disclosure. consequences. Elective treatment of an unruptured intracranial
aneurysm or unruptured brain AVM is not without risk, and
© 2023 American Academy decisions to treat should consider patient and anatomical factors, as well as the
of Neurology. risk of repair. One “cannot make an asymptomatic person feel better.”1 A
584 APRIL 2023

clinician with a patient who has either a brain aneurysm or AVM is often faced
with the dilemma of what to do. Thus, to provide a practical guide for the
clinician, this article describes the epidemiology, natural history, pathogenesis,
diagnosis, treatment, and risks of treatment of unruptured intracranial
aneurysms and AVMs.
CEREBRAL ANEURYSMS
An aneurysm is a bulge or “balloon” that develops from a weak point of an
artery, commonly at an arterial bifurcation. Aneurysms are thought to be
acquired rather than congenital, with an estimated prevalence of 3% in the adult
population.2 This rate is higher than previously reported and is reflective of the
increased use of noninvasive imaging.3 A higher prevalence of unruptured
intracranial aneurysm is seen in women, people age 30 years or older (compared
with those younger than 30), those with a family history of intracranial
aneurysm or prior subarachnoid hemorrhage, and those with autosomal
dominant polycystic kidney disease.2 A 2% rate of unruptured intracranial
aneurysm is present in autopsy series, of which multiple aneurysms are seen in
22% of patients.4 Vessel degeneration and hemodynamic factors may lead to
changes in sheer stress and flow patterns, which may result in aneurysm growth
or rupture.
Natural History of an Unruptured Intracranial Aneurysm

It is possible that aneurysms that are found incidentally are not the same as the
aneurysms that bleed. In fact, most unruptured aneurysms will never rupture.
While aneurysm rupture is infrequent, it can be associated with a high morbidity
and mortality.5 The natural history of intracranial aneurysm rupture risk varies
with the aneurysm’s size and location, as reported by ISUIA (International Study
of Unruptured Intracranial Aneurysms) and a Japanese cohort.6,7 ISUIA reported
on the 5-year rupture risk of 2686 unruptured, untreated cerebral aneurysms,
most of which were detected incidentally (TABLE 10-16). In UCAS (Unruptured
Cerebral Aneurysm Study of Japan), 6697 aneurysms were studied showing an
Five-year Unruptured Intracranial Aneurysm Rupture Risk from ISUIAa TABLE 10-1
<7 mm 7-12 mm 13-24 mm >25 mm

b c
Group 1 Group 2
d
Anterior circulation (n=1037) 0 0 0 3.0% 6.4%
Cavernous carotid (n=210) 0 1.5% 2.6% 14.5% 40%

e
Posterior/posterior communicating artery 2.5% 3.4% 14.5% 18.4% 50%
ISUIA = International Study of Unruptured Intracranial Aneurysms

a
Reprinted from Wiebers DO, et al, Lancet.6 © 2003 Elsevier Ltd.
b
Patients in Group 1 had unruptured intracranial aneurysm and no subarachnoid hemorrhage history.
c
Patients in Group 2 had unruptured intracranial aneurysm and subarachnoid hemorrhage history from a separate aneurysm.
d
Anterior circulation includes the anterior communicating or anterior cerebral artery, internal carotid artery (not cavernous carotid), and middle
cerebral artery.
e
Posterior circulation includes vertebrobasilar, posterior cerebral, or posterior communicating artery (although embryologically and anatomically,
posterior communicating artery aneurysms originate from anterior circulation).

UNRUPTURED INTRACRANIAL ANEURYSMS AND BRAIN ARTERIOVENOUS MALFORMATIONS
overall rate of rupture of approximately 1% per year with a rate of 1.1%, 3.4%,
9.1%, and 76.3%, for 5 mm to 6 mm, 7 mm to 9 mm, 10 mm to 24 mm, and greater
than or equal to 25 mm aneurysms, respectively.7 In addition to size and location,
patients with a family history of aneurysms have a 1.2-times to 5-times higher risk
of unruptured intracranial aneurysm rupture compared with patients with
sporadic unruptured intracranial aneurysm.8,9
A pooled analysis of individual patient data from six prospective studies
(including ISUIA and UCAS) including 8382 patients and 10,272 unruptured
aneurysms led to the development of the PHASES score, including six predictors
TABLE 10-2 Risk Factors for Aneurysm Rupture According to the PHASES Rupture Risk
Scorea
Risk factor for aneurysm rupture Points

Population
North American, European (other than Finnish) 0
Japanese 3
Finnish 6
Hypertension
No 0
Yes 1
Age
Younger than 70 years 0
70 years or older 1
Size of aneurysm
<7.0 mm 0
7.0–9.9 mm 3
10.0–19.9 mm 6
≥20 mm 10
Earlier subarachnoid hemorrhage
Yes 0
No 1
Site of aneurysm
Internal carotid artery 0
Middle cerebral artery 2
Anterior cerebral artery, posterior communicating artery, and posterior circulation 4
PHASES = population, hypertension, age, size of aneurysm, earlier subarachnoid hemorrhage from another
aneurysm, and site of aneurysm.
a
Modified with permission from Greving JP, et al, Lancet Neurol.10 © 2014 Elsevier Ltd.
586 APRIL 2023

for rupture based on 5-year data estimates: population, hypertension, age, size KEY POINTS
of aneurysm, earlier subarachnoid hemorrhage (SAH) from another aneurysm,
● An estimated 3% of the
and site of aneurysm (TABLE 10-2).10 Of note, sex, smoking status at the time of population has an
aneurysm detection, and presence of multiple aneurysms had no effect on the unruptured intracranial
risk of rupture in the PHASES study. These factors were associated with aneurysm.
aneurysm rupture in some observational studies. The unruptured intracranial
● The risk of rupture for an
aneurysm treatment score (UIATS) differs from PHASES in that it incorporates
asymptomatic unruptured
the risk of treatment, which is important when counseling a patient for intracranial aneurysm is
intervention. UIATS was developed via Delphi consensus among a estimated at 0.3% to 1% per
multidisciplinary group of 69 specialists and incorporates patient age, risk year.
factors, clinical symptoms, and quality of life; aneurysm size, morphology,
● The risk of aneurysm
location, and growth; and treatment factors such as age-related risk, aneurysm rupture increases with
size–related risk, and aneurysm complexity–related risk (FIGURE 10-1).11 aneurysm size, a family
history of aneurysm, and
Intracranial Aneurysm Growth prior subarachnoid
hemorrhage from another
Intracranial aneurysm growth can be conceptualized as macroscopic (ie, aneurysm.
visualized on a radiological study) and microscopic (ie, ascertained at the
molecular level). Mathematical simulations of prospective aneurysm series ● An aneurysm that is
suggest that intracranial aneurysm growth takes on a nonlinear or stochastic documented to have growth
on serial imaging carries a
trajectory.3 Aneurysm growth is more likely to be detected in larger aneurysms
higher risk of rupture than an
than in smaller ones.12 Moreover, several reports describe the uncommon aneurysm that has not been
formation of de novo aneurysms that can develop over a short period of time (ie, documented to grow.
weeks to months), particularly in patients who have had a previous SAH from an
index aneurysm, and subsequently have another SAH from a de novo aneurysm
not previously present.3
If and when an aneurysm is documented to have grown on a radiologic
study, it is worthwhile for the clinician to look at the images and measure the
dimensions for agreement. An aneurysm that has demonstrated growth is
associated with an increased risk of rupture compared with one that has not,13,14
and the patient should be referred for consideration of aneurysm repair, by either
endovascular or open surgical methods.
Unruptured Symptomatic Aneurysm

Patients who present with symptomatic unruptured aneurysms related to
aneurysm mass effect are uncommon, but warrant careful attention. While
headache is a common presentation in many patients with brain aneurysms, it
is important to distinguish headache from usual causes versus thunderclap
headache. In general, the treatment of a brain aneurysm does not provide
headache relief. Moreover, a patient may present with a subacute or acute
third nerve palsy from the compressive effect of an ipsilateral posterior
communicating artery aneurysm, which is indicative of impending rupture, in
which case urgent treatment is indicated. A patient who presents with more
indolent gradual onset of cranial nerve palsy related to the compression mass
effect of a large cavernous aneurysm would also be a good candidate for
treatment, which would usually involve endovascular flow diversion to
reduce the aneurysm mass effect (whereas coils may still exhibit a mass effect
related to the coil). Rarely, patients can present with progressive vision loss
related to ipsilateral compression of the optic nerve by a large ophthalmic
aneurysm, in which case treatment with endovascular flow diversion
is indicated.

FIGURE 10-1
Unruptured intracranial aneurysm treatment score (UIATS).
Reprinted with permission from Etminan N, et al, Neurology.11 © 2015 American Academy of Neurology.
588 APRIL 2023

Management Considerations
In the absence of randomized clinical trial data, the effectiveness of routine
unruptured intracranial aneurysm treatment to prevent rupture is uncertain.15,16
The decision for treatment of incidentally discovered unruptured aneurysms
should follow a balanced discussion based on natural history data,
patient-specific factors, and the risk and benefit stratification for the applicable
treatment modalities. The patient’s age and anticipated life expectancy, the
aneurysm’s size and morphology, and documented aneurysm growth are often
factors that influence the decision of whether intervention should be
considered.15,17 The 2022 European Stroke Organization guidelines recommend
treatment if the estimated 5-year rupture risk exceeds the risk of intervention.17
Conservative Management
Incidental (<5 mm) aneurysms with no other associated risk factors (eg,
daughter sac, documented growth, family history, multiple aneurysms, SAH
history, hypertension, smoking) are commonly managed conservatively.18
Patients often have anxiety related to their diagnosis. Patient education regarding
the incidental finding of their aneurysm, natural history of aneurysm rupture,
and symptoms to be aware of (ie, sudden onset of the worst headache of their
life, in which case they should present to the emergency room), as well as
reassurance regarding long-term follow-up, are important. Describing the risk of
rupture per year or the likelihood of the aneurysm not rupturing (eg, “There is a
99% or 99.5% chance per year that your aneurysm will not cause any bleeding.”)
may help to reassure the patient.
As part of conservative management, vascular risk factors should be reviewed
and modified, particularly smoking and hypertension.15 Patients being treated
with aspirin or antithrombotic medications for other indications (eg, coronary
artery disease, stroke, atrial fibrillation), should usually be counseled to continue
these medications as the risk of a vascular event (eg, stroke in a patient with atrial
fibrillation) is greater than the risk of a rupture of the asymptomatic unruptured
intracranial aneurysm. Antithrombotic medications are not known to trigger an
aneurysmal rupture, but in the event of a rupture, it is likely that antithrombotic
drugs make coagulation mechanisms less effective.19 A prospective study in
Finland of 132 patients with acute ischemic stroke with unruptured intracranial
aneurysm who underwent IV thrombolysis reported that none of the 141 saccular
unruptured intracranial aneurysms (mean diameter 4.7 mm ± 3.8 mm) ruptured
after IV thrombolysis, whereas three patients with large fusiform basilar artery
unruptured intracranial aneurysms had fatal ruptures at 27 hours, 43 hours, and
19 days after IV thrombolysis. Of note, all three of the latter patients were also
treated with anticoagulation after IV thrombolysis.20
In ISUIA, patients who used aspirin 3 times weekly to daily had lower odds of
hemorrhage (adjusted odds ratio, 0.27; 95% confidence interval, 0.11 to 0.67;
P = .03) compared with those who had never taken aspirin.21 Chronic
inflammation could play a role in aneurysm wall degeneration and rupture risk,
which may explain the protective effect of aspirin.3 As such, for patients with
asymptomatic unruptured intracranial aneurysm who require aspirin for another
cardiovascular or cerebrovascular indication, the ISUIA data suggest that its
administration is not contraindicated. Given the potential for confounding or
other bias in these observational data, further studies are warranted before
treating a patient with unruptured intracranial aneurysm empirically with

aspirin, in the absence of another indication.17 PROTECT-U (Acetylsalicylic Acid

plus Intensive Blood Pressure Treatment in Patients with unruptured intracranial
aneurysm, NCT03063541) is an ongoing randomized trial testing whether aspirin
and intensive blood pressure treatment (<120 mm Hg) with a home blood
pressure measuring device reduces the risk of aneurysm rupture or growth
compared with standard care (ie, no aspirin, blood pressure management
according to standard care).
FOLLOW-UP IMAGING. For long-term conservative management of unruptured

intracranial aneurysm, serial imaging with magnetic resonance angiography
suffices in most cases for follow-up, usually every year or every other year
depending on the patient and aneurysm factors.15 CT angiography may be used
in patients with contraindications for MRI. The optimal frequency and duration
of follow-up are not well established. In older patients with comorbidities and in
whom treatment risk is considered to outweigh the benefits, repeat imaging may
not be necessary as it may not change management unless other symptoms arise.
Endovascular or Surgical Treatment

Patient-specific desires or the presence of risk factors may encourage
consideration of endovascular or surgical treatment in a patient with an
unruptured intracranial aneurysm.16,22 The introduction of the detachable
platinum coil in the early 1990s led to a paradigm shift in brain aneurysm
treatment by introducing a minimally invasive treatment option as compared
with open surgical clipping. ISAT (International Subarachnoid Aneurysm Trial)
randomized patients with a ruptured aneurysm that could be treated with either
coiling or clipping. In this study, endovascular coiling was shown to be an
effective technique in preventing aneurysm rerupture and also showed better
1-year clinical outcomes compared with patients who underwent surgical
clipping.23,24 Following this landmark trial, additional endovascular therapy tools
for the treatment of aneurysms evolved, including the use of intracranial stents,
balloons, flow-diverters, and intrasaccular devices.
CASE 10-1 A 45-year-old woman presented with bilateral tension headache, which
had persisted for 3 months. Neuroimaging showed an unruptured left
carotid terminus 9-mm aneurysm. She had no family history of aneurysm
and was not a smoker.
She was referred to a neurointerventionalist and was counseled on the
options for treatment, including conservative management, coiling, and
surgical clipping. The benefits and risks of each modality were discussed
with the patient. The patient’s neurologist recommended treatment of
the aneurysm. The patient declined clipping and elected to undergo
coiling of the aneurysm, which was performed without complication.
COMMENT Due to her young age and the size of her aneurysm, this patient was a good
candidate for treatment.
590 APRIL 2023

COIL EMBOLIZATION. Since Guido Guglielmi first introduced electrolytically KEY POINT
detachable platinum microcoils in the early 1990s, technologic advancements
● ISAT (International
have resulted in efficacious endovascular treatment of complex aneurysms.25 Subarachnoid Aneurysm
Coiling involves the placement of an initial framing coil into the aneurysm dome Trial) demonstrated better
under real-time digital subtraction fluoroscopy. Additional filling coils of varying outcomes among patients
shape, softness, and successively diminishing size are deployed until complete with ruptured aneurysms
who underwent coiling
angiographic occlusion is obtained. Improved detachment mechanisms,
compared to those who
stretch-resistant coils, complex three-dimensional shapes, and different caliber underwent surgical clipping.
coils have been designed to minimize procedural complications, expand the
endovascular treatment indications for patients with brain aneurysms, and
reduce delayed recanalization (CASE 10-1).26
BALLOON REMODELING. Initially described by Jacques Moret and colleagues,27 the

balloon remodeling technique treats broad-neck aneurysms by protecting the
parent vessel from coil prolapse. Positioned in the parent artery, a small balloon
microcatheter is intermittently inflated and deflated across the aneurysm neck
(FIGURE 10-2). This provides temporary support for coils, which are then
deployed through a second microcatheter located within the aneurysm sac.
Balloon remodeling can lead to more effective parent vessel reconstruction. In
a review of their initial experience, the Moret group documented complete
angiographic occlusion in 20 of 21 broad-necked cerebral aneurysms treated via
balloon-assisted coil embolization with complication rates no greater than
primary coil embolization.27
Balloon assistance has greatly facilitated the endovascular treatment of
wide-neck ruptured cerebral aneurysms in the acute phase, allowing for
mechanical coil support and vessel remodeling without the need for antiplatelet
therapy that is typically necessary with stent-assisted coiling. Balloon-assisted
coiling also makes possible what can be a life-saving opportunity for
hemostasis in the event of intraprocedural rupture, allowing time for the
neurointerventionist to pack the aneurysm with coils while the balloon is
inflated in the parent artery to prevent blood from entering the aneurysm
(FIGURE 10-2). In a series of patients with ruptured aneurysms treated by coiling,
the use of a hemostatic balloon across the aneurysm neck was associated with
better clinical outcomes in the setting of inadvertent intraprocedural aneurysm
rupture compared with no balloon usage.28 This adjunctive technique extends the
option for endovascular aneurysm treatment to patients with less favorable
anatomy.
STENT-ASSISTED COIL EMBOLIZATION. In some challenging broad-neck cerebral

aneurysms, an endoluminal or endovascular stent construct may be considered
as supportive scaffolding. Nitinol self-expanding stents with either open- or
closed-cell configurations have been designed for this use.29 A stent is deployed
across the aneurysm neck and the coiling microcatheter is placed into the sac
through the stent interstices. An alternative method is to first position the coiling
microcatheter within the aneurysm dome and then hold the distal microcatheter
tip in position through subsequent stent deployment. Stent-assisted coil
embolization is generally reserved for the treatment of unruptured aneurysms.
Most physicians are reluctant to deploy stents in the setting of subarachnoid
hemorrhage due to the requirement of dual antiplatelet therapy with its use and
the potential hemorrhagic complications associated with a ventricular drain.30

FIGURE 10-2
Balloon assist. A patient in their 40s presents with a ruptured right 3-mm superior
cerebellar artery aneurysm, as seen on subtraction angiography (A, arrow). After placement
of a coil using angiographic roadmapping (B, arrow), follow-up subtraction angiography
shows contrast extravasation (C, arrow). The balloon is immediately inflated (D, arrow,
unsubtracted angiogram), and after additional coiling, hemostasis is achieved as shown on
follow-up subtraction angiography (E). The patient has a follow-up Glasgow Coma Scale
score of 5.
Durability of Aneurysm Treatment

Incomplete occlusion and subsequent recanalization rates following coil
embolization and surgical clipping31 have raised concerns regarding the
durability of endovascular treatment for cerebral aneurysms.32,33 Risk factors for
aneurysm recurrence after coiling include wide-neck aneurysms (≥4 mm), large
aneurysms (>10 mm), and incomplete aneurysm occlusion at the time of
treatment.34 Residual microcirculatory flow may remain even in tightly packed
lesions. This has prompted the development of novel techniques such as
flow-diverting and intrasaccular devices.
FLOW DIVERSION. The advent of endovascular flow-diversion devices is a

paradigm shift in the treatment strategy for large, broad-neck aneurysms.
Circumferential, endoluminal, parent-vessel reconstruction may allow complete
aneurysmal occlusion by reconstruction of a segmentally diseased vessel in the
absence of direct endovascular embolization of the aneurysm sac (FIGURE 10-3).
The PUFS (Pipeline for Uncoilable or Failed Aneurysms) trial was a multicenter,
prospective study of an embolization flow diverter device.35 In this study, 108
patients with unruptured large wide neck aneurysms of the internal carotid
artery were enrolled. Complete angiographic aneurysm occlusion was observed
in 73.6% of treated aneurysms, and six patients (5.6%) experienced a major
ipsilateral stroke or neurologic death.
Three randomized trials have compared flow diversion to other techniques for
the treatment of intracranial aneurysms. FIAT (Flow Diversion in Intracranial
Aneurysm Treatment) was a pragmatic randomized care trial comparing flow
diversion to the alternative standard management option (ie, observation,
coiling, parent vessel occlusion, or clipping).36 The trial was a prototype in its
methodology as a care trial, integrated as part of clinical practice, designed to be
inclusive,37 and permitted a comparator intervention that was prespecified
before randomization. In FIAT, death or dependency results were similar
between flow-diversion and alternative standard management option groups
(16/138 versus 12/137, relative risk 1.33; 95% confidence interval, 0.65 to 2.69,
P = .44), and the primary efficacy endpoint of poor outcome (defined as residual
aneurysm, aneurysm rupture, progressive mass effect at follow-up, or death or
592 APRIL 2023

KEY POINT
● Endovascular techniques
that are commonly used in
the treatment of brain
aneurysms include coiling,
balloon remodeling,
stent-assisted coiling,
intrasaccular flow
disruption, and flow
diversion.
FIGURE 10-3
Flow diverter. A 76-year-old woman presents with 7 years of progressive right eye ptosis.
A giant, calcified mass is seen on head CT (axial [A-C], coronal [D], and sagittal views [E]).
Angiography revealed a partially thrombosed aneurysm, which demonstrates stagnation
after deployment of a flow diverter (F, arrows depict proximal and distal landing of the
flow diverter). At 6-months follow-up, the aneurysm is closed on digital subtraction
angiography (G).

dependency) was lower in the flow-diversion group compared with the

alternative standard management option group (30.9% versus 45.6%; absolute
risk difference, 14.7% [95% confidence interval, 3.3% to 26.0%, P = .014]).
PARAT (Parent Artery Reconstruction for Large or Giant Cerebral Aneurysms
using the Tubridge Flow Diverter) was a randomized trial in China that
demonstrated a higher rate of aneurysm obliteration with flow diversion
compared with stent assisted coiling, but with a high rate of ischemic
complications in both groups (9.8% had ischemic events in the flow diverter
group versus 9.7% in the stent-assisted coil group).38 A randomized trial in Russia
demonstrated better outcomes in patients with endovascular flow diversion
compared with occlusion with bypass surgery in the treatment of
complex aneurysms.39
INTRASACCULAR FLOW DISRUPTORS. Intrasaccular flow disruptor devices were

developed for wide-neck bifurcation aneurysm treatment (FIGURE 10-4). These
aneurysms are usually located at the middle cerebral artery, basilar artery, or
anterior communicating artery. The WEB-IT (Woven EndoBridge Intrasaccular
Therapy) study was a prospective study evaluating the safety and efficacy of a flow
disruptor device for wide-neck bifurcation aneurysms.40 Of the 148 patients who
received the flow disruptor device, only one developed delayed parenchymal
hemorrhage 3 weeks after treatment. There were no primary safety events between
30 days and 1 year. At 1-year follow-up, adequate occlusion was achieved in 85% of
patients. The authors concluded that the flow disruptor device can be a good option
for patients with wide neck bifurcation aneurysms. Pretreatment with dual
antiplatelet agents is often performed prior to flow disruptor device use in the event
that a stent may be required for adjunctive treatment. There is no standard
antiplatelet regimen after flow disruptor device deployment or any requirement for
antiplatelet maintenance, but patients are often maintained on low-dose aspirin,
with such decisions and the duration of therapy made on a case-by-case basis.41
FIGURE 10-4
A patient in their 60s presents with left parietal hemorrhage and is found to have an incidental
basilar tip aneurysm measuring 8 × 6 mm on subtraction angiography (A). An intrasaccular
flow disruptor device is deployed as seen on unsubtracted fluoroscopy (B, arrow). At
9-months follow-up, good occlusion of the aneurysm with a small neck remnant (C) can be
seen on subtraction angiography.
594 APRIL 2023

The risks of endovascular treatment and open surgical treatment of saccular KEY POINTS
unruptured intracranial aneurysm were evaluated by Algra and colleagues42 in a
● Higher angiographic
systematic review and meta-analysis of over 100,000 patients. Across 74 studies, obliteration rates of
the pooled risk for endovascular treatment was 4.96% (95% confidence interval, unruptured intracranial
4.00% to 6.12%) with a case-fatality rate of 0.30% (95% confidence interval, aneurysms have been
0.20% to 0.40%). For surgical clipping, the complication risk was 8.34% (95% reported with flow diversion
compared to alternative
confidence interval, 6.25% to 11.10%) with a case-fatality rate of 0.10% (95%
standard techniques.
confidence interval, 0.00% to 0.20%). Stenting (odds ratio, 3.43; 95% confidence
interval, 1.45 to 8.09) and stent-assisted coiling (odds ratio, 1.82; 95% confidence ● Ischemic complications
interval, 1.16 to 2.85) were associated with an increased complication risk related to flow diversion are
compared to no stent use, whereas balloon-assisted coiling was not. estimated to occur in up to
9.8% of cases.
UNRUPTURED INTRACRANIAL ANEURYSM TRIALS. The question of whether a patient ● There are no completed
with an unruptured, asymptomatic intracranial aneurysm should be treated has randomized trials to inform
not been answered in a randomized clinical trial. TEAM (Trial of Endovascular treatment of unruptured
aneurysms, but several are
Aneurysm Management) was an international, prospective, randomized clinical ongoing.
trial comparing endovascular coiling versus conservative management in
patients with an unruptured intracranial aneurysm. The trial was halted in 2009 ● The decision to treat an
due to low recruitment.43,44 intracranial aneurysm is
based on the natural history
The CAM (Comprehensive Aneurysm Management) study is an ongoing
of risk of rupture, patient
pragmatic trial to manage patients with unruptured intracranial aneurysm into a and aneurysmal anatomical
paradigm of a care trial. The study proposes systematic randomization of factors, and the risk of
consecutive patients with unruptured intracranial aneurysm between curative repair.
versus conservative management, and endovascular versus surgical treatment,
with a prospective registry arm.45 The CURES (Collaborative UnRuptured
Endovascular versus Surgery) trial is another pragmatic randomized trial
comparing the results of surgical clipping and endovascular treatment of
unruptured intracranial aneurysm. Interim analysis demonstrated no difference
in morbidity between surgical clipping or endovascular coiling at 1 year.46
CEREBRAL ARTERIOVENOUS MALFORMATIONS

A brain AVM is a cluster of arterial and venous communications with no
intervening capillary network. The tangle of vessels between the artery and vein
is the nidus (in Latin, a nidus is a nest), which is where arteriovenous shunting
occurs. Over time, the high shunt of flow directly from the artery to the vein can
result in arterial steal, arterialization of the venous structures, and venous
outflow obstruction.47 Occasionally, there are one or more feeder arterial,
intranidal or venous aneurysms that accompany an AVM, with intranidal
aneurysms (FIGURE 10-548) thought to correlate with bleeding risk.48,49
Brain AVMs were once thought to be congenital; however, most brain AVMs
are sporadic and do not have an underlying genetic cause. Hereditary
hemorrhagic telangiectasia (also known as Osler-Weber-Rendu syndrome), an
autosomal dominant condition characterized by skin telangiectasia, recurrent
epistaxis, and gastrointestinal bleeding, is the most common cause of inherited
brain AVMs (FIGURE 10-6).48 Hereditary hemorrhagic telangiectasia is most
commonly caused by pathogenic mutations in the genes ENG, ALK, and
SMAD4,50 while capillary malformation–AVM syndrome is associated with
mutations in the gene RASA1.51
The incidence of brain AVM hemorrhage is estimated at 0.5 per 100,000
people per year.52 The estimated annual hemorrhage rate of a brain AVM is

FIGURE 10-5
Nidal aneurysm. A, CT of right parietal hemorrhage. B, Cerebral angiography of right
parasagittal arteriovenous malformation (AVM) supplied by the right distal anterior cerebral
artery (arrowhead ), draining to the superior sagittal sinus. C, Microcatheter injection:
magnified sagittal view of AVM nidus with aneurysmal appearance (arrow).
Reprinted from Pikula A, et al, Neurology.48 © 2009 American Academy of Neurology.
between 1% and 4%.53,54 Cerebral AVMs may become symptomatic at any time,
with a mean presentation age of 31 years.55 The most common presentation of
brain AVM is intracranial hemorrhage, followed by seizure and focal neurologic
deficits.54 In the absence of seizure or hemorrhage, focal neurological deficits
associated with initial presentation in brain AVM are uncommon.56 Although the
bleeding pattern associated with brain AVM is most often intracerebral,
subarachnoid or intraventricular hemorrhage may occur.
AVM rupture accounts for roughly 2% of all intracranial hemorrhages, yet
these patients usually have better outcomes than patients with intracerebral
hemorrhage from other causes such as primary or hypertensive hemorrhage.57
Significant morbidity and mortality have been reported after AVM rupture in
other series.58 The risk of rebleeding in patients who initially present with
rupture may approach 6% to 17% during the first year before stabilizing to
a baseline level after 3 years.59 Increasing age and hemorrhagic presentation
were noted as predictors of hemorrhage at follow-up in a large patient-level
FIGURE 10-6
Skin telangiectasias (A) and lip telangiectasias (B) in a patient with Osler-Weber-Rendu
syndrome.
Reprinted from Pikula A, et al, Neurology.48 © 2009 American Academy of Neurology.
596 APRIL 2023

meta-analysis.54 In this meta-analysis, the risk of first hemorrhage with KEY POINTS
unruptured brain AVM was 1.3% (95% confidence interval, 1.0 to 1.7) per year
● The risk of an
compared to a risk of rehemorrhage with ruptured brain AVM of 4.8% (95% asymptomatic, unruptured
confidence interval, 3.9 to 5.9).54 Other factors including deep brain location and brain arteriovenous
exclusive deep venous drainage have been associated with hemorrhage at malformation (AVM) rupture
presentation in patients with brain AVMs.60 is estimated at 1.3% per year.
Uncertainty about the natural history of unruptured AVMs and optimal
● Age and prior AVM
management options led to ARUBA (A Randomized Trial of Unruptured Brain hemorrhage are risk factors
Arteriovenous Malformations).61 This multicenter trial compared a treatment for future AVM hemorrhage.
strategy consisting of endovascular therapy, neurosurgery, radiosurgery, or a
combination of these therapies with that of conservative medical management. ● Conservative
management, endovascular
Enrollment was stopped early when an interim analysis of 226 patients (110 embolization, radiation, and
medical management, 116 medical management plus intervention) with a mean operative resection are four
follow-up of 50.4 months showed that the incidence of death or symptomatic modalities that can be
stroke was lower with medical management (15 of 110, 3.39/100 patient-years) considered in the treatment
of a patient with brain AVM
than with interventional therapy (41 of 116, 12.32/100 patient-years). In a with a multidisciplinary
subgroup analysis of patients in the ARUBA trial with unruptured brain AVM team; the modalities can be
who were symptomatic (eg, seizure, focal deficit), the point estimates for the performed either in isolation
primary outcome of symptomatic stroke or death favored medical management. or in combination.
The management of cerebral AVMs relies on one or a combination of four
modalities: conservative medical management, endovascular embolization,
microneurosurgery, and radiosurgery. The goal of intervention is to cure the
AVM via closure of the nidus and arteriovenous shunting. Among the
multidisciplinary group of clinicians who are involved in the care of brain AVM
management, lack of agreement is not uncommon.62 The Spetzler-Martin
grading scale predicts the neurosurgical risk based on the AVM nidus size,
location, and type of drainage (deep versus superficial). The endovascular
approach to brain AVM is to target high-risk elements such as intranidal
aneurysms, fistulous or high-flow feeders, as well as reducing the nidus size or
technical challenges before definitive radiation treatment or surgical resection. In
patients with brain AVM with low numbers of feeding arteries and draining
veins, endovascular cure can be achieved.
Embolization
A diagnostic angiogram is important to understand the angioarchitecture of an
AVM. Closure of the nidus with liquid embolic material rather than feeder artery
occlusion decreases the development of alternative feeder collateral channels to
the nidus.63 Staged reduction of the AVM nidus over two or three sessions
reduces the risk of edema or hemorrhagic complications related to normal
perfusion breakthrough.64 In an awake patient, selective Wada testing may
inform functional assessment of the territory under consideration for
embolization as well as reveal supply to eloquent cortex via en passage vessels.65
Under roadmap guidance, a microcatheter is advanced distally to the feeder
artery in proximity to the AVM. Angiography is analyzed for en passage supply or
cortical capillary blush. Several agents may be considered for AVM embolization.
POLYVINYL ALCOHOL. Polyvinyl alcohol particles were the first agent approved by
the US Food and Drug Administration (FDA) for intravascular use and have
been replaced by liquid embolic agents. Nidal recanalization is the main
limitation associated with particle embolization. Sorimachi and colleagues66

reported a 43% rate of AVM enlargement after particle embolization and of five
cases with complete obliteration, four had nidal recanalization.
N-BUTYL CYANOACRYLATE. n-butyl cyanoacrylate is an adhesive liquid agent that

polymerizes on contact with an ionic solution such as blood, saline, or contrast
medium. A noninferiority randomized trial demonstrated that n-butyl-
cyanoacrylate was equivalent to polyvinyl alcohol in achieving reduction of AVM
nidal volume and feeding vessels.67 The durability of AVM treatment was more
favorable in the n-butyl-cyanoacrylate group, with a lower rate of recanalization
compared to that reported with polyvinyl alcohol.67 Subsequently, the use of
n-butyl-cyanoacrylate for AVM embolization received FDA approval.
ETHYLENE VINYL ALCOHOL COPOLYMER. Ethylene vinyl alcohol copolymer is a liquid

embolic agent that exhibits slow solidification, which permits prolonged
controlled injections. Complete AVM obliteration can be achieved with
prolonged intranidal injection of the agent; however, morbidity and mortality
rates are estimated at up to 7% and 1.4%, respectively.68,69
Transvenous embolization is a relatively recent technique that may achieve
AVM obliteration, particularly in the setting of indirect feeder arteries, small
nidi, a single draining vein, or deep location.70,71 The TATAM (Transvenous
Approach for the Treatment of Cerebral Arteriovenous Malformations) trial is an
ongoing randomized trial testing the hypothesis that transvenous embolization is
superior to transarterial embolization for AVM obliteration.72
Stereotactic Radiotherapy
Stereotactic radiosurgery induces progressive occlusion of an AVM by using
high-dose targeted beams of photons or protons on the nidus. A radiation source
TABLE 10-3 Spetzler-Martin Grading Scalea
Lesion characteristic Pointsb
Size
Small (<3 cm) 1
Medium (3-6 cm) 2
Large (>6 cm) 3
Location
Noneloquent 0
Eloquent 1
Veins
Superficial 0
Deep 1
a
Modified with permission from Lawton MT, et al, Neurosurgery.75 © 2010 Wolters Kluwer Health.
b
Lower grade (lower point total) indicates a lower risk of surgical treatment.
598 APRIL 2023

delivers precise treatment using a navigation system. The AVM exposed to KEY POINT
radiation undergoes endothelial damage and thickening of the intimal layer or
● A randomized trial
sclerosis, which leads to thrombosis of the nidal vessels. There is a latency to the demonstrated that, overall,
progressive obliteration of the AVM which takes approximately 2 to 4 years. patients with unruptured
Successful obliteration with radiosurgery depends on several factors including AVMs who were
nidus volume and vessel density, radiation dose, and lesion location.73 This conservatively managed had
better outcomes than
therapy offers a noninvasive intervention; however, complete obliteration may
patients who underwent
require up to 5 years of treatment and associated parenchymal radiation injury intervention mostly with
can complicate outcomes. Radiotherapy is one of several approaches to AVM endovascular embolization.
treatment that can be an adjunctive or singular treatment for selected patients.
Microsurgery
Microsurgery by operative removal of the AVM is an important strategy in the
consideration of AVM treatment modalities. Preparation with three-dimensional
mapping of the lesion and functional cortical mapping of structures near the
nidus are usually planned. Isolation and disconnection of the feeding arteries are
performed in a circumferential manner to expose the AVM along with dissection
of the nidus from the surrounding brain parenchyma. After disconnection of all
feeders from the pial and parenchymal surfaces, the vein can be disconnected
and the nidus removed.74 The Spetzler-Martin classification estimates
neurosurgical risk by the AVM nidus size (small: 0 cm to 3 cm; medium: 3 cm to
6 cm; large: >6 cm), eloquence, and pattern of drainage (deep or superficial),
classified from Grade I to Grade VI (TABLE 10-3).75 Grade I malformations are
small, superficial, and in a noneloquent territory. Grade VI AVMs are large, deep
lesions and not operable.76
Post-ARUBA
Unsurprisingly, the ARUBA trial caused significant controversy after the release
of its results, which indicated worse outcomes in patients with unruptured brain
AVM undergoing intervention compared to medical management.77 The
neurosurgical and neurointerventional communities criticized the qualifications
of practitioners involved in the trial, selection bias of patients into the trial, and
short-term follow-up.78 In the author’s opinion, the principal investigators of the
ARUBA trial are to be commended for their response to criticisms of this trial: (1)
the investigators in the trial were experienced and prolific authors in brain AVM
publications77; (2) across 39 centers, 61% of eligible patients were enrolled and
randomized into the trial77; (3) 5-year long-term follow-up results confirmed the
1-year outcome data.61
Following the ARUBA trial results, a decrease in elective AVM interventions
has been reported.79 Subsequently, a study utilizing the National Inpatient Sample
reported an increase in brain AVM admissions after 2014 with ruptured status
compared to a preceding era (34.4% versus 13.3%, P < .001).80 These findings are to
be interpreted with caution because of the reliance on administrative coding in
National Inpatient Sample–related studies, the lower proportion of patients with
unruptured AVM being admitted to hospitals for treatment, the potential for
confounders, and the unknown denominator of unruptured brain AVM in the
outpatient setting.
In light of these findings, a patient with unruptured brain AVM should be
counseled on the natural history of the disease, the results of the ARUBA trial,
and treatment options as described above. In a patient with prior ruptured AVM,

consideration for curative treatment and discussion with a multidisciplinary

team should be the goal, particularly if there are risk factors for bleeding such as
intranidal aneurysm. In response to the ARUBA trial, the TOBAS (Trial of Brain
AVMs) study is a pragmatic, prospective, multicenter randomized controlled
trial and ongoing registry which offers a care trial context for brain AVM
treatment including conservative management, radiosurgery, endovascular
embolization and surgical resection.81 The study includes two nested randomized
trials and a multimodality prospective registry.82,83
CONCLUSION
Patients who present with unruptured brain aneurysm or brain AVM should be
counseled on the natural history of the disease and any related consequences, and
vascular risk factors should be modified. The decision to offer treatment should
take into consideration the patient’s life expectancy and comorbidities, as well as
the estimated risk of rupture of the brain aneurysm or AVM and its anatomical
features. Larger or growing aneurysms are at higher risk for future hemorrhage,
whereas larger AVMs have a higher risk of complications during treatment. No
clinical trial for the prevention of unruptured intracranial aneurysm has been
completed, although several are ongoing. A randomized clinical trial
demonstrated that preventive interventional treatment of unruptured brain
AVM posed a greater risk than conservative medical management. Conservative
management of unruptured brain AVM is therefore recommended. Patients with
a history of a prior ruptured AVM should be referred for treatment, particularly
if there are risk factors for rupture such as intranidal aneurysm.
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2015;16(1):497. doi:10.1186/s13063-015-1019-0
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Stroke Rehabilitation REVIEW ARTICLE

and Motor Recovery C O N T I N U UM A U D I O
ONLINE
By Michael W. O’Dell, MD
ABSTRACT
OBJECTIVE: Up to 50% of the nearly 800,000 patients who experience a new
or recurrent stroke each year in the United States fail to achieve full
independence afterward. More effective approaches to enhance motor
recovery following stroke are needed. This article reviews the
rehabilitative principles and strategies that can be used to maximize
post-stroke recovery.
LATEST DEVELOPMENTS: Evidence dictates that mobilization should not begin

prior to 24 hours following stroke, but detailed guidelines beyond this are
lacking. Specific classes of potentially detrimental medications should be
avoided in the early days poststroke. Patients with stroke who are unable to
return home should be referred for evaluation to an inpatient rehabilitation CITE AS:
facility. Research suggests that a substantial increase in both the dose and CONTINUUM (MINNEAP MINN)
intensity of upper and lower extremity exercise is beneficial. A clinical trial
DISEASE):605–627.
supports vagus nerve stimulation as an adjunct to occupational therapy for
motor recovery in the upper extremity. The data remain somewhat mixed Address correspondence to
as to whether robotics, transcranial magnetic stimulation, functional Dr Michael W. O’Dell, MD,
NeuroRehabilitation
electrical stimulation, and transcranial direct current stimulation are better Consultants–New York City, c/o
than dose-matched traditional exercise. No current drug therapy has been Manhattan Medicine, 300 East
proven to augment exercise poststroke to enhance motor recovery. 56th St, New York, NY 10021,
mio2005@med.cornell.edu.
ESSENTIAL POINTS: Neurologists will collaborate with rehabilitation RELATIONSHIP DISCLOSURE:
professionals for several months following a patient’s stroke. Many Dr O’Dell has received personal
compensation in the range of $0
questions still remain about the ideal exercise regimen to maximize motor to $499 for serving as an officer
recovery in patients poststroke. The next several years will likely bring a or member of the board of
directors for Franklin College of
host of new research studies exploring the latest strategies to enhance Indiana, and in the range of $500
motor recovery using poststroke exercise. to $4999 for serving on a
scientific advisory or data safety
monitoring board for Merz
Pharmaceuticals, LLC.
I
n the first hours after a stroke, neurologists work with emergency medicine PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
physicians, interventional radiologists, and neurosurgeons to minimize
Dr O’Dell discusses several
infarct size by converting ischemic penumbra to salvaged brain tissue.1 clinical trials involving the use of
That salvaged tissue then translates into the preservation of limb movement, investigational drugs, none of
which are US Food and Drug
mobility, communication, cognition, and eventually independence. While Administration (FDA) approved
neurologic interventions often focus on how damaged brain tissue relates to for use in people with stroke.
symptoms, rehabilitation interventions often focus on how symptoms relate
to performance or function. Among the numerous manifestations of stroke, © 2023 American Academy
motor recovery typically predominates rehabilitation discussions partly because of Neurology.

STROKE REHABILITATION AND MOTOR RECOVERY
of its importance in physical independence but also because it is so obvious and

observable.2,3 The distinction between motor recovery and functional recovery
in stroke rehabilitation is critical.4
Motor recovery is the partial or complete improvement of an individual’s motor
symptoms such as weakness, coordination, fine control, or ataxia. The patient
gets better. Motor recovery occurs either passively, as the hostile environment at
the site of stroke resolves,5 or actively, as a result of remedial rehabilitation
strategies (ie, exercise).4
Functional recovery, in contrast, is a partial or complete improvement in an
individual’s performance of activities of daily living (ADLs), instrumental ADLs
(eg, housekeeping, cooking, washing clothes, paying bills), mobility (eg,
transfers, wheelchair use, walking), or communication. The patient does better.4
Because functional recovery is possible even in the complete absence of motor
recovery, a summary of the therapeutic scope of rehabilitation, as it applies to
stroke, is warranted.6
FIGURE 11-1
A conceptual model of stroke rehabilitation interventions in neurology and rehabilitation
(based on the International Classification of Functioning, Disability and Health [ICF]). The
figure depicts the universe of human health (green oval) and its four domains (red boxes)
as described by the ICF: health condition or disorder (disease or cellular-level domain),
body functions and structures (symptoms or organ-level domain), activities (performance
or function or person-level domain), and participation (community and role integration of
societal domain). These domains are impacted by both environmental and personal factors
(purple boxes). Most interventions in neurology (blue box) occur at the level of treating
underlying disease to prevent the subsequent development of symptoms that might
eventually cause disability. Rehabilitation intervention (orange box) generally occurs after
symptoms related to the stroke have already developed and fall into six broad categories
(numbered green boxes).
Data from DeLisa J, et al6 and World Health Organization.9
606 APRIL 2023

Prevention of secondary, non-neurologic disability, such as using range of KEY POINTS
motion to prevent ankle contractures and minimizing bed rest to prevent
● Motor recovery is the
deconditioning, is far superior to re-establishing function once lost. Remedial partial or complete
strategies are used to directly treat symptoms resulting from a stroke such as improvement of an
weakness, aphasia, attention deficit, and dysphagia. These remedial strategies individual’s motor
are almost always based on exercise or involve methods to augment the effects symptoms such as
weakness, coordination,
of exercise and will be discussed in the following sections. Compensatory
fine control, or ataxia
strategies take advantage of the systems unaffected by stroke such as using the following a stroke.
intact, unaffected arm to eat and dress or unaffected leg to help walking.
These strategies can immediately increase performance even in the complete ● Functional recovery is a
absence of symptom resolution. An individual’s environment can be modified partial or complete
improvement in an
by using ramps, lowered counter tops, or widened doorways. Likewise, the individual’s performance of
individual’s performance can be modified using upper or lower extremity activities of daily living,
bracing, functional electrical stimulation,7 or assistive and mobility devices. instrumental activities of
To be successful, these approaches all require patient participation and the daily living (eg,
housekeeping, cooking,
recognition that rehabilitation is an active process that cannot be done to washing clothes, paying
someone. Rehabilitation therapists and physicians recognize that when bills), mobility (eg, transfers,
motivation, cognition, depression, or anxiety are barriers to learning and wheelchair use, walking) or
patient participation in exercise, those barriers must be addressed using a communication.
range of techniques.6
All therapeutic strategies are important and necessary in stroke rehabilitation.8
For patients in the early stages after severe stroke, compensatory techniques are
mandatory to maximize independence, minimize burden of care, and facilitate
home discharge in an environment of increasingly short hospital stays.
Remediation, on the other hand, tends to predominate in mild to moderate stroke
and in the outpatient setting.8 Rehabilitation and neurologic interventions for
symptoms and function are best conceptualized within the context of the World
Health Organization’s International Classification of Functioning, Disability and
Health (FIGURE 11-1).9
Any review of stroke rehabilitation and recovery must necessarily be limited
in scope. This article presents the topic in three sections: (1) rehabilitation issues
the neurologist will encounter in acute care, (2) a narrative of what occurs during
the inpatient and outpatient stroke rehabilitation, and (3) a review of the
principles of exercise in stroke rehabilitation and the main strategies to enhance
exercise in stroke recovery.
REHABILITATION ISSUES IN ACUTE CARE

In acute care, the rehabilitation team will vary by hospital and by the severity
and specific deficits of each patient. The complicated nature of rehabilitation
treatment requires the subspecialization of therapists into the disciplines of
physical therapy, occupational therapy, and speech-language pathology. The
updated American Heart Association/American Stroke Association (AHA/ASA)
2018 Guidelines for the Early Management of Patients With Acute Ischemic
Stroke recommends a “formal assessment” by each of these disciplines before
discharge from acute care.1 In reality, rehabilitation therapists commonly
“cross-treat” impairments from other disciplines, especially cognitive and
communication deficits that impact learning and participation. For all
disciplines, a clear understanding of a patient’s baseline level of function is
critical given that recurrent stroke and medical comorbidities often contribute to
some degree of pre-admission deficits.

The Acute Care Rehabilitation Team

Physical therapists address a patient’s mobility, whether the patient is lying in
bed, using a wheelchair, or walking. Assessment of safety awareness, fall risk,
and the ability to multitask physical and cognitive demands simultaneously all
potentially impact discharge disposition. Physical therapists assess if patients
need a handheld mobility device, which depends on the extent of hemiparesis,
balance deficit, and other presentation specifics such as lateropulsion.10 Ankle
bracing is often deferred to an inpatient rehabilitation facility or the outpatient
setting. Careful positioning and frequent repositioning of the arms and trunk by
medical staff will minimize soft tissue shortening, shoulder subluxation, and
plantarflexion contracture (ie, foot drop).11 Occupational therapists evaluate the
relative contributions of weakness, sensory loss, incoordination, apraxia,
neglect, and cognition in performing a range of self-care activities. Safety
awareness during transfers, toileting, and standing ADLs are also particularly
important to a patient’s discharge disposition. Upper extremity loss of joint range
at the fingers and wrist can be minimized with a resting splint set in slight wrist
extension to help offset the flexor tendon shortening that occurs with
hypertonia. Arm support using a pillow or wheelchair tray is always preferred
over a sling, which only promotes unwanted adduction and internal rotation
tightness at the shoulder.12 Occupational therapy expertise in visual and
cognitive assessment may be diagnostically valuable to the neurologist should the
discovery of subtle visual deficits or unexpected cognitive findings occur during
higher-level functional activities.
Speech-language pathologists assess and treat communication deficits
stemming from impairments in language (aphasia), articulation and phonation
(dysarthria), motor planning (verbal apraxia), or from underlying cognitive
deficits.13 These impairments often coexist. The 2021 VERSE (Very Early
Rehabilitation for Speech) clinical trial found that a high-dose language
intervention (an extra 20 aphasia treatment sessions starting before day 15 and
ending before week 4) was no better or worse than usual care.14 Speech-language
pathologists are also key team members in screening for and treating
stroke-related swallowing dysfunction.15 Although the 2018 AHA/ASA
guidelines cited insufficient data,1 a more inclusive 2021 meta-analysis concluded
that dysphagia screening in acute stroke care was associated with lower risk of
pneumonia, death, and dependency.16
Physiatrists (physical medicine and rehabilitation physicians) work
closely with therapists to identify factors—whether medical, neurologic,
musculoskeletal, or psychological—limiting the mobilization of the patient
with acute stroke and to strategize how to effectively overcome these factors.
With training grounded in the management of neurologic, cardiopulmonary,
and musculoskeletal disability, physiatrists are well positioned to collaborate
with neurologists to evaluate, differentiate, and manage primary and secondary
disability in both the acute and chronic stages of stroke. Physiatrists also
advise neurologists in the complicated process of determining discharge
disposition.17
Acute Care Interventions

An area of debate is the timing to safely begin mobilization exercises after acute
stroke. Early brain plasticity and avoidance of the complications of bed rest and
immobility are benefits of early mobilization.18 However, AVERT (A Very Early
608 APRIL 2023

Rehabilitation Trial After Stroke) found that starting mobility training within KEY POINT
24 hours after stroke decreased the odds of achieving a favorable modified
● Although further research
Rankin Scale (mRS) score (defined by ≤2 at 3 months) compared with standard is clearly required, the 2018
care.18 Stroke progression and 14-day mortality were also more common in the American Heart
early mobilization group, with the greatest risk in patients aged older than Association/American
80 years and in those with intracranial hemorrhage.19,20 Compared with the usual Stroke Association
guidelines recommend that
care group, the treatment group initiated sitting, standing, and walking earlier
specialized acute stroke
(18.5 versus 22.4 hours poststroke), more frequently (6.5 versus 3.0 sessions), and units “incorporate
for longer (31 versus 10 minutes per day). No differences were found in patients rehabilitation” into their
who received or did not receive thrombolysis therapy, and data suggested that care and discourage
mobilization prior to
while increased exercise intensity (more minutes) may be detrimental to
24 hours poststroke, but
outcome, increased frequency (more sessions) may actually be beneficial.19 The otherwise make only very
AMOBES (Active Mobility Very Early After Stroke) trial found no benefit to general recommendations.
high-intensity (45 versus 20 minutes) daily physical therapy initiated within
72 hours of stroke, but was likely grossly underpowered, and the sample was
over-represented by participants with severe stroke.21 Although further research
is clearly required, the 2018 AHA/ASA guidelines recommend that specialized
acute stroke units incorporate rehabilitation into their care and discourage
mobilization prior to 24 hours poststroke, but otherwise make only very
general recommendations.1 Until more clinically useful early mobilization
guidelines are widely available,20 acute care rehabilitation goals should include
safely initiating mobilization; monitoring the stability and functional impact of
motor, sensory, language, and cognitive deficits; preventing musculoskeletal,
pulmonary, and skin complications; and preparing the patient and family for the
next phase of rehabilitation, whether that be in an inpatient or outpatient
setting.19
The pharmacologic enhancement of recovery from stroke (see Exercise
Approaches section) has received much attention22-24; however, from the early
animal studies by Feeney and colleagues,25 certain medication classes have also
been considered detrimental to recovery.26-29 On the basis of both clinical and
animal data, detrimental classes commonly include benzodiazepines,28,30
first-generation antipsychotic medications,25,28 centrally acting antihypertensive
agents,28 and the antiepileptic agents phenytoin and phenobarbital.31,32 Avoiding
these medication classes during acute stroke care is especially critical given the
greatest impact is likely to occur early after stroke presentation and in those with
more severe injury.26,31
Outcome prediction after stroke and the natural history of stroke are
somewhat related topics, and both are of great importance to patients and
society.33 It is generally accepted that most natural motor recovery occurs during
the first 3 to 6 months poststroke and then the patient achieves a plateau.26 Some
authors maintain that motor recovery can continue up to a year.34 Defining a
plateau at the functional or activity level is especially confounded by the ceiling
effects of assessment scales, definitions of “clinically significant,” and important
change at the individual level not captured when analyzing mean change across
groups.35 A variety of methods (clinical, technologic, and imaging)36 have been
used in the first week poststroke to predict recovery at both the impairment and
activity levels.37 One of the best-known methods is the Predicting Recovery
Potential (PREP) algorithm, which combines clinical assessment of shoulder
abduction and finger extension along with neuroimaging and neurophysiologic
assessment to predict Action Research Arm Test scores at 12 weeks poststroke.38

The widespread use of electronic health records makes a recently described

computerized method using only repeated shoulder abduction and finger
extension assessments to predict 6-month Action Research Arm Test scores
particularly appealing.33 This is usually the Fugl-Meyer Assessment, with scores
ranging from 0 to 66 for the upper extremity. For example, if the initial
Fugl-Meyer Assessment in acute care is 32/66, then the patient can be expected to
gain 70% of the remaining points on the scale (about 24) and achieve a maximum
score of about 56 within 3 to 6 months. However, the calculation is accurate in
only about 70% of people with stroke (the so-called “fitters”).39 Imaging has been
suggested to help distinguish “fitters” from “nonfitters.”40 Although appealing,
the theory has been widely criticized based on mathematical coupling,41,42 poor
applicability in severe impairment,43 significant sensitivity to ceiling effects,41,42
and poor discrimination with quality-of-life measures.44
Inpatient Rehabilitation Referral

Whether to transfer to inpatient rehabilitation is among the final decisions for a
patient with moderate or severe stroke on the acute neurology service. Occurring
a mean of only 9 days after admission to acute care in the United States,45 transfer
to rehabilitation can be complicated by confusion, contradiction, and
inconsistency because of an uneven availability of acute rehabilitation beds,
variable insurance criteria, complicated referral patterns, and a myriad of federal
regulations for these diagnosis-related group–exempt rehabilitation units.17
Although patient preferences should be taken into consideration, neurologists
should clearly understand and educate their patients on the differences in care
provided by an inpatient rehabilitation facility and skilled nursing facility or
“subacute” rehabilitation unit. In an inpatient rehabilitation facility, federal
oversight guarantees an intensity of rehabilitation therapy, nursing staffing,
physician oversight, and team coordination that rarely exists in a skilled nursing
facility. Using sophisticated statistical modeling to minimize referral biases, a
comparison of more than 33,000 inpatient rehabilitation facility and 66,000
skilled nursing facility Medicare beneficiaries undergoing stroke rehabilitation
found double the gains in self-care and mobility among the inpatient
rehabilitation facility group compared with the skilled nursing facility group.46
The difference in self-care was the equivalent to that of requiring maximal
assistance from another person versus needing only another person present but
no physical assistance (ie, needing continued institutionalization among the
skilled nursing facility group versus ready-for-home discharge for the inpatient
rehabilitation facility group).46 Other studies have underscored the value of
organized inpatient stroke rehabilitation in maximizing functional status,
minimizing medical complications, decreasing 30-day readmission rates, and
reducing mortality.47-49 The 2016 AHA/ASA Guidelines for Adult Stroke
Rehabilitation and Recovery state that, when available, all patients with stroke
who cannot return home should be evaluated for an inpatient rehabilitation
facility at the conclusion of an acute hospitalization.50 In 2021, the AHA/ASA also
put forth an acute care stroke rehabilitation performance measure stating that
“[p]eople with stroke who qualify for, would benefit from, and have geographic
access to [inpatient rehabilitation facility] IRF care should receive acute inpatient
rehabilitation in an IRF.”51 Based on evidence and guidelines, it is appropriate for
the neurologist to advocate for their patients with stroke who cannot return
home to receive inpatient rehabilitation facility assessments. Admission to a
610 APRIL 2023

skilled nursing facility, without inpatient rehabilitation facility consideration, KEY POINT
only for the sake of expediency to decrease acute care lengths of stay, to maintain
● Admission to a skilled
historical referral patterns, or to prevent “bleed” outside of a constituent health nursing facility, without
care system should be viewed as incompatible with best practices. That said, the inpatient rehabilitation
intensity of an inpatient rehabilitation facility naturally excludes some patients facility consideration, for
with stroke who are medically or cognitively unable to participate. These the sole purpose of
decreasing acute care
individuals are more suitable for skilled nursing facility–based rehabilitation
lengths of stay, maintaining
programs and include patients with concomitant neurologic disease like historical referral patterns,
dementia or moderate Parkinson disease or significant medical issues such as or preventing “bleed”
poorly controlled congestive heart failure or pulmonary disease, active cancer, outside of a constituent
health care system should
advanced bilateral lower extremity osteoarthritis, or peripheral vascular disease
be viewed as incompatible
in the setting of poor surgical risk. with best practices.
In summary, rehabilitation plays an increasingly important role during the
first several days following a stroke as a patient becomes medically and
neurologically stable. A variety of rehabilitation professionals will use both
remedial and compensatory strategies to gradually mobilize a patient and help
the neurologist to monitor motor and functional stability and recovery. The
neurologist can avoid detrimental medications that may slow recovery and
should feel confident in advocating for an inpatient rehabilitation facility
evaluation before discharge for patients who cannot return home. At the
conclusion of acute care, about 44% of patients with stroke will be discharged to
some type of inpatient rehabilitation and another 12% will be discharged home
with home care.51 Earlier initiation of transfer to inpatient rehabilitation, when
possible, is likely beneficial.52 In addition, many patients with stroke will
participate in an outpatient rehabilitation program on discharge from acute care
or after an inpatient rehabilitation stay. Although acute stroke care has been far
better developed than post–acute stroke care in the United States,53 patients with
stroke can expect to enter a new phase of treatment and recovery postdischarge
that will potentially last several months and introduce them to new rehabilitation
providers and settings (CASE 11-1).
INPATIENT AND OUTPATIENT REHABILITATION

Perhaps no better manifestation of “health care team” exists than what occurs
during an inpatient rehabilitation facility stay. Lead by a physiatrist (or similarly
qualified physician), a group of up to seven disciplines provides highly
coordinated medical, physical, and psychosocial care over 3 to 4 hours of therapy
and 20 to 21 hours of nursing care, 6 days a week for 1 to 3 weeks. Rehabilitation
nursing serves as the glue that holds together the inpatient rehabilitation facility
experience. These nurses, many of whom are certified rehabilitation registered
nurses, have additional training and expertise in recognizing cognitive and
language impairments and in managing and preventing bowel, bladder, and skin
complications. In addition to providing traditional medical nursing, they
integrate ADLs and toileting, transfer, and mobility skills learned during
rehabilitation therapies into the remainder of the day. Physical and occupational
therapists and speech-language pathologists build on the treatments discussed
above in the acute care setting. Greater emphasis is placed on improving activity
endurance, strengthening, and cognitive task demands. Far more time and
emphasis are placed on the treatment of language disorders at an inpatient
rehabilitation facility compared with acute care. Likewise, dysphagia treatment
starts in earnest, including muscle strengthening exercises, peripheral

stimulation, and compensatory techniques.54 Nutritionists help track caloric

needs in the setting of potential dysphagia, depression, chronic illness, and other
conditions impacting intake and appetite. Therapeutic recreation provides
structured treatment for cognitive, motor, and language impairments during
social interactions disguised as enjoyable “nonmedical” activities. Screening by
neuropsychologists not only delineates the scope of cognitive deficits, but also
provides guidance for therapists in areas of cognitive weakness for remedial
therapy and strengths to leverage compensatory strategies. Social work assumes
dual roles of logistics for discharge planning and psychological counseling for
patients and their families at, perhaps, one of the most stressful times in
their lives.
The medical philosophy at an inpatient rehabilitation facility is quite different
from the rest of the hospital. Referring and consulting physicians are sometimes
perplexed that procedures and conditions easily accomplished and treated on a
medical floor are challenging at an inpatient rehabilitation facility. Succinctly
put, patients are admitted to an inpatient rehabilitation facility primarily to be
mobilized rather than receive medical care (although a great deal of medical care
is typically provided). Any condition, development, or workup detracting from
that mobilization must be addressed off the unit. If the patient cannot move (ie,
CASE 11-1 A 65-year-old man presented to the emergency department with a blood
pressure of 190/140 mm Hg, a severe left hemiparesis, and moderate
dysarthria. He had woken up that morning with left-sided weakness but
decided to “wait it out” until lunch, when his speech began slurring. He
had previously been independent. MRI showed a large right middle
cerebral artery infarction, and he was past the window for thrombolysis.
The patient was admitted for blood pressure control and evaluation. A
swallowing screen performed by a speech-language pathologist
indicated silent aspiration, and a modified diet with thickened liquids was
ordered. Physical and occupational therapies were initiated after
24 hours, revealing that moderate assistance was required for dressing,
toileting, transfers, and walking, which was complicated by neglect and
poor safety awareness. Inpatient rehabilitation was recommended and
the patient was transferred to an inpatient rehabilitation facility. At
5 days poststroke, progress was initially limited by shoulder pain,
managed by an occupational therapist with taping, and by depression,
treated by a physiatrist with pharmacotherapy. The speech-language
pathologist focused on exercises to strengthen muscles for both
swallowing and articulation, with good results. Robotics were used to
enhance lower extremity exercise and functional electrical stimulation
was used to enhance upper extremity exercise. After 16 days, the patient
was discharged home from inpatient rehabilitation able to walk with a
cane and supervision and needed assistance only for lower extremity
dressing. He was on a regular diet and liquids and speech intelligibility
was 90%.
The patient initiated an outpatient rehabilitation program 3 days a
week with a speech-language pathologist, physical therapist, and
612 APRIL 2023

attend and participate in rehabilitation therapies), they cannot remain at an
inpatient rehabilitation facility; therefore, in addition to leading the
rehabilitation team, the essential task of the attending physiatrist is to ensure
that patients at the inpatient rehabilitation facility are medically stable
and free of pain and mood disturbances or other issues so that they can
participate in therapy, remain on the unit, and benefit from the rehabilitation
experience.
Most patients will see at least some, if not substantial, functional progress
during a typical 1- to 3-week inpatient rehabilitation facility stay. Patients and
families should understand that rehabilitation admissions are relatively short. In
the United States in 2021, the mean length of stay at inpatient rehabilitation
facilities for patients with stroke was 14.1 days.45 Patients in an inpatient
rehabilitation facility will probably see more progress and independence with
walking and mobility than with ADLs and self-care. An assistive device for
mobility may still be required at discharge (or even hands-on assistance of a
family member), but most patients will be able to get around in their home. In
their 2020 study, Moore and colleagues55 implemented a high-intensity stepping
protocol during inpatient rehabilitation. By increasing the total number of daily
steps by 32% and achieving 70% to 85% of the maximum heart rate, the
occupational therapist, who used transcranial direct current stimulation

in his treatment program. A left ankle-foot orthosis was prescribed to
facilitate walking. Outside of therapy sessions, the patient joined a
walking group to increase cardiovascular fitness. Although the recovery
of his strength was not complete, he was independent in walking without
an assistive device (although slow) and independent in all activities of
daily living (primarily with the right hand using the left hand as an assist).
This case demonstrates several key aspects of stroke rehabilitation and COMMENT
recovery. Prevention of further disability is illustrated by dysphagia
screening to minimize aspiration pneumonia. Mobilization should be
initiated only after 24 to 48 hours poststroke with safety awareness being a
priority, which is important in discharge planning. All patients with stroke
who cannot return home should be evaluated for an inpatient rehabilitation
facility. Stroke recovery is dependent on exercise, and exercise is an active
process contingent on participation. Pain, mood disorders, and medical
instability are frequently barriers to participation and must be addressed
when they occur. A variety of strategies were used during inpatient and
outpatient rehabilitation to enhance poststroke exercise in his care
including robotics and transcranial direct current stimulation. Although this
patient had an incomplete motor recovery, he did have a nearly complete
functional recovery.

high-intensity group achieved faster gait speeds and better balance and
endurance at inpatient rehabilitation facility discharge. Likewise, another
2020 study showed increased stepping activity during an inpatient
rehabilitation facility stay led to better outcomes even a year later.56 The
degree of independence achieved in ADLs is more variable and depends on the
severity of impairment, side of weakness, and hand dominance. A reasonable
degree of independence can be expected, with mild weakness in the dominant
arm or any degree of weakness in the nondominant arm. An accurate prediction
is elusive because patterns of proximal and distal weakness, the degree of sensory
deficits, coordination, apraxia, and cognitive and communication status all play a
role in the final level of independence. Gains made during the inpatient
rehabilitation facility stay are predictive of both short-term disability57 and
long-term mortality.58 In about 10% of cases, a patient with stroke will be
discharged from an inpatient rehabilitation facility to a skilled nursing facility.45
Reasons for this include the family being unable to provide care at home or the
patient awaiting return of bowel or bladder continence, needing cognitive
supervision despite good physical recovery, or having a specific physical barrier
at home (eg, bathroom on the second floor or a three-story or four-story walk-up
apartment in urban areas.)
Most patients discharged from an inpatient rehabilitation facility to home will
continue rehabilitation in an outpatient setting. This could include one to three
therapies two to three times a week for a few weeks or a few months. As detailed
in the following section on exercise approaches, this likely represents a gross
underdosing of therapy.59-61 The program will likely continue strengthening and
improvement of fine motor coordination, but cardiovascular conditioning and
high-level balance training will also become a greater focus. Aerobic conditioning
is important not only from a recovery standpoint, but also from a secondary
stroke prevention perspective.62,63 Patients will also be expected to carry out a
home exercise program under the supervision of their therapist. Most outpatient
therapy will be remedial. A long-term challenge for any person with stroke is
actually using their affected extremities, especially when the nondominant upper
extremity is involved. While understandable (ie, using a weak, possibly
insensate, uncoordinated hand can be slow, unsightly, embarrassing, and
frustrating), this barrier of “learned nonuse,” as posited by Taub,64 becomes a
major obstacle to the patient and rehabilitation team. Potential function in an
affected limb lies fallow as a patient gradually “learns” it is easier and more
efficient to use the unaffected limb. The rehabilitation process itself may
inadvertently contribute to learned nonuse if compensation is overly emphasized
relative to remediation.
A variety of other rehabilitation-related events may occur in the outpatient
setting. The use of an ankle-foot orthosis or other brace may occur at this time,
depending on the relative presentation of anterior leg dorsiflexion weakness
versus posterior leg plantarflexion spasticity. Botulinum toxin treatment can be
considered in the latter case.65 For individuals with reasonable cognitive ability
whose mobility has not improved to the point of community ambulation, an
assessment for a scooter or power mobility may be appropriate. In addition to
physiatry, physician referrals to urology for bladder management, psychiatry for
severe depression or anxiety, and orthopedic surgery for upper or lower
extremity tendon releases may be appropriate if there are intractable hygiene
issues or unmet function goals.
614 APRIL 2023

EXERCISE-BASED STRATEGIES TO ENHANCE MOTOR RECOVERY KEY POINTS
AFTER STROKE
● In addition to leading the
Much of the rehabilitation experience—whether inpatient, outpatient, or at rehabilitation team, the
home—as it relates to motor recovery after acute care discharge revolves around essential task of the
exercise. Some of the recovery following stroke occurs passively, without attending physiatrist is to
exercise, with the resolution of acute edema and diaschisis and normalization of ensure that patients at the
inpatient rehabilitation
cell properties, ion levels, and neurotransmitters in the immediate vicinity of the
facility are medically stable
infarction.5,66 The physiologic basis of motor recovery resulting from active and free of pain and mood or
exercise is beyond the scope of this discussion66 but includes axonal sprouting,67 other issues to the degree
long-term potentiation, so-called “hebbian plasticity,”66 unmasking of latent that they can participate in
therapy, remain on the unit,
tracts,5 and cellular proliferation zones.68 In 2019, Maier and colleagues69
and benefit from the
outlined 15 principles of neurorehabilitation after stroke (TABLE 11-1). Although rehabilitation experience.
all are important, two principles seem to be the most consistently cited as
defining an effective exercise program following stroke: task-specific exercise ● Most patients discharged
and repetition or mass practice.26,69,70 For a hand to recover, muscles of the hand from an inpatient
rehabilitation facility to
specifically must be repeatedly exercised. For walking to improve, the muscles home will continue
involved in walking must be exercised extensively. Other important aspects of rehabilitation in an
exercise after stroke include variability (both within and between sessions), outpatient setting. This
increasing difficulty, simultaneous sensory stimulation (visual, auditory, haptic), could include one to three
therapies, two to three
and explicit feedback on performance.69 If the characteristics and content of times a week from a few
exercise constitute the science of stroke rehabilitation, equally important must be weeks to a few months,
the art of rehabilitation as practiced by an outstanding therapist. Key is a which likely represents a
therapist’s ability to tailor exercises to individual patients at a level that is gross underdosing of
therapy.
challenging but not overly frustrating; to provide assistance when needed, but
only just enough to finish that repetition; to choose short-term and long-term ● If the characteristics and
goals that progressively achieve the next functional level but not too aggressively content of exercise
or easily; and to provide constant encouragement and positive feedback.69 This constitute the “science of
personalized interaction between patient and rehabilitation therapist is simply stroke rehabilitation,”
equally important must be
the secret ingredient that may never be fully elucidated or accurately or the “art of rehabilitation” as
consistently replicated in any clinical trial of motor recovery following stroke. practiced by an outstanding
As suggested below, the requirement of active engagement in exercise therapist.
following stroke inherently carries a presumption of participation. The
● Significant questions
management of this aspect of stroke rehabilitation is overlooked and remain surrounding the ideal
underappreciated. In the inpatient setting, medical complications like orthostatic exercise protocol following
hypotension, underlying cardiac and pulmonary disease, and preventable stroke, despite numerous
complications like deep venous thrombosis and infections of the lungs and large clinical trials over the
past 2 decades.
bladder often limit participation. It falls to the physician on the team to prevent
and treat these conditions. In both the inpatient and outpatient realms, any type
of pain must be diagnosed and treated promptly with a regimen having the least
possible impact on cognition. If depression, anxiety, or poor initiation limit active
participation, motivational techniques, counseling, or medications must be
considered to maximize participation as quickly as possible. Frustration, anger,
inadequate coping skills, and poor adjustment to disability are other factors that
can undermine participation on a given day or over a longer time. Close
communication, coordination, and management among therapists and
physicians is required to identify and minimize the impact on progress.
Exercise Approaches
Regardless of whether the upper2 or lower limb is predominantly affected,70 few
patients with stroke experience a full recovery. Significant questions remain

surrounding the ideal exercise protocol following stroke, despite numerous large
clinical trials over the past 2 decades. As mentioned previously, the AVERT
Trial18 demonstrated that exercise delivered too soon after stroke can be
detrimental. The VECTORS (Very Early Constraint-Induced Movement during
Stroke Rehabilitation) trial71 compared high-intensity constraint-induced motor
therapy to dose-matched constraint-induced motor therapy and usual care in an
inpatient rehabilitation facility setting. While no difference was found between
the usual care and dose-matched constraint-induced motor therapy groups, the
high-intensity constraint-induced motor therapy group had a worse outcome,
demonstrating that more exercise is not always better. The 2021 CPASS (Critical
Period After Stroke Study) provided an additional 20 hours of therapy at three
TABLE 11-1 Fifteen Principles of Neurorehabilitation Exercisea,b
Neurorehabilitation Exercise
Principle Definition Examples
Massed practice (repetitive Exercise episodes with very brief to no Assuring that an adequate number of
practice) rest breaks; prolonged and repeated use repetitions of a given movement are
of the more affected limb implemented over a course of treatment to
achieve a given goal
Spaced practice Training is structured to provide rest The use of objective or subjective
break between repetitions or sessions assessments or a predetermined schedule
to provide rest breaks during a therapy
session
Task-specific practice Conditions during training should match Aligning an exercise program with the
the conditions during testing (or most-impaired limb or muscle groups, or
performance) with the goal of a specific functional task
Dosage Multiple dimensions: number of training Increasing the intensity, frequency, or

hours per time period, frequency and complexity of exercises over time to
duration of training sessions, intensity increase difficulty or variability over time
Goal-oriented practice Motor training to achieve a goal (eg, Therapists negotiating reasonable and
combing one’s hair) is more effective attainable functional goals for an individual
than training the individual muscles session or over the course of several
and movements required to complete sessions
the task
Variable practice Providing variable tasks (or intensity) A therapist randomizing the types,
within (and between) training session(s) difficulty, and nature of exercise during a
given session and between sessions
over time
Increasing difficulty Increasing the difficulty of a task in “Shaping” in constraint-induced motor

relationship to the skill of the performer therapy; increasing resistance or
repetitions of exercises over time;
integrating individual limb movement into
more complex activities of daily living
Multisensory stimulation The perception and integration of one or Haptic, visual, and auditory stimuli utilized in
more senses during the performance of upper extremity robotics and brain-
an action computer interfaces; use of a mirror to
visualize movement during therapy
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different time periods during the first year after stroke compared with a
control.72 The additional dose delivered 2 to 3 months following stroke yielded
greater gains at 1 year compared with doses delivered earlier than 30 days, after
6 months, or in the control group.
Therefore, the timing of exercise after stroke also matters. Over the past
2 decades, several variations on a standard poststroke exercise program have
been examined. One of the few proven treatments for motor recovery following
stroke is constraint-induced motor therapy. Designed to thwart learned nonuse,64
classic constraint-induced motor therapy forces a huge amount of use in the
affected upper extremity over a short period of time (about 2 weeks). The
EXCITE trial demonstrated that, compared with usual and customary care,
Neurorehabilitation Exercise
Principle Definition Examples
Rhythmic cueing Synchronizing (training) movements to Use of a metronome to initiate or increase

rhythmic patterns speed to a repetitive movement; use of
regular tones to facilitate gait in Parkinson
disease or for persons with stroke on a
treadmill
Explicit feedback or knowledge Verbal, terminal, or augmented feedback A therapist providing detailed feedback to
of results about goal achievement a participant regarding the quality or
accuracy of a movement or task
Implicit feedback or knowledge Verbal descriptions, demonstrations, Biofeedback; use of sound or visual colors
of performance or replay of recordings of movement when an action crosses a minimal
execution as feedback threshold; use of virtual reality technology
Modulate effector selection The tendency to overuse the Constraint-induced motor therapy;
nonimpacted extremity while underusing overutilizing compensatory over remedial
the impacted extremity strategies
Action observation or embodied Observing the movement of another A therapist demonstrating to a participant a
practice individual to improve the participant’s given action or task prior to actual attempt
movement
Mental practice or mental imagery Mentally simulating actions without overt Participant imagining a given movement
behavior of the movement prior to or independently of an actual
exercise in therapy
Social interaction Behavior in which the participant’s Friends and family encouraging both
actions are both a response to and a training and the goal of independence;
stimulus for the counterpart’s behavior development of a therapeutic alliance
between a participant and therapist;
recovery in an enriched environment
a
Data from Maier M, et al, Front Syst Neurosci.69
b
In practice, there is overlap among these 15 principles and research has often not been able to isolate a specific principle for study. Some of the
evidence for these principles was derived from the study of healthy individuals. The schema provides a framework for the description and
understanding of exercise (and experience) after stroke, and other neurologic conditions or injuries.

constraint-induced motor therapy led to significant gains in the use of the

affected arm in 222 participants 3 to 12 months poststroke and that gains lasted
2 years after the trial.73,74 Despite this, constraint-induced motor therapy is labor
intensive (6 hours a day, 5 days a week, for 2 weeks), expensive, logistically
challenging, and very frustrating for the patient; therefore, modified
constraint-induced motor therapy designs have been proposed75 but not widely
implemented. Among patients with voluntary finger extension, modified
constraint-induced motor therapies initiated about a week poststroke and lasting
5 weeks were beneficial for up to 12 weeks but were not sustained at 26 weeks.76
The ICARE (Interdisciplinary Comprehensive Arm Rehab Evaluation) trial
compared three rehabilitation approaches: a structured, task-oriented, upper
extremity training program of 30 hours over 10 weeks; a dose-matched
occupational therapy program; and monitoring of those among 361 participants
who were a mean of 46 days poststroke with moderate impairment.77 No
significant differences were found in the primary outcome measures among the
three groups.
Recent studies using much higher doses of exercise have reported more
favorable results. The Queen Square program60 provided 90 hours of therapy
over 3 weeks in 224 participants with chronic stroke (median time poststroke was
18 months) with significant gains in impairment and activity lasting 6 months
after the trial. Combining these data with the less intense therapy provided in the
Rehabilitation Gaming System dataset, Ballester and colleagues61 retrospectively
reported greater Fugl-Meyer Assessment gains with greater intensity
rehabilitation and when initiated earlier following stroke. A 2019 trial by Cramer
and colleagues59 found that among 124 participants who were 4 to 36 weeks
poststroke and who were randomly assigned to 36 sessions (70 minutes each over
6 to 8 weeks), therapy delivered via telerehabilitation was noninferior to that
delivered in clinic. Collectively, these studies suggest current clinical practice
significantly underdoses upper limb rehabilitation following stroke. Regarding
the lower extremities, the LEAPS (Locomotor Experience Applied Post Stroke)
trial compared 54 hours of body weight–supported treadmill training over 12 to
16 weeks either 2 or 6 months poststroke to standard home physical therapy
2 months poststroke.78 Again, no difference was seen between the three groups
regarding walking speed, motor recovery, balance, or quality of life at 1 year
poststroke. Like the upper extremity, lower extremity and ambulatory strategies
focus on increased stepping (with or without orthotics) and higher exercise
intensities and, possibly, the use of mechanical devices in more severe
impairment (see the following section on robotics).70 Other recent novel
variations on poststroke exercise with favorable initial results include mirror
therapy79 and virtual reality.80
Given the challenges, expense, and logistics of providing ever greater doses of
exercise, identifying strategies to augment the effect of exercise on recovery after
stroke is desirable. This perhaps has been the most active area of research in
stroke recovery, ranging from the acute through the chronic phases. And yet,
what has been broadly consistent since the time of Feeney and colleagues’25
animal drug studies 40 years ago is that active exercise is still the crucial
component and the active ingredient in stroke recovery. With only a few notable
exceptions,81 technologic, mechanical, or biological strategies have been
implemented as an adjunct to active exercise. Categories of strategies to augment
the impact of exercise include pharmacologic enhancement, robotics, functional
618 APRIL 2023

electrical stimulation, neuromodulation (invasion and noninvasive), and others, KEY POINTS
including regenerative techniques.82
● Given the challenges,
expense, and logistics of
Pharmacologic Approaches providing ever greater doses
The search for a “magic pill” to cure motor deficits after stroke is appealing but of exercise, identifying
has remained elusive. The mechanisms by which medications facilitate recovery strategies to augment the
effect of exercise on
could include changes at a physiologic level by enhancing plasticity82 resulting
recovery after stroke is
from exercise or at a behavioral level by facilitating better attention or motivation desirable.
resulting in better participation or enhanced mass practice.24 Among the older
studies, initial reports of dopamine agonists such as amphetamine and levodopa ● To date no pharmacologic
were encouraging, but subsequent trials failed to replicate the initial results.22,24 agents in well-designed
randomized clinical trials
In 2019, the large, well-designed randomized clinical trial of co-careldopa have clearly demonstrated
during early rehabilitation (DARS [Dopamine Augmented Rehabilitation in enhanced motor recovery
Stroke]) failed to demonstrate an impact on independent walking or most after stroke.
secondary outcomes.83 Two small studies reported mixed results with the
acetylcholinesterase inhibitor donepezil.24 Great enthusiasm was generated by
the 2011 FLAME (Fluoxetine for Motor Recovery After Acute Ischaemic Stroke)
trial, which demonstrated impressive upper and lower extremity motor gains
associated with the selective serotonin reuptake inhibitor (SSRI) fluoxetine.84
This optimism has been dispelled over the past few years with the subsequent
publication of three very large clinical trials: AFFINITY (Assessment oF
FluoxetINe In sTroke recoverY),85 EFFECTS (Efficacy oF Fluoxetine-a
randomisEd Controlled Trial in Stroke),86 and FOCUS (Effects of Fluoxetine on
Functional Outcomes After Acute Stroke)87; all three studies failed to
demonstrate a difference between the fluoxetine and placebo groups on the mRS
at 6 months and two of the three studies failed at 12 months. Solid criticisms of
these trials include the failure to couple medications with active exercise3 and
reservations in using the mRS as a primary outcome measure.3,88 Finally, a 2020
large randomized clinical trial of S44819 (a γ-aminobutyric acid [GABA] α-5
antagonist) in participants 2 to 6 days poststroke revealed no therapeutic effect
between placebo and two different doses on mRS at 90 days.89 Thus, to date no
pharmacologic agents in well-designed randomized clinical trials have clearly
demonstrated enhanced motor recovery after stroke.
Robotics
Robotics have been implemented in stroke recovery for nearly 2 decades for both
the upper and lower extremities.90 Robots can be either wearable (exoskeletons)
or end effectors (ie, essentially used as a piece of exercise equipment).91 As end
effectors, advantages include a huge increase in the number of repetitions and
better participation by using enjoyable games and visual, auditory, and haptic
stimulation. Some devices also collect objective kinematic data and other
parameters to track progress. On the downside, these devices tend to be very
expensive.90 The clinical data on robotics are underwhelming, with most studies
and meta-analyses finding their efficacy no better than dose-matched usual care.
The 2019 RATULS (Robot Assisted Training for the Upper Limb After Stroke)
trial92 did not find upper extremity robotics treatment better than dose-matched
traditional rehabilitation therapy or usual care. Two other recent upper extremity
robotics clinical trials reported similar findings.93,94 There may be an advantage
to lower extremity robotics in patients with severe stroke.70,91 Clinical data on the
use of exoskeleton devices in stroke are scant, and their roles are unknown at this

time.95,96 Despite an underwhelming track record, upper and lower extremity

robotics and exoskeletal devices are commonly offered at larger rehabilitation
centers.
Functional Electrical Stimulation

Neuromuscular stimulation uses electricity to facilitate the peripheral
contraction of a paralyzed muscle that is still innervated, as is the case in an upper
motor neuron lesion like stroke.97 A variety of systems are available
(eg, transcutaneous, percutaneous, and implantable) that have been used to treat
spasticity and muscle atrophy. Some evidence suggests that neuromuscular
stimulation enhances motor recovery, termed a therapeutic effect.7,97,98 More
recently, implantable systems have been used to treat poststroke shoulder pain,
as well.99 Functional electrical stimulation is a subcategory of neuromuscular
stimulation in which the stimulation is manipulated to produce purposeful
muscle movements. Although this can be applied in the arm, functional electrical
stimulation is more often used in the leg to dorsiflex the ankle in the swing phase
of gait to compensate for foot drop after stroke, also known as the training effect
or orthotic effect.7 Compared with an ankle-foot orthosis, lower extremity
functional electrical stimulation may decrease the physiologic cost of gait (based
on resting and working heart rate and walking speed) but does not improve gait
speed.100 A recent meta-analysis found moderate evidence that functional
electrical stimulation results in improvements at an activity level, more so in the
arm than in the leg.101
Neuromodulation
Neuromodulation alters cortical activity in the brain with the goal of augmenting
the effect of exercise to enhance recovery from stroke. Modulation can be either
excitatory or inhibitory, depending on the target, and is more or less spatially
focused, depending on the delivery system.102 The stimulation can be provided
invasively (ie, implanted vagus nerve stimulation [VNS] or epidural stimulation)
or noninvasively (ie, repetitive transcranial magnetic stimulation and
transcranial direct current stimulation). An encouraging clinical trial from 2021
used VNS, a surgically implanted device similar to that used in epilepsy, which
provides a nonlocalized release of neurotransmitters in the central nervous
system.103 Dawson and colleagues103 had therapists use a hand-held device to
activate the VNS device while patients performed active upper extremity
exercise. Among 108 participants about 3 years poststroke, VNS or sham
stimulation was combined with 27 hours of occupational therapy over 6 weeks.
The VNS group was about twice as likely to achieve a clinically meaningful
gain on Fugl-Meyer Assessment and three times as likely to do so on the Wolf
Motor Function Test compared with the control group. Adverse events were
mild and expected. A 2021 meta-analysis, which included the 2021 VNS trial
mentioned above and noninvasive devices, confirmed that VNS is effective for
facilitating recovery of upper extremity function.104 Other invasive options
include epidural stimulation. The 2016 EVEREST trial105 neurosurgically
implanted epidural stimulation arrays over the motor cortex in 94 participants
(mean 5 years poststroke) followed by 6 weeks of therapy. Although no
difference was found in the primary endpoint between the experimental and
control groups, participants who responded to motor stimulation testing at
baseline appeared to do better.
620 APRIL 2023

Repetitive transcranial magnetic stimulation uses a noninvasive, magnetic KEY POINTS
field to alter excitability of brain tissue with good spatial accuracy.102 The
● Despite an
technology can be used to either stimulate or inhibit cortical activity, usually underwhelming track
before exercise is introduced. The upper extremity, not the lower extremity, is the record, upper and lower
usual target owing to its relatively more superficial and accessible location on the extremity robotics and
motor homunculus. In a meta-analysis of studies prior to 2018, He and exoskeletal devices are
commonly offered at larger
colleagues106 found low-frequency repetitive transcranial magnetic stimulation
rehabilitation centers.
had a positive effect on motor recovery for grip strength and lower limb as
measured by the Fugl-Meyer Assessment. Not included in that analysis, ● Compared to an
however, was the 2018 trial NICHE (Navigated Inhibitory rTMS to ankle-foot orthosis, lower
Contralesional Hemisphere Trial).107 In 197 participants 3 to 12 months extremity functional
electrical stimulation may
poststroke, NICHE failed to demonstrate an upper extremity effect of decrease the physiologic
low-frequency repetitive transcranial magnetic stimulation administered to the cost of gait (based on resting
unaffected cortex prior to 18, 1-hour therapy sessions over 6 weeks. No and working heart rate and
differences were found for the Fugl-Meyer Assessment or any secondary walking speed) but does not
improve gait speed.
outcome between the repetitive transcranial magnetic stimulation and sham
groups. Conversely, a 2021 systematic review concluded that high-frequency ● The vagus nerve
repetitive transcranial magnetic stimulation to the ipsilateral cortex results in stimulation group in one trial
decreased upper extremity impairment.108 This technology has also been used in was about twice as likely to
achieve a clinically
the treatment of aphasia109 and other impairments.102
meaningful gain on the
Transcranial direct current stimulation delivers a small electrical current Fugl-Meyer Assessment and
(1 mA to 2 mA) through the scalp and skull to the cortex, altering the excitability 3 times as likely to improve
of brain tissue.102 As opposed to repetitive transcranial magnetic stimulation, on the Wolf Motor Function
Test compared with the
transcranial direct current stimulation is generally applied during exercise or
control group.
activity and has less spatial accuracy. Although transcranial direct current
stimulation is more limited in its ability to penetrate the deeper cerebral
structures, it is technically easier and somewhat safer to use than transcranial
magnetic stimulation and therefore has been somewhat more widely
implemented in a clinical setting. A 2021 meta-analysis found modest evidence
that transcranial direct current stimulation improved ADLs, but not limb
strength, neglect, or cognition,110 and it had variable effects on walking and
ambulation after stroke.111 The results appear to be a bit more promising when
function is used as the outcome of the meta-analysis.112
Miscellaneous Strategies
Several regenerative approaches have been used over the past several years to
enhance stroke recovery,2,81,113 with several trials ongoing.81 All regenerative
approaches remain investigational only. Regenerative cell lines have been
derived from various sources (eg, mesenchymal, hemopoietic) and delivered
intravenously, intraarterially, and intracranially.81 Results have reflected good
safety and emerging evidence of efficacy.114,115 Unlike the other strategies
discussed above, many clinical trials examining stem cells did not include
formal exercise therapy as part of the protocols. The CARS (Cerebrolysin and
Recovery After Stroke) trial was a randomized clinical trial that studied a porcine
neuropeptide, which was started 24 to 72 hours after stroke in 208 participants
and continued daily for 3 weeks along with a standard inpatient rehabilitation
program.116 The CARS trial found a beneficial effect at the impairment and
global outcomes levels with a favorable safely profile. Growth factors have
been examined, with granulocyte colony-stimulating factor perhaps being the
most promising, but with no clear positive results to date.82 Other emerging

KEY POINT strategies include the use of monoclonal antibodies2 and brain-computer
interfaces.82,90
● Defining the optimal
nature, characteristics,
In summary, the past decade has shed light on a few promising strategies to
intensity, and timing of a enhance motor recovery resulting from exercise following stroke. The
patient’s participation in underlying reasons for numerous recent unsuccessful trials in this area have been
task-specific and eloquently reviewed and discussed by Stinear and colleagues.3 The most
repetitious exercise to
straightforward, but not necessarily the easiest or most practical, strategy may be
maximize motor recovery
constitutes the fundamental simply increasing the dose and intensity of exercise, although this should
challenge in stroke probably not be done too soon after stroke. Although constraint-induced motor
rehabilitation. therapy has been demonstrated to be effective, the ideal timing and format of
other general exercise strategies that might be widely implemented are yet to be
determined. The strategies with the best data to date are VNS and transcranial
direct current stimulation, with encouraging results on mirror therapy, virtual
reality, and porcine neuropeptide. Results of functional electrical stimulation,
transcranial magnetic stimulation, and robotics are mixed, and little evidence
supports any type of pharmacologic intervention.
CONCLUSION
The practicing neurologist will consult and collaborate with rehabilitation
professionals from the first days through at least the first several months
following a stroke as their patients complete inpatient and outpatient
rehabilitation. Neurologists play an important role in patient advocacy for stroke
recovery, especially during acute care, in minimizing potentially detrimental
medications and arranging inpatient rehabilitation facility evaluation when
appropriate. Understanding the principles of and evidence behind early
mobilization and exercise strategies to facilitate motor recovery and the
philosophy of rehabilitation management will allow the neurologist to reinforce
the importance of patient engagement and participation, ensuring the best
possible recovery, level of independence, and quality of life. Many questions
remain about the rehabilitation process and the best strategies to enhance motor
recovery through exercise following stroke. Defining the optimal nature,
characteristics, intensity, and timing of a patient’s participation in task-specific
and repetitious exercise to maximize motor recovery constitutes the
fundamental challenge of stroke rehabilitation.
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PRACTICE ISSUES
The Transformation of
Documenting and Coding
for Neurologic Hospital
Inpatient and
Observation Services
By Raissa Villanueva, MD, MPH, FAAN; Neil A. Busis, MD, FAAN;
Bruce H. Cohen, MD, FAAN; Luana Ciccarelli, CPC, CRC
CITE AS: ABSTRACT

Landmark changes to documenting and coding for office or other
2023;2 9 ( 2 , C E R E B R O V A S C U L A R
DISEASE):628–640. outpatient evaluation and management (E/M) codes were implemented on
January 1, 2021. To decrease clinicians’ administrative burden, many
Address correspondence to documentation requirements were eliminated. In addition, major changes
Dr Raissa Villanueva, University
of Rochester Medical Center,
were made in how medical decision making and time spent on the
919 Westfall Road, Suite 220, date of the encounter are used to determine the level of service. On
Rochester, NY 14618, January 1, 2023, these changes were extended to inpatient and observation
raissa_villanueva@urmc.
rochester.edu. E/M services. The level of service in both inpatient and outpatient settings
can now be selected based on the total time dedicated to the patient’s
care on the day of the encounter or the new method of medical decision
Dr Villanueva has received
personal compensation in the making. This article discusses the optimal ways to document and code for
range of $500 to $4999 for inpatient hospital and observation encounters after January 1, 2023.
serving as a speaker for the
American Academy of
Neurology (AAN) and as the
AAN’s alternate advisor to the
American Medical INTRODUCTION
I
Association’s CPT Editorial n January 2021, major revisions to evaluation and management (E/M) codes
Panel. Dr Villanueva has a
noncompensated relationship were implemented in Current Procedural Terminology (CPT) codes in
as a practice management response to requests by the Centers for Medicare & Medicaid Services (CMS)
committee member with the
and others to simplify documentation, decrease administrative burden on
American Headache Society
that is relevant to the American clinicians when documenting office or other outpatient clinical encounters,
Academy of Neurology and make clinical notes more reflective of what clinicians do during these visits.1
interests or activities.
Continued on page 640
These changes required documentation of only a medically appropriate history
and examination. The calculation of level of service could use two different
methods: either what was done or the time spent on the date of the encounter.
UNLABELED USE OF Both methods were changed significantly from previous rules established in 19952
PRODUCTS/INVESTIGATIONAL and 1997.3
USE DISCLOSURE:
The first change was to make medical decision making the sole determinant of
Drs Villanueva, Busis, and Cohen
and Ms Ciccarelli report no what was done, eliminating mandated elements of history and physical
disclosures. examination. Medical decision making includes three domains, each with four
© 2023 American Academy
different levels of complexity: (1) number of problems addressed, (2) amount of
of Neurology. data reviewed or analyzed, and (3) risk of morbidity and mortality of patient
628 APRIL 2023

management. The level of complexity of the highest two of the three domains is
used to determine the level of service when billing based on medical
decision making.1
The second change redefines time as the total time spent on the date of the
encounter rather than what was considered “typical time” with the requirement
that at least 50% of the typical time be spent performing counseling and
coordination of care. For the outpatient setting, time is defined by a range of
minutes for each level of service. It includes time spent before, during, and after
the encounter on the calendar day of the encounter. The new definition of time
includes all relevant face-to-face and non–face-to-face activities.
Beginning January 2023, similar changes were applied to E/M services in all
settings.4-6 All E/M services neurologists perform, including hospital inpatient
and observation, can now be billed based on medical decision making or total
time. Hospital inpatient and observation services have been combined into a
single family of codes that are applicable to all initial and subsequent encounters
in the hospital setting. Although consultation codes were also revised,
Medicare, many Medicaid programs, and most commercial payers do not
currently cover them.7 Services that exceed the maximum time assigned to the
longest inpatient initial or subsequent encounters are reported by adding
prolonged services code 99418 to the base code. This is analogous to code 99417
used for outpatient services. Medicare does not cover either 99417 or 99418.
Instead, CMS established longer time thresholds for prolonged E/M services in
outpatient and inpatient settings and uses their own G codes to document
these encounters.7
HISTORY AND EXAMINATION

Best medical practice for any encounter should always include a medically
appropriate history, physical examination, or both, as determined by the
physician or other qualified health care professional. The elements previously
referred to as “bullets” within the history of present illness and the details
of the past medical, social, and family history, and review of systems are no
longer required for code selection. Similarly, elements of the physical
examination listed in the neurology single system examination in 19973 and the
general medical examination in 19952 are no longer mandated for selecting a
level of service.
Other Tests or Services on the Date of an E/M Encounter

Ordering, performing, and interpreting diagnostic tests or studies during a
patient encounter are not included in determining the levels of E/M services
when the professional interpretation of those tests or studies is reported and
billed separately by the same physician or other qualified health care professional
reporting the E/M service. For example, if an EEG was obtained and interpreted
by the same physician who is providing the E/M service on the same date, a
professional fee can be submitted for interpreting the EEG, but that study cannot
be counted as an element of data reviewed by that physician to determine the
level of service for the E/M code. Another clinician caring for that patient may
review the EEG report and count their review as an element of data review. The
data elements reviewed for a specific test (such as a lipid profile performed on a
specific date) can only be counted once by the ordering provider—on the date of
the encounter that the test is ordered.

CODING FOR NEUROLOGIC HOSPITAL INPATIENT AND OBSERVATION SERVICES
HOSPITAL INPATIENT AND OBSERVATION CARE SERVICES

For inpatient hospital and observation services, there are three levels of service
for each of the two subcategories of hospital encounters: initial and subsequent
encounters. Initial service is selected when the patient has not received any
professional services from a physician or other qualified health care professional
of the exact same specialty and subspecialty who belongs to the same group
practice during the current inpatient stay.6 Subsequent service codes are selected
when the patient has already received care from someone in the same group
practice during the current inpatient stay.6 When a hospital stay transitions from
observation status to inpatient or vice versa, it is considered a single stay.6
The levels of service of the initial and subsequent E/M codes are differentiated
by medical decision making or total time that must be met or exceeded
(CODING TABLE 1). Either level of medical decision making or total time can be
chosen to determine the level of the service for an E/M encounter.
MEDICAL DECISION MAKING

Medical decision making is categorized as straightforward, low, moderate, or
high. The three domains of medical decision making defined for the new
inpatient E/M codes parallel the outpatient code rules established in 20211:
u Number and complexity of problems addressed

u Amount or complexity of data reviewed or analyzed
u Risk of complications or morbidity and mortality of patient management
To qualify for a given level of medical decision making, one must meet the
highest level in two of the three domains. Level 1 is straightforward or low
CODING TABLE 1 Medical Decision Making and Time for Inpatient or Observation
Encountersa
Medical decision making CPT code History Exam Time (minutes)
Initial encounter
Straightforward or low 99221 Medically appropriate Medically appropriate 40 or more
Moderate 99222 Medically appropriate Medically appropriate 55 or more

b
High 99223 Medically appropriate Medically appropriate 75 or more
Subsequent encounters

c
CPT = Current Procedural Terminology.

a
CPT © 2023 American Medical Association.6 All rights reserved. CPT is a registered trademark of the American Medical Association.
b
For services of 90 minutes or longer, use prolonged services code 99418. For Medicare, for services of 105 minutes or longer, use prolonged
services code G0316.
c
For services of 65 minutes or longer, use prolonged services code 99418. For Medicare, for services of 80 minutes or longer, use prolonged
services code G0316.
630 APRIL 2023

medical decision making, level 2 is moderate, and level 3 is high. Only a few
additional elements in the problem and risk domains were added in 2023 to
reflect inpatient and observation services.
Problems
This domain includes any problems addressed during the inpatient hospital
encounter. Comorbidities not addressed during the encounter cannot be used for
determining the level of this domain. For example, hypertension and
hyperlipidemia are often relevant problems in a patient with stroke during a
hospital encounter as part of the discussion of secondary stroke prevention,
and medications to address these issues may be prescribed. However, if
discussion and management of these issues are delegated to another physician or
other qualified health care professional they cannot be used to determine the
number and complexity of problems addressed. CPT defines a problem as
“a disease condition, illness, injury, symptom, sign, finding, complaint or
other matter addressed at the encounter with or without a diagnosis being
established at the time of the encounter.”6 The 2023 problem domain differs
from the 2021-2022 outpatient medical decision making in only two components:
1 stable, acute illness; or 1 acute, uncomplicated illness or injury requiring
hospital inpatient or observation level of care.1,4-6 Because testing and
evaluations may occur during a hospital stay, the final diagnosis may be
different from the presenting symptoms. The highest risk problem in the
differential diagnosis (eg, one acute or chronic illness or injury that poses
a threat to life or bodily function6) that is considered can be used to determine
the level of the encounter. For example, if the risk of stroke is high in a patient’s
presentation, that patient will meet the high-risk category for problems
addressed, regardless of whether a stroke is eventually diagnosed.
Problems addressed during the initial encounter may differ from problems
addressed in subsequent encounters. If a problem is not at treatment goal, such as
elevated blood pressure despite antihypertensive medications, then that problem
is not considered “stable” as stated in the CPT manual.6
Number and Complexity of Problems Addressed
◆ Low
◇ 2 or more self-limited or minor problems; OR
◇ 1 stable chronic illness; OR
◇ 1 acute uncomplicated illness or injury; OR
◇ 1 stable acute illness (new for 2023); OR
◇ acute uncomplicated illness or injury requiring hospital inpatient or observation level of
care (new for 2023)
◆ Moderate
◇ 1 or more chronic illnesses with exacerbation, progression, or side effects of
treatment; OR
◇ 2 or more stable chronic illnesses; OR
◇ 1 undiagnosed new problem with uncertain prognosis; OR
◇ 1 acute illness with systemic symptoms; OR
◇ 1 acute complicated injury

◆ High
◇ 1 or more chronic illnesses with severe exacerbation, progression, or side effects of
treatment; OR
◇ 1 acute or chronic illness or injury that poses a threat to life or bodily function
CPT © 2023 American Medical Association. All rights reserved. CPT is a registered trademark of the
American Medical Association.
Data
This category parallels the outpatient E/M medical decision making table without
any changes from 2021-2022 outpatient rules. There are 3 different categories of
data to be analyzed or reviewed: limited, moderate, and extensive. For the
limited data category, either category 1 or an assessment requiring an
independent historian is met. For the moderate category, 1 of the 3 categories of
data must be met, and for the extensive category, 2 of the 3 categories must be
met. Please refer to the complete Levels of Medical Decision Making (MDM)
table from the American Medical Association for more information.6
Data Categories
Limited Data
(Must meet the requirements of at least 1 of the 2 categories)
Category 1: Tests and documents

u Any combination of 2 from the following:
◇ Review of prior external note(s) from each unique source;
◇ review of the result(s) of each unique test;
◇ ordering of each unique test
OR
Category 2: Assessment requiring an independent historian(s)
Moderate Data
(Must meet the requirements of at least 1 out of 3 categories)
OR
Extensive Data
(Must meet the requirements of at least 2 out of 3 categories)
Category 1: Tests, documents, or independent historian(s)
u Any combination of 3 from the following:

◇ Review of prior external note(s) from each unique source;
◇ Review of the result(s) of each unique test;
◇ Ordering of each unique test;
◇ Assessment requiring an independent historian(s)
OR
Category 2: Independent interpretation of tests
u Independent interpretation of a test performed by another physician/other qualified health

care professional (not separately reported);
632 APRIL 2023

OR
Category 3: Discussion of management or test interpretation
u Discussion of management or test interpretation with external physician/other qualified

health care professional/appropriate source (not separately reported)
ANALYZED. When tests are ordered by another physician or other qualified health
care professional, such as the emergency department physician ordering a
complete blood cell count (CBC) and complete metabolic profile (CMP), but the
laboratory results are interpreted by the neurologist, they are counted as
reviewing results of two tests.
INDEPENDENT INTERPRETATION OF TEST. Although the report from the radiologist is

typically available in the medical record, neurologists will often perform and
document their personal review of imaging. If this was done, the neurologist
should document that neuroimaging was personally reviewed and state a brief
impression of the imaging findings.
For category 3, an interactive exchange must take place between clinicians
that results in a decision, not necessarily an action, about patient care. Routing a
chart note would not count as an interactive exchange. The exchange does not
have to be synchronous but must be initiated and completed within a short time
so that an intervention can occur, if necessary.
Risk
Risks associated with management decisions regarding a condition are distinct
from the risks of those problems. There are three levels of risk for this domain:
low, moderate, and high. Two additional examples were added for 2023 as
noted below.
Risk of Complications or Morbidity or Mortality of Patient Management

◆ Low risk
◇ Low risk of morbidity from additional diagnostic testing or treatment
◆ Moderate risk
◇ Examples only:
→ Any prescription drug management
→ Decision regarding minor surgery with identified patient or procedure risk factors
→ Decision regarding elective major surgery without identified patient or procedure risk
factors
→ Diagnosis or treatment significantly limited by social determinants of health
◆ High risk
◇ Examples only:
→ Drug therapy requiring intensive monitoring for toxicity
→ Decision regarding elective major surgery with identified patient or procedure risk
factors
→ Decision regarding emergency major surgery
→ Decision regarding hospitalization or escalation of hospital-level care (new for 2023)

→ Decision not to resuscitate or to de-escalate care because of poor prognosis

→ Parenteral controlled substances (new for 2023)
TIME
When time is the determinant of the level of service for an encounter, total
time on the calendar date, from midnight to midnight, of the encounter is
used. This includes face-to-face time and non–face-to-face time personally
spent by the physician or qualified health care professional on that day. When
the service is continuous before and through midnight, all the time may be
applied to the reported date of the service. Activities that can be counted are
unchanged from 2021-2022 outpatient time rules. Counseling and coordination
of care can be included in total time, but the requirement that more than 50%
of the time was spent in these activities to bill based on time is no longer
required.6
◆ The following activities can be included when summing total time on the calendar day:
◇ Preparing to see the patient
◇ Obtaining or reviewing a separately obtained history
◇ Performing a medically appropriate examination, evaluation, or both
◇ Counseling and educating the patient, family, or caregiver
◇ Ordering medications, tests, or procedures
◇ Referring to and communicating with other health care professionals
◇ Documenting clinical information in the electronic or other health record
◇ Independently interpreting results and communicating to the patient, family, or caregiver
◇ Care coordination not separately reported
◆ Time does not count for:
◇ Any services reported separately

◇ Travel
◇ General teaching that is not specific to a patient’s management
To prevent confusion, the number of minutes should be clearly documented

in the note for that encounter only when time is used to choose the level of
service. The attending physician is the billing provider for patients seen in
teaching hospitals with trainees. The time spent by residents taking the history
and performing the physical examination does not count if the attending
physician is not present. Time spent teaching by the attending neurologist that is
specific to the patient’s case does count when doing time-based billing.
Same Day Admission and Discharge Hospital Inpatient or Observation

Care Services
When patients are admitted and discharged on the same date of service, codes
99234-99236 should be used. These codes require two or more encounters on the
same date (CODING TABLE 2). If the admission and discharge are done during a
634 APRIL 2023

single encounter, then the initial hospital service codes 99221, 99222, or 99223 can
be used.
Prolonged Services When Billing Based on Time

There are two different methods to code for services that exceed the maximum
time of the highest level of initial or subsequent inpatient or observation E/M
encounters. For initial services of 90 minutes or longer in patients not billing
through Medicare, use prolonged initial services code 99418.6 For patients
using Medicare, use prolonged services code G0316 for initial services of
105 minutes or longer.7 For subsequent services of 65 minutes or longer in
patients not billing through Medicare, use prolonged services code 99418.6 For
patients using Medicare, use prolonged services code G0316 for subsequent
services of 80 minutes or longer.7 Multiple units of prolonged services codes can
be used. It is important to review your payers’ policies prior to submission of a
prolonged services encounter to ensure coverage.
99418: Prolonged inpatient or observation evaluation and management services time with
or without direct patient contact beyond the required time of the primary service when the
primary service level has been selected using total time, each 15 minutes of total time6
G0316: Prolonged hospital inpatient or observation care evaluation and management
services beyond the total time for the primary service (when the primary service
has been selected using time on the date of the primary service); each additional 15 minutes
by the physician or qualified healthcare professional, with or without direct patient contact7
CPT © 2023 American Medical Association. All rights reserved. CPT is a registered trademark
of the American Medical Association.
Non–Face-to-Face Work Outside Day of Encounter

For non–face-to-face work that includes a minimum of 60 minutes or more of total
time on a date outside the calendar day of the encounter, 99358 can be used. For every
30 minutes or more above the 60-minute time, the add-on code 99359 can be
used.
Consultation E/M Codes 99252-99255

Effective January 1, 2023, both the level 1 office consultation code, 99241, and the
corresponding inpatient consultation code, 99251, have been deleted and are no
longer valid codes. Consultation codes are not currently reimbursed by Medicare.
Reimbursement by commercial payers for consultation codes varies by payer. If
payers will not cover consultation codes then inpatient or observation codes (initial
Admission and Discharge on Same Day for Hospital Inpatient or CODING TABLE 2
Observation Carea
Medical decision Making CPT code History Exam Time (minutes)

CPT = Current Procedural Terminology.

a
CPT © 2023 American Medical Association.6 All rights reserved. CPT is a registered trademark of the American Medical Association.

and subsequent encounters) should be reported instead. Consultations are

provided at the request of another physician or other qualified health care
professional to recommend care for a specific problem. When consulting, a written
report must be completed and sent to the requesting physician. Because only one
consultation may be reported by a consultant per admission, any subsequent
encounters by the consultant should be reported as subsequent inpatient
codes 99231-99233.
CASE 1
A 68-year-old woman with hypertension and diabetes was evaluated by a
neurologist in the emergency department (ED). The neurologist decided to
admit the patient to the neurology service for a probable stroke. Upon
talking to the patient and corroborating her history with her husband
moments after she arrived at the hospital, the neurologist confirmed that
the patient was last known well when she went to sleep but awoke the next
morning with mild weakness of her left side and slight slurring of her
speech. On examination, the patient had slight flattening of the left
nasolabial fold with some associated dysarthria, mild left pronator drift,
and 4+/5 power in the proximal left leg. Her National Institutes of Health
Stroke Scale (NIHSS) score was 4. The neurologist reviewed some basic
laboratory tests that were drawn in the ED, which included a CBC, CMP,
and prothrombin time and international normalized ratio (INR). A CT of the
head and CT angiogram (CTA) of the head and neck were ordered by the ED
and independently interpreted by the neurologist. In addition to the
history, examination, and review of imaging, the patient was counseled on
the diagnosis of ischemic stroke and anticipated diagnostic testing. The
total time spent on this encounter was 58 minutes.
DISCUSSION
For this patient, the level of service is an initial encounter in the inpatient hospital
setting since she was admitted from the ED for a possible stroke. Therefore,
CPT 99221-99223 are the code options available.
If the patient is in designated observation status, now no differentiation exists
between an initial inpatient hospital encounter or an initial observation
encounter; they both use the same codes 99221-99223. The next step is to
determine if the level of the new patient admission or observation should be
chosen based on medical decision making or total time. The components of
medical decision making include problems addressed, data reviewed and
analyzed, and risk of patient management.
Problem Addressed
This acute stroke meets the criteria of “1 acute or chronic illness or injury that
poses a threat to life or bodily function,”6 and therefore meets the criteria of a
“high” level in this category.
Data Reviewed and Analyzed

During this initial hospital encounter, a CBC and CMP were reviewed, as well as
prothrombin time and INR. These three test panels, along with the history
636 APRIL 2023

obtained from the patient’s husband, meet category 1, which is any combination
of three pieces of data. The neurologist then independently interprets the head
CT and CTA of the head and neck separately from the radiologist, which meets
category 2 in data reviewed. Given that criterion for category 1, review of three
elements of data, and category 2, independent interpretation of diagnostic testing
are met, the data analysis and review is “extensive” since it meets the
requirements of at least 2 of 3 categories in this domain.
Risk of Patient Management

Given the likely diagnosis of right hemispheric stroke based on her symptoms,
the decision to hospitalize and admit the patient from the ED is considered a high
level of risk of patient management.
If one selected the level of service based on medical decision making, because
all three medical decision making domains are at high levels, the code should
be 99223.
If this initial hospital encounter is billed based on time, a minimum of
55 minutes was met, supporting 99222. Code 99223 could not be chosen because
less than 75 minutes of total time was spent.
If the level of service by medical decision making and time do not agree, the
neurologist can choose either method to determine the E/M code. If time is used,
the total time on the date of service must be documented in the note. To prevent
confusion, it is better to omit time if medical decision making is used to
determine the level of service.
CASE 2
A 59-year-old man was admitted 5 days previously with right-sided
weakness and loss of sensation. His initial neurologic evaluation at
admission included a blood pressure of 190/105 mm Hg and a head CT
showed an acute hemorrhage in the left thalamus. Repeat brain imaging
two days later showed a stable hemorrhage size without resolution of the
edema noted initially, and his systolic blood pressure improved to 140 mm
Hg with a nicardipine infusion. On day 5 of his inpatient hospital stay, a
subsequent neurologic examination is notable for decreased sensation to
all modalities in the right face, arm, and leg, and the patient has an NIHSS
score of 1. As part of the subsequent inpatient hospital encounter, the
neurologist counseled the patient extensively on his pertinent risk factors
for brain hemorrhage, including hypertension and tobacco use. The total
time spent face-to-face and non–face-to-face on the calendar day of the
encounter was 38 minutes.
DISCUSSION
This patient is being seen for a follow-up (subsequent) inpatient hospital
encounter on day 5 of his hospital stay, so the level of service options to use are
codes 99231-99233.
Problems Addressed
During the first several days, the acute hemorrhage can be considered as “one
acute or chronic illness or injury that poses a threat to life or bodily function”6

because it meets the high-risk category even several days after the hemorrhage if
documented as such. At some point in time, typically days after the acute phase
of a thalamic hemorrhage, the hemorrhage is no longer acute and fails to meet a
high-risk level.
Data Reviewed and Analyzed

The repeat head CT that was individually reviewed by the neurologist meets
category 2 of independent interpretation of tests even if it was ordered by that
neurologist if the neurologist enters their own findings in the note. Copy and
paste of the official report does not count. The data reviewed or analyzed meet
the moderate category if laboratory tests were reviewed including CBC,
prothrombin time or INR, and a CMP, and a third repeat head CT was ordered. If
the repeat head CT was ordered by the neurologist, it would only count toward
one part of category 1 in data reviewed; therefore, this would meet a moderate
category for data reviewed.
Risk of Patient Management

This encounter meets the high-risk inpatient management element if the area of
edema worsens and a higher level of care is required, for example, if the patient
needs more intensive monitoring in the intensive care unit. Without the need
to escalate the level of care to an intensive care unit setting, documenting the
continued cerebral edema, and lack of improvement in the neurologic examination,
this patient is still in the moderate risk category for patient management.
Given that at least two of the three elements meet the moderate category of
risk, this encounter would meet the moderate level of 99232 if billed based on
medical decision making.
If this subsequent hospital encounter is billed based on time, 38 minutes were
spent supporting 99232. Code 99233 could not be chosen because less than
50 minutes of total time was spent.
If the level of service by medical decision making and time do not agree, the
neurologist can choose either method to determine the E/M code. If time is used,
the total time on the date of service must be documented in the note. To prevent
confusion, it is better to omit time if medical decision making is used to
determine the level of service.
CASE 3
A 57-year-old woman is seen by a neurologist in a subsequent inpatient
hospital encounter on day 4 during hospitalization for left hemispheric
stroke. She was initially seen on admission when she presented with
expressive aphasia and was treated with intravenous thrombolysis. Her
language had slowly improved during her hospital stay, and no symptoms
suggested recurrent cerebral ischemia. Testing during her hospitalization
included an MRI that showed a small stroke in the left frontal lobe, an MR
angiogram that showed no significant extracranial carotid or intracranial
stenosis, and an echocardiogram that revealed no obvious source of
cardioembolism. The results of her diagnostic testing, the cryptogenic
nature of her stroke, and the role of additional cardiac monitoring to
evaluate for occult atrial fibrillation are reviewed with the patient. The
total time spent face-to-face with the patient, husband, and family
638 APRIL 2023

members in addition to non–face-to-face time reviewing all the testing
completed to date is 80 minutes.
DISCUSSION
Given the lengthy discussion with the patient and her family members during
this inpatient hospital encounter, use of a prolonged services code in addition to
code 99233 is appropriate. Because the total time on the calendar day of the
encounter was 80 minutes the billing physician would report codes 99233 and
99418. Code 99233 accounts for the initial 65 minutes and the additional
15 minutes are reported using the prolonged service code 99418.
CONCLUSION
For 2023, changes similar to those instituted previously for outpatient E/M codes
to determine level of service based on time or medical decision making have now
been implemented for hospital inpatient services codes.4-6 Observation services
are combined with hospital inpatient initial (99221-99223) and subsequent
encounter codes (99231-99233). A few updates to the CPT medical decision
making table were included to reflect changes pertinent to inpatient services.6
Administrative burden on clinicians should be lessened. Neurologists should
revise existing note templates to optimize use of these new codes or risk coding
incorrectly and spending unnecessary time and effort to meet documentation
requirements that no longer exist.
Experience with the new codes is limited because they were implemented so
recently. Payers may differ in how they interpret the proper use of these new
codes. The best current example is how CMS codes for prolonged services using
different threshold times and codes.7 Additional nuances in the proper use of the
2023 E/M codes may become evident as stakeholders gain more experience with
these new rules. As was the case with the 2021 outpatient E/M changes,
clarifications and editorial revisions from CPT may be promulgated in the future.
REFERENCES
1 Villanueva R, Busis NA, Cohen BH, Ciccarelli L. The 3 Centers for Medicare & Medicaid Services.
transformation of documenting and coding: 1997 Documentation guidelines for evaluation
evaluation and management codes for and management services. Accessed
outpatient neurology services. Continuum March 2, 2023. cms.gov/outreach-and-
(Minneap, Minn) 2021;27(6, Behavioral Neurology education/medicare-learning-network-
and Psychiatry):1790-1808. doi:10.1212/ mln/mlnedwebguide/downloads/
CON.0000000000001090 97docguidelines.pdf
2 Centers for Medicare & Medicaid Services. 4 American Medical Association. CPT evaluation
1995 Documentation guidelines for evaluation and management code and guideline changes.
and management services. Accessed March 2, Accessed March 2, 2023. ama-assn.org/system/
2023. cms.gov/outreach-and-education/ files/2023-e-m-descriptors-guidelines.pdf
medicare-learning-network-
5 Levy B, Hollman P. E/M 2023: advancing
mln/mlnedwebguide/downloads/
landmark revisions across more settings of care.
95docguidelines.pdf
American Medical Association webinar. August 9,
2022. Accessed March 2, 2023.
onlinexperiences.com/scripts/Server.nxp?
LASCmd=AI:4;F:QS!10100&ShowUUID=
98A70232-4FEF-4C61-B831-BEA285CA81AA.

6 American Medical Association. Current 7 Centers for Medicare & Medicaid Services.
procedural terminology (CPT) 2023. American Revisions to payment policies under the
Medical Association, 2023. Medicare physician fee schedule quality
payment program and other revisions to Part B
for CY 2023. Accessed March 2, 2023.
cms.gov/medicare/medicare-fee-service-
payment/physicianfeesched/pfs-federal-
regulation-notices/cms-1770-f
DISCLOSURE
as a consultant for CoA Therapeutics/BridgeBio and
Continued from page 628 Neuroene Therapeutics; in the range of $500 to
$4999 for serving as a consultant for Abliva AB,
Dr Busis has received personal compensation in the Astellas Pharma Inc, Modis/Zogenix, PTC
range of $0 to $499 for serving as an editor, Therapeutics, and Reneo Pharmaceuticals, Inc. The
associate editor, or editorial advisory board institution of Dr Cohen has received research
member for Neurology Today from the American support from Abliva, BioElectron Technologies/PTC
Academy of Neurology (AAN) and in the range of Therapeutics, Astellas Pharma Inc, Reneo
$500 to $4999 for serving as a speaker for the AAN Pharmaceuticals, Inc., and Stealth BioTherapeutics,
and as the AAN’s primary advisor to the American Inc. Dr Cohen has received publishing royalties from
Medical Association’s CPT Editorial Panel. Dr Cohen a publication relating to health care and has
has received personal compensation in the range of noncompensated relationships as the president of
$500 to $4999 for serving as a speaker for the the board of directors of the Child Neurology
American Academy of Neurology (AAN) and as an Society and as a member of the board of directors
AAN advisor to the American Medical Association’s of the Child Neurology Foundation that are relevant
CPT Editorial Panel. Dr Cohen has received personal to the American Academy of Neurology interests or
compensation in the range of $0 to $499 for serving activities. Ms Ciccarelli reports no disclosure.
640 APRIL 2023

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POSTREADING TEST
ARTICLE 1: DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
1 Which of the following characteristics of an acute stroke increases the

likelihood that the stroke will not be visualized on the diffusion-
weighted imaging sequence of a brain MRI?
A brainstem location
B cardioembolic source
C diameter greater than 2 cm
D onset greater than 12 hours before the scan
E symptoms present on awakening
2 A 74-year-old right-handed man awoke 3 days ago with nonfluent

verbal output and mild weakness of the right arm and the right side of
his face. His deficits have not improved or gotten worse since then. He
initially insisted that the symptoms would resolve on their own, just as
they had in the past, but when he still had trouble lifting things, he
agreed to seek medical attention. Imaging of which of the following
arteries is a class 1 recommendation of the American Heart Association/
American Stroke Association?
A extracranial internal carotid

B extracranial vertebral
C intracranial internal carotid
D intracranial vertebral
E middle cerebral
3 Paroxysmal atrial fibrillation must be detected within what time period

after a stroke for the benefit of anticoagulation to outweigh the risk?
A 3 weeks
B 3 months
C 1 year
D 3 years
E unknown
4 Children with sickle cell disease should be routinely screened using

which of the following imaging modalities?
A catheter angiography
B CT angiography
C magnetic resonance angiography (MRA)
D transcranial Doppler
E transesophageal echocardiography
644 APRIL 2023

ARTICLE 2: INTRAVENOUS THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE
5 A 58-year-old woman with multiple vascular risk factors presents to the

emergency department 1 hour after the onset of left-sided weakness.
Her National Institutes of Health Stroke Scale (NIHSS) score is 0. Which
of the following deficits that would not have been measured during
NIHSS testing could be an indication for IV thrombolysis in this patient?
A dysarthria
B hand weakness
C hemispatial neglect
D limb ataxia
E sensory loss
6 A 57-year-old man presents to the emergency department at 7:00 AM

after waking at 6:30 AM with right-sided weakness and expressive
language difficulties. He was last known well when he went to sleep at
midnight. His National Institutes of Health Stroke Scale score is 10, and
a head CT shows no acute hemorrhage. Assuming he meets other
inclusion and exclusion criteria for IV thrombolysis, which of the
following additional imaging findings is required to administer IV
thrombolytics to this patient?
A favorable ratio of penumbral tissue volume compared to core

volume
B lack of early ischemic changes
C no additional imaging findings are required
D occlusion of a large intracranial vessel
E thrombolytics should not be administered regardless of additional
imaging findings
7 Which of the following outcomes is associated with the use of a mobile

stroke unit?
A higher rate of intracranial hemorrhage

B increased likelihood of administering thrombolytics to stroke
mimics
C lower expenses
D more patients treated with thrombolysis in the first hour after
stroke
E reduced disparities in acute stroke treatment

POSTREADING TEST
ARTICLE 3: MECHANICAL THROMBECTOMY FOR ACUTE ISCHEMIC STROKE
8 A patient suddenly developed aphasia and right hemiparesis 50 minutes

earlier during a health care maintenance examination. No
contraindications to IV thrombolysis exist. Which of the following
approaches to the administration of IV thrombolytic therapy is most
appropriate?
A administer IV thrombolytic therapy at a reduced dose if imaging

shows large vessel occlusion and endovascular treatment can be
initiated within 3 hours of symptom onset
B administer IV thrombolytic therapy at full dose regardless of
feasibility and timing of endovascular treatment
C base decisions regarding IV thrombolytic therapy on the patient’s
platelet count
D delay treatment with IV thrombolysis until a vascular imaging study
has been completed
E withhold IV thrombolytic therapy if imaging shows large vessel
occlusion and endovascular treatment can be initiated within
3 hours of symptom onset
9 The effectiveness of endovascular therapy is unknown in patients with

acute ischemic stroke who have which of the following attributes?
A chronic atrial fibrillation

B combination of diabetes and prior stroke
C National Institutes of Health Stroke Scale score greater than 18
D National Institutes of Health Stroke Scale score less than 6
E patent foramen ovale
ARTICLE 4: DIAGNOSIS AND MANAGEMENT OF CARDIOEMBOLIC STROKE
10 A 71-year-old woman with hypertension is admitted with an ischemic

stroke. Cardiac telemetry reveals atrial fibrillation. Transesophageal
echocardiography shows left atrial enlargement and severe mitral valve
stenosis. Chronic treatment with which of the following antithrombotic
agents is indicated for secondary stroke prevention in this patient?
A apixaban
B aspirin
C dabigatran
D rivaroxaban
E warfarin
646 APRIL 2023

11 Which of the following is a biomarker of atrial dysfunction that may be
associated with increased risk of ischemic stroke and increased rate of
atrial fibrillation detection after cryptogenic stroke?
A mitral valve prolapse on echocardiography

B plasma N-terminal pro b-type natriuretic peptide
C premature ventricular contractions on Holter monitoring
D serum troponin T
E U wave on electrocardiography
12 In a patient with ischemic stroke who is found to have a patent foramen

ovale (PFO), which of the following findings on diagnostic studies
increases the likelihood that the PFO is pathogenic rather than
incidental?
A atrial septal aneurysm

B internal carotid artery dissection
C left ventricular hypertrophy
D small right-to-left shunt
E subcortical infarct location
13 Short-term anticoagulation is indicated for patients with ischemic

stroke and which of the following associated conditions?
A aortic arch atheroma greater than 4 mm in size

B atrial myxoma
C infective endocarditis
D left ventricular dysfunction with thrombus
E non-ST segment myocardial infarction
14 Which of the following underlying conditions should be considered in

an adult patient without atherosclerotic risk factors who has ischemic
stroke in the setting of acute ascending aortic dissection?
A heroin abuse
B Kawasaki disease
C Marfan syndrome
D patent foramen ovale
E thrombotic thrombocytopenic purpura

POSTREADING TEST
ARTICLE 5: DIAGNOSIS AND MANAGEMENT OF LARGE ARTERY

ATHEROSCLEROSIS
15 A 70-year-old woman presents to the emergency department because

2 hours earlier she suddenly developed a right facial droop, weakness of
her right arm, and difficulty coming up with words. The symptoms
completely resolved within 45 minutes. She has a history of
hypertension and hyperlipidemia but takes no medications. She has
smoked a pack of cigarettes a day for the past 50 years. Her blood
pressure is 150/90 mm Hg, her neurologic examination is normal, and
an MRI shows scattered areas of increased T2 signal consistent with
chronic ischemia, but no evidence of acute ischemia. Carotid
ultrasound shows 40% to 60% stenosis of the left internal carotid
artery. In addition to initiating treatment for hypertension and
hyperlipidemia, which medication regimen would be most
appropriate?
A aspirin alone
B aspirin plus clopidogrel
C aspirin plus warfarin
D clopidogrel alone
E warfarin alone
16 Which trend over the past few decades is the major rationale for
conducting a new clinical trial of carotid endarterectomy for
asymptomatic high-grade carotid stenosis?
A advances in intensive medical therapy

B improvements in study design and statistical analysis
C increased prevalence of obesity
D reduced prevalence of stroke
E refinements in surgical technique
17 What is the primary reason that the absolute risk reduction was so
much greater in studies of endarterectomy for high-grade symptomatic
carotid stenosis than it was in studies of endarterectomy for high-grade
asymptomatic stenosis?
A differences in medical management between the asymptomatic

and symptomatic studies
B differences in surgical technique between the asymptomatic and
symptomatic studies
C lower baseline risk of stroke in patients with asymptomatic
stenosis
D lower risk of surgical complications in patients with symptomatic
stenosis
E reduced efficacy of medical management in patients with
symptomatic stenosis
648 APRIL 2023

18 In CREST (Carotid Revascularization Endarterectomy versus Stenting
Trial), the largest randomized trial to-date comparing carotid
endarterectomy to carotid angioplasty and stent, endarterectomy was
associated with a statistically significant increase in which of the
following?
A death
B perioperative myocardial infarction
C perioperative stroke
D postprocedural ipsilateral stroke
E the primary study endpoint, which was any periprocedural stroke,
myocardial infarction, or death, or postprocedural ipsilateral
stroke
19 Which treatment is indicated in a 68-year-old man who experienced a

right frontoparietal stroke and is found to have 80% stenosis of the
right middle cerebral artery, with no hemodynamically significant
stenosis elsewhere?
A antiplatelet medication
B apixaban
C extracranial-intracranial bypass surgery
D stenting of the right middle cerebral artery
E warfarin
ARTICLE 6: DIAGNOSIS AND MANAGEMENT OF CEREBRAL SMALL

VESSEL DISEASE
20 A 75-year-old man with hypertension and cognitive impairment

undergoes brain MRI, which reveals two 5-mm-round areas of signal
hypointensity on gradient recalled echo (GRE) in cerebral hemispheric
white matter that are isointense on T1-weighted, fluid-attenuated
inversion recovery (FLAIR), and diffusion-weighted imaging. Which
of the following radiographic phenotypes of cerebral small vessel
disease does this patient most likely have?
A cerebral microbleed
B lacune of presumed vascular origin
C recent small subcortical infarct
D white matter hyperintensity
E widened perivascular spaces

POSTREADING TEST
21 Which of the following is the most common location of lacunar

infarcts?
A cerebellum
B medulla
C midbrain
D putamen
E subcortical white matter
22 An 82-year-old man with hyperlipidemia has two 20-minute episodes

of sensory loss and paresthesias involving the right arm. Brain MRI
demonstrates cortical superficial siderosis involving sulci of the left
parietal lobe as well as a right occipital microbleed. Which of the
following is the most likely diagnosis?
A arteriovenous malformation
B cerebral amyloid angiopathy
C cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL)
D hypertensive intracerebral hemorrhage
E remote cerebral infarct with seizure
ARTICLE 7: DIAGNOSIS AND MANAGEMENT OF CEREBRAL VENOUS

THROMBOSIS
23 Which of the following are more common in patients with arterial

strokes than in patients with cerebral venous thrombosis?
A bilateral focal deficits

B headaches
C lethargy and confusion
D seizures
E symptoms maximal at onset
24 A 34-year-old woman on a combination estrogen-progestin oral

contraceptive developed a headache 4 days ago and has been getting
gradually worse. She noted weakness of the right leg on awakening this
morning, which has also been getting worse. Her examination reveals
mild right leg weakness, and imaging shows a thrombus in the superior
sagittal sinus, with a small region of hemorrhage in the paramedian left
frontal cortex. Which of the following treatments would be most
appropriate?
A activated prothrombin complex concentrate

B low-molecular-weight heparin
C protamine
D vitamin K
E warfarin
650 APRIL 2023

25 Which of the following treatment modalities is recommended for
patients with cerebral venous thrombosis due to vaccine-induced
immune thrombotic thrombocytopenia?
A aspirin
B clopidogrel
C heparin
D IV immunoglobulin (IVIg) and nonheparin anticoagulation
E ticagrelor
ARTICLE 8: CERVICAL ARTERY DISSECTION
26 Traumatic vertebral artery dissections most commonly involve which

of the following arterial segments?
A V1 (preforaminal)
B V2 (transverse processes of C6 through C2)
C V3 (transverse process of C2 to foramen magnum)
D V4 (intracranial)
27 Which of the following connective tissue disturbances is most likely in

a young adult patient with cervical artery dissection following minor
trauma?
A α1-antitrypsin deficiency
B connective tissue alterations without hereditary disease
C Marfan syndrome
D no connective tissue disturbance
E vascular Ehlers-Danlos syndrome type IV
28 Which of the following is a predisposing factor for spontaneous

cervical artery dissection?
A diabetes mellitus
B hyperlipidemia
C obesity
D older age
E oral contraceptive use

POSTREADING TEST
29 Which of the following statements regarding the treatment of

spontaneous cervical artery dissection is best supported by currently
available evidence?
A anticoagulation is superior to antiplatelet therapy

B antiplatelet therapy is superior to anticoagulation
C endovascular interventions are superior to antithrombotic therapy
D no significant difference exists between antiplatelet therapy and
anticoagulation
E no significant difference exists between endovascular
interventions and antithrombotic therapy
ARTICLE 9: PEDIATRIC ISCHEMIC STROKE
30 Which of the following ischemic stroke presentations is more common

in children than in adults?
A aphasia
B diplopia
C hemiparesis
D neglect
E seizure
31 Which of the following is the most common cause of stroke in a

previously healthy child?
A acquired heart disease

B focal cerebral arteriopathy
C hereditary thrombophilia
D intracranial atherosclerosis
E patent foramen ovale
32 After 1 year of treatment for primary stroke prevention, a 15-year-old

child with sickle cell disease is interested in stopping exchange
transfusion therapy. The middle cerebral artery velocities on
transcranial Doppler have normalized, and a brain MRI and MR
angiography (MRA) show no silent cerebral infarcts and no
arteriopathy. Which of the following management strategies may be
appropriate as a substitute for exchange transfusion therapy?
A aspirin
B continue exchange transfusion therapy, no substitutions should
be considered
C hydroxyurea at the maximum tolerated dose
D simple transfusion therapy
E stem cell transplant
652 APRIL 2023

33 An 8-year-old child had an ischemic stroke involving the territory of
the left posterior cerebral artery. The child does not have sickle cell
disease, and evaluation reveals no cardioembolic source or coagulation
disorder. Which of the following treatments should be started for
secondary stroke prevention?
A apixaban
B aspirin
C clopidogrel
D enoxaparin
E plasma exchange
34 Acute perinatal arterial ischemic stroke is most likely to present with

which of the following clinical manifestations?
A abnormal suck
B hemiparesis
C focal motor seizures
D infantile spasms
E weak cry
ARTICLE 10: MANAGEMENT OF UNRUPTURED INTRACRANIAL ANEURYSMS

AND BRAIN ARTERIOVENOUS MALFORMATIONS
35 Which of the following parameters has the strongest positive

correlation with the risk of rupture of an unruptured intracranial
aneurysm?
A age at onset of menarche

B frequency of marijuana use
C number of additional unruptured intracranial aneurysms
D quantity of cigarettes smoked per day
E size of the aneurysm
36 In the multicenter ARUBA (A Randomized Trial of Unruptured Brain

Arteriovenous Malformations) trial, the incidence of death or
symptomatic stroke was lowest in patients treated with which of the
following approaches?
A conservative medical management

B embolization
C embolization followed by microsurgery
D microsurgery
E stereotactic radiotherapy

POSTREADING TEST
ARTICLE 11: STROKE REHABILITATION AND MOTOR RECOVERY
37 During the acute poststroke period, which of the following

rehabilitation interventions has been demonstrated to improve
outcome?
A bracing at the ankle

B constraint-induced motor therapy
C dysphagia screening
D high-dose language therapy
E high-intensity physical therapy initiated within 72 hours
38 Which of the following medications has been demonstrated to be

detrimental to recovery in the early poststroke period?
A fluoxetine
B hydralazine
C levetiracetam
D phenytoin
E sertraline
39 At the time of discharge from a typical 1- to 3-week inpatient

rehabilitation facility stay, patients with stroke are most likely to see
the most progress and independence in which of the following
activities?
A bathing and showering

B dressing
C meal preparation
D using the toilet
E walking
40 Which of the following strategies in addition to standard exercise

therapy is best supported by evidence to enhance motor recovery
after stroke?
A granulocyte colony-stimulating factor therapy

B implanted vagus nerve stimulation
C robotics
D stem cell administration
E transcranial magnetic stimulation
654 APRIL 2023

Postreading
SELF-ASSESSMENT
AND CME
Self-Assessment and
CME Test—Preferred
Responses
By Douglas Gelb, MD, PhD, FAAN; Allyson R. Zazulia, 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 article topic. The comments and references included
with each question are intended to encourage independent study.
US PARTICIPANTS: Upon
completion of the Postreading Self-Assessment and
CME Test and issue evaluation online at continpub.com/CME, participants
may earn up to 20 AMA PRA Category 1 Credits™ toward SA-CME. US
participants have up to 3 years from the date of publication online to earn
SA-CME credits.
CANADIAN PARTICIPANTS: This program is an Accredited Self-Assessment

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

POSTREADING TEST—PREFERRED RESPONSES
ARTICLE 1: DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
1 The preferred response is A (brainstem location). Patients with posterior

circulation stroke are 5 times more likely to have diffusion-weighted
imaging–negative stroke than patients with anterior circulation stroke.
For more information, refer to page 415 of the Continuum article
“Diagnostic Evaluation of Stroke Etiology.”
2 The preferred response is A (extracranial internal carotid). Because of

the compelling evidence for revascularization in a patient with
symptomatic high-grade stenosis of the extracranial portion of the
internal carotid artery, imaging of that portion of the artery is a class 1
recommendation of the American Heart Association/American Stroke
Association. The evidence for intervention with the extracranial
vertebral arteries or intracranial arteries is less compelling. For more
information, refer to page 417 of the Continuum article “Diagnostic
Evaluation of Stroke Etiology.”
3 The preferred response is E (unknown). The likelihood of detecting

paroxysmal fibrillation after a stroke increases with increasing duration
of cardiac rhythm monitoring, but it is not known how frequently atrial
fibrillation must occur for the benefit of anticoagulation to outweigh the
risk. For more information, refer to page 419 of the Continuum article
“Diagnostic Evaluation of Stroke Etiology.”
4 The preferred response is D (transcranial Doppler). Children with sickle

cell disease should be routinely screened with transcranial Doppler.
Elevated middle cerebral artery velocities can identify the children at
greatest risk for stroke, who should be treated with exchange
transfusions that can dramatically reduce their risk of stroke. For more
information, refer to page 421 of the Continuum article “Diagnostic
Evaluation of Stroke Etiology.”
ARTICLE 2: INTRAVENOUS THROMBOLYSIS FOR ACUTE ISCHEMIC STROKE
5 The preferred response is B (hand weakness). Although patients with

acute ischemic stroke and a low National Institutes of Health Stroke
Scale (NIHSS) score will usually recover without thrombolysis, such
patients should be assessed for the presence of a disabling deficit that
would warrant thrombolysis treatment. This includes deficits not
measured by the NIHSS such as hand weakness and truncal/gait ataxia.
“Intravenous Thrombolysis for Acute Ischemic Stroke.”
656 APRIL 2023

6 The preferred response is A (favorable ratio of penumbral tissue
volume compared to core volume). This patient is outside the
traditional window for IV thrombolysis since he was last known well
7 hours earlier, but he may still be a thrombolysis candidate based on
tissue window if imaging demonstrates that the infarct core is small
relative to the region of hypoperfused tissue still at risk. This is the basis
for “wake-up” imaging protocols that allow patients to be treated up to
9 hours after last known well. For more information, refer to page 432 of
the Continuum article “Intravenous Thrombolysis for Acute Ischemic
Stroke.”
7 The preferred response is D (more patients treated with thrombolysis

in the first hour after stroke). Because mobile stroke units can deliver
recombinant tissue plasminogen activator (rtPA) on the scene,
treatment in the first hour after stroke onset is 10 times more likely to
occur than with usual care in an emergency department. Since
treatment by mobile stroke units involves patient evaluation and CT
reading by stroke experts, neither bleeding or inappropriate use of
thrombolytics are increased relative to usual care. For more information,
refer to page 432 of the Continuum article “Intravenous Thrombolysis
for Acute Ischemic Stroke.”
ARTICLE 3: MECHANICAL THROMBECTOMY FOR ACUTE ISCHEMIC

STROKE
8 The preferred response is B (administer IV thrombolytic therapy at full

dose regardless of feasibility and timing of endovascular treatment).
Although some studies have suggested that the effectiveness of
endovascular treatment for acute ischemic stroke is not enhanced by
administering IV thrombolytic therapy to patients who are eligible for it,
other studies have suggested the opposite. A recent meta-analysis
failed to demonstrate noninferiority for purely endovascular therapy.
The current best practice is still to administer intravenous thrombolytic
therapy to all patients with acute ischemic stroke who are eligible for it,
regardless of whether endovascular therapy is planned. For more
information, refer to page 448 of the Continuum article “Mechanical
Thrombectomy for Acute Ischemic Stroke.”
9 The preferred response is D (National Institutes of Health Stroke Scale

score less than 6). Most trials of endovascular therapy for acute
ischemic stroke have excluded patients with a National Institutes of
Health Stroke Scale score less than 6, so the effectiveness of
endovascular therapy has not been established in this setting. For more
information, refer to page 449 of the Continuum article “Mechanical
Thrombectomy for Acute Ischemic Stroke.”

ARTICLE 4: DIAGNOSIS AND MANAGEMENT OF CARDIOEMBOLIC STROKE
10 The preferred response is E (warfarin). While direct oral

anticoagulants have been demonstrated to be at least as efficacious
and safer (ie, lower risk of intracranial hemorrhage) than warfarin in
patients with nonvalvular atrial fibrillation, patients with valvular atrial
fibrillation (ie, moderate to severe mitral valve stenosis or mechanical
valve replacement) were excluded from trials of these agents. In
addition, dabigatran was demonstrated to increase both
thromboembolism and bleeding complications compared to warfarin
in patients with mechanical heart valves. Thus, warfarin is the
antithrombotic treatment of choice in patients with valvular atrial
fibrillation. For more information, refer to page 464 of the Continuum
article “Diagnosis and Management of Cardioembolic Stroke.”
11 The preferred response is B (plasma N-terminal pro b-type natriuretic

peptide). The presence of atrial dysfunction in patients with
cryptogenic stroke may identify a subset of patients at increased risk
for recurrent stroke. Several biomarkers for atrial dysfunction have
been identified, such as left atrial enlargement, frequent premature
atrial contractions, atrial fibrosis, and N-terminal pro b-type natriuretic
peptide. For more information, refer to page 467 of the Continuum
article “Diagnosis and Management of Cardioembolic Stroke.”
12 The preferred response is A (atrial septal aneurysm). Since patent

foramen ovale (PFO) is found in approximately one-quarter of the
general population, it is important to determine the likelihood that a
PFO is pathogenic when considering treatment in patients with stroke.
PFO is more likely to be pathogenic in those with a large shunt,
associated atrial septal aneurysm, or both, as well as in young patients
without conventional vascular risk factors who have cryptogenic
cortical stroke. For more information, refer to page 471 of the
Continuum article “Diagnosis and Management of Cardioembolic
Stroke.”
13 The preferred response is D (left ventricular dysfunction with

thrombus). Left ventricular thrombus is associated with an increased
risk of stroke, systemic embolism, and death, and evidence exists that
anticoagulation can reduce the risk of these events. Current guidelines
recommend vitamin K antagonist therapy for at least 3 months;
limited support exists for use of direct oral anticoagulants. For more
information, refer to page 477 of the Continuum article “Diagnosis and
Management of Cardioembolic Stroke.”
658 APRIL 2023

14 The preferred response is C (Marfan syndrome). Aside from
hypertension and atherosclerosis, several genetic, connective tissue,
and inflammatory disorders can increase the risk of ascending aortic
dissection. These include such conditions as Marfan syndrome,
Ehlers-Danlos syndrome type IV, Loeys-Dietz syndrome, Turner
syndrome, giant cell arteritis, and syphilis. For more information, refer
to page 477 of the Continuum article “Diagnosis and Management of
Cardioembolic Stroke.”
ARTICLE 5: DIAGNOSIS AND MANAGEMENT OF LARGE ARTERY

ATHEROSCLEROSIS
15 The preferred response is B (aspirin plus clopidogrel). The 2021

American Heart Association/American Stroke Association guidelines
state that for patients with recent minor (National Institutes of Health
Stroke Scale score of ≤3) noncardioembolic ischemic stroke or high-risk
transient ischemic attack (ABCD2 [age, blood pressure, clinical features,
duration, diabetes] score ≥4), dual antiplatelet therapy (specifically,
aspirin plus clopidogrel) should be initiated early, ideally within 12 to
24 hours of symptom onset and at least within 7 days of onset, and
continued for 21 to 90 days, followed by single antiplatelet therapy, to
reduce the risk of recurrent ischemic stroke. Dual antiplatelet therapy
with aspirin and ticagrelor is another option, but it is associated with a
higher risk of serious bleeding. For more information, refer to page 487
of the Continuum article “Diagnosis and Management of Large Artery
Atherosclerosis.”
16 The preferred response is A (advances in intensive medical therapy).

When the initial trials of endarterectomy were conducted, statins were
not commonly used, hypertension was treated less aggressively than it
is now, targets for other risk factors were not specified, and fewer
management options were available for some of those risk factors. The
absolute risk reduction demonstrated in those trials was low, and it is
possible that the subsequent advances in intensive medical therapy
might eliminate or even reverse the benefit that was previously found.
“Diagnosis and Management of Large Artery Atherosclerosis.”
17 The preferred response is C (lower baseline risk of stroke in patients

with asymptomatic stenosis). The relative risk reduction resulting from
endarterectomy for high-grade carotid stenosis was not very different in
the studies of asymptomatic stenosis from what it was in the studies of
symptomatic stenosis, but the baseline risk of stroke in asymptomatic
patients was much lower, translating into a much lower absolute risk
reduction. For more information, refer to page 493 of the Continuum
article “Diagnosis and Management of Large Artery Atherosclerosis.”

18 The preferred response is B (perioperative myocardial infarction). In

CREST (Carotid Revascularization Endarterectomy versus Stenting
Trial), endarterectomy was associated with a statistically significant
increase in perioperative myocardial infarction and a statistically
significant decrease in perioperative stroke, with no statistically
significant difference in death or the primary study endpoint, which
was any periprocedural stroke, myocardial infarction, or death, or
postprocedural ipsilateral stroke. For more information, refer to
page 491 of the Continuum article “Diagnosis and Management of Large
Artery Atherosclerosis.”
19 The preferred response is A (antiplatelet medication). Current

guidelines recommend intensive medical management, including
antiplatelet medication. In the SAMMPRIS (Stenting and Aggressive
Medical Management for Preventing Recurrent Stroke in Intracranial
Stenosis) trial, the antiplatelet regimen was a combination of aspirin
and clopidogrel for 90 days, followed by aspirin alone. For more
Management of Large Artery Atherosclerosis.”
ARTICLE 6: DIAGNOSIS AND MANAGEMENT OF CEREBRAL SMALL VESSEL

DISEASE
20 The preferred response is A (cerebral microbleed). Six radiographic

phenotypes of cerebral small vessel disease include recent small
subcortical infarct, white matter hyperintensity, lacune of presumed
vascular origin, widened perivascular spaces, cerebral microbleed, and
brain atrophy. The finding of small areas of signal hypointensity on
blood-sensitive sequences (gradient recalled echo [GRE],
susceptibility-weighted imaging [SWI], T2*-weighted imaging) that are
isointense on T1-weighted, fluid-attenuated inversion recovery (FLAIR),
and diffusion-weighted imaging is consistent with cerebral
microbleed. For more information, refer to page 506 of the Continuum
article “Diagnosis and Management of Cerebral Small Vessel Disease.”
21 The preferred response is D (putamen). Lacunar infarcts are small

subcortical infarcts commonly due to small vessel disease. The most
common locations in descending order of frequency are the putamen,
caudate, thalamus, pons, internal capsule, and subcortical white
matter. For more information, refer to page 506 of the Continuum
article “Diagnosis and Management of Cerebral Small Vessel Disease.”
660 APRIL 2023

22 The preferred response is B (cerebral amyloid angiopathy). This
patient with transient focal neurologic episodes and imaging evidence
for a cortical microbleed and superficial siderosis meets criteria for
probable cerebral amyloid angiopathy. For more information, refer to
page 512 of the Continuum article “Diagnosis and Management of
Cerebral Small Vessel Disease.”
ARTICLE 7: DIAGNOSIS AND MANAGEMENT OF CEREBRAL VENOUS

THROMBOSIS
23 The preferred response is E (symptoms maximal at onset). The focal

deficits that occur in patients with cerebral venous thrombosis are
often progressive, whereas those that occur in patients with arterial
strokes are more often maximal at onset. Headaches, seizures,
bilateral focal deficits, and subacute encephalopathy with lethargy
and confusion are more common with cerebral venous thrombosis
than with arterial strokes. For more information, refer to page 525 of
the Continuum article “Diagnosis and Treatment of Cerebral Venous
Thrombosis.”
24 The preferred response is B (low-molecular-weight heparin).

Current guidelines for the treatment of cerebral venous thrombosis
recommend initiation of parenteral anticoagulation with
unfractionated or low-molecular-weight heparin prior to transitioning
to oral anticoagulants, even when concurrent intracerebral
hemorrhage is present. A meta-analysis suggested a nonsignificant
trend toward improved functional outcomes and mortality with
low-molecular-weight heparin relative to unfractionated heparin,
without a difference in rates of bleeding. For more information, refer
to page 529 of the Continuum article “Diagnosis and Treatment of
Cerebral Venous Thrombosis.”
25 The preferred response is D (IV immunoglobulin [IVIg] and

nonheparin anticoagulation). Based on data from patients with
heparin-induced thrombocytopenia, current guidelines recommend
that patients with vaccine-induced immune thrombotic
thrombocytopenia should be treated with nonheparin anticoagulation
and IVIg. Antiplatelet medications should be avoided. For more
Treatment of Cerebral Venous Thrombosis.”

ARTICLE 8: CERVICAL ARTERY DISSECTION
26 The preferred response is C (V3 [transverse process of C2 to foramen

magnum]). Traumatic vertebral artery dissections most commonly
affect the V3 segment of the vertebral artery, which spans from the
transverse process of C2 to the foramen magnum at the skull base.
Spontaneous vertebral artery dissections most commonly involve
either the V3 segment or the more proximal V2 segment pertaining to
the transverse processes of C6 through C2. For more information, refer
to page 541 of the Continuum article “Cervical Artery Dissection.”
27 The preferred response is B (connective tissue alterations without

hereditary disease). Nearly all patients with cervical artery dissection
have skeletal, skin, craniofacial, or ocular abnormalities suggestive of
connective tissue abnormalities without an established hereditary
connective tissue disease. Fewer than 2% of patients with cervical
artery dissection are found to have a monogenic connective tissue
disease such as vascular Ehlers-Danlos syndrome. This suggests that
cervical artery dissection is a multifactorial disease with environmental
factors serving as potential triggers in patients who have a genetic
predisposition. For more information, refer to page 542 of the
Continuum article “Cervical Artery Dissection.”
28 The preferred response is E (oral contraceptive use). In addition to

environmental factors and connective tissue abnormalities, several
other predisposing factors have been associated with spontaneous
cervical artery dissection including oral contraceptive use, migraine,
recent infection, and pregnancy or postpartum period. For more
information, refer to page 544 of the Continuum article “Cervical
Artery Dissection.”
29 The preferred response is D (no significant difference exists between

antiplatelet therapy and anticoagulation). The best available data
suggest no difference between antiplatelet therapy and
anticoagulation in preventing stroke in patients with (extracranial)
spontaneous cervical artery dissection. Factors such as the presence
of intraluminal thrombus and infarct size may impact the decision.
Endovascular interventions for cervical artery dissection are
supported by only low-level evidence. No randomized controlled trials
have compared endovascular to medical management; thus, such
treatment is typically reserved for patients with recurrent ischemic
events despite antithrombotic therapy. For more information, refer to
page 553 of the Continuum article “Cervical Artery Dissection.”
662 APRIL 2023

ARTICLE 9: PEDIATRIC ISCHEMIC STROKE
30 The preferred response is E (seizure). Most acute ischemic strokes

in both children and adults present with focal neurologic deficits.
However, children are more likely than adults to present with
seizure, stuttering symptom onset, or complain of headache as a
part of the stroke syndrome. This is one of the contributing factors
to early misdiagnosis in children. For more information, refer to
page 567 of the Continuum article “Pediatric Ischemic Stroke.”
31 The preferred response is B (focal cerebral arteriopathy). Acute or

chronic cerebral arteriopathies are identified in up to one-half of children
with ischemic stroke. An acute, unilateral, monophasic focal cerebral
arteriopathy is the most common cause of ischemic stroke in a
previously healthy child. These focal cerebral arteriopathies are
presumed to be inflammatory in nature based on vessel wall imaging,
although intracranial dissection can also be present. For more
information, refer to page 574 of the Continuum article “Pediatric
Ischemic Stroke.”
32 The preferred response is C (hydroxyurea at the maximum tolerated

dose). Regular transfusion therapy reduces the risk of stroke in children
with sickle cell disease and arteriopathy (as defined by elevated middle
cerebral artery velocities on transcranial Doppler) by 92%. The TWiTCH
(TCD With Transfusions Changing to Hydroxyurea) trial demonstrated
that selected patients with normalization of transcranial Doppler
velocities after a period of transfusion therapy could safely transition
to hydroxyurea. Although continued transfusion therapy is an option, it
carries a higher risk of complications such as iron overload and
infection. After a year of chronic transfusion therapy, a brain MRI and
intracranial MR angiography (MRA) should be done to exclude
arteriopathy or silent cerebral infarcts. If a child meets these criteria,
providers should discuss with families whether treatment with
hydroxyurea is preferable. For more information, refer to page 576 of
the Continuum article “Pediatric Ischemic Stroke.”
33 The preferred response is B (aspirin). Guidelines recommend aspirin

for secondary stroke prevention in children with ischemic stroke who
do not have sickle cell disease or a cardioembolic source. For more
information, refer to page 577 of the Continuum article “Pediatric
Ischemic Stroke.”

34 The preferred response is C (focal motor seizures). Focal motor

seizures and encephalopathy are the most common presenting clinical
manifestations of ischemic stroke in infancy. For more information,
refer to page 566 of the Continuum article “Pediatric Ischemic Stroke.”
ARTICLE 10: MANAGEMENT OF UNRUPTURED INTRACRANIAL ANEURYSMS

AND BRAIN ARTERIOVENOUS MALFORMATIONS
35 The preferred response is E (size of the aneurysm). The risk of

aneurysmal rupture increases with increasing size of the aneurysm. A
pooled analysis of six prospective studies found no effect of sex,
tobacco use, or the presence of multiple aneurysms on the risk of
aneurysmal rupture. No evidence exists that marijuana use or age at
onset of menarche affects the risk of aneurysmal rupture. For more
information, refer to page 586 of the Continuum article “Management
of Unruptured Intracranial Aneurysms and Brain Arteriovenous
Malformations.”
36 The preferred response is A (conservative medical management). The

multicenter ARUBA (A Randomized Trial of Unruptured Brain
Arteriovenous Malformations) trial was stopped early when an interim
analysis showed that the incidence of death or symptomatic stroke
was lower in patients treated with conservative medical management
than with interventional approaches. For more information, refer to
page 597 of the Continuum article “Management of Unruptured
Intracranial Aneurysms and Brain Arteriovenous Malformations.”
ARTICLE 11: STROKE REHABILITATION AND MOTOR RECOVERY
37 The preferred response is C (dysphagia screening). Swallowing

assessment for dysphagia screening in the acute stroke setting has
been demonstrated to be associated with a reduced risk of
pneumonia, dependency, and death. To date, very early mobilization
and high-intensity therapy in the acute period have not been
demonstrated as beneficial; in fact, available data suggest such
interventions may be detrimental. Other rehabilitation goals in the
acute period include safe initiation of mobilization; prevention of
musculoskeletal, pulmonary, and skin complications; and preparation
for the next phase of rehabilitation. For more information, refer to
page 608 of the Continuum article “Stroke Rehabilitation and Motor
Recovery.”
664 APRIL 2023

38 The preferred response is D (phenytoin). Clinical and animal data have
demonstrated several classes of medication to be detrimental to
recovery when administered in the acute period after stroke. These
include the antiepileptic medications phenytoin and phenobarbital,
benzodiazepines, first-generation antipsychotic medications, and
centrally acting antihypertensive medications. For more information,
refer to page 609 of the Continuum article “Stroke Rehabilitation and
Motor Recovery.”
39 The preferred response is E (walking). Most patients with stroke will

see functional improvement during an inpatient rehabilitation stay.
Progress and independence with walking and mobility are more
common than with activities of daily living and self-care. For more
information, refer to page 613 of the Continuum article “Stroke
Rehabilitation and Motor Recovery.”
40 The preferred response is B (implanted vagus nerve stimulation). The

strategies with the best data to date for enhancing motor recovery are
implanted vagus nerve stimulation and transcranial direct current
stimulation in concert with standard exercise therapy. The other
strategies listed have mixed or negative results. For more information,
refer to page 622 of the Continuum article “Stroke Rehabilitation and
Motor Recovery.”

LIST OF ABBREVIATIONS
Cerebrovascular Disease LDL Low-density lipoprotein

LMWH Low-molecular-weight heparin
MCA Middle cerebral artery
MELAS Mitochondrial encephalopathy, lactic acidosis,
ADLs Activities of daily living and strokelike episodes
AHA American Heart Association MI Myocardial infarction
aHIT Autoimmune heparin-induced thrombocytopenia MoCA Montreal Cognitive Assessment
aPTT Activated partial thromboplastin time MRA Magnetic resonance angiography
ASA American Stroke Association mRS Modified Rankin Scale
ASH American Society of Hematology MRV Magnetic resonance venography
ASPECTS Alberta Stroke Program Early CT Score NIHSS National Institutes of Health Stroke Scale
AVM Arteriovenous malformation NINDS National Institute of Neurological Disorders and Stroke
BP Blood pressure PADMAL Pontine autosomal dominant microangiopathy
and leukoencephalopathy
CAA Cerebral amyloid angiopathy
PASCAL Patent foramen ovale–Associated Stroke Causal
CADASIL Cerebral autosomal dominant arteriopathy with Likelihood
subcortical infarcts and leukoencephalopathy
PedNIHSS Pediatric National Institutes of Health Stroke Scale
CARASIL Cerebral autosomal recessive arteriopathy with
subcortical infarcts and leukoencephalopathy PET Positron emission tomography
CBC Complete blood cell count PFO Patent foramen ovale
CHADS2 Congestive heart failure, hypertension, age 75 years or PF4 Platelet factor 4
older, diabetes mellitus, previous stroke PICA Posterior inferior cerebellar artery
CHA2DS2- Congestive heart failure, hypertension, age 75 years or PRES Posterior reversible encephalopathy syndrome
VASc older, diabetes mellitus, stroke, vascular disease, age PT Prothrombin time
65 to 74 years, sex category [female sex] score
RACE Rapid Arterial oCclusion Evaluation
CNS Central nervous system
RoPE Risk of Paradoxical Embolism
cSAH Convexal subarachnoid hemorrhage
RPR Rapid plasma reagin
CSVD Cerebrovascular small vessel disease
SAH Subarachnoid hemorrhage
CTA Computed tomography angiography
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2
CTP Computed tomography perfusion
SBP Systolic blood pressure
CVT Cerebral venous thrombosis
SCD Sickle cell disease
DOAC Direct oral anticoagulant
SOE Source of embolism
DSA Digital subtraction angiography
SWI Susceptibility-weighted imaging
DWI Diffusion-weighted imaging
rtPA Recombinant tissue plasminogen activator
ELISA Enzyme-linked immunosorbent assay
TCD Transcranial Doppler
EMS Emergency medical services
TEE Transesophageal echocardiography
ESO European Stroke Organization
TFNE Transient focal neurological episode
ESUS Embolic stroke of undetermined source
TIA Transient ischemic attack
FDA US Food and Drug Administration
TTE Transthoracic echocardiogram
FLAIR Fluid-attenuated inversion recovery
TTR Time in therapeutic range
GABA γ-aminobutyric
-aminobutyric acid
UIATS Unruptured intracranial aneurysm treatment score
Hb Hemoglobin
VITT Vaccine-induced immune thrombotic
HIT Heparin-induced thrombocytopenia thrombocytopenia
HIV Human immunodeficiency virus VNS Vagus nerve stimulation
ICA Internal carotid artery
ICH Intracerebral hemorrhage
INR International normalized ratio
IVIg IV immunoglobulin
© 2023 American Academy of Neurology.

ARTICLE 1: DIAGNOSTIC EVALUATION OF
STROKE ETIOLOGY
James F. Meschia, MD, FAAN. Continuum (Minneap Minn).
April 2023; 29 (2 Cerebrovascular Disease):412–424.
ABSTRACT
OBJECTIVE:
Precise therapies require precise diagnoses. This article provides an evidence-based approach
to confirming the diagnosis of ischemic stroke, characterizing comorbidities that provide insights
into the pathophysiologic mechanisms of stroke, and identifying targets for treatment to
optimize the prevention of recurrent stroke.
LATEST DEVELOPMENTS:
Identifying the presence of patent foramen ovale, intermittent atrial fibrillation, and unstable
plaque is now routinely included in an increasingly nuanced workup in patients with stroke, even
as ongoing trials seek to clarify the best approaches for treating these and other comorbidities.
Multicenter trials have demonstrated the therapeutic utility of patent foramen ovale closure in
select patients younger than age 60 years. Insertable cardiac monitors detect atrial fibrillation
lasting more than 30 seconds in about one in ten patients monitored for 12 months following a
stroke. MRI of carotid plaque can detect unstable plaque at risk of being a source of cerebral
embolism.
ESSENTIAL POINTS:
To optimize the prevention of recurrent stroke, it is important to consider pathologies of
intracranial and extracranial blood vessels and of cardiac structure and rhythm as well as other
inherited or systemic causes of stroke. Some aspects of the stroke workup should be done
routinely, while other components will depend on the clinical circumstances and preliminary
testing results.
KEY POINTS
• The stroke workup is the set of diagnostic tests performed to gain insight into modifiable risk factors and
stroke mechanism. The stroke workup has fixed and variable components, the latter being contingent on
clinical circumstances, initial testing, and therapeutic objectives.
• Recent American Heart Association guidelines on secondary stroke prevention include an algorithm for
performing an evidence-based diagnostic evaluation.

• Three or more transient ischemic attacks in a 2-week period in the same arterial distribution suggest an
unstable atherosclerotic plaque as a mechanism.
• A stroke evaluation should include examining the patient for preceding strokes or transient ischemic attacks,
atherosclerotic risk factors, head or neck trauma or radiation therapy, migraines, and a family history of
stroke or dementia.
• Nearly 5% of strokes, most of which are lacunar and infratentorial, have a National Institutes of Health Stroke
Scale (NIHSS) score of 0. Although these strokes are usually not treated with thrombolytics, they are
nonetheless important to recognize because the stroke recurrence rates for NIHSS 0 and non-0 strokes are
very similar.
• Nearly 7% of acute ischemic strokes do not have a focal area of restricted diffusion on initial
diffusion-weighted imaging. Patients with posterior circulation stroke are 5 times as likely to have
diffusion-weighted imaging–negative stroke as patients with anterior circulation stroke.
• CT angiography in the oblique and axial planes is the imaging modality of choice for identifying carotid webs.
• Long-term cardiac rhythm monitoring detects severalfold more cases of atrial fibrillation than routine
inpatient monitoring following a stroke (12.1% versus 1.8%), although the minimum burden of intermittent atrial
fibrillation to justify anticoagulation remains uncertain.
• Transesophageal echocardiography may be less sensitive in detecting patent foramen ovale than contrasted
transthoracic echocardiography.
• To diagnose embolic stroke of undetermined source, patients should have a stroke workup that includes, at a
minimum, brain imaging, ECG, transthoracic echocardiography, cardiac monitoring for at least 24 hours, and
imaging of both intracranial and extracranial arteries.
• The yield of testing for genetic stroke syndromes is much higher when patients have a positive family history
or a plethora of recurrent strokes and a paucity of conventional risk factors, particularly if the strokes are due
to small vessel disease.
• Patients with aseptic cerebral venous thrombosis should be screened for thrombophilia.
• A C-reactive protein level higher than 10 mg/L should raise suspicion for stroke caused by endocarditis.
ARTICLE 2: INTRAVENOUS
THROMBOLYSIS FOR ACUTE ISCHEMIC
STROKE
James C. Grotta, MD, FAAN. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
This article reviews the history of IV thrombolysis, its current indications and implementation,
the duality of the “time is brain” versus “tissue clock” approaches, the impact of endovascular
thrombectomy on IV thrombolysis, the emergence of tenecteplase, and future research
directions.
The growing use of factor Xa inhibitors has increasingly caused patients with stroke to be
excluded from treatment with IV thrombolysis. Important geographic, socioeconomic, sex, race,
and ethnic disparities have been identified in the implementation of IV thrombolysis and need to
be overcome. IV thrombolysis substantially improves outcomes when provided within the first

golden hour after stroke onset in patients treated in mobile stroke units, supporting the “time is
brain” concept and encouraging the possible value of more widespread implementation of the
mobile stroke unit approach. At the same time, other studies have shown that IV thrombolysis
can be successful in patients whose “tissue clock” is still ticking up to 9 hours after stroke onset
or in patients who awaken with their stroke, as demonstrated by favorable imaging profiles.
These considerations, along with the emergence of endovascular thrombectomy, have fostered
examination of our care systems, including the “drip and ship” versus direct to comprehensive or
endovascular thrombectomy stroke center approaches, as well as the possibility of skipping IV
thrombolysis in certain patients treated with endovascular thrombectomy. Data suggesting that
tenecteplase is at least noninferior to alteplase, as well as its more convenient dosing, has led to
its increased use. Ongoing studies are evaluating newer thrombolytics and adding
antithrombotic therapy to IV thrombolysis.
ESSENTIAL POINTS:
IV thrombolysis remains the most common acute stroke treatment. Advances in acting faster to
treat stroke have increased its efficacy, and advances in imaging have expanded its use.
However, implementing these advances and overcoming disparities in IV thrombolysis use
remain major challenges.
KEY POINTS
• Extensive clinical trial data and “real world” experience support the efficacy and safety of recombinant
tissue plasminogen activator (rtPA) as the primary treatment for acute ischemic stroke.
• An improving deficit or low National Institutes of Health Stroke Scale score does not exclude a patient from
receiving rtPA if, after a careful neurologic history and examination, the stroke-related deficit would be
disabling if it persisted without treatment.
• While rtPA is approved by the US Food and Drug Administration (FDA) for only up to 3 hours after symptom
onset, data and guidelines support its use for up to 4.5 hours after symptom onset.
• The use of factor Xa inhibitors is an increasing cause of exclusion from treatment with IV thrombolysis.
• Use of emergency department telestroke, bringing stroke treatment to the patient’s home via mobile stroke
units, improved telecommunication, and other devices will help increase the use of IV thrombolysis.
• There are many disparities in the availability and use of IV thrombolysis, and overcoming them is an important
priority for improving stroke outcomes.
• The sooner IV thrombolysis is delivered after symptom onset, the better the outcome; if treatment can be
given in the first golden hour via mobile stroke units or by expedited emergency department care, two-thirds
of patients will recover with no disability.
• Advanced imaging reveals that the temporal progression of stroke is different in each patient; outcomes with
treatment out to 9 hours after symptom onset in imaging-selected patients may result in comparable benefit
to earlier treatment.
• Regional systems of care must balance the need to administer IV thrombolysis as soon as possible to those
who qualify while also identifying and expediting triage of patients with large vessel occlusion to the nearest
endovascular thrombectomy center.
• IV thrombolysis can dissolve 20% to 30% of large vessel occlusion clots and should not be withheld in patients
meeting treatment criteria except in rare circumstances.
• Compared with rtPA, tenecteplase is more convenient, delivers the full dose faster, and produces
comparable outcomes, but is not yet approved by the FDA for IV thrombolysis.
• Research is ongoing to study the wider implementation of mobile stroke units in speeding up the delivery of
IV thrombolysis to patients with stroke.

ARTICLE 3: MECHANICAL
THROMBECTOMY FOR ACUTE ISCHEMIC
STROKE
Sunil A. Sheth, MD. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Endovascular stroke therapy has greatly improved the ability to treat the deadliest and most
disabling form of acute ischemic stroke. This article summarizes some of the recent innovations
in this field and discusses likely future developments.
At present, there is robust activity to improve all facets of care for patients with large vessel
occlusion stroke, including better prehospital routing, more efficient in-hospital screening,
expanding indications for thrombectomy eligibility, innovating novel thrombectomy devices,
and improving the effects of recanalization on clinical outcomes. In addition, the integration of
endovascular stroke therapy (EVT)—an emergent and frequently off-hours procedure that
requires a specialized team of nurses, technologists, and physicians—into acute stroke care has
transformed referral patterns, hospital accreditation pathways, and physician practices. The
eligibility for the procedure will potentially continue to grow to include patients screened
without advanced imaging, larger core infarcts, and more distal occlusions.
ESSENTIAL POINTS:
In this review, we discuss the current state of EVT and its implications for practice, and present
three cases that highlight some of the directions in which the field is moving.
KEY POINTS
• Endovascular therapy has become the consensus approach for appropriately selected patients and can
produce dramatic improvements in clinical outcomes for patients with large vessel occlusion.
• Several endovascular therapy trials published in 2015 established the treatment as clearly beneficial
compared to medical management.
• Because neurologists are frequently the frontline evaluators of patients with large vessel occlusion acute
ischemic stroke and serve as the gatekeepers for the procedure, they must have a basic understanding of the
risks, benefits, and technical aspects of endovascular stroke therapy.
• Despite this growth in endovascular stroke therapy performance, a large proportion of patients receive their
acute ischemic stroke care at hospitals not capable of performing endovascular stroke therapy.
• The challenge of how to balance the availability of sufficient daytime neurointerventional elective work with
the need for additional physicians to sustainably cover the call burden remains unsolved.
• One of the lingering obstacles to endovascular treatment access remains the absence of a uniformly
accepted neurointerventional accreditation system for training and certification.
• The efficacy of endovascular stroke therapy for large vessel occlusion acute ischemic stroke is highly time
sensitive and bringing appropriate patients directly to endovascular stroke therapy–performing centers may
accelerate treatment times and possibly improve clinical outcomes.

• Given the known adverse effects on clinical outcomes with delays in IV thrombolysis, accurate large vessel
occlusion detection in the field to ensure that non–large vessel occlusion patients do not suffer from delays
in IV recombinant tissue plasminogen activator (rtPA) is now of heightened importance.
• As clinical experience with endovascular stroke therapy has grown, the need for CTP to screen patients has
been called into question.
• Two ongoing randomized clinical trials—MR CLEAN LATE and RESILIENT Extend—are evaluating the efficacy
of endovascular stroke therapy in late-window patients without relying on CTP.
• The consensus remains to treat with IV rtPA in all eligible patients, including those with large vessel occlusion
acute ischemic stroke for whom endovascular stroke therapy may be needed.
• Two studies, both performed in China, demonstrated superiority of endovascular stroke therapy over
medical management alone in patients with basilar artery large vessel occlusion acute ischemic stroke, in
both the early time window (<12 hours from last known well in ATTENTION) and late time window (6 to
24 hours from last known well in BAOCHE).
• The natural history for patients with large vessel occlusion acute ischemic stroke presenting in the late
treatment window is poor, with over 80% having substantial disability.
• One of the interpretations of the large effect sizes seen in DAWN and DEFUSE 3 is a need to shift from
time-based selection paradigms to an imaging-based one.
• Some of the key questions to ask regarding the results of large core trials will be the extent of clinical
improvement and the proportion of patients who achieve good quality of life, rather than slightly less but still
severe disability.
• Improvement in device technology was likely an important factor in the success of the 2015 thrombectomy trials.
• The goal of endovascular stroke therapy procedures has become achieving complete reperfusion
(thrombolysis in cerebral infarction grade 3) with a single pass, termed the first pass effect. This bar has
become the new standard by which device performance can be measured.
• Intracranial atherosclerotic disease can lead to large vessel occlusion acute ischemic stroke through several
different mechanisms, including artery-to-artery distal embolization, in situ parent vessel occlusion,
occlusion of a perforator branch adjacent to the intracranial atherosclerotic disease plaque, or
hypoperfusion related to high-grade stenosis.
• Despite the greater than 90% substantial recanalization rates that can be achieved with modern endovascular
stroke therapy, about 50% of patients still do not achieve functional independence after treatment.
• While its results will need to be replicated, the CHOICE trial provides one of the first treatment approaches
for microvascular dysfunction.
ARTICLE 4: DIAGNOSIS AND

MANAGEMENT OF CARDIOEMBOLIC
STROKE
Shadi Yaghi, MD, FAHA. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Cardioembolic stroke accounts for nearly 30% of ischemic strokes. Prompt diagnosis of the
underlying mechanism may improve secondary prevention strategies. This article reviews recent
randomized trials, observational studies, case reports, and guidelines on the diagnosis and
treatment of cardioembolic stroke.

Several pathologies can lead to cardioembolic stroke, including atrial fibrillation, aortic arch
atheroma, patent foramen ovale, left ventricular dysfunction, and many others. Secondary
stroke prevention strategies differ across these heterogeneous mechanisms. In addition to
medical treatment advances such as the use of direct oral anticoagulants in patients with atrial
fibrillation, surgical treatments such as closure of patent foramen ovale have been shown to
reduce the risk of recurrent stroke in select patients. Furthermore, left atrial appendage
occlusion is a promising strategy for patients with atrial fibrillation who are candidates for
short-term oral anticoagulation therapy but not long-term oral anticoagulation therapy.
ESSENTIAL POINTS:
A thorough diagnostic evaluation is essential to determine cardioembolic causes of stroke. In
addition to risk factor management and lifestyle modifications, identification and targeting of
the underlying cardioembolic stroke mechanisms will lead to improved stroke prevention
strategies in patients with cardioembolic stroke.
KEY POINTS
• Direct oral anticoagulants are at least as effective as warfarin in stroke prevention in atrial fibrillation and
have lower risk of intracranial hemorrhage.
• There is growing evidence to support left atrial appendage occlusion as an alternative to oral anticoagulation
in patients with atrial fibrillation.
• In patients with acute cardioembolic stroke treated with oral anticoagulants, treatment is generally started
without bridging with heparin or low-molecular-weight heparin.
• In patients with atrial fibrillation and ischemic stroke despite anticoagulation a full diagnostic evaluation is
important to rule out alternative mechanisms such as small vessel disease or large artery atherosclerosis that
are not necessarily related to the atrial fibrillation and thus do not signify anticoagulation failure.
• In addition to atrial biomarkers, certain left atrial appendage biomarkers may indicate an increased risk of
atrial thromboembolism.
• Patent foramen ovale (PFO) is a congenital septal defect that is present in nearly 25% of the population and is
associated with a right-to-left shunt, which is more prominent during Valsalva maneuvers.
• Evidence suggests that transcranial doppler is superior to transthoracic echocardiography in diagnosing a
right-to-left cardiac shunt.
• Transesophageal echocardiography provides the best views of the septum and thus is best at visualizing the
PFO and associated abnormalities such as atrial septal aneurysm.
• In patients with cryptogenic stroke in the setting of a PFO, medical and in certain cases surgical management
are recommended for secondary stroke prevention.
• In the absence of another indication for anticoagulation, antiplatelet therapy may be reasonable for
secondary stroke prevention in patients with ischemic stroke in the setting of a PFO.
• Atheromas of the aortic arch, particularly when large or mobile, have been suggested to cause ischemic
stroke by artery-to-artery embolism.
• The secondary prevention of ischemic stroke in the setting of aortic arch atherosclerosis consists of risk
factor modification, high-intensity statin therapy, and antiplatelet therapy.
• Spontaneous aortic dissections can be seen in patients with Marfan syndrome, familial thoracic aortic
aneurysm or dissection, bicuspid aortic valve, Loeys-Dietz aneurysm syndrome, and vascular Ehlers-Danlos
syndrome (Ehlers-Danlos syndrome type IV).
• In patients with systolic heart failure, studies have shown an increased ischemic stroke risk with low left
ventricular ejection fraction.
• In patients with ischemic stroke and low ejection fraction, prolonged cardiac rhythm monitoring is important
to look for atrial fibrillation which would lead to anticoagulation therapy.

• In the setting of a low ejection fraction and evidence of a left ventricular thrombus with or without ischemic
stroke, patients should receive at least 3 months of anticoagulation with warfarin and until repeat cardiac
imaging shows resolution of the thrombus.
• Clinical trials are needed to test the safety and efficacy of direct oral anticoagulants when compared to
aspirin in patients with left ventricular dysfunction, particularly those with low ejection fraction and with an
ischemic stroke.
• There is an increased ischemic stroke risk in patients with an acute myocardial infarction, and this risk is
particularly high in the first 12 weeks after myocardial infarction.
• In patients with myocardial infarction and left ventricular thrombus with or without ischemic stroke,
anticoagulation treatment should be initiated for at least 3 months pending resolution of the thrombus on
follow-up cardiac imaging.
• Valvular pathologies that are associated with increased stroke risk are prosthetic heart valves, rheumatic
heart disease, and both infective and noninfective endocarditis.
• In patients with an ischemic stroke in the setting of a bioprosthetic valve, a diagnostic evaluation is needed to
exclude valve failure, thrombosis, or infection as an etiology.
• Direct oral anticoagulants are not recommended in patients with mechanical heart valves.
• Ischemic stroke risk in patients with rheumatic mitral disease has been suggested to be linked to atrial
fibrillation, particularly since studies demonstrating such associations did not involve cardiac monitoring.
• In patients with marantic endocarditis in the setting of cancer, treatment entails management of the
underlying malignancy as well as antithrombotic therapy.
• In patients with ischemic stroke in the setting of Libman-Sacks endocarditis, guidelines suggest
anticoagulation with heparin or low-molecular-weight heparin instead of oral anticoagulation if deemed safe,
but these suggestions lack high-level supporting evidence.
• Left-sided cardiac tumors such as atrial myxomas and fibroelastomas are very rare causes of ischemic stroke.
• While the optimal stroke prevention strategy for patients with ischemic stroke and left sided cardiac tumors
is unknown, in addition to antithrombotic treatment, surgical tumor resection is a reasonable approach.

MANAGEMENT OF LARGE ARTERY
ATHEROSCLEROSIS
Seemant Chaturvedi, MD, FAAN, FAHA. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Ischemic stroke due to large vessel atherosclerosis is a significant cause of stroke globally. With
the aging population, the number of people with atherosclerotic stroke will increase in the
coming decades. This article reviews the recent developments in the assessment and treatment
of extracranial and intracranial atherosclerotic disease.
More intensive dual antiplatelet therapy can now be recommended for patients with transient
ischemic attack or stroke. More stringent blood pressure and lipid control is also advised. The
need for carotid revascularization will likely decrease in the coming decades because of
advances in multimodal medical therapy; in particular, the role of revascularization for treating

asymptomatic carotid stenosis is controversial. Patients with symptomatic intracranial
stenosis should receive intensive medical therapy. Interest in high-resolution carotid plaque
imaging is growing.
ESSENTIAL POINTS:
The prevention of stroke due to large vessel atherosclerosis has improved owing to advances in
medical therapies. The role of carotid revascularization is unclear for many patient subgroups.
KEY POINTS
• Clinical trials that compared carotid endarterectomy versus medical therapy for the treatment of patients
with carotid stenosis are more than 25 years old and some consider these data to be obsolete.
• In previous trials, several subgroups of symptomatic patients had enhanced benefit from carotid
endarterectomy.
• Beyond the periprocedural period, long-term rates of stroke appear similar between patients treated with
carotid endarterectomy and carotid artery stenting.
• Timing of revascularization and patient age should be considered in selecting between carotid
endarterectomy and carotid artery stenting.
• Transcarotid artery revascularization is an emerging revascularization technique, but randomized studies
are lacking.
• It is unclear if carotid revascularization is useful for asymptomatic carotid stenosis.
• For asymptomatic carotid stenosis, men derive greater benefit from revascularization compared
with women.
• Microemboli detection using transcranial Doppler can be useful for risk stratification in patients with
asymptomatic carotid stenosis.
• There is not an established role for proximal vertebral artery stenosis stenting.
• From a global perspective, intracranial atherosclerosis is a leading cause of stroke.
• Intracranial atherosclerosis needs to be distinguished from recanalized emboli and vasculopathies.
• Intensive medical therapy is essential in the management of patients with intracranial atherosclerosis.
• Intracranial stenosis has a high stroke recurrence rate.
• Stenting is not recommended as a first-line treatment for patients with intracranial atherosclerotic disease.
• Nonstenotic plaques with complex features are potentially linked with otherwise cryptogenic strokes.

MANAGEMENT OF CEREBRAL SMALL
VESSEL DISEASE
Anjail Sharrief, MD, MPH, FAHA. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Cerebral small vessel disease (CSVD) is a common neurologic condition that contributes to
considerable mortality and disability because of its impact on ischemic and hemorrhagic stroke
risk and dementia. While attributes of the disease have been recognized for over two centuries,
gaps in knowledge remain related to its prevention and management. The purpose of this review
is to provide an overview of the current state of knowledge for CSVD.

CSVD can be recognized by well-defined radiographic criteria, but the pathogenic mechanism
behind the disease is unclear. Hypertension control remains the best-known strategy for stroke
prevention in patients with CSVD, and recent guidelines provide a long-term blood pressure
target of less than 130/80 mm Hg for patients with ischemic and hemorrhagic stroke, including
those with stroke related to CSVD. Cerebral amyloid angiopathy is the second leading cause of
intracerebral hemorrhage and may be increasingly recognized because of newer, more sensitive
imaging modalities. Transient focal neurologic episodes is a relatively new term used to describe
“amyloid spells.” Guidance on distinguishing these events from seizures and transient ischemic
attacks has been published.
ESSENTIAL POINTS:
CSVD is prevalent and will likely be encountered by all neurologists in clinical practice. It is
important for neurologists to be able to recognize CSVD, both radiographically and clinically,
and to counsel patients on the prevention of disease progression. Blood pressure control is
especially relevant, and strategies are needed to improve blood pressure control for primary
and secondary stroke prevention in patients with CSVD.
KEY POINTS
• Cerebral small vessel disease (CSVD) contributes to significant morbidity and mortality through its impact on
stroke risk, cognitive decline, and dementia.
• Several modifiable clinical risk factors are associated with the development of CSVD, including
hypertension, obstructive sleep apnea, diabetes mellitus, hyperlipidemia, and tobacco use.
• CSVD is increasingly recognized as a dynamic, whole-brain disorder characterized by endothelial
dysfunction and alterations in the function of the neurovascular unit. A better understanding of the
underlying mechanisms may help to identify therapeutic targets for treatment.
• There are six radiographic phenotypes of CSVD: (1) recent small subcortical infarct, (2) white matter
hyperintensity, (3) lacune of presumed vascular origin, (4) widened perivascular spaces, (5) cerebral
microbleed, and (6) brain atrophy.
• Small vessel ischemic (lacunar) stroke is the most commonly encountered acute clinical manifestation of
CSVD. It represents 20% to 30% of ischemic stroke cases.
• Hypertension, diabetes mellitus, and tobacco use are important risk factors for small vessel ischemic stroke,
and hyperlipidemia may also contribute to risk.
• The American Heart Association/American Stroke Association (AHA/ASA) Guideline for the Prevention of
Stroke in Patients with Stroke and Transient Ischemic Attack includes a class 1 (level of evidence B-R)
recommendation for target blood pressure less than 130/80 mm Hg for patients with ischemic stroke.
• Given the relationship between uncontrolled blood pressure and recurrent stroke risk, cognitive decline, and
dementia after stroke, interventions to improve blood pressure control in all stroke survivors, including those
with small vessel stroke, are urgently needed.
• The Boston criteria 2.0 can be used to diagnose cerebral amyloid angiopathy (CAA) based on radiographic
features, clinical characteristics, and histopathologic samples when available.
• Radiographic findings in CAA include cortical hemorrhage, cerebral microbleeds, superficial siderosis,
convexal subarachnoid hemorrhage, silent infarcts, white matter hyperintensities, and MRI-visible
perivascular spaces in the centrum semiovale.
• Episodes of CAA-related intracerebral hemorrhage (ICH) can recur over weeks, months, or years, with a
yearly ICH recurrence risk of 7.4% in CAA compared to 1.1% per year in CAA-unrelated ICH.
• Transient focal neurological episodes associated with CAA can present as short (typically less than
30 minutes) disturbances in motor, sensory, language, or visual function which may be difficult to distinguish
from transient ischemic attack or seizure.

• Patients who have CAA without ICH may have abnormal cognitive profiles in the absence of self-reported
cognitive deficits. The cognitive profile appears to be more similar to that seen with vascular cognitive
impairment; that is, impairments in executive function and processing with relatively preserved memory.
• There are no specific management guidelines for reducing ICH recurrence risk in patients with CAA; however,
the most recently published AHA/ASA guideline for the management of patients with ICH recommend
reducing blood pressure for patients with spontaneous ICH (class 1 recommendation) and suggest a blood
pressure target of less than 130/80 mm Hg (class 2a recommendation).
• Migraine is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy (CADASIL) presenting often, but not always, in the third decade of life.
• As CADASIL inheritance is autosomal dominant, significant family history also supports the diagnosis, but
given the possibility of variable presentation within families and the possibility of sporadic mutation, the
absence of family history does not exclude CADASIL as a potential diagnosis.
• Clinical management of CADASIL and cerebral autosomal recessive arteriopathy with subcortical strokes
and leukoencephalopathy (CARASIL) involves management of known vascular risk factors, including
hypertension and tobacco use, which have been shown to contribute to poorer outcomes in patients
with CADASIL.
ARTICLE 7: DIAGNOSIS AND TREATMENT

OF CEREBRAL VENOUS THROMBOSIS
Ava L. Liberman, MD. Continuum (Minneap Minn). April 2023;
29 (2 Cerebrovascular Disease):519–539.
ABSTRACT
OBJECTIVE:
Cerebral venous thrombosis (CVT), thrombosis of the dural sinus, cerebral veins, or both, is a
rare cerebrovascular disease. Although mortality rates after CVT have declined over time, this
condition can result in devastating neurologic outcomes. This article reviews the latest literature
regarding CVT epidemiology, details new factors associated with the development of CVT, and
describes advances in CVT treatment. It also contains a discussion of future directions in the
field, including novel diagnostic imaging modalities, and potential strategies to reduce the risks
associated with CVT.
The incidence of CVT may be as high as 2 per 100,000 adults per year. It remains a difficult
condition to diagnose given its variable clinical manifestations and the necessity of neuroimaging
for confirmation. The COVID-19 pandemic has revealed a novel CVT trigger, vaccine-induced
immune thrombotic thrombocytopenia (VITT), as well as an association between COVID-19
infection and CVT. Although VITT is a very rare event, timely diagnosis and treatment of CVT due
to VITT likely improves patient outcomes. Direct oral anticoagulants are currently being used to
treat CVT and emerging data suggest that these agents are as safe and effective as vitamin K
antagonists. The role of endovascular therapy to treat CVT, despite a recent clinical trial,
remains unproven.
ESSENTIAL POINTS:
The incidence of CVT has increased, outcomes have improved, and the use of direct oral
anticoagulants to treat CVT represents an important advance in the clinical care of these
patients. Rates of CVT as a complication of COVID-19 vaccines using adenoviral vectors are very

low (<5 per million vaccine doses administered), with the benefits of COVID-19 vaccination far
outweighing the risks.
KEY POINTS
• Unlike arterial strokes, cerebral venous thrombosis (CVT) has a wide spectrum of clinical presentations,
tends to affect younger patients with a female predominance, and is often nonapoplectic in onset.
• The latest annual CVT incidence ranges from 1.32 to 2 per 100,000 adults based primarily on data from
high-income countries.
• Conditions associated with CVT can be classified as either predisposing (eg, genetic prothrombotic diseases,
antiphospholipid syndrome, cancer) or precipitating (eg, oral contraceptives, infections).
• Data from a 2021 study suggest that a rare but demonstrable association between CVT and COVID-19
infection exists, although the underlying mechanisms of this association are uncertain.
• In patients with neurologic symptoms and COVID-19 infection, a high index of suspicion for CVT should be
encouraged, and treatment of CVT should be initiated as soon as possible.
• The entity implicated in the rare but potentially devastating cases of CVT and thrombocytopenia following
adenovirus-based COVID-19 vaccine administration is now called vaccine-induced immune thrombotic
thrombocytopenia (VITT), or thrombosis with thrombocytopenia syndrome.
• In patients with CVT with symptom onset within 4 to 42 days after having received a COVID-19 vaccine using
adenoviral vectors, following an algorithmic approach to evaluate and treat VITT is advised.
• Presentations of CVT can be roughly divided into four syndromes: (1) isolated headache or increased
intracranial pressure, (2) focal neurologic presentations, (3) subacute encephalopathy, and (4) cavernous
sinus syndrome with multiple cranial neuropathies.
• A key feature of focal neurologic deficits due to CVT is that they are frequently progressive in nature in
contrast to arterial strokes which tend to be maximal at onset.
• Contrast-enhanced brain MRI provides detailed information about the brain parenchyma and is probably
more accurate for diagnosing CVT than non-contrast-enhanced magnetic resonance venography sequences.
• Both the American Heart Association/American Stroke Association (AHA/ASA) and the more recently
published European Stroke Organization (ESO) guidelines recommend initiation of parenteral anticoagulation
with unfractionated or low-molecular-weight heparin prior to transitioning to oral anticoagulants for CVT
treatment.
• The ACTION-CVT study and other retrospective treatment studies are prone to confounding by indication;
nevertheless, there do not seem to be major safety issues with the use of direct oral anticoagulants as
opposed to vitamin K antagonists in clinical practice.
• As in heparin-induced thrombocytopenia, therapeutic anticoagulation with non-heparin anticoagulants is the
primary treatment for VITT with or without CVT.
• Despite the low quality of evidence, the ESO guidelines now strongly recommend using decompressive
surgery for patients with acute CVT and parenchymal lesions with impending herniation to prevent death as a
randomized controlled trial is unlikely for ethical and feasibility reasons.
• In general, CVT has a favorable outcome with an in-hospital mortality rate ranging from 1% to 4% and from 8%
to 10% during long-term follow-up.

ARTICLE 8: CERVICAL ARTERY
DISSECTION
Setareh Salehi Omran, MD. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Cervical artery dissection is a common cause of stroke in young adults. This article reviews the
pathophysiology, etiology and risk factors, evaluation, management, and outcomes of
spontaneous cervical artery dissection.
Cervical artery dissection is believed to be a multifactorial disease, with environmental factors
serving as possible triggers in patients who have a genetic predisposition to dissection
formation. Cervical artery dissection can cause local symptoms or ischemic events, such as
ischemic stroke or transient ischemic attack. Neuroimaging is used to confirm the diagnosis;
classic findings include a long tapered arterial stenosis or occlusion, dissecting aneurysm,
intimal flap, double lumen, or intramural hematoma. Patients with cervical artery dissection who
present with an acute ischemic stroke should be evaluated for IV thrombolysis, endovascular
therapy eligibility, or both. Antithrombotic therapy with either anticoagulation or antiplatelet
treatment is used to prevent stroke from cervical artery dissection. The risk of recurrent
ischemia appears low and is mostly limited to the first two weeks after symptom onset.
ESSENTIAL POINTS:
Cervical artery dissection is a known cause of ischemic strokes. Current data show no difference
between the benefits and risks of anticoagulation versus antiplatelet therapy in the acute phase
of symptomatic extracranial cervical artery dissection, thereby supporting the recommendation
that clinicians can prescribe either treatment. Further research is warranted to better
understand the pathophysiology and long-term outcomes of cervical artery dissection.
KEY POINTS
• The overall incidence of cervical artery dissection is low at 2.6 to 3.0 per 100,000 people per year.
• Dissections result from the separation of the arterial wall layers causing the formation of a false lumen that
allows blood to enter the vessel wall.
• Dissections can cause subintimal or subadventitial hematomas. Subintimal hematomas may lead to
intraluminal stenosis or occlusion. Subadventitial hematomas can cause eccentric hematoma growth and
aneurysm formation.
• A small portion of cervical artery dissection cases (nearly 2%) have been linked to monogenic connective
tissue diseases, such as vascular Ehlers-Danlos syndrome.
• Apart from monogenic disorders, which encompass a small group of cervical artery dissection cases, genetic
factors may play a role in a more multifactorial process leading to cervical artery dissection.
• Minor cervical trauma precedes nearly 41% of identified spontaneous cervical artery dissection cases. These
minor traumas can be subtle and involve hyperextension, lateroversion, or rotation of the neck.
• Pregnancy and the postpartum period, oral contraceptive use, migraine, recent infection, and vascular risk
factors have all been associated with cervical artery dissection.
• Common local signs and symptoms of cervical artery dissection include new-onset headache, neck pain,
cranial and cervical neuropathies, Horner syndrome, and pulsatile tinnitus.

• Ischemic strokes from cervical artery dissection are usually due to artery-to-artery embolism of intraluminal
thrombus formed at the site of intraluminal stenosis. Less commonly, ischemia may result from
hypoperfusion distal to a high-grade intraluminal stenosis or occlusion.
• Subarachnoid hemorrhage may result from intracranial extension of a dissection. Intracranial arteries lack
external elastic lamina and have a thinner media, making them more prone to aneurysm formation and
subsequent rupture.
• The majority of ischemic events from cervical artery dissection occur within the first 1 to 2 weeks after
symptom onset.
• The diagnosis of cervical artery dissection should be suspected in patients with acute onset of local
symptoms of headache, neck pain, Horner syndrome, or any combination of the three, particularly if they are
associated with an ipsilateral ischemic stroke.
• The most commonly used imaging modalities include CT and CT angiography (CTA), or MRI and magnetic
resonance angiography (MRA) of the head and neck.
• MRI in cervical artery dissection may show a pathognomonic crescent sign. The crescent sign is formed by an
eccentric rim of hyperintensity, corresponding to intramural hematoma, surrounding a hypointense arterial
lumen on axial cross-sectional T1-weighted sequences. The combination of MRA with T1-weighted axial
cervical MRI imaging with fat suppression allows for better visualization of intramural hematomas.
• CTA is an efficient tool with high sensitivity and specificity for diagnosing cervical artery dissection.
However, image interpretation may be limited due to inaccurate contrast bolus timing or streak artifacts from
implants or beam-hardening artifacts.
• Diagnostic cerebral angiography continues to be the gold standard for identifying cervical artery dissection.
However, given the high sensitivity and specificity of noninvasive imaging methods, digital subtraction
angiography is rarely needed, unless the clinical suspicion for a dissection continues to remain high despite
negative noninvasive imaging.
• All patients with acute ischemic stroke from cervical artery dissection should be evaluated to determine
eligibility for IV thrombolysis and endovascular therapy.
• Endovascular therapy should be considered in select patients with cervical artery dissection with acute
ischemic stroke from a large vessel occlusion. This includes patients with tandem occlusions, although the
optimal treatment method is still being explored.
• The most recent American Heart Association (AHA) guidelines recommend either warfarin or aspirin in
patients with recent ischemic stroke or transient ischemic attack from extracranial cervical artery dissection.
• The AHA recommends at least 3 months of antithrombotic therapy in patients with recent stroke or transient
ischemic attack from cervical artery dissection, but the optimal duration of treatment is unclear.
• Most cases of vessel recanalization after cervical artery dissection occur within the first few months after the
initial event (16% at 1 month, 50% at 3 months, and 60% at 6 and 12 months). Initial occlusion reduces the
likelihood of complete recanalization, whereas the presence of only local signs and symptoms increases the
odds of complete recanalization.
• Repeat neurovascular imaging is typically done 3 to 6 months after symptom onset or diagnosis with the goal
of assessing recanalization status of affected arteries and guiding ongoing antithrombotic treatment in
cervical artery dissection.
• The rate of recurrent ischemic stroke after cervical artery dissection is low at around 2% to 4% at 3 months
and 2.5% at 12 months. The greatest risk of recurrent ischemic stroke is within the first 2 weeks of diagnosis.
Dissecting aneurysms do not appear to be associated with an increased risk of recurrent stroke.
• The rate of cervical artery dissection recurrence is uncertain, ranging from 2% to 9.2% within the first
1 to 3 months. The highest risk of cervical artery dissection recurrence is within the first month of the
initial dissection.

ARTICLE 9: PEDIATRIC ISCHEMIC
STROKE
Christine Fox, MD, MAS. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Pediatric cerebrovascular disease is one of the leading causes of death and disability in children.
Survivors of childhood stroke and their families are often left to cope with long-lasting sequelae,
such as barriers to school reentry and long-term challenges in attaining independence as adults.
Because childhood stroke is rare and providers may not be familiar with the disorder, this article
reviews the risk factors, acute management, and sequelae of ischemic stroke in children.
High-quality evidence has resulted in an organized approach to emergent treatment of ischemic
stroke in adults, but most front-line providers are less prepared for emergent stroke
management in children. The level of evidence for reperfusion therapies in children remains low
but is growing. Thrombolysis and thrombectomy are sometimes considered for hyperacute
treatment of stroke in children. Readiness for pediatric stroke at regional centers should include
an organized approach to pediatric stroke triage and management based on extrapolation from
adult stroke trials, expert consensus, and emerging pediatric studies.
ESSENTIAL POINTS:
This review provides up-to-date information about ischemic stroke risk factors and management
in children. Preparation for rapid stroke diagnosis and management in children may improve
outcomes.
KEY POINTS
• Perinatal arterial ischemic stroke occurs in approximately 1 in 3000 live full-term births, which makes the
weeks around birth one of the highest-risk time periods for stroke to occur.
• Most children with acute ischemic stroke present with focal neurologic deficits similar to adults with stroke.
Unlike adults, children may have a stuttering rather than an abrupt symptom onset and also commonly
present with headache or seizure.
• Although a myriad of chronic and acute conditions can predispose a child to have a stroke, many children
who present with an initial stroke have no significant medical history and were previously considered
to be healthy.
• As evidence grows, guidelines have cautiously moved from recommending against IV thrombolysis or
thrombectomy outside of a research study toward a discussion of selecting children who may benefit from IV
thrombolysis and endovascular thrombectomy in certain circumstances.
• Although guidelines support consideration of IV thrombolysis or thrombectomy in children in specific
circumstances on a case-by-case basis, these treatments are not considered a requirement. Hyperacute
treatment decisions should be made in conjunction with neurologists with expertise in the treatment of
children with stroke.
• MRI and MR angiography or CT and CT angiography are both reasonable options as initial imaging modalities
to evaluate for a suspected childhood stroke, taking timing, circumstances, and available resources into
account. In either case, obtaining vascular imaging in addition to brain tissue imaging is crucial to identify a
large vessel occlusion or an arteriopathy that influences management.

• Because of the prevalence of arteriopathies in childhood stroke with subsequent cerebrovascular narrowing
or loss of normal hemodynamic compensatory mechanisms, in the setting of acute stroke collateral cerebral
flow should be supported by initial fluid resuscitation if needed, keeping the head of bed flat, instituting
bedrest, and avoiding hypotension.
• Congenital heart disease or acquired heart disease are major risk factors for perinatal or childhood stroke,
together accounting for almost one-third of arterial ischemic strokes in children.
• Systematic quality measures that preemptively identify children for closer postprocedural neurologic
monitoring after higher-risk cardiac procedures are key to reducing time to stroke detection and increasing
opportunities for rapid treatment.
• Cerebral arteriopathy is present in up to half of all children with ischemic stroke and is a risk factor for initial
stroke as well as stroke recurrence.
• The acute management of a suspected stroke in children with sickle cell disease differs from other stroke
etiologies and should be focused on providing an emergent blood transfusion.
• Assessment of function by a rehabilitation specialist and consideration of inpatient rehabilitation are
recommended for children following stroke.
• Children benefit from early recognition of stroke and should be transferred to a hospital that can provide
definitive care as soon as safely possible, but systems of care for children with stroke lag behind those
for adults.
• Structured and organized health systems that improve the speed of triage, transport, and treatment of
children in medical centers with established pediatric stroke guidelines are still lacking in many
geographic areas.
ARTICLE 10: MANAGEMENT OF

UNRUPTURED INTRACRANIAL
ANEURYSMS AND BRAIN
ARTERIOVENOUS MALFORMATIONS
Thanh Ngoc Nguyen, MD, FRCPc, FSVIN, FAHA. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Managing a patient with an unruptured brain aneurysm or brain arteriovenous malformation
(AVM) can lead to uncertainty about preventive treatment. While the bleeding risks are low, the
morbidity or mortality associated with a hemorrhagic event is not insignificant. The objective of
this article is to review the natural history of these vascular entities, the risk factors for
hemorrhage, preventive treatment options, and the risks of treatment.
Randomized trials to inform preventive treatment strategies for unruptured intracranial
aneurysms and brain AVMs are ongoing. Higher angiographic obliteration rates of unruptured
intracranial aneurysms have been reported with the flow-diversion technique compared with
alternative standard techniques. One randomized trial for unruptured brain AVMs showed a
higher rate of morbidity and mortality in patients who underwent interventional treatment
compared with observation.

ESSENTIAL POINTS:
The decision to treat a patient with a brain aneurysm should consider patient factors, the
patient’s life expectancy, aneurysm anatomical factors, and treatment risks. Patients with
unruptured brain AVMs should be observed in light of recent clinical trial data or enrolled in an
ongoing clinical trial.
KEY POINTS
• An estimated 3% of the population has an unruptured intracranial aneurysm.
• The risk of rupture for an asymptomatic unruptured intracranial aneurysm is estimated at 0.3% to 1% per year.
• The risk of aneurysm rupture increases with aneurysm size, a family history of aneurysm, and prior
subarachnoid hemorrhage from another aneurysm.
• An aneurysm that is documented to have growth on serial imaging carries a higher risk of rupture than an
aneurysm that has not been documented to grow.
• ISAT (International Subarachnoid Aneurysm Trial) demonstrated better outcomes among patients with
ruptured aneurysms who underwent coiling compared to those who underwent surgical clipping.
• Endovascular techniques that are commonly used in the treatment of brain aneurysms include coiling,
balloon remodeling, stent-assisted coiling, intrasaccular flow disruption, and flow diversion.
• Higher angiographic obliteration rates of unruptured intracranial aneurysms have been reported with flow
diversion compared to alternative standard techniques.
• Ischemic complications related to flow diversion are estimated to occur in up to 9.8% of cases.
• There are no completed randomized trials to inform treatment of unruptured aneurysms, but several
are ongoing.
• The decision to treat an intracranial aneurysm is based on the natural history of risk of rupture, patient and
aneurysmal anatomical factors, and the risk of repair.
• The risk of an asymptomatic, unruptured brain arteriovenous malformation (AVM) rupture is estimated
at 1.3% per year.
• Age and prior AVM hemorrhage are risk factors for future AVM hemorrhage.
• Conservative management, endovascular embolization, radiation, and operative resection are four
modalities that can be considered in the treatment of a patient with brain AVM with a multidisciplinary team;
the modalities can be performed either in isolation or in combination.
• A randomized trial demonstrated that, overall, patients with unruptured AVMs who were conservatively
managed had better outcomes than patients who underwent intervention mostly with endovascular
embolization.
ARTICLE 11: STROKE REHABILITATION

AND MOTOR RECOVERY
Michael W. O’Dell, MD. Continuum (Minneap Minn).
ABSTRACT
OBJECTIVE:
Up to 50% of the nearly 800,000 patients who experience a new or recurrent stroke each year in
the United States fail to achieve full independence afterward. More effective approaches to
enhance motor recovery following stroke are needed. This article reviews the rehabilitative
principles and strategies that can be used to maximize post-stroke recovery.

Evidence dictates that mobilization should not begin prior to 24 hours following stroke, but
detailed guidelines beyond this are lacking. Specific classes of potentially detrimental
medications should be avoided in the early days poststroke. Patients with stroke who are unable
to return home should be referred for evaluation to an inpatient rehabilitation facility. Research
suggests that a substantial increase in both the dose and intensity of upper and lower extremity
exercise is beneficial. A clinical trial supports vagus nerve stimulation as an adjunct to
occupational therapy for motor recovery in the upper extremity. The data remain somewhat
mixed as to whether robotics, transcranial magnetic stimulation, functional electrical
stimulation, and transcranial direct current stimulation are better than dose-matched traditional
exercise. No current drug therapy has been proven to augment exercise poststroke to enhance
motor recovery.
ESSENTIAL POINTS:
Neurologists will collaborate with rehabilitation professionals for several months following a
patient’s stroke. Many questions still remain about the ideal exercise regimen to maximize motor
recovery in patients poststroke. The next several years will likely bring a host of new research
studies exploring the latest strategies to enhance motor recovery using poststroke exercise.
KEY POINTS
• Motor recovery is the partial or complete improvement of an individual’s motor symptoms such as weakness,
coordination, fine control, or ataxia following a stroke.
• Functional recovery is a partial or complete improvement in an individual’s performance of activities of daily
living, instrumental activities of daily living (eg, housekeeping, cooking, washing clothes, paying bills),
mobility (eg, transfers, wheelchair use, walking) or communication.
• Although further research is clearly required, the 2018 American Heart Association/American Stroke
Association guidelines recommend that specialized acute stroke units “incorporate rehabilitation” into their
care and discourage mobilization prior to 24 hours poststroke, but otherwise make only very general
recommendations.
• Admission to a skilled nursing facility, without inpatient rehabilitation facility consideration, for the sole
purpose of decreasing acute care lengths of stay, maintaining historical referral patterns, or preventing
“bleed” outside of a constituent health care system should be viewed as incompatible with best practices.
• In addition to leading the rehabilitation team, the essential task of the attending physiatrist is to ensure that
patients at the inpatient rehabilitation facility are medically stable and free of pain and mood or other issues
to the degree that they can participate in therapy, remain on the unit, and benefit from the rehabilitation
experience.
• Most patients discharged from an inpatient rehabilitation facility to home will continue rehabilitation in an
outpatient setting. This could include one to three therapies, two to three times a week from a few weeks to a
few months, which likely represents a gross underdosing of therapy.
• If the characteristics and content of exercise constitute the “science of stroke rehabilitation,” equally
important must be the “art of rehabilitation” as practiced by an outstanding therapist.
• Significant questions remain surrounding the ideal exercise protocol following stroke, despite numerous
large clinical trials over the past 2 decades.
• Given the challenges, expense, and logistics of providing ever greater doses of exercise, identifying
strategies to augment the effect of exercise on recovery after stroke is desirable.
• To date no pharmacologic agents in well-designed randomized clinical trials have clearly demonstrated
enhanced motor recovery after stroke.
• Despite an underwhelming track record, upper and lower extremity robotics and exoskeletal devices are
commonly offered at larger rehabilitation centers.

• Compared to an ankle-foot orthosis, lower extremity functional electrical stimulation may decrease the
physiologic cost of gait (based on resting and working heart rate and walking speed) but does not improve
gait speed.
• The vagus nerve stimulation group in one trial was about twice as likely to achieve a clinically meaningful gain
on the Fugl-Meyer Assessment and 3 times as likely to improve on the Wolf Motor Function Test compared
with the control group.
• Defining the optimal nature, characteristics, intensity, and timing of a patient’s participation in task-specific
and repetitious exercise to maximize motor recovery constitutes the fundamental challenge in stroke
rehabilitation.

Issue Overview
Cerebrovascular Disease, Volume 29, Number 2, April 2023
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:
 Recognize the appropriate testing for patients to confirm and characterize stroke, gain
insights into the pathophysiologic mechanisms of stroke, and optimize prevention of
recurrent stroke
 Implement the data supporting the use of IV thrombolysis for the treatment of acute
ischemic stroke
 Describe the clinical evidence, patient selection, and treatment considerations for the use
of endovascular therapy in patients with acute ischemic stroke
 Perform the diagnostic evaluation and management of patients with cardioembolic stroke
 Recognize the expanded intensive medical therapies and the resulting improved outlook
for patients with stroke due to large vessel atherosclerosis
 Discuss various clinical presentations, describe key radiographic characteristics, discuss
risk factors associated with primary causes, and identify common and uncommon causes
of cerebral small vessel disease
 Define cerebral venous thrombosis, describe the anatomy, pathophysiology, and four
common clinical manifestations of the disease, identify radiographic features of the
disease, and recognize new evidence regarding the use of direct oral anticoagulants and
endovascular therapy to treat cerebral venous thrombosis
 Discuss the pathophysiology, risk factors, presentation, diagnosis, management, and
prognosis of cervical artery dissection, including choosing between antiplatelet and
anticoagulation therapy for stroke prevention
 Recognize the signs and symptoms of stroke in children, assess candidacy for hyperacute
or acute treatment strategies, and evaluate pediatric stroke risk factors
 Describe the natural history of unruptured brain aneurysms and brain arteriovenous
malformations, and identify the risk factors for hemorrhage, preventive treatment options,
and the risks of treatment
 Recognize the processes of and team members participating in inpatient and outpatient
stroke rehabilitation and identify the recent clinical research regarding strategies to
enhance motor recovery resulting from exercise following stroke
Core Competencies
This Continuum: Lifelong Learning in Neurology Cerebrovascular Disease issue covers the
following core competencies:
 Patient Care and Procedural Skills
 Medical Knowledge
 Practice-Based Learning and Improvement

 Interpersonal and Communication Skills
 Professionalism
 Systems-Based Practice

Contributors
Hooman Kamel, MD, MS, Guest Editor
Vice Chair for Research, Department of Neurology, Weill Cornell Medicine, New York, New
York
Relationship Disclosure: Dr Kamel has received personal compensation in the range of $10,000 to $49,999 for
serving as an editor, associate editor, or editorial advisory board member for the Journal of the American Medical
Association Neurology, and in the range of $50,000 to $99,999 for serving on an endpoint adjudication committee
for Boehringer-Ingelheim.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Kamel reports no disclosure.
Neil A. Busis, MD, FAAN

Associate Chair, Technology and Innovation, Department of Neurology, NYU Langone Health,
New York, New York
Relationship Disclosure: Dr Busis has received personal compensation in the range of $0 to $499 for serving as an
editor, associate editor, or editorial advisory board member for Neurology Today from the American Academy of
Neurology (AAN) and in the range of $500 to $4999 for serving as a speaker for the AAN and as the AAN’s
primary advisor to the American Medical Association’s CPT Editorial Panel.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Busis reports no disclosure.
Seemant Chaturvedi, MD, FAAN, FAHA

Stewart J. Greenebaum Endowed Professor of Stroke Neurology, University of Maryland School
of Medicine, Baltimore, Maryland
Relationship Disclosure: Dr Chaturvedi has received personal compensation in the range of $500 to $4999 for
serving as a consultant for AstraZeneca and on a scientific advisory or data safety monitoring board for the
University of Calgary, and in the range of $10,000 to $49,999 for serving as an editor, associate editor, or editorial
advisory board member for the American Heart Association and as an expert witness for Ramar & Paradiso (Troy,
MI) and Cole, Scott, & Kissane (Palm Beach, FL). The institution of Dr Chaturvedi has received research support
from the National Institute of Neurological Disorders and Stroke.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Chaturvedi reports no disclosure.
Luana Ciccarelli, CPC, CRC

Associate Director, Medical Economics and Practice, American Academy of Neurology,
Minneapolis, Minnesota
Relationship Disclosure: Ms Ciccarelli reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Ms Ciccarelli reports no disclosure.
Bruce H. Cohen, MD, FAAN

Director, The NeuroDevelopmental Science Center, Akron Children’s Hospital, Akron, Ohio
Relationship Disclosure: Dr Cohen has received personal compensation in the range of $500 to $4999 for serving as
a speaker for the American Academy of Neurology (AAN) and as an AAN advisor to the American Medical
Association’s CPT Editorial Panel. Dr Cohen has received personal compensation in the range of $0 to $499 for
serving as a consultant for CoA Therapeutics/ BridgeBio and Neuroene Therapeutics; in the range of $500 to $4999
for serving as a consultant for Abliva AB, Astellas Pharma Inc, Modis/Zogenix, PTC Therapeutics, and Reneo

Pharmaceuticals, Inc. The institution of Dr Cohen has received research support from Abliva, BioElectron
Technologies/ PTC Therapeutics, Astellas Pharma Inc, Reneo Pharmaceuticals, Inc., and Stealth BioTherapeutics,
Inc. Dr Cohen has received publishing royalties from a publication relating to health care and has noncompensated
relationships as the president of the board of directors of the Child Neurology Society and as a member of the board
of directors of the Child Neurology Foundation that are relevant to the American Academy of Neurology interests or
activities.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Cohen reports no disclosure.
Christine Fox, MD
Associate Professor of Neurology and Pediatrics, University of California San Francisco, San
Francisco, California
Relationship Disclosure: The institution of Dr Fox has received personal compensation in the range of $500 to
$4999 for serving as a consultant for Competitive Drug Development International Ltd, research support from the
American Heart Association/Bugher Foundation, and from the National Institutes of Health/National Institute of
Neurological Disorders and Stroke, and has received publishing royalties from a publication relating to health care.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Fox discusses the use of thrombolysis and
thrombectomy for the treatment of stroke in children.

Director of Stroke Research and Mobile Stroke Unit at the Memorial Hermann Hospital, Texas
Medical Center in Houston, Texas
Relationship Disclosure: Dr Grotta has received personal compensation in the range of $5000 to $9999 for serving
on a scientific advisory or data safety monitoring board for Haemonetics and Prolong Pharmaceuticals and in the
range of $10,000 to $49,999 for serving as a consultant for Frazer Ltd and on a scientific advisory or data safety
monitoring board for Acticor Biotech. The institution of Dr Grotta has received research support from Chiesi, CSL
Behring, and Genentech. Dr Grotta has received publishing royalties from publications relating to health care.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Grotta reports no disclosure.
Ava L. Liberman, MD
Assistant Professor, Weill Cornell Medicine, New York, New York
Relationship Disclosure: The institution of Dr Liberman has received research support from the National Institutes
of Health.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Liberman reports no disclosure.
James F. Meschia, MD, FAAN

Professor of Neurology; Frances Bartlett Kinne Professor, Mayo Clinic, Jacksonville, Florida
Relationship Disclosure: The institution of Dr Meschia has received research support from the National Institute of
Neurological Disorders and Stroke.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Meschia reports no disclosure.
Thanh Ngoc Nguyen, MD

Director of Interventional Neurology and Neuroradiology, Boston Medical Center; Professor of
Neurology, Neurosurgery, and Radiology, Boston University Chobanian and Avedisian School
of Medicine, Boston, Massachusetts
Relationship Disclosure: Dr Nguyen has received personal compensation in the range of $0 to $499 for serving on a
scientific advisory or data safety monitoring board for the National Institutes of Health, and in the range of $500 to
$4999 for serving on a scientific advisory or data safety monitoring board for Avania, Idorsia Pharmaceuticals, and
Vesalio, and as an editor, associate editor, or editorial advisory board member for the American Heart Association.
The institution of Dr Nguyen has received research support from Medtronic and the Society of Vascular and
Interventional Neurology.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Nguyen reports no disclosure.
Professor Emeritus of Rehabilitation Medicine, Department of Rehabilitation Medicine, Weill
Cornell Medicine, New York, New York
Relationship Disclosure: Dr O’Dell has received personal compensation in the range of $0 to $499 for serving as an
officer or member of the board of directors for Franklin College of Indiana, and in the range of $500 to $4999 for
serving on a scientific advisory or data safety monitoring board for Merz Pharmaceuticals, LLC.
Unlabeled Use of Products/Investigational Use Disclosure: Dr O’Dell discusses several clinical trials involving the
use of investigational drugs, none of which are US Food and Drug Administration (FDA) approved for use in people
with stroke.
Setareh Salehi Omran, MD

Assistant Professor of Neurology, University of Colorado School of Medicine, Aurora, Colorado
Relationship Disclosure: Dr Salehi Omran reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Salehi Omran reports no disclosure.
Anjail Sharrief, MD, MPH, FAHA

Associate Professor of Neurology, McGovern Medical School, University of Texas Health
Sciences Center, Houston, Texas
Relationship Disclosure: The institution of Dr Sharrief has received research support from the National Institutes of
Health and from the University of Houston. Dr Sharrief has a non-compensated relationship as a consultant with
Abbot Laboratories that is relevant to the American Academy of Neurology interests or activities.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Sharrief reports no disclosure.
Sunil Sheth, MD
Associate Professor, Department of Neurology; Director, Division of Vascular and Interventional
Neurology, University of Texas Health Sciences Center, Houston, Texas
Relationship Disclosure: Dr Sheth has received personal compensation in the range of $500 to $4999 for serving as
a consultant for CERENOVUS and Imperative Care, and in the range of $100,000 to $499,999 for serving as a
consultant for Penumbra Inc.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Sheth reports no disclosure.

Raissa Villanueva MD, MPH, FAAN
Division Chief, General Neurology Division, University of Rochester Medical Center,
Rochester, New York
Relationship Disclosure: Dr Villanueva has received personal compensation in the range of $500 to $4999 for
serving as a speaker for the American Academy of Neurology (AAN) and as the AAN’s alternate advisor to the
American Medical Association’s CPT Editorial Panel. Dr Villanueva has a noncompensated relationship as a
practice management committee member with the American Headache Society that is relevant to the American
Academy of Neurology interests or activities.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Villanueva reports no disclosure.
Shadi Yaghi, MD
Associate Professor of Neurology, Brown University, Providence, Rhode Island
Relationship Disclosure: Dr Yaghi reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Yaghi reports no disclosure.
Self-Assessment and CME Test Writers
Douglas J. Gelb, MD, PhD, FAAN

Professor of Neurology, University of Michigan, Ann Arbor, Michigan
Relationship Disclosure: Dr Gelb has received personal compensation in the range of $500 to $4999 for serving as a
multiple-choice question writer for Continuum with the American Academy of Neurology. Dr Gelb has received
publishing royalties from a publication relating to health care.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Gelb reports no disclosure.
Allyson R. Zazulia, MD
Professor of Neurology and Radiology; Associate Dean for Continuing Medical Education,
Washington University, St. Louis, Missouri
Relationship Disclosure: Dr Zazulia reports no disclosure.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Zazulia reports no 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 authors 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 continuing medical education (CME) and self-assessment
offerings. For detailed instructions regarding Continuum CME and self-assessment activities,
visit continpub.com/CME.
The review articles emphasize clinical issues emerging in the field in recent years. Case reports
and vignettes are used liberally, as are tables and illustrations. Audio interviews with the authors
of Continuum articles are published alongside each article, and 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.

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APRIL 2023

VOL. 29 NO. 2 Cerebrovascular Disease

410 Editor’s Preface

412 Diagnostic Evaluation of Stroke Etiology

425 Intravenous Thrombolysis for Acute Ischemic Stroke

443 Mechanical Thrombectomy for Acute Ischemic Stroke

462 Diagnosis and Management of Cardioembolic Stroke

486 Diagnosis and Management of Large Artery Atherosclerosis

501 Diagnosis And Management of Cerebral Small Vessel Disease

519 Diagnosis and Treatment of Cerebral Venous Thrombosis

540 Cervical Artery Dissection

584 Management of Unruptured Intracranial Aneurysms and Brain

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

628 The Transformation of Documenting and Coding for Neurologic

SELF-ASSESSMENT AND CME

402 Learning Objectives and Core Competencies

641 Instructions for Completing Postreading Self-Assessment and CME

643 Postreading Self-Assessment and CME Test

655 Postreading Self-Assessment and CME Test—Preferred Responses

List of Abbreviations (Back Cover)

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

Hooman Kamel, MD, MS Seemant Chaturvedi, MD,

404 APRIL 2023

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

Unlabeled Use of Products/Investigational

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

Ava L. Liberman, MD Thanh Ngoc Nguyen, MD

Relationship Disclosure: Dr Nguyen has

Unlabeled Use of Products/Investigational

406 APRIL 2023

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

Unlabeled Use of Products/Investigational

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

Relationship Disclosure: Dr Yaghi reports no

Unlabeled Use of Products/Investigational

Self-Assessment and CME Test Writers

Allyson R. Zazulia, MD Douglas J. Gelb, MD, PhD,

Unlabeled Use of Products/Investigational

408 APRIL 2023

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

Progress and Promise in Stroke

410 APRIL 2023

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

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

LATEST DEVELOPMENTS: Identifying the presence of patent foramen ovale,

412 APRIL 2023

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

merely stroke, must be obtained to properly assess potential heritable risk

414 APRIL 2023

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

CASE 1-1 A 93-year-old man with hypertension presented to the emergency

416 APRIL 2023

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CERVICOCEPHALIC ARTERIAL IMAGING

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

418 APRIL 2023

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

CARDIAC RHYTHM ASSESSMENT

STRUCTURAL CARDIAC IMAGING

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rare, such as atrial myxoma, papillary fibroelastoma, and valvular vegetations.

EMBOLIC STROKE OF UNDETERMINED SOURCE