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Brain
Embolism
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NEUROLOGICAL DISEASE AND THERAPY

Advisory Board

Gordon H. Baltuch, M.D., Ph.D.


Department of Neurosurgery
University of Pennsylvania
Philadelphia, Pennsylvania, U.S.A.

Cheryl Bushnell, M.D., M.H.S.


Duke Center for Cerebrovascular Disease
Department of Medicine, Division of Neurology
Duke University Medical Center
Durham, North Carolina, U.S.A.

Louis R. Caplan, M.D.


Professor of Neurology
Harvard University School of Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts, U.S.A.

Mark A. Stacy, M.D.


Movement Disorder Center
Duke University Medical Center
Durham, North Carolina, U.S.A.

Mark H. Tuszynski, M.D., Ph.D.


Professor of Neurosciences
Director, Center for Neural Repair
University of California—San Diego
La Jolla, California, U.S.A.
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Brain
Embolism

edited by
Louis R. Caplan
Beth Israel Deaconess Medical Center
Boston, Massachusetts, U.S.A.

Warren J. Manning
Beth Israel Deaconess Medical Center
Boston, Massachusetts, U.S.A.

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Preface

In medicine, as in other areas of life, interest and emphasis on various topics go through
periods of ups and downs. Brain embolism was defined by most physicians during the
middle years of the twentieth century as embolism to the brain arising from clots, bacteria,
and other substances that came from the heart. During the last three decades, technology
has been introduced that can show brain infarction during life and can detect embolic par-
ticles passing through arteries that supply the brain. These more recent brain and vascular
studies showed that the great majority of brain ischemic events are caused by embolism.
However, not all of the embolic particles arise from the heart. Many come from the aorta,
from systemic veins, and from the cervico-cranial arteries. This knowledge has led to a
return to the original definition of embolism, that is, blockage of an artery by material orig-
inating from a distant site.
The process of brain embolism is complex. There are a variety of donor sites and
sources of embolic material. The particles that embolize also vary greatly. Emboli travel
to many different recipient sites. Whether or not the emboli cause brain infarction is
also complex and depends on other factors, including the vascular endothelium at the reci-
pient site and the blood together with its constituents. No prior monographs have covered
the complex topic of brain embolism in depth, stimulating us to try and fill this gap in the
literature. Drs. Willis Hurst, Marc Chimowitz, and Caplan authored a monograph nearly a
decade ago entitled Clinical Neurocardiology that contained a single chapter on brain
embolism. The time has come for an updated review of this important topic.
To ensure a thorough review of the topic, we recruited experts in areas of knowledge
that we believed would enhance the monograph. Dr. Warren Manning, a cardiologist, con-
tributed chapters related to cardiac origin and therapy for cardiac lesions that can lead to
brain embolism. We also enlisted the help of experts in neck and transcranial ultrasound
technology (Professor Michael Hennerici and his colleagues at the University
of Heidelberg in Germany, and Dr. Carlos Molina (Barcelona, Spain) and Dr. Alexei
Alexandrov (Houston, Texas, U.S.A.). Dr. Gregory del Zoppo added his considerable
expertise about blood and endothelial factors that contribute to thromboembolism.
The first part of the book begins with a historical review of the subject. Knowing
where a topic has been is key to recognizing where it now is and where it is most likely
headed in the future. This is followed by an overview that introduces the three main
dramatists personae in the theatre of brain embolism—donor sites, embolic substances,
and recipient sites. Pathological, clinical, and diagnostic aspects related to the recipient
sites of brain emboli are explored in detail, followed by detailed analyses of the donor

iii
iv Preface

source of emboli—the heart, aorta, and cervico-cranial brain supply arteries. Next, the
pathophysiology of embolism and the role of the blood, vascular endothelium, and neu-
rovascular unit are explored. The nature of embolic substances is discussed, including
their usual sources and clinical features. The monograph also reviews therapeutics and
analyzes the effectiveness and risks of the various treatments employed. Finally, we
look to the future.

Louis R. Caplan
Warren J. Manning
Boston 2006
Contents

Preface . . . . iii
Contributors . . . . xi

Part I: Historical Background and Overview


1. Historical Background: Development of Ideas and Knowledge
about Stroke and Brain Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Louis R. Caplan
Early Writers—Description of Apoplexy and
Interest in Anatomy . . . . 1
The 18th Century: Morgagni—The Beginning of
Modern Pathology . . . . 3
The First Half of the 19th Century—Recognition of Brain
Infarction and a Relationship with Heart Disease . . . . 4
The Second Half of the 19th Century—Cardiac Embolism
Becomes an Established Clinical Entity . . . . 7
The First Half of the 20th Century—An Emphasis on
Vascular Anatomy . . . . 8
Data Banks and Stroke Registries . . . . 13
New Technology and Further Studies Clarify More Potential
Donor Sources of Emboli . . . . 17
Brain and Vascular Investigations Bring Embolism to the Forefront
as the Major Cause of Brain Infarction . . . . 18
References . . . . 19

2. Overview: The Major Components of Brain Embolism . . . . . . . . . . . . . . . 25


Louis R. Caplan
The Recipient Arteries . . . . 25
The Embolic Material . . . . 27
The Donor Source . . . . 28
References . . . . 29

v
vi Contents

Part II: Recipient Arteries and Brain Ischemia


3. Recipient Artery: Anatomy and Pathology . . . . . . . . . . . . . . . . . . . . . . . . . 31
Louis R. Caplan
Examining Recipient Arteries to Separate Embolism
and Thrombosis . . . . 31
Hemorrhagic Infarction . . . . 33
Location, Types, and Size of Embolic Brain Infarcts . . . . 36
References . . . . 58

4. Recipient Artery: Clinical Symptoms and Signs of


Brain Ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Louis R. Caplan
General Clinical Features and Diagnosis . . . . 61
Anterior Carotid Artery Circulation Embolism . . . . 67
Posterior Circulation Vertebro-Basilar Arteries Embolism . . . . 70
References . . . . 77

5. The Eye as the Recipient Artery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81


Louis R. Caplan
Anatomy of the Arteries that Supply the Eye . . . . 81
Clinical Symptoms and Signs of Eye Ischemia . . . . 83
Methods of Investigating the Eye as a Recipient
Site of Embolism . . . . 87
Differential Diagnosis of Retinal Embolism . . . . 88
Usual Sources of Retinal Embolism . . . . 89
Treatment . . . . 90
References . . . . 90

6. Imaging Evaluation: Recipient Artery Sites . . . . . . . . . . . . . . . . . . . . . . . . 93


Louis R. Caplan
Brain Neuroimaging . . . . 93
Intracranial Vascular Imaging . . . . 97
Magnetic Resonance Perfusion Imaging and Complete
Magnetic Resonance Protocols . . . . 101
Computed Tomography Perfusion and Complete Computed
Tomography Protocols . . . . 104
Other Techniques for Studying Perfusion . . . . 106
References . . . . 109

7. Transcranial Doppler Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113


Carlos A. Molina and Andrei V. Alexandrov
Introduction . . . . 113
TCD Diagnosis of Arterial Occlusions . . . . 114
TCD Monitoring During Thrombolysis . . . . 117
Detection of Intracranial Artery Stenosis and
Artery-to-Artery Embolism . . . . 121
Emboli Monitoring . . . . 122
Detection of Right-to-Left Shunts . . . . 123
References . . . . 124
Contents vii

Part III: Donor Sources—Nature, Frequency, Recognition


8. Cardiac Sources of Embolism: The Usual Suspects . . . . . . . . . . . . . . . . . 129
Louis R. Caplan and Warren J. Manning
Arrhythmias . . . . 130
Cardiac Valve Disease . . . . 131
Aortic Valve Disease . . . . 132
Infective Endocarditis . . . . 137
Noninfective Fibrous and Fibrinous Endocardial Lesions
(Including Valve Strands) . . . . 139
Myocardial and Cardiac Chamber Lesions . . . . 144
Cardiac Myxomas and Other Tumors . . . . 147
Paradoxical Embolism and Cardiac Septal Lesions . . . . 148
References . . . . 151

9. Cardiac Source of Embolism: Pathophysiology and Identification . . . . . . 161


Warren J. Manning
Major Sources of Emboli . . . . 161
Left Atrial Anatomy and Imaging . . . . 161
Left Atrial Thrombi . . . . 162
Mitral Stenosis . . . . 163
Atrial Fibrillation . . . . 165
Left Ventricular Thrombi . . . . 169
Myocardial Infarction . . . . 170
Dilated Cardiomyopathy . . . . 171
Prosthetic Valve Thrombi . . . . 171
Aortic Atherosclerosis . . . . 171
Infective Endocarditis . . . . 172
Valvular Calcification . . . . 173
Valve Excrescences . . . . 173
Mitral Annular Calcification . . . . 174
Intracardiac Tumors . . . . 174
Left Atrial Spontaneous Echo Contrast . . . . 175
Abnormalities of the Interatrial Septum . . . . 176
Imaging Procedures . . . . 179
Summary and Recommendations . . . . 179
References . . . . 180

10. The Aorta as a Donor Source of Brain Embolism . . . . . . . . . . . . . . . . . . . 187


Louis R. Caplan
Early Pathology-Based Reports of
Embolism from the Aorta . . . . 187
Aortic Atherosclerosis . . . . 187
Heart Surgery and Aortic Atherosclerosis . . . . 191
Encephalopathy, Cognitive, and Neurobehavioral
Abnormalities After Heart Surgery . . . . 194
Imaging of the Proximal Aorta . . . . 196
References . . . . 198
viii Contents

11. Arterial Sources of Embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203


Louis R. Caplan
Diseases, Pathology, and Pathophysiology . . . . 203
Atherosclerosis . . . . 203
Arterial Dissections . . . . 205
Fibromuscular Dysplasia . . . . 205
Arterial Aneurysms and Dolichoectatic Arteries . . . . 208
Distribution of Arterial Lesions . . . . 209
Relation of Symptoms to Severity of
Atherosclerotic Arterial Stenosis . . . . 213
Imaging and Laboratory Evaluation of Potential Donor
Sources of Embolism . . . . 216
References . . . . 219

12. Ultrasound of Cervical Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223


Michael Hennerici, Hansjoerg Baezner, and Michael Daffertshofer
Intima – Media Thickness: The Initial Stage
of Arterial Disease . . . . 223
Plaque Development: The Intermediate Stage
of Arterial Disease . . . . 226
Plaque Development: The Final Stage . . . . 234
References . . . . 236

Part IV: Pathophysiology


13. Vascular Hemostasis and Brain Embolism . . . . . . . . . . . . . . . . . . . . . . . . 243
Gregory J. del Zoppo
Thrombosis and the Pathophysiology
of Brain Ischemia . . . . 244
Cerebrovascular Thrombosis . . . . 245
Hemorrhagic Transformation . . . . 247
Stroke and Consumptive Coagulopathy . . . . 248
Platelet Activation . . . . 249
Thrombin Generation . . . . 249
Fibrin Degradation . . . . 249
Endogenous Protective Mechanisms . . . . 250
Cerebrovascular Reservoir . . . . 250
Collateral Circuits . . . . 250
Microvessel-Associated Protection . . . . 250
Endogenous Thrombus Lysis . . . . 251
Vascular Matrix Degradation . . . . 251
Modulation of Thrombin Activity . . . . 252
Microvessel Integrity, Hemostasis, and Selective
Neuron Vulnerability . . . . 253
Summary . . . . 253
References . . . . 254
Contents ix

Part V: Embolic Materials


14. Embolic Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259
Louis R. Caplan
Cardiac-Origin Substances . . . . 259
Arterial Origin Sources . . . . 264
Substances that Originate from Outside the
Cardiovascular Systems . . . . 264
Fat Embolism . . . . 264
Air Embolism . . . . 268
Tumor Embolism . . . . 269
Foreign Body Embolism . . . . 270
References . . . . 271

Part VI: Treatment


15. Treatment of the Acute Embolic Event . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
Louis R. Caplan
Reperfusion . . . . 277
Anticoagulation . . . . 282
Neuroprotective Agents . . . . 283
Managing Brain Edema and Mass Effect . . . . 284
References . . . . 284

16. Cardiac Source of Embolism: Treatment . . . . . . . . . . . . . . . . . . . . . . . . . 289


Warren J. Manning
Atrial Fibrillation . . . . 289
New Onset Atrial Fibrillation . . . . 289
Recurrent or Persistent Atrial Fibrillation . . . . 297
Atrial Fibrillation Risk Profile . . . . 298
Combination Therapy . . . . 300
Abnormalities of the Interatrial Septum . . . . 309
References . . . . 311

17. Treatment of Aortic and Arterial Sources . . . . . . . . . . . . . . . . . . . . . . . . 319


Louis R. Caplan
Treatment of Aortic Atheromatosis . . . . 319
Treatment of Arterial Source Emboli . . . . 320
Substances that Alter Fibrinogen Concentrations . . . . 323
Anticoagulants . . . . 324
Surgical and Interventional Treatments . . . . 326
References . . . . 328

Part VII: The Future


18. A Look Towards the Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335
Louis R. Caplan and Warren J. Manning
Diagnostic Advances . . . . 335
x Contents

Therapeutic Advances . . . . 338


Thrombolysis . . . . 338
Mechanical Devices . . . . 338
Antiplatelet Agents . . . . 339
Anticoagulants . . . . 339
Neuroprotectants . . . . 340
Personnel and Systems of Care . . . . 340
Index . . . . 341
Contributors

Andrei V. Alexandrov Departments of Neurology and Radiology, University of


Texas Health Sciences Center, Houston, Texas, U.S.A.
Hansjoerg Baezner Department of Neurology, University of Heidelberg,
Universitätsklinikum Mannheim, Mannheim, Germany
Louis R. Caplan Division of Cerebrovascular Disease, Harvard Medical School, and
Beth Israel Deaconess Medical Center, Boston, Massachusetts, U.S.A.
Michael Daffertshofer Department of Neurology, University of Heidelberg,
Universitätsklinikum Mannheim, Mannheim, Germany
Michael Hennerici Department of Neurology, University of Heidelberg,
Universitätsklinikum Mannheim, Mannheim, Germany
Warren J. Manning Department of Medicine, Cardiovascular Division,
Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston,
Massachusetts, U.S.A.
Carlos A. Molina Neurovascular Unit, Vall d’Hebron Hospital, University of
Barcelona, Barcelona, Spain
Gregory J. del Zoppo Department of Molecular and Experimental Medicine,
The Scripps Research Institute, La Jolla, California, U.S.A.

xi
PART I: HISTORICAL BACKGROUND AND OVERVIEW

1
Historical Background: Development
of Ideas and Knowledge about Stroke
and Brain Embolism

Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

In order to know where we are now and where we are headed in the future, we must know
where we and our predecessors have been. History adds a broadening dimension to knowl-
edge. For this reason, I begin this monograph on brain embolism with a historical chapter
that briefly reviews the development of ideas about embolism and stroke. Clearly, recog-
nition of the clinical entity “stroke” preceded thought and data about stroke mechanisms,
so that the history of stroke is indelibly interwoven into the history of brain embolism.

EARLY WRITERS—DESCRIPTION OF APOPLEXY


AND INTEREST IN ANATOMY

The earliest physicians described clinical phenomenology to give a reasonable prognosis


about the outcome in individual patients. Hippocrates (circa 400 B.C.E. ) was probably the
first to write about the medical aspects of stroke (1 –5). Hippocrates and his followers were
mostly interested in predicting the outcome of an illness for the patient and his family.
Hippocrates was a keen observer, who urged for a careful observation and recording of
phenomenology. Hippocrates wrote in his aphorisms on apoplexy, “persons are most
subject to apoplexy between the ages of forty and sixty,” and attacks of numbness
might reflect “impending apoplexy” (1,5). In reference to an apoplectic attack,
Hippocrates wrote, “During the spasms the loss of speech for a long time is unfortunate;
if present for a short time it proclaims a paralysis of the tongue, of the arm, or of parts on
the right side.” Hippocrates also noted some anatomical features. He observed that there
were many blood vessels connected to the brain, most of which were “thin,” but two (the
carotid arteries) were stout. The Greeks recognized that interruption of these blood vessels
to the brain could cause loss of consciousness; so they named the arteries carotid, from the
Greek word Karos, meaning “deep sleep” (1 – 5).
Centuries after Hippocrates, a Greek physician Claudius Galenus, usually referred
to as Galen of Pergamon (130 – 199 C.E. ), described the anatomy of the brain and its

1
2 Caplan

blood vessels from dissections of animals. Galen’s early writings emphasized observation
and experimentation, but later works combined theorizing and speculation, in which he
attributed disease to disequilibrium between various putative body humors and secretions,
such as water, blood, phlegm, bile, and so forth (4). Galen and his extensive writings
dominated the 1300 years following his death. During the ensuing Dark and Middle
ages, persons claiming to be physicians gained knowledge solely from studying the
Galenic texts, considered at the time to be the epitome of all medical wisdom. Andreas
Vesalius (1514 – 1564) challenged the Galenic tradition by dissecting humans and
relying on his own personal observations, instead of on Galen’s writings (2 – 4,6).
Vesalius’s dissections were published in a volume entitled De Humani Corpis Fabrica
(usually referred to as the Fabrica), which contained the detailed drawings that his
collaborator and young artist Jan Kalkar reproduced as woodcuts and copper plates.
The seventh book of the Fabrica contains 15 diagrams of the brain. These were the
most detailed neuroanatomical studies upto that point.
During the last half of the seventeenth century, two physicians, Johann Jakob
Wepfer (1620 –1695) and Thomas Willis (1621 – 1675), made important anatomical and
clinical observations. Wepfer wrote a popular treatise on apoplexy, that was originally
published in 1658 and had five subsequent editions (7,8). Wepfer performed meticulous
examinations of the brains of patients dying of apoplexy. He described the carotid
siphon and the course of the middle cerebral artery. He recognized that the carotid and
vertebral arteries could become hard and obstructed and speculated that the blockage
could prevent sufficient nutrition from reaching the brain (7,8). Wepfer was the first to
show clearly that bleeding in the brain was an important cause of apoplexy.
Sir Thomas Willis (Fig. 1) was born shortly after the deaths of Queen Elizabeth
and William Shakespeare. Willis was a successful practicing physician and a very

Figure 1 Sir Thomas Willis. Source: From Ref. 145.


Development of Ideas and Knowledge about Stroke and Brain Embolism 3

accomplished organizer, researcher, and teacher. He performed autopsies on his patients


and did extensive anatomical dissections, especially on the brain (9,10). Sir Christopher
Wrenn, the renowned architect and artist, worked with him and was responsible for the
engraved plates in Willis’ Cerebri Anatome (9 –11). Willis became the Sedleian Professor
of Natural Philosophy at Oxford University. His anatomy book contains very detailed
descriptions of the brain stem, cerebellum, cerebral hemispheres, and the ventricles of
the brain. Willis recognized transient ischemic attacks and described cases in which
“both carotid arteries were choked up so that not the least drop of blood could pass
through either of them” (9 – 11).

THE 18TH CENTURY: MORGAGNI—THE BEGINNING OF


MODERN PATHOLOGY

During the eighteenth century, one of the true giants of medical history, Giovanni Battista
Morgagni (1682 – 1771), focused his attention on pathology and the cause of diseases
(2,4). Until then, anatomy and prognosis were emphasized. Morgagni, a distinguished pro-
fessor of anatomy at the University of Padua, had a vision that the key to understanding
disease was to perform thorough necropsies on humans with illnesses and to correlate
the pathological findings with the symptoms during life. Although the clinicopathological
method is now taken for granted, this was a new approach for eighteenth-century phys-
icians. Morgagni labored many years to meticulously collect material for his epic work,
De Sedibus et Causis Morborum per Anatomen Indagatis, which was published when
he was 79 years old (2,4,12). De Sedibus is a five-volume work organized in the form
of 70 letters to a young man, describing the cases collected.
The first volume of De Sedibus was entitled Disease of the Head. Morgagni’s
clinical descriptions of patients were detailed in the book, but it contained no formal phys-
ical or neurological examinations, because these were not performed during his time.
Chapter two in this volume was titled Of the Apoplexy in General, and succeeding chapters
were on serous and sanguineous apoplexy. He recognized that the causes of apoplexy were
heterogeneous. “Of the many who died of apoplexy in the same month, or even in the same
day, all did by no means discover the same injuries to the brain; but some of these
appearances were widely different from others, and proceeded from different causes”
(12). Morgagni was the first to separate intracerebral hemorrhage from cases of apoplexy
in which there was no bleeding. However, he did not clearly describe brain infarcts but
continued to refer to an excess of fluid (“serum”) in the cranial cavity (serous apoplexy).
Morgagni described cases of intracerebral hemorrhage and recognized that paralysis was
on the side of the body opposite the brain lesion.
The first volume also contains clear descriptions of vascular lesions. In one patient,
who died suddenly and who had preceding attacks of vertigo, Morgagni noted, “In the left
vertebral artery, very near to its anastamosis with the other arteries, were thin small plates,
some resembling a tendinous, some a cartilaginous, and others a bony consistency” (12).
Commenting on a diseased artery in another patient, Morgagni wrote, “I opened both of
these arteries, and on their internal surfaces I found a little white body, thickish, somewhat
hard and even almost cartilaginous; and it could not but happen that they must, in some
measure stop up the cavity as they protruded internally” (12). Morgagni also noted
heart disease in many patients, although he did not posit embolism. “In the pericardium
was a proper quantity of water, with a flaccid heart. . . . A heart of this kind, indeed,
does not seem to have been able to propel the blood” (12).
4 Caplan

Morgagni’s work shifted the emphasis of physicians from anatomy alone to inquiry
about diseases and their pathology, causes, and clinical manifestations during life. The
way was prepared for clinicians and pathologists to further their knowledge about stroke.

THE FIRST HALF OF THE 19TH CENTURY—RECOGNITION OF BRAIN


INFARCTION AND A RELATIONSHIP WITH HEART DISEASE

During the early years of the nineteenth century, physicians began to recognize the
occurrence of brain infarction and observed that heart disease was common in patients
with apoplexy. A very influential treatise on apoplexy was written by a prominent Irish
physician John Cheyne (1777 – 1836). Cheyne’s book, which appeared in 1812, was titled
Cases of Apoplexy and Lethargy with Observations upon the Comatose Diseases (2,3,13).
Cheyne separated the phenomenology of lethargy and coma from apoplexy. Cheyne’s
description of the neurological abnormalities was more detailed than those of his prede-
cessors, and the “morbid appearances” of the patients’ brains were emphasized, following
the example of Morgagni. The pathological findings included descriptions of brain soften-
ing and intracerebral and subarachnoid hemorrhages. Cheyne wrote that sanguineous
apoplexies were much more common than serous, and he noted, “The causes of serous
apoplexy are involved in great obscurity” (13). Cheyne also wrote, “Inordinate contrac-
tions of the heart have been mentioned as a cause of apoplexy. They have preceded apo-
plexy, and are probably connected to the disease . . . they may prove the immediate cause
of the fit, by throwing blood with violence upon the brain” (13). Remember that at that
time there was no method of measuring blood pressure, and physicians posited increased
circulation as a potential cause of intracranial hemorrhage.
John Cooke (1756 – 1838), a physician at the London Hospital, summarized the
history of neurological thought concerning apoplexy in his Croonian lecture in 1819
(3,14). John Abercrombie (1780 – 1844) contributed a more detailed clinical classification
of apoplexy in his general neurology text published in 1828 (15). He used the presence of
headache, stupor, paralysis, and outcome to separate apoplectics into different clinical
groups. He also described brain infarcts more clearly than his predecessors and speculated
about their cause. Abercrombie described infarcts (referred to as ramollissements, a
French term meaning softening) as follows: “a peculiar softening of the brain . . . it consists
in a part of the cerebral substance being broken down in a soft pulpy mass, retaining its
natural color, but having lost its cohesion and consistence” (15). Later in the text, he
wrote, “This peculiar softening of the cerebral matter is analogous to gangrene in other
parts of the body . . . like gangrene it may arise from inflammation and failure of the
circulation from disease of the arteries” (15).
George Burrows (1801 –1881) a physician at St. Bartholomew’s Hospital in London
published a monograph in 1846 that emphasized brain – heart relationships (16). He
entitled the book On Disorders of the Cerebral Circulation and on the connection
between Affections of the Brain and Diseases of the Heart. Burrows, a general physician,
noted “the full extent of the influence of diseases of the heart in disturbing the functions,
or producing actual structural changes in other organs, and especially of the brain, has
not been thoroughly estimated” (16). He analyzed 132 examples of apoplexy and
sudden hemiplegia and noted that about three-fifth had unequivocal signs of cardiac
disease—either hypertrophy, dilatation, valvular disease, or some combination of these
lesions” (16).
William S. Kirkes was one of the first physicians to emphasize the relationship of
endocarditis to brain infarcts (17). In 1852, he described three patients. The first was a
Development of Ideas and Knowledge about Stroke and Brain Embolism 5

woman of 34, who had a loud systolic murmur and suddenly became speechless and hemi-
plegic. At necropsy, the mitral valve contained large excrescences, and the middle cerebral
artery was occluded by a firm fibrinous plug. The brain beyond the occlusion and the
spleen and kidney were also infarcted, and an iliac artery was also occluded by embolic
material. The other two patients had cardiac valvular vegetations and brain infarcts and
died of endocarditis (17). Kirkes concluded that the vegetative materials must have
mixed with the circulating blood to disseminate into the brain and visceral arteries.
During the middle years of the nineteenth century, dissemination of knowledge
about the pathology of neurological diseases and stroke came with the publication of
four atlases, each containing plates of brain and vascular lesions. Hooper’s atlas, published
in 1828, clearly illustrated pontine and putaminal hemorrhages (18). Cruveilher (1835 –
1842) (19), Carswell (1838) (20), and Bright (1831) (21) also published atlases containing
lithographs of systemic and neuropathological lesions. Richard Bright, better known for
his work on nephritis, collected more than 200 neuropathological cases and specimens
(2) and presented illustrations of 25 nervous-system specimens, including cerebro-
vascular cases, in his volume on nervous-system disorders (2,21). Bright illustrated the
external aspect and a coronal section of the brain in a patient who died of an acute
large brain infarct, involving most of the territory of the middle cerebral artery. In
1836, Bright published a paper on the clinical and necropsy findings in patients with
abnormalities of the arteries of the brain (22).
Clinicians of this era recognized that arteries and veins could become occluded, but
the cause of the occlusions and their relationship to brain and other organ softening was
not clarified. Thrombi and coagula in the vascular system were discovered at necropsy,
but observers debated whether or not these formed postmortem or during life. During
the late 18th and early 19th centuries, two major figures, John Hunter (1728 –1793) in
England and Cruveilhier in France, thought that coagula were caused by inflammation
in the veins (23). Hunter, an English surgeon, writing in 1793 noted the frequency of
vein inflammation after surgery and after phlebotomies and postulated that venous
thrombi formed as exudates from the walls of blood vessels (24). If adhesions did not
form in the vessels, the clots could be swept into the general circulation. Cruveilhier
wrote that coagulation in veins was the earliest sign of phlebitis. He even stated that
“phlebitis dominates all pathology” (19). Thrombi within arteries and the heart were
attributed at that time to a similar inflammatory arteritis. Inflammation was considered
the cause of thrombosis.

Virchow Defines and Describes Embolism


Rudolph Virchow (1821 – 1902) (Fig. 2) deserves the major credit for describing the
process of in situ antimortem thrombosis with subsequent embolism. In a remarkable
series of observations and experiments, he analyzed the relationship between thrombi
and infarction, locally and at a distance (25). Among 76 necropsies performed in 1847,
he found thrombi in the veins of the extremities in 18 patients and within the pulmonary
arteries in 11 patients (23,25). He reasoned that the bloodstream emanating from these
veins must have been the conduit for transportation of these thrombi to such distant
sites as the lung arteries. He then experimented on animals to study the fate of foreign
materials placed in veins. He then sought and found obstruction of brain, splenic, renal,
and limb arteries at necropsy in patients who had cardiac valve disease and left atrial
thrombi. He thus systematically proved that in situ thrombosis and embolism were the
causes of infarction and that the process was not dependent on inflammation. Within
the period of two years, he established that blood clots need not form at the sites where
6 Caplan

Figure 2 Rudolph Ludwig Carl Virchow. Source: From Ref. 146.

they were discovered at necropsy but could be carried by the blood stream from peripheral
veins to the pulmonary arteries and from the left atrium to the brain and other peripheral
arteries. Virchow also was the first to introduce the name fibrinogen into clinical medicine.
Johannes Müller in 1832 introduced the term fibrin to describe the insoluble substance
within thrombi. Fibrinogen was used by Virchow to name the soluble plasma precursor
to fibrin.

Arterial Occlusion and Embolism as the Cause of Infarction


Present day physicians now take for granted the concept that infarction is due to lack of
blood supply and nutrition caused by blockage of arteries supplying areas of ischemia.
But early observers referred to focal necrotic regions using nonspecific descriptive
terms, such as softenings, ramollissements, and encephalomalacia. These brain softenings
were not clearly attributed to ischemia until the middle years of the 19th century (23).
Rene Laennec (1781 – 1826), the French physician who introduced the stethoscope into
clinical medicine, was probably the first to use the word infarction for the process in
the lungs, which had been called pulmonary apoplexy (4,23,26). Physicians did not
appreciate the clinical features of coronary thrombosis and myocardial infarction until
the report of James Herrick in 1912 (27), and cardiologists did not clarify the relationship
between angina pectoris, coronary artery occlusion, and myocardial infarction until the
1940s (28). Interest in the causes of brain ischemia probably began with Wepfer, who
recognized that, at necropsy, there often was an obstruction of blood flow caused by the
disease of arterial walls (7). Abercrombie had likened brain softening to gangrene in
other organs (15). Cruveilhier and Carswell documented arterial obliterations at necropsy
in cases of peripheral gangrene (23).
Virchow discussed the clotting of blood within vessels and emphasized that local
factors within arterial walls could promote clotting as well as general thrombosis diffusely
Development of Ideas and Knowledge about Stroke and Brain Embolism 7

within small vessels. He introduced the terms thrombus, thrombosis, embolus, and embo-
lism (23). In his summary of the medical literature, Virchow cited 11 examples of pub-
lished cases of embolic disease although in none was the fundamental process
appreciated, the embolic plugs usually being attributed to arterial inflammation (23,25).

THE SECOND HALF OF THE 19TH CENTURY—CARDIAC


EMBOLISM BECOMES AN ESTABLISHED CLINICAL ENTITY

John Lidell wrote an influential monograph on apoplexy that was published in 1873 (29).
He gave his book the long title A Treatise on Apoplexy, cerebral hemorrhage, cerebral
embolism, cerebral gout, cerebral rheumatism, and epidemic cerebro-spinal meningitis
(29). He clearly stated, “cerebral anemia, for example, from embolism of the cerebral
arteries, often induces the symptoms of apoplexy” (29). He noted that the term embolism
was derived from the Greek word 1mbolo6 meaning a plug. An artery becomes “plugged
up with a clot of blood, or a concretion of fibrin, or a fragment of broken-down tissue
which has been brought by the circulating blood from some distant part” (29). He cited
the paper by William Kirkes (17) and summarized three of Kirkes’s cases, all of whom
had large brain infarcts and diseased mitral valves at necropsy. He commented, “It is
plain that embolism produced by dislodgement of matter from the mitral valve was the
cause of the brain symptoms” (29).
Sir William Osler (Fig. 3) in his popular textbook of medicine noted that embolism
“in the great majority of cases comes from the left heart and is either a vegetation or, more
commonly of a recurrent endocarditis.” Rheumatic mitral stenosis, thrombi within the
left auricular appendage, and aortic atheromas were also mentioned by Osler as sources

Figure 3 Sir William Osler. Source: From Ref. 147.


8 Caplan

of emboli (30). In his Gulstonian lectures, Osler defined the clinical findings in patients
with endocarditis and emphasized the neurological sequelae (31). Neurological texts,
for example, the popular monograph of William Gowers, also discussed brain embolism
related to cardiac valve disease (32). Gowers notes, “the source of the plug must be some-
where between the lungs and the brain—in the pulmonary veins, the left side of the heart,
the commencement of the aorta, or the large arteries of the neck” (32). Charles Dana
authored the other popular neurology text at the turn of the century (33). Dana noted
that the usual source was acute or recurrent endocarditis. “The embolic plug cuts off
the blood supply from a certain area of brain tissue” (33). He described red and white soft-
ening. By the start of the twentieth century, the phenomenology of brain embolism from
rheumatic mitral stenosis and from infective endocarditis was very well known.

THE FIRST HALF OF THE 20TH CENTURY—AN EMPHASIS


ON VASCULAR ANATOMY

Anatomists and researchers during the early years of the 20th century became very
interested in the blood vessels that supply blood to the brain, including the cerebral
hemispheres, basal ganglia, brainstem, and cerebellum. Duret (34,35), working in the
laboratory of Charcot in France, and Stopford (36) in England meticulously dissected
the arteries that supply blood to the brainstem. Charles Foix (1882 – 1927) (Fig. 4), who
worked in the clinics and pathology laboratories at the Salpetriere Hospital in Paris,
gave a better picture of arterial anatomy (37). Foix and his colleagues defined the
distribution and localization of brain infarcts (“ramollissements”) and the neurological
abnormalities present during life. In addition, they clarified and illustrated the anatomical

Figure 4 Charles Foix.


Development of Ideas and Knowledge about Stroke and Brain Embolism 9

distribution of the main intracranial arteries and their usual branches and regions of supply
(37 –45). They studied, analyzed, reported, and illustrated their findings in both the
anterior and posterior circulations in detail. During the four short years, between 1923
and 1927, Foix et al. (37 – 45) defined the arterial distribution of the brain.

Charles Foix and Colleagues Examined the Arteries that


Supplied Brain Infarcts
The early writings of Foix, his students, and colleagues were concerned mostly with
vascular anatomy, distribution of infarcts, and clinical –anatomical correlation. Only a
few weeks before his premature death, Foix, along with Hillemand and Ley, presented
a preliminary report to the Medical Society of the hospitals of Paris on the vascular path-
ology found in arteries supplying regions of brain softening (46). They carefully examined
the arteries that their anatomical researches had shown, that supplied the regions of brain
infarction. Until that time, although clinicians recognized that extracranial and intracranial
arteries were often diseased at necropsy, there was little interest in the mechanism of
occlusion because no treatment was available and there was no way of imaging the arteries
or the brain during life.
Among the 56 necropsied patients, the artery supplying the infarct was completely
occluded in only 12 patients, subtotally, and incompletely occluded in 14, but in 30, the
supply artery was widely patent (46). Foix et al. (46) proposed four possible explanations
for the frequent lack of arterial occlusion at necropsy: (i) the occlusion might follow brain
softening and might have developed later, (ii) embolism with passage of embolic material
by the time of autopsy, (iii) insufficiency (“l’insuffisance cardio-arterielle”), that is, more
proximally located circulatory failure, and (iv) vasospasm (“spasme arterielle”). This
paper, which now would qualify as only an abstract, opened the door for inquiry about
the mechanisms of brain infarction.

Kubik and Adams—Occlusion of the Basilar Artery:


Separating Thrombosis In Situ from Embolism
Certainly, one of the most important and influential reports in the field of cerebrovascular
disease was the report on basilar artery occlusion by Charles Kubik and Raymond Adams
(Fig. 5) published in 1946 (47). This report was one of the most complete and most
detailed clinical-pathological studies of any vascular syndrome. This was not the first
publication about occlusion of the basilar artery; there had been prior reports of single
or a few cases (48). Pines and Gilinsky had described a patient with a likely embolic
occlusion of the rostral basilar artery (48,49). The report of Kubik and Adams (47) was
distinguished because of the large number of patients (18 patients), the meticulous dissec-
tion and illustration of the brain lesions at the various brainstem levels, delineation of the
nature of the vascular occlusion, a discussion of separation of in situ thrombosis from
embolism, and the detailed descriptions of the clinical symptoms and signs.
At the time of their report, the authors were both neuropathologists working in the
necropsy laboratories at the Massachusetts General Hospital and the Boston City Hospital
in Boston. They examined some of the patients during life and later reviewed their clinical
charts. The extent and location of the thrombosis correlated well with the areas of
brainstem infarction, and usually only a portion of the basilar artery was occluded (47).
They attributed 11 of the basilar artery occlusions to in situ thrombosis engrafted upon
arteriostenosis. Seven occlusions were considered embolic on the basis of the location,
morphology, and appearance of the thrombi found at postmortem. In all the cases
10 Caplan

Figure 5 Raymond Adams.

attributed to in situ thrombosis, there was extensive underlying arteriostenosis of the


basilar artery with severe luminal narrowing by plaque. The occlusion always involved
at least two segments of the basilar artery. The thrombosed portion of the basilar artery
in these cases was “distended, firm, and rigid and the thrombus could not be displaced
by pressure” (47). In some cases, microscopic analysis of the thrombus revealed that
different portions of the clot must have formed at different times. In cases attributed to
embolism to the basilar artery, the clot was usually lodged in the distal portion of the
basilar artery at its bifurcation. Embolic plugs occasionally lodged in the regions of the
basilar artery that were narrowed by atheromatous plaques. Therefore, the presence of
plaques alone did not separate thrombosis from embolism. Focal regions of layered
thrombi could be superimposed on the firm nonadherent emboli. All of the infarcts
were grossly “pale” and “anemic,” but some contained petechial hemorrhages visible
under the microscope within zones of infarcted tissue (47). The symptoms in most patients
began abruptly, and all the cases were fatal (otherwise, the patient would not have reached
their pathology laboratory). Recognition of the clinical signs should allow for accurate
antemortem diagnosis of basilar artery occlusion. In fact, at the end of the article, the
author reported the clinical findings that led them to suspect basilar artery thrombosis
in seven patients who were still alive (47). Unfortunately, with the limited technology
available at the time, there was no safe way during life to document the nature of the
vascular lesion.

Miller Fisher—Carotid Artery Disease, Transient Ischemic Attacks,


and Artery-to-Artery Embolism
During the first half of the 20th century and before that time, brain infarcts were usually
attributed to occlusion of intracranial arteries. In the reports of Kubik and Adams, the
Development of Ideas and Knowledge about Stroke and Brain Embolism 11

Figure 6 C. Miller Fisher and Louis R. Caplan.

occlusion involved the basilar artery, an important intracranial artery. Most anterior circu-
lation infarcts were attributed to occlusion of the middle cerebral artery. As in the report
(47), clinicians of that era thought that strokes generally came abruptly without warning
but often progressed after the onset of ischemia.
Shortly after the second world war, Miller Fisher (Fig. 6), a clinician and neuro-
pathologist who worked first in Canada and later at the Massachusetts General Hospital
with Dr. Adams, turned his attention to carotid artery disease. Fisher’s first paper on occlu-
sion of the internal carotid artery appeared in 1951 (50), just five years after the report of
Kubik and Adams. Several years later, he published a second paper on carotid artery
disease that amplified the findings of the initial report (51). He made four key observations
that had an important influence on the approach of clinicians to patients with brain ische-
mia: warning spells preceded strokes, occlusive disease was often in the neck, eye ische-
mia was a frequent type of warning, and the mechanism of brain infarction was artery-to-
artery embolism from the internal carotid artery into its intracranial artery branches. He
noted the very frequent occurrence of temporary warning episodes in his patients with
carotid artery disease, which he dubbed transient ischemic attacks (TIAs), that preceded
and presaged later strokes. Prior to Fisher, a few scattered mentions of transient
warning spells can be found in the literature, but practicing physicians in 1950 were gen-
erally unaware of their existence.
The occlusive disease was in the internal carotid artery in the neck where it was
potentially reachable by surgery. This was the first emphasis on occlusive disease in the
neck. J. Ramsey Hunt had previously published a report on the role of the carotid artery
in causing brain ischemia in 1914 (52). Hunt wrote, “The object of the present study is
to emphasize the importance of obstructive lesions of the main arteries of the neck in
the causation of softening of the brain” (52). In this paper, he mentioned attacks of tran-
sient hemiplegia, but this report had not received much attention before Fisher. Several
years after Fisher’s report, Hutchinson and Yates began to systematically dissect and
12 Caplan

examine the cervicocranial arteries in the neck (53,54). They found a high frequency of
occlusive disease in the cervical vertebral arteries near their origins from the subclavian
arteries. Vertebral artery occlusive disease in the neck seemed to parallel carotid occlusive
disease, leading Hutchinson and Yates to coin the term “carotico-vertebral” stenosis (54).
These reports alerted physicians that brain ischemia was often caused by disease in the
neck, a location more accessible than the intracranial arteries.
Fisher’s reports on carotid artery occlusion emphasized the occurrence of intra-
arterial embolism, arising from proximal arterial occlusive lesions, as a very important
cause of ischemic stroke (50,51). Chiari in 1896 described a patient with an apparent cer-
ebral embolus in whom no cardiac source could be found at necropsy. He opened the
carotid artery in its entire length and found thrombus deposited upon an atherosclerotic
lesion in the proximal internal carotid artery (55). Chiari then studied 400 cases and in
seven cases found thrombus within the carotid artery in the neck, and in four cases cerebral
embolism had occurred. He emphasized that embolism from the carotid artery in the neck
was an important source of brain embolism. The reports of Chiari and Hunt went unno-
ticed until Fisher’s landmark paper.
Before Fisher’s papers, in the early 1950s, brain embolism was invariably attributed
to a cardiac source. Torvik and Jorgenson (56 – 59) published extensive reports that ana-
lyzed necropsy findings in relation to carotid artery occlusions and brain infarcts found
among 994 patients that came to autopsy in Oslo, Norway. They reported the vascular
and brain findings and accompanying clinical course in patients with brain infarcts and
vascular lesions. The internal carotid artery in the neck and head were about equally
involved. They attempted to separate those cases caused by primarily arterial thrombosis
and intra-arterial embolism from those related to cardiac origin embolism (56 – 59).
In 1986, Fisher and his neurosurgical colleague Robert Ojemann published a
detailed report on the gross and microscopic findings within surgical specimens of the
carotid artery (60). This information was also the main topic of Fisher’s Willis lecture
at an American Heart Association International Stroke meeting. The specimens clearly
showed thrombi within the artery that were the source of artery-to-artery embolism.
Fisher noted that some of the patients who developed carotid artery occlusion and
brain infarcts had previous attacks of transient monocular visual loss on the side ipsilateral
to the carotid occlusion and on the opposite side of the hemiparesis (50,51). He later
published an article that described and illustrated the findings in the retina seen with an
opthalmoscope in patients who had transient visual loss (61).

Fisher and Adams and Hemorrhagic Brain Infarcts


Both Fisher and Adams were experienced neuropathologists. They began to notice that in
some patients with hemorrhagic brain infarcts, careful dissection of the supply arteries at
necropsy failed to show an arterial occlusion proximal to the hemorrhagic changes in the
brain. They then systematically and extensively studied their necropsy material to define
the mechanism of hemorrhagic infarction in the brain (62,63). They found that embolism
was the major cause of hemorrhagic infarction. Obstruction of a brain-supplying artery
caused ischemia to neurons and ischemic damage to blood vessels within the area of ische-
mia. When the obstructing embolus moved distally, the previously ischemic region was
reperfused with blood. The damaged capillaries and arterioles within that region were
no longer competent, and blood leaked into the surrounding infarcted tissue. Figure 3 in
Chapter 3 shows an illustrative case from the report of Fisher and Adams.
Development of Ideas and Knowledge about Stroke and Brain Embolism 13

Fisher reviewed the past literature on hemorrhagic infarction and brain embolism
(23). On the basis of these ideas, Fisher and Adams were able to posit that the essential
cause of hemorrhagic infarction was reperfusion of the previous ischemic tissue. The
other mechanism that caused hemorrhagic infarction besides embolism was systemic
hypoperfusion. After cardiac arrest or shock, the reinstitution of effective circulation
after a prolonged period of brain hypoperfusion can lead to hemorrhage within border-
zone infarcts. These hemorrhagic changes were bilateral and scattered, as opposed to
the hemorrhagic changes in brain embolism that were within discrete unilateral infarcts.
These observations emphasized to clinicians the importance of brain embolism as a
cause of stroke and that hemorrhagic changes were a reliable sign of embolism.

DATA BANKS AND STROKE REGISTRIES

During the middle years of the twentieth century, clinicians had become very interested in
clinical phenomenology by personally studying and describing small groups of patients. A
major focal point was the clinical differentiation between brain hemorrhage and brain
infarction and characterizing the differential diagnostic features found among the
various mechanisms of brain infarction.
In 1935, Charles Aring and Houston Meritt performed necropsies in a group of
patients at the Boston City Hospital, in order to clarify the differential diagnostic features
between brain hemorrhages and infarcts (64). Of the 245 cases, 15% had hemorrhages
(intracerebral or subarachnoid), 82% had ischemic infarcts called “thrombotic,” and only
3% were considered to have embolic brain infarcts (64). Aring and Meritt used the term
“embolic” to mean cardiac-origin embolism. They classified patients’ infarcts and
strokes as embolic only if there was a recognized cardiac source. Furthermore, at that
time, the only accepted cardiac sources were rheumatic mitral valve stenosis with atrial
fibrillation and recent myocardial infarction. This cardiogenic definition of embolism
endured during the next 40 years. During the middle decades of the twentieth century,
many of the mechanisms and subtypes of brain infarction and hemorrhage were further
clarified. Lacunar infarcts, internal carotid artery stenosis and occlusion, intracranial
artery occlusive disease, and other conditions were studied, and their clinical and pathologi-
cal findings were reported. As more and more sophisticated technology able to effectively
image brain and vascular structures became available, clinical diagnosis of these stroke sub-
types was greatly facilitated. During the 1970s and 1980s, these technological advances
made it possible to define clinical, imaging, and laboratory findings in patients with nonfa-
tal, even minor strokes, transient ischemic attacks, and prestroke vascular lesions. With
more advanced knowledge of clinical and morphological features, clinicians sought
more quantitative data. How often did lacunar infarcts, cardio-embolic brain infarcts,
and intracerebral hemorrhages occur? How often did each of many clinical symptoms
and signs occur in each subtype of stroke? Clinicians realized that valid statistically mean-
ingful data could not be collected unless large number of patients with a wide spectrum of
representative cases were studied and analyzed. The advent of computers in medicine in the
1970s greatly facilitated the storage and analysis of the large quantities of complex data.
Collection of data on large number of stroke patients began with the series of
surveys conducted by Dalsgaard-Nielsen in Scandinavia (65) and with retrospective
reviews of series of patients seen by clinicians at the Mayo Clinic in Rochester, Minnesota
(66,67). These early databases recorded a relatively high rate of brain infarcts versus
hemorrhages (.4/1). Embolism was infrequently diagnosed with ranges of 3% to 8%
14 Caplan

of strokes. These studies were based on chart reviews and preceded computed tomography
(CT) scanning and modern cardiac technological evaluation.
The Harvard Cooperative Stroke Registry (HSR) in the early 1970s was the first
computer-based registry of prospectively studied stroke patients (68). My colleagues
and I adopted a different approach to the diagnosis of brain embolism. Diagnostic criteria
in the HSR emphasized the recipient artery and not the source. Embolism was diagnosed
when there was a sudden obstruction of a large intracranial artery or one of its branches.
The embolus could arise from any source but predominantly the heart or one of the
cervico-cranial arteries that supply the brain. A sudden onset neurologic deficit and an
arteriogram that showed blockage of an intracranial artery not due to local atherosclerosis
were the most common evidence for embolism. Echocardiography was not available at
that time, and only about half the patients had cranial CT. Angiography, when performed
within 48 hours, often showed an abrupt cut-off of an intracranial artery supplying the
region of infarction. Some of the patients had cardiac disease, especially atrial fibrillation.
Others had proximal arterial lesions that were presumed to be the donor source of artery-
to-artery embolism. In the HSR, using this approach, 31% of patients were classified as
having strokes due to brain embolism.
During the 1970s and 1980s, a number of other hospital-based stroke registries and
databases also provided quantitative information about clinical and laboratory phenomena
and diagnoses (69 – 73). Community-based studies in South Alabama (74); Framingham,
Massachusetts (75); Oxfordshire in Great Britain (76); the Lehigh Valley in Pennsylvania
(77), and various regions in North Carolina, Oregon, and New York (78) generated
important epidemiological data. In general, there was less technological evaluation in
these community-based patients compared to the hospital-based registries. During the
1990s, a number of other hospital-based registries were able to take advantage of
modern technology to clarify stroke subtypes (79 – 84). The hospital-based registries
that followed the HSR and all of the modern registries found a relatively high rate of
brain embolism varying between 22% and 46% (84,85). The frequency of the various
stroke subtypes is noted in Table 1. Stroke registries and data banks have undoubtedly
assisted collection and analysis of a wide variety of clinical, radiological, laboratory,
pathological, and epidemiological information (86,87).

Technological Advances Allow More Accurate Diagnosis of Stroke


Subtypes and Cardiac and Vascular Lesions
Egas Moniz introduced dye contrast angiography into clinical medicine in 1927 (88,89).
His early studies used contrast agents later shown to be quite hazardous. Moreover, cut-
downs were needed to introduce the contrast. Moniz (88) illustrated examples of occlusive
lesions of neck arteries in his monograph on cerebral angiography and in a monograph on
carotid artery occlusion (90,91). When I was a stroke fellow in 1969, the favored technique
for angiography was direct puncture of the neck arteries. Contrast was hand-injected, and
films were hand-pulled either rapidly or slowly depending on the estimated rapidity of the
brain circulation. Only one plane, anteroposterior or lateral posterior, could be filmed after
each contrast injection. Complication rates were relatively high. An advance was made
when Seldinger, in 1953 (92), described catheter-based angiography, but the Seldinger
technique of opacifying cervico-cranial arteries by introducing a catheter into the
femoral artery and directing it into the neck arteries, and then introducing contrast did
not become widespread until the 1970s.
Until the mid-1970s, there was no method of imaging the brain other than pneu-
moencephalography, in which air introduced by lumbar puncture opacified the cerebral
Table 1 Relative Frequencies of the Various Stroke Subtypes in Published Stroke Registries

Registry NEMCPCR HSR PSDB SDB LSR MRSR Austin SR BSR Athens SR GSDB Arcadia SR

Years 1988– 96 1972– 76 1978– 81 1983– 86 1982– 87 1979– 82 1972– 80 1987– 94 1992– 97 1998 –99 1993– 95
N 407 694 1158 1805 1000 540 673 2500 1042 5017 555
% Men 63% 53% 56% 47% 61.5% 52% 57% 57% 58% 57.6% 56%
Mean age 60.5 64.4 63 65 60.8 63 64.8 68 70.2 65.9 75.4
% Ischemic 100% 83.4% 80% 68% 82% 78% 94% 84% 85% 100% 86%
Embolism 40% 31% 28% 39%a 36%b 22% 46%b 46%
Cardiac 24% 19% 20% 18% 8% 31% 38% 25.6% 28%
Large artery 32% 40% 24% 9% 25.5% 23% 32% 15.5% 9% 20.9% 17%
Penetrating artery 14% 23% 14% 27% 15% 38% 23% 10% 20% 20.5% 15%
% Infarcts p circ 100% 37% of LA NS NS 26% NS 11.5% 26.7% 29% NS NS
a
Embolism recalculated using HSR criteria (85).
b
Cardiac þ large artery without stenosis.
Abbreviations: Arcadia SR, Arcadia Stroke Registry (101); Athens SR, Athens Stroke Registry (95); Austin SR, Austin Stroke Registry (116); BSR, Besancon Stroke Registry (94,100);
GSDB, German Stroke Data Bank (102); HSR, Harvard Stroke Registry (89); LA, large artery; LSR, Lausanne Stroke Registry (92); MRSR, Michael Reese Stroke Registry (90);
N, number of cases; NEMCPCR, New England Medical Center Posterior Circulation Registry; NS, not stated; p circ, posterior circulation; PSDB, Pilot Stroke Data Bank (99);
SDB, Stroke Data Bank (91); SR, Stroke Registry.
Development of Ideas and Knowledge about Stroke and Brain Embolism
15
16 Caplan

ventricles and the cisterns but did not show brain tissue. Hounsfield, working at the
research laboratories of EMI in Britain, originated the concept of CT (3,93). The instru-
ment was first tried at the Atkinson-Morley’s Hospital in London (3). CT scanners were
first introduced into North America in 1973. Films from first-generation scanners
were quite primitive, but by the late 1970s, third-generation scanners had made CT a
very clinically useful, almost indispensable, diagnostic technique. By the mid-1980s,
CT was readily available throughout North America and most of the Western Europe.
CT allowed clear distinction between brain ischemia and hemorrhage and allowed
definition of the size and location of most brain infarcts and hemorrhages.
The advent of magnetic resonance imaging (MRI) into clinical medicine in the
mid-1980s was a further major advance (93). MRI proved superior to CT in imaging
lesions abutting on bony surfaces, posterior fossa lesions, showing old hemosiderin-
containing hemorrhages, and imaging vascular malformations. MRI also made it possible
to visualize lesions in different planes by providing sagittal, coronal, and horizontal
sections. More recently, improved filming techniques have made it possible to image
the brain vasculature through the techniques of magnetic resonance angiography
(MRA) (94) and CT angiography (CTA) (95).
Ultrasound was introduced into clinical medicine in 1961 by Franklin et al. (96),
who used Doppler shifts of ultrasound to study blood flow in canine blood vessels (96).
B-mode ultrasound was used to show images of the extracranial carotid arteries non-
invasively. By the early 1980s, B-mode, continuous-wave, and pulsed-Doppler technology
could reliably detect severe extracranial vascular occlusive disease in the carotid and
vertebral arteries in the neck. Sequential ultrasound studies allowed physicians to learn
the natural history of the development and progression of plaques and occlusive lesions
and to correlate the occurrence and severity of disease and of the thickness of the
intimal and medial coats of the arteries with stroke risk factors, symptoms, and treatment.
In 1982, Aaslid et al. (97) introduced a high-energy bidirectional pulsed-Doppler system
that used low frequencies to study intracranial arteries, transcranial Doppler ultrasound
(TCD). TCD made noninvasive detection of severe occlusive disease in the major intra-
cranial arteries possible during life, as well as sequential study of the lesions (98). TCD
made it possible to estimate the effect of neck occlusive disease on intracranial perfusion
(98). In 1990, Spencer et al. (99) described that Doppler signals felt to represent solid
material emboli were released from carotid artery plaques during carotid artery surgery.
Later experimental and clinical studies showed that intracranial arteries could be mon-
itored using TCD to detect microembolic signals (100,101). In this technique, transcranial
Doppler probes are positioned over brain arteries, most often the middle and posterior
cerebral arteries on each side. When particles pass through the arteries being monitored,
they produce an audible chirping noise and high-intensity transient signals visible on an
oscilloscope. The signal character depends on the nature of the particles (gas, thrombus,
calcium, cholesterol crystal etc.), particle size, and particle transit time. Preliminary
studies showed that patients with cardiac lesions and those with symptomatic occlusive
lesions in the neck had a relatively high frequency of intracranial microembolic signals.
Introduction of echocardiography and ambulatory cardiac rhythm monitoring in the
1970s and 1980s greatly improved cardiac diagnoses and detection of potential cardio-
genic sources of embolism. By the early 1990s, clinicians could safely define the
nature, extent, and location of most important brain, cardiac, and vascular lesions in
stroke patients. Accurate diagnosis using modern technology facilitated clinical-imaging
correlations in patients with TIAs and strokes, and this paved the way for monitoring the
effects of various treatments. Patients with vascular risk factors could be studied and
lesions found by imaging could be potentially treated to prevent cerebrovascular events.
Development of Ideas and Knowledge about Stroke and Brain Embolism 17

By the end of the twentieth century, advanced brain imaging with CT, MRI, and
newer magnetic resonance (MR) modalities, including fluid attenuating inversion recov-
ery (FLAIR) images, diffusion-weighted images (DWI), perfusion-weighted images
(PWI), susceptibility-weighted (also called T2 ) images, functional MRI (fMRI), and
MR spectroscopy (MRS), were able to show clinicians the location, severity, and potential
reversibility of brain ischemia. Vascular lesions could be quickly and safely defined using
CT angiography, MR angiography, and extracranial and transcranial ultrasound.

NEW TECHNOLOGY AND FURTHER STUDIES CLARIFY MORE


POTENTIAL DONOR SOURCES OF EMBOLI

At the time of Aring and Meritt (64), the only heart disorders accepted as sources of embo-
lism were rheumatic valve disease with atrial fibrillation, bacterial endocarditis, prosthetic
heart valves (although their use was not common), myxomas and other cardiac tumors, and
acute myocardial infarction. The advent of better diagnostic technology to investigate
cardiac and vascular lesions led to the recognition of many conditions that previously
were not known to be important donor sources of embolism.
Fisher was among the first to warn the general medical community about the embo-
logenic potential of atrial fibrillation (102,103). Fisher et al. performed necropsy examin-
ations on 333 patients with atrial fibrillation and 58 patients with ischemic heart disease
without known atrial fibrillation. Among the atrial fibrillation patients, embolism was
found in 41% of those with mitral valve disease, 35% of those with ischemic heart
disease, 35% of those with both mitral valve and ischemic heart disease, and in 17% of
those with other heart disease, whereas only 7% of the nonfibrillators had embolism
(102). The authors concluded, “these findings suggest a high risk of embolism from
atrial fibrillation of any origin” (102). Fisher later urged anticoagulation of patients
with atrial fibrillation warning that the first stroke was often devastating (103). At first car-
diologists did not accept the idea that such a common disorder could be a frequent cause
of brain infarction. Epidemiological studies from Framingham (104,105) and elsewhere
(106) showed definitively that atrial fibrillation was not only a definite embolic source,
in fact, it was probably the commonest cardiac condition leading to brain embolism.
Other cardiac conditions are now known commonly or occasionally to provide the
source for embolization to systemic arteries and the brain. The sick-sinus syndrome, like
atrial fibrillation, can be associated with poor atrial contraction and clot formation in the
left atrium (107). Swirling echo dense particles (often referred to as smoke), when seen in
the heart on echocardiography, for example in patients with atrial fibrillation, often
foretell a risk of embolism (108).
Although rheumatic and infective valvular lesions were long considered to be
potentially embologenic, echocardiography and clinical studies soon implicated mitral
valve prolapse with myxomatous degeneration of the valve (109), mitral annulus calcifi-
cation (110), and fibrotic valve disease associated with systemic lupus erythematosis
(Libman-Sacks endocarditis), the antiphospholipid antibody syndrome (111,112) and
cancer (nonbacterial thrombotic endocarditis) as important potential sources of embolism.
Even fibrotic valve strands were potentially embolic (113,114). Imaging of patients with
coronary artery disease showed that many had ventricular aneurysms or hypokinetic, or
akinetic, segments that harbored thrombi (115,116). Echocardiography also showed that
atrial septal dysfunction in the form of atrial septal defects, patent foramen ovale, and
atrial septal aneurysms were more frequent than previously thought and that these
lesions were very common in patients with strokes of uncertain cause (117,118).
18 Caplan

Although it was widely known that the aorta was very often the seat of severe
atherosclerosis, the role of aortic plaques as donor sources of brain embolism was only
recently emphasized. Tunick et al. (119,120) were among the first to report cases of
brain embolism that arose from protruding aortic atheromas.
Pierre Amarenco and his clinical and pathology colleagues (121), working in Paris,
then systematically showed that ulcerated atheromas in the aorta at necropsy and protrud-
ing atheromas found during transesophageal echocardiography (122) were prevalent in
stroke patients, especially those in whom no other cause was found. Further echocardio-
graphic studies in New York (123) and France (124) confirmed the importance of
protruding mobile aortic atheromatous plaques as a donor source of brain embolism.
Since Fisher’s reports on carotid artery disease in the early 1950s (50,51), the
medical community knew that carotid artery disease was an important cause of stroke
but the mechanism was not clear—hypoperfusion and/or embolism. Pessin et al. (125)
in 1980 showed that clinical findings differed depending on the appearance of the
carotid artery lesion on angiography (125). Certain appearances favored embolism.
Studies of specimens of the carotid artery removed surgically (60,126) and at necropsy
(127) showed that stenotic ulcerated plaques often with plaque ruptures, which brought
the content of the plaque into contact with the luminal contents, had precipitated the
formation of red-erythrocyte thrombi often engrafted upon white platelet – fibrin
thrombi. Most patients with severe stenosis had mural thrombi or platelet-fibrin aggregates
within arterial ulcerations, irregularities, and crevices. These thrombi then often embo-
lized into systemic and brain arteries. Ultrasound studies of carotid plaque morphology
confirmed the morphological data (128,129). Michael Hennerici and I then postulated
that hyperperfusion and embolism were complementary in causing brain infarction as
decreased perfusion led to diminished washout and clearance of emboli (130).
Extracranial arterial occlusion caused transient hypoperfusion and transient brain
ischemia or minor infarction, whereas major deficits and sizable brain infarction were
always explained by intracranial arterial embolism. Carotid (131) and vertebral artery
dissections (132,133) were also recognized as important sources of artery-to-artery
embolism.

BRAIN AND VASCULAR INVESTIGATIONS BRING EMBOLISM TO THE


FOREFRONT AS THE MAJOR CAUSE OF BRAIN INFARCTION

Only very recently have studies documented the great importance and ubiquity of intracra-
nial embolism, arising from the heart, the aorta, and the cervico-cranial arteries as the
cause of transient brain ischemia and infarction. In the Harvard Stroke Registry, cerebral
angiography performed within 48 hours after the onset of the symptoms of ischemic stroke
showed a high incidence of intracranial arterial occlusion, whereas studies after 48 hours
were often normal (69). Ringelstein et al. (134) studied the pathogenesis of brain infarcts
in 107 patients with cervical internal carotid artery occlusions. Angiography in 15 of 21
patients (71%) showed an “occlusio supra occlusionem,” that is, artery-to-artery emboli
that arose from the carotid artery occlusion blocking intracranial arteries (134). Fieschi
et al. (135) performed angiography within six hours of the onset of the symptoms of
brain ischemia and showed complete arterial occlusions by thrombi in 76% of patients;
most of the occlusions (66%) were intracranial. In a trial of patients screened for acute
treatment with intravenous recombinant tissue plasminogen activator (rtPA), 112 of 139
patients (80%) had arterial occlusions on angiography performed within eight hours of
the onset of symptom (136,137). In a study of thrombolytic treatment of patients with
Development of Ideas and Knowledge about Stroke and Brain Embolism 19

acute brainstem ischemia, a high proportion had occlusions within the intracranial
posterior circulation (138). Monitoring of the intracranial arteries of patients using TCD
has shown a very high frequency of intracranial embolism in patients with potential
donor sources of embolic materials (139 –144).

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24 Caplan

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2
Overview: The Major Components of
Brain Embolism
Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

There are three important actors, dramatis personae, in the drama of brain embolism: the
recipient artery that catches and receives the embolic material, even temporarily; the
embolic material itself—the stuff that makes up the emboli; and the donor source from
which the embolic material originates (Fig. 1). I find it useful to think of the brain embo-
lism triad as birds and nests. The bird (embolic material) arises from a nest (donor source)
and often flies from the nest to rest on a distant tree branch or other destination (recipient
artery) (Fig. 2) (1). All of the actors in the drama play important roles, but each role has its
own unique character and significance in the play. Of course, there are many nests, many
birds, and many different destinations to which they fly.

THE RECIPIENT ARTERIES

The recipient artery determines to a large extent the clinical symptoms and signs. When a
recipient extracranial or intracranial artery is blocked, blood flow to that area of the brain,
which is supplied by the blocked artery, suddenly becomes insufficient. Less fuel in the
form of oxygen and sugar reaches the brain. The lack of energy causes the brain region
to interrupt its normal functioning. The neurological symptoms that result from the arterial
blockage depends on the area of brain that is underperfused. If an embolus blocks a pos-
terior cerebral artery (PCA) supplying the visual cortex, loss of vision in the opposite
visual field might result. If an embolus blocks the left middle cerebral artery (MCA),
the right limbs might become weak and numb, and the patient might not be able to
speak normally. An embolus to an intracranial vertebral artery (ICVA) might cause loss
of function of the cerebellum with resultant loss of the ability to walk normally. The
symptoms do not depend on the nature of the embolic material. Of course, the recipient
artery cannot tell what is blocking it. The brain region supplied only knows that it is
not getting enough energy to continue to function as before.
Whether the symptoms are transient or persist depends very much on the fate of the
embolus. Angiographic and ultrasound studies confirm that emboli move (2 – 6). An
embolus very often moves through a recipient artery so quickly that either no obstruction

25
26 Caplan

Figure 1 Drawing showing the major players: the donor sources, including the heart, aorta,
cervico-cranial arteries, embolus, and recipient artery. a, cardiac wall; b, atrial septal abnormality;
c, internal carotid artery; d, anterior cerebral artery embolus. Source: From Ref. 11.

or a very transient obstruction occurs. These transient passing emboli can be identified as
high-intensity transient signals (HITS) that pass quickly under an ultrasound probe moni-
toring an intracranial artery. No symptoms result. Alternatively, depending on the size and
nature of the embolic material, the embolus could rest long enough to interrupt function
and cause brain ischemia but short enough that when the embolus passes no permanent
infarction has developed. The temporary symptoms that result would be classified as a
transient ischemic attack (TIA). If the embolus stays long enough, infarction occurs, in
which case the symptoms and signs may or may not persist, depending on the location
and size of the brain infarct.
The great majority of emboli that go into an internal carotid artery (ICA) from the
heart or aorta, or arise from the ICA, go into the ipsilateral middle cerebral artery (MCA).
The embolus might rest first within the ICA in the neck or the ICA intracranially and then
go into the proximal MCA or the superior or inferior division of the MCA or into one of the
smaller (MCA) cortical branches (7,8). Occasionally, the embolus might go into other
branches of the intracranial ICA, the ipsilateral anterior cerebral artery (ACA) or the anterior
choroidal artery (AChA). If an embolus goes into a vertebral artery in the neck or arises from
an extracranial vertebral artery (ECVA), most often it will travel rostrally into the ipsilateral
intracranial vertebral artery (ICVA), or go even further to reach the basilar artery bifurcation
or one or both PCAs or the superior cerebellar arteries (SCAs) located at the top of the
The Major Components of Brain Embolism 27

Figure 2 A bird leaving its nest.

basilar artery (9,10). If the embolus is large enough, it could obstruct the basilar artery itself
leading to severe brainstem ischemia or infarction. At times, a number of different arteries
are blocked.

THE EMBOLIC MATERIAL

Like nests, birds that occupy the nests are also heterogeneous. The nature of the embolic
material determines the most likely prophylaxis and treatment. Emboli that arise from the
heart often consist of red erythrocyte –fibrin thrombi that form in inefficiently beating atria
or on the surface of myocardial infarcts or within ventricular aneurysms. Figure 3 shows a
red thrombus that embolized to an MCA. White platelet –fibrin thrombi form along
irregular valvular surfaces and prosthetic valves. Often, white thrombi form the nidus
for a superimposed red thrombus so that both are involved in the thromboembolism.
Calcium present in calcific aortic valves and in mitral annuli calcifications can break
loose and embolize. Bacteria and fungi engrafted upon valves in patients with infective
endocarditis can travel into the bloodstream and into the brain and systemic arteries.
Tumor tissues from cardiac myxomas and fibroelastomas can form the matter of emboli.
Similarly, emboli arising from the aorta consist of very different substances. White
platelet –fibrin thrombi form in crevices and irregular surfaces. These white clots activate
the coagulation cascade and promote red thrombi, which form on their surface. Red
thrombi often form within ulcers or regions of plaque rupture. Red and white thrombi
often break off and reach the brain. Cholesterol crystals within aortic plaques or
28 Caplan

Figure 3 An embolus within the middle cerebral artery at necropsy. The inset shows the clot
removed from the artery.

complex plaques themselves can travel to the brain. Calcium may also be a component of
aortogenic emboli.
Artery-to-artery emboli have the same basic components as those that arise from the
aorta: calcium, cholesterol fragments, red and white clots, and so forth. Occasionally,
air, fat, and foreign materials enter the blood stream and embolize to the brain and
other viscera.
Acute treatment should consider the nature of the embolic material—the stuff.
Thrombolytic drugs, such as recombinant tissue plasminogen activator (rt-PA), can lyse
red clots but are ineffective against white clots. On the other hand, glycoprotein
IIB/IIIA inhibitors that are active against platelet-fibrin bridges can potentially lyse
white clots. These treatments are likely to be ineffective against calcium, cholesterol
crystals, tumor fragments, infective agents, and foreign matter. A mechanical method of
retrieving emboli might be able to snare a number of different materials. Similarly,
prophylaxis against re-embolization, secondary prevention, must consider the nature of
the embolic material. The most effective prophylaxis against embolism in patients with
infective endocarditis is antibacterial and antifungal agents.

THE DONOR SOURCE

The preceding sections have already enumerated the usual nests— the heart, the aorta, and
the extracranial and intracranial arteries. Secondary prevention also depends on the nature
of the donor sources. Atrial fibrillation might respond to antiarrythmics. Intra-atrial septal
abnormalities and defects can be repaired. Ventricular aneurysms can be resected. Abnor-
mal valves can be repaired or replaced by prosthetic valves. Cardiac tumors can be
removed. Surgeons have operated on protruding aortic atheromas and, in the future,
these lesions might be dealt with using endovascular techniques. Clearly arterial lesions
The Major Components of Brain Embolism 29

are often repaired surgically or using endovascular technology in the form of angioplasty
and/or stenting.
In the ensuing chapters of this book, I and others describe and elaborate on these
three major components of the brain embolism triad. We describe their nature in much
more detail and the related symptoms and signs, diagnosis, prognosis, outcomes, and
treatments. All too long, clinicians have focused on the nests and have lost sight of the
birds and their customary destinations and habits. Clinicians must refocus on all three
characters or else they will be unable to understand the drama of embolism.

REFERENCES

1. Caplan LR. Of birds, and nests, and brain emboli. Rev Neurol 1991; 147:265 – 273.
2. Dalal P, Shah P, Sheth S, et al. Cerebral embolism: angiographic observations on spontaneous
clot lysis. Lancet 1965; 1:61 –64.
3. Liebeskind A, Chinichian A, Schechter M. The moving embolus seen during cerebral angiogra-
phy. Stroke 1971; 2:440 – 443.
4. Caplan LR, Allam GJ, Teal PA. The moving embolus. J Neuroimag 1993; 3:195– 197.
5. Daffertshofer M, Ries S, Schminke U, Hennerici M. High-intensity transient signals in patients
with cerebral ischemia. Stroke 1996; 27:1844 –1849.
6. Sliwka U, Lingnau A, Stohlmann W-D, et al. Prevalence and time course of microembolic
signals in patients with acute strokes, a prospective study. Stroke 1997; 28:358 – 363.
7. Gacs G, Merer FT, Bodosi M. Balloon catheter as a model of cerebral emboli in humans. Stroke
1982; 13:39 – 42.
8. Helgason C. Cardioembolic stroke topography and pathogenesis. Cerebrovasc Brain Metab Rev
1992; 4:28 – 58.
9. Caplan LR. Top of the basilar syndrome: selected clinical aspects. Neurology 1980; 30:72– 79.
10. Caplan LR. Posterior circulation disease: clinical findings, diagnosis, and management. Boston:
Blackwell Science, 1996.
11. Caplan LR. Caplan’s Stroke: A Clinical Approach. 3rd ed. Boston: Butterworth-Heinemann,
2000:19, figure 2.2.
PART II: RECIPIENT ARTERIES AND BRAIN ISCHEMIA

3
Recipient Artery: Anatomy and Pathology

Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

EXAMINING RECIPIENT ARTERIES TO SEPARATE


EMBOLISM AND THROMBOSIS

Examination of the recipient artery and any blood coagulation material within the artery
has often been used to separate in situ thrombosis from embolism. Figure 1 shows an artery
distended with an embolus, and Figure 2 shows the embolic clot that was removed from
the artery. Kubik and Adams (1), in their classic report on basilar artery thrombosis
published in 1946, paid particular attention to distinguishing embolism and thrombosis
at necropsy. “Thrombosis of the basilar artery could usually be recognized at a glance.
The thrombosed portion of the vessel was distended, firm, and rigid and the thrombus
could not be displaced by pressure. . . . In embolism, the embolus was usually lodged in
the distal portion of the artery.” In all cases attributed to in situ thrombosis, there was
extensive underlying atherostenosis of the basilar artery with severe luminal narrowing
by plaque. In some patients, microscopic analysis of thrombi revealed that different por-
tions of the clots must have formed at different times. Embolic plugs occasionally lodged
in regions of the artery that were narrowed by atheromatous plaques. The presence of
plaques alone did not separate thrombosis from embolism. Focal regions of layered
thrombi could be superimposed on firm nonadherent emboli (1).
Torvik and Jorgenson (2) commented in 1969 on the morphology within recipient
arteries. “The diagnosis of thrombosis (in situ) was based on the demonstration of a
red, laminated intravascular plug which was firmly and extensively attached to the
vessel wall. Sharply-delimited plugs which were only loosely attached to the arterial
wall were rated as embolic. In occlusions more than a few days old, invasion of the
plug by fibroblasts and capillaries over a wide segment of the arterial wall was considered
to be diagnostic of a thrombus. Organization from only a small segment of the vessel wall
in occlusions which were more than a few days old was regarded as an indication of embo-
lism.” Torvik and Jorgenson (2) also commented on materials found within small vessels
beyond the region of transient or persistent occlusion. Fibrin-rich masses were often found
in distal arteries in patients with brain embolism, whereas platelet aggregates were more
often found in patients with presumed in situ occlusions. “Platelet aggregates were fre-
quently found in both arteries and veins within the infarcted tissue, in the adjacent area,
and the overlying or more distant leptomeninges. Many of the aggregates were completely
31
32 Caplan

Figure 1 A clot distending an intracranial artery (black arrow) at an arterial bifurcation photo-
graphed at necropsy.

occluding the vessel; others appeared to have been floating free or else they formed mural
thrombi showing a limited contact with the inner lining of the vessel. All stages in the
transformation of platelet aggregates to fibrin-rich masses were represented but most of
the aggregates appeared fresh with little or no fibrin” (2).
Emboli often distend the recipient artery but are not adherent to the arterial wall.
They tend to lodge at bifurcations of arteries. Most often, there is an absence of severe
atherosclerosis in the region of the recipient artery where the embolus lodges. The pre-
sence of cardiac, aortic, and proximal arterial lesions at necropsy is also helpful in
attempting to distinguish embolic from thrombotic occlusions. The location, size, and
nature of the resulting brain infarct too can give clues to the embolic nature of the vascular
occlusive process.

Figure 2 The clot removed from the artery.


Recipient Artery: Anatomy and Pathology 33

HEMORRHAGIC INFARCTION

When embolism causes brain infarction, the infarcts often become hemorrhagic. Miller
Fisher and Raymond Adams (3 – 5) extensively studied their necropsy material to
define the mechanism of hemorrhagic brain infarction. Obstruction of a brain-supplying
artery causes ischemia to neurons and also leads to ischemic damage to the capillaries
and small blood vessels within the area of ischemia. When the obstructing embolus
moves distally, at least partially recanalizing the previously blocked artery, the region
that was previously ischemic becomes reperfused with blood, often under normal arterial
pressure. The damaged capillaries and arterioles within that region are no longer compe-
tent, and blood leaks into the surrounding infarcted tissue. An example of this mechanism
is shown in Figures 3A and B from the Fisher and Adams study (4,5). An embolus must
have initially blocked the main stem middle cerebral artery (MCA) in this patient, before
the origin of the lenticulostriate branches, causing ischemia to the basal ganglia, internal
capsule, and the superficial cortical territories supplied by the MCA. The embolus then
must have moved distally and at necropsy had passed beyond the lenticulostriate
branches but continued to obstruct the MCA more distally (Fig. 3B). The reperfused
deep basal ganglionic region was hemorrhagic at necropsy, whereas the superficial terri-
tory of the MCA, which was never reperfused, showed a bland infarct (Fig. 3A) (3 – 5).
The essential cause of hemorrhagic infarction is reperfusion of previously ischemic
tissue. Reperfusion occurs most often after passage of emboli and recanalization of the
recipient artery. Sometimes, collateral vascular channels can provide enough reperfusion
to cause bleeding into infarcts (6). Most often, petechial hemorrhages and stippling within
areas of brain necrosis are found. In the great majority of patients, hemorrhagic infarction
consists of diapedesis of red blood cells into infarcted tissue. Often the appearance is that
of randomly scattered petechial hemorrhages or a confluent purpuric pattern spread
throughout the infarct (7). Figures 4 and 5 show well-defined hemorrhagic infarcts
caused by emboli to MCA branches. In Figure 4, an embolus has blocked an anterior
branch of the superior division of the MCA, whereas in Figure 5 a more posterior superior
division MCA branch was the recipient artery. In some brain infarcts, especially large ones
involving more than one lobe, localized homogeneous collections of blood (intracerebral
hematomas) can develop within regions of hemorrhagic infarction. In most patients with
hemorrhagic infarcts, the hemorrhagic transformation does not cause worsening of the
clinical symptoms and signs. The hemorrhagic changes are usually found on routine
follow-up especially when T2 -weighted magnetic resonance imaging (MRI) scans are per-
formed. Bleeding into dead tissue does not alter clinical findings unless a large space-
taking hematoma develops.
The other cerebrovascular condition that often causes hemorrhagic infarction
besides embolism is systemic hypoperfusion. After cardiac arrest or shock, the reinstitu-
tion of effective circulation after a prolonged period of decreased blood pressure and
blood flow severe enough to have caused hypoperfusion of the brain can lead to hemor-
rhage within border-zone infarcts. Hemorrhagic regions within brain infarcts are quite
commonly found in patients with brain embolism. In two series, the investigators pro-
spectively studied the frequency of hemorrhagic infarction on sequential planned brain-
imaging scans. Yamaguchi et al. (8) compared the findings on computed tomography
(CT) scans performed three to 10 days after stroke in 120 patients who had embolic
brain infarcts with 109 patients whose infarcts were considered due to thrombosis that
had formed locally, in situ within the intracranial arteries. Hemorrhagic infarcts were
found in 45 patients (40%) who had embolic infarcts, compared to 2 (1.8%) patients
with local thrombosis-related infarcts (8). Okada et al. (9) studied 160 patients who had
34 Caplan

Figure 3 (A) Coronal section of the brain at necropsy showing a hemorrhagic infarction on the right
involving the caudate nucleus and putamen, regions supplied by the lenticulostriate branches of the
right middle cerebral artery. (B) Drawing of the intracranial internal carotid artery and its branches
at necropsy. An embolus (hatched region) was found in the distal portion of the mainstem middle
cerebral artery beyond the lenticulostriate branches that supply the caudate nucleus and putamen.
This embolus, at one time, must have blocked these penetrating branches and then moved more distally
in the artery. Abbreviations: Antr CA, anterior cerebral artery; ICA, internal carotid artery; MCA,
middle cerebral artery; P. Comm, posterior communicating arteries. Source: From Ref. 5.

brain infarcts presumed to be caused by embolism by performing CT scans every 10 days


during hospitalization. Hemorrhagic infarction was found on the CT scan at some time
during the course in 65 (40.6%) patients. Hemorrhagic changes were found on the
initial CT scan performed during the first four days in only 10 patients (6%), while the
remainder of the hemorrhagic infarcts were found on follow-up CT scans (9). Studies
using CT scans at the New England Medical Center in Boston showed that all the cerebral
(10) and cerebellar (11) hemorrhagic infarcts that were studied and reported in patients
Recipient Artery: Anatomy and Pathology 35

Figure 4 A hemorrhagic infarct (white arrow) involves the territory of an anterior branch of the
superior division of the middle cerebral artery at necropsy. There is also a small region of hemor-
rhagic infarction in the basal ganglia (small black arrow).

were attributable to brain embolism. MRI is more sensitive than CT in detecting small
hemorrhages and hemorrhagic infarction, so that sequential MRI would most likely
show a frequency of .50% for hemorrhagic changes in patients with embolic brain
infarcts.

Figure 5 Cut section of the posterior portion of the brain at necropsy. A very well-
circumscribed, triangular-shaped, very hemorrhagic infarct is seen within the parietal lobe on the
left of the picture (white arrow). This infarct was the result of an embolus to a posterior branch
of the superior division of the middle cerebral artery. Source: From Ref. 5.
36 Caplan

When studied, anticoagulation of patients with hemorrhagic infarction due to brain


embolism did not cause an increase in bleeding (10). Physicians are accustomed to treating
patients with hemoptysis caused by pulmonary embolism with heparin followed by cou-
madin. Patients with pulmonary embolism-related hemoptysis have beefy, hemorrhagic
lung infarcts and yet heparin does not seem to create a major risk for further symptomatic
lung bleeding. The situation is similar within the brain. Recent studies have shown that
anticoagulation of patients with hemorrhagic infarcts in the brain caused by dural
venous sinus occlusions have better outcomes if treated with anticoagulants (12 – 14).
However, anticoagulation, especially using an intravenous bolus dose of heparin does
carry a risk of hematoma formation in patients with large brain infarcts, even when hemor-
rhagic changes are not present on the acute brain-imaging scans.

LOCATION, TYPES, AND SIZE OF EMBOLIC BRAIN INFARCTS


Anterior Vs. Posterior Circulation Localization
About 80% of emboli that arise from the heart go into the anterior (carotid artery) circula-
tion, equally divided between the left and right sides. The remaining 20% of emboli go
into the posterior (vertebral and basilar arteries) circulation, a rate roughly equal to the
proportion of the blood supply that goes into the vertebrobasilar arteries. In the Harvard
Stroke Registry (15), 78% of emboli caused clinical anterior circulation ischemia,
whereas the frequency of anterior circulation embolism was 85% in the Michael Reese
Stroke Registry (16), 70% in the Lausanne Stroke Registry (17), 73% in the Besancon
Stroke Registry (18,19), and 71% in the Athens Stroke Registry (20). The average of
the frequencies of anterior circulation localization approximates about 80%, which is
the expected frequency according to the proportion of blood flow.
The recipient artery destination depends on the size and nature of the particles and
their origin. Calcific particles from heart valves or mitral annular calcifications are less
mobile and adapt less well to the shape of their recipient artery resting place than red
(erythrocyte-fibrin) and white (platelet-fibrin) thrombi. The circulating blood stream
seems to be able to somehow bypass obstructing cholesterol crystal emboli, especially
in the retinal arteries. Emboli that originate in patients with patent foramen ovale and
atrial septal defects more often than expected reach locations within the posterior circula-
tion (21,22). Among one large series, 42.7% of strokes were located within the posterior
circulation in patients with patent foramen ovale, atrial septal aneurysm, or both, com-
pared to 35.4% of posterior circulation location in patients without cardiac atrial septal
abnormalities (21). In another series, among patients with large patent foramen ovales,
8 of 14 strokes involved the posterior circulation (22). Posterior circulation symptoms
and infarcts are also found more commonly than expected after cardiac catheterization
with or without coronary angiography (23,24). In one series 6 of 10 ischemic events
that followed cardiac catheterization could be localized to the posterior circulation (23).
In another series, among 37 ischemic events complicating cardiac catheterization, 20
(54%) had a vertebro-basilar territory localization (24).

Anterior Circulation Sites and Types of Embolic Infarcts


Within the anterior and posterior circulations there are predilection sites for the destination
of embolic particles. Large emboli entering a common carotid artery (CCA) could
become lodged in the common or internal carotid artery (ICA), especially if atheromatous
Recipient Artery: Anatomy and Pathology 37

plaques had already narrowed the lumens of these arteries. Only large emboli are likely
to be able to block the carotid arteries in the neck. Torvik and Jorgenson in their study
of autopsy material identified patients who had embolism to the carotid arteries (2,25).
In India, in years past it was customary in patients with embolism arising from rheumatic
mitral stenosis to surgically remove large emboli from the recipient carotid arteries in
the neck.
If emboli are able to pass through the carotid arteries in the neck, the next potential
lodging place is the intracranial ICAs (top-of-the carotid or carotid T portion) at their
bifurcation into the anterior cerebral (ACA) and middle cerebral (MCA) arteries.
Figure 6 is a drawing of the ICA showing the major intracranial branches. Bifurcations
are frequent resting places for emboli. Emboli that pass through the carotid intracranial
bifurcations most often go into the MCAs and their branches. Gacs et al. (26) showed
that balloon emboli placed in the circulation nearly always followed the same pathway
and ended up in the MCAs and their branches. Embolism in experimental animals,
produced by the introduction of silicone cylinders or spheres, elastic cylinders, and auto-
logous blood clots, also showed a very high incidence of MCA territory localization (27).
Emboli often pass into the superior and inferior divisions of the MCA and the cortical
branches of these divisions. The superior division supplies the cortex and white matter
above the sylvian fissure, including the frontal and superior parietal lobes. The inferior
division supplies the area below the sylvian fissure, including the temporal and inferior
parietal lobes. Figure 7 is a drawing of the convexal surface of the brain that shows the
divisions of the MCA and their main branches. Figure 8 is a drawing of a cut section of
the brain showing the supply zones of the different cerebral arteries. The MCA supplies

Figure 6 Anteroposterior views of branches of the internal carotid artery. Abbreviations: ACA,
anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PCA, posterior
cerebral artery. Source: From Ref. 14.
38 Caplan

Figure 7 Drawing of the lateral surface of the brain showing the superior and inferior trunk
divisions of the middle cerebral artery and their branches. Drawn by Dr. Juan Sanchez Ramos.
Abbreviations: MCA, middle cerebral artery. Source: From Ref. 5.

most of the convexal surface of the brain and the basal ganglia. The ACA supplies the
paramedian frontal lobe. Emboli seldom go into the penetrating artery (lenticulostriate
arteries) branches of the MCAs or the penetrators from the ACAs because these vessels
originate at an angle of about 908 from the parent arteries.

Figure 8 Artist’s drawing of the blood supplies of the various cerebral arteries. Coronal view: The
right side depicts territories supplied by the anterior cerebral artery, middle cerebral artery (MCA),
posterior cerebral artery (PCA), and anterior choroidal artery (AChA). The left side depicts individ-
ual vessels: (a) basilar artery; (b) thalamoperforators that originate in the PCA; (c) AChA; (d) MCA;
(e) lenticulostriate arteries. Abbreviations: ACA, anterior cerebral artery; MCA, middle cerebral
artery; PCA, posterior cerebral artery; AChA, anterior choroidal artery. Source: From Ref. 14.
Recipient Artery: Anatomy and Pathology 39

Figure 9 Drawings from computed tomography scans of patients with embolic brain infarcts in
the middle cerebral artery distribution. (A) Striatocapsular infarct; (B,C) Deep basal ganglionic-
capsular and superficial territory infarcts (D,I) Entire middle cerebral artery territory infarcts;
(E,F,G) Right side: superior division infarcts; (H) Left side: inferior division infarcts; (G) Left
side: (H) Right side: small cortical branch territory infarcts. Source: From Ref. 5.

Embolism into the MCAs can cause a variety of different patterns of infarction.
Figure 9 shows drawings of CT scans of nine patients with MCA embolic infarcts, and
Figures 10– 18 are imaging scans of patients with embolism involving the MCA terri-
tory. It is essential for clinicians to be able to recognize the various patterns of infarc-
tion. Blockage of the mainstem MCA before the lenticulostriate branches can cause a
large infarct that encompasses the entire MCA territory, including the deep basal
ganglia and internal capsule as well as the cerebral cortex and subcortical white
matter of both the suprasylvian and infrasylvian MCA territories (Figs. 9D and 9I).
Sometimes, the cortical territory of the MCA is infarcted, but the deep basal ganglionic
and internal capsule is relatively spared (Fig. 10). In some patients, an embolus blocks
the ICA, causing infarction of the ACA territory as well as the entire MCA territory
(Fig. 11).
40 Caplan

Figure 10 Computed tomography scan showing large infarct on the right of the figure (black
arrow) in the nearly entire cortical and subcortical territory of the middle cerebral artery. The
caudate nucleus and basal ganglia are relatively spared.

Figure 11 Computed tomography scan showing a large infarct (black arrow) involving the
anterior cerebral artery territory (double arrows) as well as the entire middle cerebral artery territory
on the right of the figure. Source: From Ref. 5.
Recipient Artery: Anatomy and Pathology 41

Figure 12 Magnetic resonance imaging showing a striatocapsular infarct that involves the caudate
nucleus, internal capsule, and putamen on the right of the figure (arrowhead ).

In young patients, when the mainstem MCA is blocked, the rapid development of
collateral circulation over the convexity of the brain often leads to the superficial territory
of the MCA being spared. The clot in the mainstem MCA blocks the lenticulostriate
branches, and collateral circulation to the deep MCA territory is poor. The resultant

Figure 13 Magnetic resonance imaging scan, T2 weighted, showing a small superior division
middle cerebral artery territory infarct on the right of the figure (white arrow). Source: From Ref. 5.
42 Caplan

Figure 14 Computed tomography scan showing bilateral superior division middle cerebral artery
(MCA) territory embolic infarcts. The deep MCA territories are also infarcted.

infarct is limited to the basal ganglia and surrounding cerebral white matter and is usually
referred to as a striatocapsular infarct (Fig. 9A; 12). Passage of an embolus into the
superior division of the MCA leads to a cortical/subcortical infarct in the region of the
suprasylvian convexity [Fig. 9E, F, G, H (right side); 13]. Figure 14 shows a CT scan

Figure 15 Magnetic resonance imaging T2-weighted image showing a small inferior division
infarct on the right of the figure (white arrows). Source: From Ref. 5.
Recipient Artery: Anatomy and Pathology 43

Figure 16 Superficial and deep infarcts. (A) computed tomography scan showing deep striatocap-
sular infarct (arrowhead) and inferior division middle cerebral artery (MCA) territory infarct (small
black arrow). (B) Diffusion-weighted magnetic resonance imaging scans at different levels showing
large striatocapsular infarct in the figure on the left and small infarcts in the cortical branches of the
territories of superior and inferior division MCA territory in the figure on the right.

from an unfortunate patient who has had embolic infarctions of the superior divisions
of both MCAs. Embolism in the inferior division leads to an infarct limited to the
temporal and inferior parietal lobes below the sylvian fissure [Fig. 9H (left side), 15].
When an embolus rests first in the mainstem MCA and then travels to one of the divisional
branches, infarction involves the deep territory and cortex above or below the sylvian
fissure (Fig. 9B, C; Fig. 6A, B). Small emboli block cortical branches and cause small
cortical/subcortical infarcts involving one or several gyri [Fig. 9G (left side); Fig. 16B;
17; 18].
Occasionally, emboli block the ACA or its distal branches. This causes an infarct in
the paramedian area of one frontal lobe. Figure 19A is a necropsy specimen of an embolic
infarct involving ACA territory and Figure 19B is an MRI scan showing a typical ACA
territory infarct due to embolism.
44 Caplan

Figure 17 Magnetic resonance imaging fluid-attenuated inversion recovery image showing a


middle cerebral artery pial territory gyral infarct.

Posterior Circulation Sites


Figure 20 is a drawing of the arteries that compose the posterior circulation and the brain-
stem and cerebellar areas that they supply. Figure 21 is a drawing that shows common
locations where emboli block recipient arteries within the posterior circulation. Emboli
that enter the posterior circulation can block the vertebral arteries in the neck or intracra-
nially. Emboli that are able to pass through the intracranial vertebral arteries (ICVAs) will
usually be able to pass through the proximal and middle portions of the basilar artery,
which has a larger diameter than the ICVAs. The basilar artery becomes narrower as it
courses craniad. Emboli often block the distal basilar artery bifurcation (“top of the
basilar”) or one of its branches (28,29). The main branches of the basilar artery bifurcation
are arteries penetrating to the medial portions of the thalami and midbrain, the superior
cerebellar artery (SCA), which supplies the upper surface of the cerebellum, and the

Figure 18 Magnetic resonance imaging diffusion-weighted scans at different levels showing


multiple small middle cerebral artery pial territory infarcts.
Recipient Artery: Anatomy and Pathology 45

Figure 19 Anterior cerebral artery territory infarcts. (A) Figure 6.14 postmortem necropsy
coronal slice of brain showing a large anterior cerebral artery (ACA)-territory infarct above the
very enlarged left lateral ventricle. The corpus callosum is necrotic, and the infarct extends
toward the right cingulate gyrus. (B) Magnetic resonance imaging, T2 weighted, showing a parame-
dian ACA territory infarct. Source: From Ref. 45.

posterior cerebral arteries (PCAs), which supply the lateral portions of the thalami and the
temporal and occipital lobe territories of the PCAs. Figure 22 is an MRI that shows an
occipital and medial temporal lobe embolic infarct in the distribution of one PCA.
Figure 23 is a necropsy specimen that shows a hemorrhagic infarct in the territory of
the bilateral PCAs that resulted from an embolus to the rostral basilar artery bifurcation.
Figure 24 consists of two views of an embolic infarct to one SCA, whereas the MRIs in
Figure 25 show embolic infarcts involving the bilateral SCAs. Sometimes, infarcts are
limited to one branch of an artery that penetrates into the midbrain or thalamus
46 Caplan

Figure 20 Drawing of the arterial supply of the brainstem and cerebellum. Abbreviations: ASA,
anterior spinal artery; VA, intracranial vertebral artery; BA, basilar artery; PICA, posterior inferior
cerebellar artery; AICA, anterior inferior cerebellar artery; SCA, superior cerebellar artery; PCA,
posterior cerebral artery. Source: From Ref. 30.

Figure 21 Drawing of the base of the brain showing the most frequent sites of embolism within
the posterior circulation. The black clots are located within the left intracranial vertebral artery and in
the distal basilar artery and its left superior cerebellar and posterior cerebral artery branches. The left
temporal lobe and left cerebellum are shaded gray to show infarction. Drawn by Dari Paquette.
Source: From Ref. 30.
Recipient Artery: Anatomy and Pathology 47

Figure 22 Magnetic resonance imaging of T2-weighted axial section showing a large left occipital
lobe infarct on the right of the figure. Source: From Ref. 30.

(Fig. 26). Figure 27A is a CT scan that shows bilateral infarcts in the territory of the
thalamo-perforating arteries that emanate from the basilar artery bifurcation; Figure 28
is a necropsy specimen showing a typical bilateral “butterfly-shaped” infarct in the para-
median thalamus due to a “top-of-the-basilar” embolus. At times, rostral basilar artery
emboli cause infarcts in both thalami and both occipital lobes (Fig. 29).

Figure 23 Cut section of the posterior portion of the brain at necropsy showing a bilateral hemor-
rhagic infarct within the territories of the posterior cerebral arteries (PCA) (white arrows). The black
stippled areas within the infarct represent small hemorrhages. These infarcts are a result of a single
embolus temporarily blocking the distal bifurcation of the basilar artery impeding flow to the left and
right PCA. Source: From Ref. 5.
48 Caplan

Figure 24 Magnetic resonance imaging T2-weighted scans showing a unilateral infarct within the
territory of the medial branch of the superior cerebellar artery. (A) Sagittal section showing
the infarct (black arrow). (B) Coronal section. The black arrow points to the infarct involving the
superior vermis and medial portion of the cerebellar hemisphere. Source: From Ref. 30.

Some emboli stop at the level of one ICVA. The most frequent brain area infarcted is
the posterior inferior portion of the cerebellum in the territory of the posterior inferior cer-
ebellar artery (PICA) branch of the ICVA (Fig. 30A, B). At times, an embolus will stop at
the level of one ICVA causing a PICA territory infarct, and then the embolus or a portion
of it passes distally, causing an infarct in SCA territory on one or the other side (30).
Figure 31 is an MRI that shows a PICA territory infarct on the right of the figure and
Recipient Artery: Anatomy and Pathology 49

Figure 25 Magnetic resonance imaging T2-weighted scans showing bilateral superior cerebellar
artery territory infarcts. (A) Coronal section: the arrowhead points to the infarcts. (B) Axial section
showing the infarcts. Source: From Ref. 30.

an SCA territory infarct on the left side of the figure that resulted from a cardiogenic
embolus.

Angiographic Sites of Recipient Artery Occlusions


Cerebral angiography was used for diagnosis in the Harvard Stroke Registry (HSR), as
many patients were seen before CT scans were available (15). Table 1 shows the frequency
of embolic occlusions among the various intracranial arteries based on angiography in the
HSR. The MCAs were involved in 80% of patients; the mainstem MCA and superior div-
ision branches were the regions within the MCAs that were most often occluded (15).
50 Caplan

Figure 26 Necropsy specimen showing a unilateral midbrain infarct (large black arrow) in the
territory of a penetrating artery branch of the distal basilar artery.

In the Lausanne Stroke Registry (LSR), the distribution of infarcts in patients with poten-
tial cardiac sources of emboli was based on brain imaging, using either a CT scan or an
MRI (31). Among 1311 patients who were tabulated in the LSR, 305 (23%) had potential
cardiac sources of emboli. Table 2 shows the distribution of brain infarcts among these
305 patients (31).

Figure 27 Computed tomography scan showing bilateral large nearly symmetrical posterior
medial thalamic infarcts (white arrow) due to embolism to the “top of the basilar artery.” Source:
From Ref. 30.
Recipient Artery: Anatomy and Pathology 51

Figure 28 Bilateral, paramedian, thalamic – subthalamic artery territory butterfly-shaped infarct


(white arrows) abutting the third ventricle due to embolism to the “top of the basilar artery.”
Source: From Ref. 30.

Multiple Emboli
Another important feature of cardiac origin embolism is development of multiple cortical/
subcortical infarcts in multiple vascular territories within both anterior circulations and the
posterior circulation, especially in the absence of severe proximal arterial occlusive
lesions. Emboli arising from the aorta probably share the same patterns of infarction as
that found in cardiac-origin embolism, although recipient sites of aortic-origin emboli

Figure 29 Computed tomography scan illustrating a devastating “top of the basilar artery”
embolus. The bilateral occipital lobes in the territory of the posterior cerebral arteries (small
black arrows) and the right thalamus (white arrow) are infarcted.
52 Caplan

Figure 30 Posterior inferior cerebellar artery (PICA) territory infarcts. (A) Magnetic resonance
imaging (MRI), T2-weighted, axial-section scan showing a very large infarct (white arrows) invol-
ving the brainstem and cerebellum on one side caused by embolism to the right intracranial vertebral
artery. (B) MRI, T2-weighted, sagittal-section scan showing a PICA territory infarct (white arrow).
Source: From Ref. 30.

have not been extensively studied. Figure 32 is a CT scan that shows multiple brain
infarcts in a patient with cardiac valve disease.

Intra-arterial Emboli Vs. Cardiogenic Emboli


Emboli that arise from proximal arteries go only into branches of that artery. Repeated
embolism going into one MCA suggests an intrinsic lesion of the carotid artery on that
side. The distal termination sites within the anterior and posterior circulations are the
same as that described in cardiac origin embolism. Proximal arterial disease often
Recipient Artery: Anatomy and Pathology 53

Figure 31 Magnetic resonance imaging of a T1-weighted, coronal section showing a left posterior
inferior cerebellar artery territory infarct (white arrow) and a right superior cerebellar artery territory
infarct (black arrow) caused by an embolus to the left intracranial vertebral artery that later passed
distally.

induces circulatory changes with increased collateral circulation. The preexistence of col-
lateral circulation might limit the size of intra-arterial embolic infarcts when compared to
cardiac and aortic origin embolism, in which there is no such pre-event adaptation. The
distribution of infarcts according to superficial and deep intracranial territories also prob-
ably differs between patients with cardiac and intra-arterial sources of embolism. Table 3
shows the distribution of infarcts in the Stroke Data Bank (32). Superficial and deep
infarcts were much more often found in patients with cardiac sources of embolism (32).
Large emboli more often block the mainstem MCAs and PCAs before their penetrating
artery branches, leading to infarcts that are both deep and superficial. In contrast purely

Table 1 Vascular Recipient Arteries in the Harvard Stroke


Registry Based on Cerebral Angiography

Anterior cerebral artery 3 (3%)


Middle cerebral artery 75 (80%)
Main stem 26
Superior division 9
Superior division branch 22
Inferior division 8
Inferior division branch 1
Multiple branches 9
Posterior cerebral artery 11 (12%)
Basilar artery 5 (5%)

Source: From Ref. 12.


54 Caplan

Table 2 Topography of Infarcts in the Lausanne Stroke Registry


in Patients with Potential Cardiac Sources of Embolism

Anterior circulation 213 (70%)


Global MCA 33 (11%)
Superior division MCA 60 (20%)
Inferior division MCA 54 (18%)
Deep subcortical 56 (18%)
ACA 9 (3%)
ACA and MCA together 1 (0.3%)
Posterior circulation 69 (23%)
Brainstem 18 (6%)
Thalamus (deep PCA) 12 (4%)
Superficial PCA 21 (7%)
Superficial and deep PCA 3 (1%)
Cerebellum 10 (3%)

Abbreviations: MCA, middle cerebral artery; ACA, anterior cerebral artery;


PCA, posterior cerebral artery.
Source: From Ref. 27.

superficial infarcts were more common in patients with intra-arterial embolism in the
Stroke Data Bank (32).

Size of Infarcts
Emboli of cardiac origin are often larger than those that originate in the proximal arteries
and so the infarcts that result are, on average, larger than artery-to-artery infarcts (32 – 34).

Figure 32 Computed tomography scan showing five brain infarcts (black arrows) located in the
basal ganglia and temporal lobes bilaterally. Source: From Ref. 5.
Recipient Artery: Anatomy and Pathology 55

Table 3 Distribution of Infarcts in the Stroke Data Bank

Cardiac-origin Intra-arterial
Infarct type embolism (%) embolism (%)

Superficial infarcts 24 61
Deep small infarct 13 10
Deep large infarcts 9 16
Superficial and deep infarcts 53 13

Source: From Ref. 28.

In the Stroke Data Bank, the medium volume of infarction on CT scans in patients with
cardiac origin embolism was 2.4 times that found in patients with intra-arterial embolism,
a highly significant difference (P , 0.01) (32). In a study that included more than 2000
stroke patients, the average size of brain infarcts that causes seizures mostly due to
cardiac origin embolism was 73.7 cm3 versus 48.9 cm3 for nonembolic infarcts (35).
The presence of proximal arterial occlusion and the gradual pace of in situ arterial narrow-
ing and occlusion allow time for collateral circulation to develop and thus likely limit the
size of the infarction. In contrast, embolic occlusion of recipient arteries from a cardiac
source occurs abruptly.
A decreased level of consciousness early during the course of a stroke, a finding
likely related to the size of infarction among other factors, was also significantly more
common among Stroke Data Bank patients with cardiogenic embolism compared to
those who had intra-arterial embolism (29.8% vs. 6.1%, P , 0.01) (32).

Edema and Brain Shifts in Patients with Large Embolic Brain Infarcts
Because embolic brain infarcts, especially those caused by cardiac origin embolism, are
often large, brain swelling and mass effect often develop. Patients with very large infarcts
often worsen during the first 24 to 48 hours after their initial symptoms. The most common
infarcts that create major pressure effects are: large MCA territory infarcts [so-called
malignant MCA infarcts (36)], large infarcts caused by carotid artery occlusion that
include the MCA and also the ACA and sometimes Anterior Choroidal Artery territories,
and large cerebellar infarcts especially involving PICA cerebellum and SCA supplied
cerebellum. Probably at least 1/3 of the cerebellum on one side must be infarcted to
be likely to cause major tumoral effects (37). These large cerebellar infarcts can
compress the brainstem and the fourth ventricle leading to death if not decompressed
surgically (38 –41). Most often, pressure effects caused by swelling of large cerebral
hemisphere infarcts result in a shift of the midline without herniation of brain contents.
The brain is compartmentalized by bony fortresses (anterior, middle, and posterior
fossas) and by dural structures (falx cerebri and tentorium cerebelli), which, under
normal circumstances, contain their usual contents. When mass effects are very severe,
brain tissue bulges or spills out of its usual abode into a different compartment; this is
called “herniation” (42,43).
Brain shifts and herniations and their effects are depicted in Figure 33. The most
common are:
1. compression of the lateral ventricle with a shift in midline structures (Fig. 33A);
2. herniation of the temporal lobe through the tentorial notch, to compress the
midbrain (Fig. 33B);
56 Caplan

Figure 33 Drawings of brain shifts and herniations: Displacement of brain tissues due to mass-
producing strokes is illustrated in patients with large infarcts. (A) Hemisphere infarct causes com-
pression of the ipsilateral lateral ventricle and shift of the midline to the opposite side. (B) Large
hemisphere infarct causes uncal herniation. The medial temporal lobe exerts pressure on the
upper brainstem. (C) Frontal lobe large infarct causes herniations of the cingulum under the falx
cerebri. (D) Cerebellum infarct causes increased posterior fossa pressure with compression of the
brainstem and herniation of the cerebellum through the foramen magnum.These patterns are also
illustrated on the larger figure to the left. Source: From Ref. 14.

3. herniation of the cingulate gyrus under the falx, allowing it to reach the contral-
ateral side (Fig. 33C);
4. symmetrical, downward pressure by the swollen cerebral hemispheres on the
rostral brainstem, causing elongation;
5. herniation of the cerebellum upward through the tentorial notch, to compress the
brainstem (Fig. 33D); and
6. downward herniation of the cerebellar tonsils through the foramen magnum,
compressing the medulla and upper cervical spinal cord (Fig. 33D).

Shifts in brain contents can also lead to compression or stretch of arteries and infarc-
tion in areas of supply and also to secondary hemorrhages. The most common locations of
secondary vascular changes leading to infarction involve the PCAs where they pass
between the tentorium and the medial temporal lobe and the ACAs adjacent to the falx.
Distortion of the upper brainstem at the tentorial opening often leads to secondary hemor-
rhages in the brainstem. These usually involve the midline and paramedian vessels and
are called “Düret hemorrhages,” after the French clinician and researcher, Henri Düret,
who first described them (44). Examples of Düret hemorrhages are shown in Figures
34A and B.
The ventricular system may also be compressed at various sites. Large cerebral
infarcts can compress the ipsilateral lateral ventricles and may cause blockage of the
foramen of Monro, leading to enlargement of the contralateral lateral ventricle. Large
cerebellar infarcts can compress the fourth ventricle or cerebral aqueduct, leading to
obstructive hydrocephalus of the third and lateral ventricles (Fig. 35). Shifts in brain
contents, herniations, and secondary infarctions, as well as Düret hemorrhages and
hydrocephalus, all cause clinical worsening of signs and symptoms and often lead to
fatal outcomes.
Recipient Artery: Anatomy and Pathology 57

Figure 34 Düret hemorrhages. (A) Midline hemorrhage (black) due to compression from a
cerebral hemisphere lesion on the left side of the figure. (B) Large midline hemorrhage (black)
in the midbrain extending into the left tegmentum. There are smaller hemorrhages in the cerebral
peduncles on both sides.

Figure 35 Computed tomography scan showing a large right cerebellar infarct (black arrow) compres-
sing the brainstem. The cisterns around the brainstem are compressed and are obliterated on the scan. The
temporal horns of the lateral ventricles are dilated (white arrows).
58 Caplan

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4
Recipient Artery: Clinical Symptoms
and Signs of Brain Ischemia

Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Nearly always, the clinical presentation in patients with brain embolism relates to the
recipient artery. Blockage of a recipient artery causes brain symptoms that can be persist-
ent or transient. Factors that affect the outcome of the ischemic brain include: the size and
nature of the embolic material; any proximal circulatory insufficiency (washout) (1); frag-
mentation and passage of the embolic material distally; resistance or susceptibility to
ischemia of the brain tissue deprived of blood flow; collateral circulation; and perhaps
other factors not well understood now.

GENERAL CLINICAL FEATURES AND DIAGNOSIS


Early Clinical Course
The most common and characteristic time course in patients with embolism to brain
arteries is the very sudden onset of neurologic symptoms and signs that are maximal at
onset. After an embolus blocks a recipient artery, collateral circulation begins to
develop and some improvement may occur. The breakup and distal movement of an
embolus strongly affect the subsequent clinical course. Movement of emboli is most
common during the first 48 hours after the onset of symptom. In the Harvard Stroke
Registry (HSR), angiography performed after 48 hours in patients with clinical brain
embolism was often normal, but immediate angiography performed within hours after
the onset of symptom nearly always showed embolic intracranial occlusions (2). Others
have also shown a very high rate of angiographic detection of emboli when studies are
performed within eight hours after the onset of stroke (3 –5). Transcranial Doppler
monitoring of intracranial arteries after the onset of embolic strokes also shows a high
frequency of the passage of emboli (6,7).
Movement of emboli before the development of irreversible brain damage allows
reperfusion of previously ischemic brain tissue and is often accompanied by clinical
improvement in the symptoms and signs. However, in some patients, the embolus or its
fragments block an important distal branch leading to further ischemia and worsening
of symptoms. For example, a patient with an embolus to the left main-stem middle

61
62 Caplan

cerebral artery (MCA) might develop the sudden onset of right hemiplegia, hemisensory
loss, and aphasia. When the embolus passes and the lenticulostriate arteries supplying the
internal capsule and basal ganglia regions are reperfused, the right limb weakness might
improve. Improved cortical blood flow might be accompanied by improvement in speech.
However, if the embolus then passed into the superior division of the MCA or one of its
branches, the hemiparesis and speech deficit could worsen. The weakness might be limited
to the hand and face controlled by the precentral gyrus motor cortex regions supplied by
cortical branches of the superior division of the MCA. If the embolus had passed instead
into the inferior division of the MCA supplying the temporal lobe and occluded it or one
of its branches, the patient might then have developed a fluent Wernicke-type aphasia.
When worsening develops after initial clinical improvement in patients with brain
embolism, it usually occurs in a single step and nearly always occurs during the first 48
hours. Multiple stepwise worsening, gradual smooth worsening, and delayed worsening
are unusual. Late worsening after 48 hours should raise suspicion of hemorrhage into
the area of infarction as hemorrhagic transformation often occurs between two and
seven days after the onset of stroke. In patients with large brain infarcts, peri-infarct
edema can lead to worsening. Edema usually becomes clinically apparent from two to
four days after the onset. Table 1 shows the course of deficit in various stroke registries
comparing patients with embolism and in situ thrombosis (2,8,9).
Another pattern quite characteristic of brain embolism has been called “spectacular
shrinking deficit” by Mohr (10). This term describes sudden, complete, or nearly complete
clearing of a sudden onset of severe neurologic deficit. Most often, the patient has had a
main-stem MCA or basilar artery embolus that rapidly passed. An example of each situ-
ation from my own personal experience will illustrate this syndrome, which is diagnostic
of brain embolism.
One evening, an 82-year old woman sneezed and suddenly became unresponsive.
She was comatose when brought to the hospital. Her pupils were small and did not
react to light. Her eyes were deviated down and inward. She did not respond to stimuli.
Her electrocardiogram showed atrial fibrillation. The family was called and told that the
situation was ominous and that she might be in a terminal coma and to prepare for the
worst. Family members came to the hospital, witnessed her coma, and then went home.
Computed tomography (CT) scan was performed and was normal. The next morning,
the patient called home and requested her clothes and her toothbrush and berated the
family for not bringing these things with them.

Table 1 Early Course of Deficit in Patients with In Situ Thrombosis Versus Embolism in Various
Stroke Registries

Thrombosis Embolism
Course HSR MRSR LSR HSR MRSR LSR

Maximal at onset 40% 45% 66% 79% 89% 82%


Stepwise/stuttering 34% 30% 11% 10%
Progressive 27% 13%
Gradual smooth 13% 14% 5% 1%
Fluctuating 13% 11% 7% 5% 5%

Note: In the LSR, gradual smooth and stepwise/stuttering are considered as progressive.
Abbreviations: HSR, Harvard Stroke Registry (2); MRSR, Michael Reese Stroke Registry (8); LSR, Lausanne
Stroke Registry (9).
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 63

A 65-year old man, while eating lunch, suddenly collapsed and was brought to the
hospital. Examination showed a sleepy man who could be aroused. His eyes were conju-
gately deviated to the left. He did not speak; his right limbs were quite weak, and he did
not respond to pin or pinch on his right limbs and body. He did not respond to or look at
stimuli on his right side. CT scan was negative but transcranial Doppler ultrasound
(TCD) showed no blood flow signal in the left MCA. The family saw his poor condition
and was told that the outlook was grim. Suddenly, within an hour, the patient began to
speak and move the right limbs, and he quickly returned almost to normal. Repeat TCD
now showed normal left MCA blood flow velocities. Subsequent transesophageal echo-
cardiography evaluation showed a thrombus within the left ventricle.
The first patient had a “top of the basilar” artery embolus with temporary midbrain
and thalamic stunning (11 – 13). The coma and abnormal pupillary responses and eye
movement abnormalities were explained by ischemia within the rostral brainstem tegmen-
tum. CT confirmed that the upper brainstem dysfunction was not caused by pressure from
a large hemispheric lesion with herniation and that there was no infarction in the upper
brainstem. The embolus passed sometimes during the night. The second patient had a
main stem left MCA embolus, which caused severe but transient dysfunction of the
supply zone of that artery. The TCD confirmed blockage of the MCA, but CT showed
no infarction. The left hemisphere was temporarily stunned, that is, not receiving
enough blood containing oxygen and sugar to function normally, but was not
sufficiently deprived of fuel to develop irreversible damage. Passage of the embolus
allowed rapid recovery of left cerebral hemisphere brain function.
In one clinical study from Japan, among 118 patients who had the abrupt onset of
neurological signs, 14 had rapid clearing of their signs within 24 hours, and in 10, the
deficit cleared within four hours (14). All the 14 patients, who had spectacular shrinking
deficits, had cardiogenic embolism. Angiography in this series showed migration of
emboli in the patients with these shrinking deficits (14).

Transient Ischemic Attacks


Temporary deficits that qualify as transient ischemic attacks (TIAs) do occur in some
patients with brain embolism. In patients with arterial sources of emboli, the attacks are
always in the supply territory of the affected artery. For example, a patient with severe
atherosclerotic stenosis of the right internal carotid artery (ICA) might have attacks of
right monocular visual loss and/or spells of numbness or weakness of the left arm,
hand, face, or leg. A patient with right vertebral artery stenosis might have attacks of
double vision, dizziness, and staggering. In patients with cardiogenic or aortic origin
embolism, when attacks occur, they are random and involve different vascular territories.
One of my patients awakened one night to urinate, and after urinating developed
weakness and numbness of his left arm and leg. By the next morning, the symptoms
had cleared and he was able to use his left limbs normally. He did not tell his wife or a
doctor. He had been feeling poorly for weeks with night sweats and fever, symptoms
that he also concealed from others. The very next night, he again arose to urinate and
now found that his right hand was weak. His wife heard him return to bed and noted
that his voice was slurred and his speech did not make good sense. By the next
morning, when she brought him to the doctor, he had almost returned to normal.
CT scan showed a small left precentral gyrus infarct. The doctor was unsure whether
the patient might have been confused about the side involved in the first occurrence and
ordered noninvasive vascular studies of the extracranial and intracranial carotid and ver-
tebral artery circulations, which were normal. Subsequent testing showed that the patient
64 Caplan

had bacterial endocarditis and probably had two emboli, one to the right and the other to
the left cerebral hemispheres.
The definition of a TIA, usually cited, is that of a transient focal deficit that clears
within 24 hours. This definition is quite arbitrary, and, in fact, most TIAs clear within
one hour (15 – 20). Despite the fact that the symptoms are transient, CT and magnetic
resonance imaging (MRI) often show infarcts in regions of the brain appropriate to the
symptoms (15 – 18). The longer that symptoms last, the more likely that a brain infarct
will be present on CT or MRI scanning (17). Patients with transient focal symptoms
and patients with symptoms that persist have potentially serious cerebrovascular,
cardiac, or hematological conditions and are at risk for further strokes. Brain
ischemia deserves a thorough evaluation irrespective of the timing of clinical symptoms
(15,18 –20).

Activity at the Onset of Symptoms


In the past, clinicians thought that strokes due to in situ thrombosis usually developed
upon arising from sleep or after a nap, thrombosis having occurred while the circulation
is most sluggish. In contrast, strokes related to hemorrhage and embolism were posited to
occur during vigorous activity. Activity is thought to provoke leakage of blood from
fragile vessels and vessels damaged by hypertension and to “shake loose” potential
emboli from their nests. Studies, however, show that most strokes develop during the
morning hours between 10 am and noon, after awakening, and after daily activities
have begun, and not during sleep (21). In various stroke registries, activity at the
onset was not helpful in differentiating between the various stroke mechanisms (2,8).
Most strokes occurred during daily activities. In the Michael Reese Stroke Registry
(MRSR) only 5% of emboli and 1% of thrombotic and lacunar strokes began during
vigorous physical activity or stress (8). Occasionally, a vigorous sneeze or cough or
sudden strong body movement precipitates embolism, although the frequency of this
occurrence is relatively low. Emboli also seem to occur more often than chance after
awakening at night to urinate, a so-called “matutinal” (morning) embolus.

Systemic Embolism
Necropsy studies of patients with cardiac origin brain embolism nearly always show
embolic infarcts in other systemic organs, especially the spleen and kidneys (22). In con-
trast, the frequency of clinical recognition of systemic embolism is quite low. In various
stroke registries, the frequency of diagnosis of systemic embolism was: 2% HSR (2), 2.3%
MRSR (8), 3.6% Stroke Data Bank (SDB) (23), 3% Lausanne Stroke Registry (LSR) (9).
The highest frequency of systemic embolism, 8%, was found in a study of 60 patients
who had cardiogenic brain embolism, in which two patients had kidney and three had
peripheral limb embolism (24).
Embolism to the brain that causes ischemia almost invariably leads to transient or
persistent symptoms. The brain is like litmus paper, very sensitive to perturbations.
Systemic embolism also causes ischemia, but the symptoms are much less specific.
Embolism to a limb might cause arm pain, a leg cramp, or other transient discomfort,
symptoms that are very common and usually are explained by activity, positioning of
the limb, or some other banal everyday occurrence. Similarly, embolism to the intestinal
tract might cause stomach cramps, bowel irregularity, a bellyache—rather common and
nonspecific symptoms. Embolism to the kidneys or spleen causes flank or abdominal
discomfort rarely diagnosed as due to systemic embolism. Hematuria and the sudden
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 65

onset of severe limb ischemia are probably the only two occurrences that usually lead to
recognition of systemic embolism, especially in patients with known heart disease.

Headache
Headache is an extremely common symptom among stroke patients. Although brain tissue
contains no pain sensitive afferent nerve fibers, the vessel walls and meninges contain
many pain-sensitive nerve endings. Stretching and dilatation of arteries on the brain
surface and in the neck often cause head and neck discomfort and headache. The
frequency and causes of headache vary depending on the stroke mechanism. Some head-
aches are caused by mass effect caused by large brain infarcts with surrounding brain
edema or by hemorrhages within the brain parenchyma. Irritation of the meninges by
blood causes headache in patients with subarachnoid hemorrhage (SAH). In embolism
related to bacterial endocarditis, meningeal seeding by bacteria can be the cause of head-
ache. In patients, who have intracranial large artery occlusions, headache may be due to
distention of occluded arteries by clot, dilatation of collateral arteries, and tears within
arterial walls.
Table 2 lists the frequencies of headache at or near the onset of stroke in various
stroke registries and series (2,8,9,25,26). Headache is most frequently reported in patients
with intracerebral hemorrhage. Patients with brain embolism have headache more often
than patients with lacunar infarcts caused by penetrating artery disease but less
often than patients with occlusive disease of large extracranial and intracranial arteries.
Patients with SAH may have episodes in which a small amount of blood leaks into the sub-
arachnoid space causing what has been referred to as a “sentinel” headache.
Frequent dull or throbbing headaches are often present in the days or weeks before
ischemic stroke in patients with large artery thrombosis. These are due to distention of
occluded arteries as well as dilated collateral arteries. Headaches are rarely noted
before brain embolism except when the donor source is a large extracranial artery.

Seizures
Seizures at or near the onset of stroke are very uncommon in patients with ischemic strokes
irrespective of cause. Seizures are more common in patients with intracerebral and subar-
achnoid hemorrhages than in patients with ischemic strokes, irrespective of the mechan-
ism of the brain ischemia. In the HSR, 4% of patients with brain embolism had seizures
early in their clinical course, as compared to 0.3% of patients with large artery in situ
occlusions (2). No patient with lacunar infarction in the HSR had an early seizure, an

Table 2 Headache At or Near the Time of Onset Among Various Stroke Types in Various Stroke
Registries

Large
artery Lacunar Intracerebral
Registry thrombosis Embolism infarction hemorrhage

Harvard (2) 12% 9% 3% 33%


Lausanne (9) 17% 18% 7% 40%
Stroke Data Bank (25) 11% 10% 5% 41%
Michael Reese – Illinois (8,26) 26% 14% 6% 55%

Note: % of patients.
66 Caplan

expected finding because lacunes are, by definition, small and deep and not likely to cause
cortical irritation (2). In the SDB, only 3.1% of patients with cardiac-origin embolism had
seizures during the acute hospitalization (27), and no patient with presumed brain embo-
lism in the LSR had early seizures (9).
In a thesis that analyzed the development of seizures among 770 patients with first-
ever symptomatic supratentorial brain infarcts in the Maastricht stroke registry, the pre-
sence of cardiac-origin embolism meant that the patient had a relative risk of 5.14 of
developing an early-onset seizure, compared to patients without cardiogenic embolism
(28). Among 2000 stroke patients in another large series, patients with hemorrhagic
infarcts and large infarcts were most likely to have seizures. The average size of infarcts
in patients with seizures was 76.7 cm3 versus 45.6 cm3 in patients who did not have
seizures (29). In this series, 40% of the seizures in stroke patients occurred during the
first day and 51% during the first week; 96% of poststroke seizures occurred during the
first year after stroke (29). Seizures near the time of the onset of stroke symptoms are prob-
ably more common in patients with embolism than in nonembolic causes of ischemic
stroke. However, seizures are too infrequent in any subtype of ischemic stroke to be of
much help in differential diagnosis.

Decreased Level of Consciousness


Early decrease in the level of consciousness in ischemic stroke patients is most often due
to acute brainstem tegmental ischemia related to embolism to the basilar artery (11 – 13).
Decreased consciousness can also result from major hemispheral ischemia caused by
sudden occlusion of the major blood supply of either hemisphere. Later in the course,
during days 3 –7, persistent loss of consciousness is usually explained by brain edema
and the mass effect of large cerebellar and cerebral infarcts. Transient loss of conscious-
ness is most often seizure related or due to a cardiac arrhythmia.
Few studies have analyzed the frequency of loss of consciousness at or near the
time of stroke. In the SDB, decreased consciousness early in the stroke was present in
29.8% of patients with embolism of cardiac origin, compared to a 6.1% frequency
in patients with artery-to-artery brain embolism (27). Decreased consciousness at or
near the time of stroke is more common in patients with embolic occlusions than in
other causes of ischemic stroke and is more common in patients with cardiac origin
embolism than in those with proximal arterial sources. The larger size of emboli of
cardiac origin, as compared with emboli of arterial origin, is the probable explanation
for the difference.

Clinical Patterns of Neurologic Symptoms


Neurological diagnoses are often made by pattern matching. Clinicians match the findings
in any given patient with those usually found in patients with lesions affecting certain ana-
tomical regions. Lesions in specific anatomical loci, in turn, are associated with occlusions
of the various feeding arteries. Table 3 shows the most common brain and vascular
locations of cardio-embolic infarcts in the LSR (30). Each of these locations has charac-
teristic clinical findings. Because the findings in patients with posterior circulation embo-
lism are less well known, I will devote more discussion to the symptoms and signs in the
vertebro-basilar territory. Some necropsy specimens and imaging scans of infarcts in
various vascular territories preferentially affected by embolism have been shown in
Chapter 3. Please refer to these as the various syndromes discussed.
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 67

Table 3 Topography of Infarcts in the Lausanne Stroke Registry in


Patients with Potential Cardiac Sources of Embolism

Anterior circulation 213 (70%)


Global MCA 33 (11%)
Superior division MCA 60 (20%)
Inferior division MCA 54 (18%)
Deep subcortical 56 (18%)
ACA 9 (3%)
ACA and MCA together 1 (0.3%)
Posterior circulation 69 (23%)
Brainstem 18 (6%)
Thalamus (deep PCA) 12 (4%)
Superficial PCA 21 (7%)
Superficial and deep PCA 3 (1%)
Cerebellum 10 (3%)

Abbreviations: MCA, middle cerebral artery; ACA, anterior cerebral artery;


PCA, posterior cerebral arteries.

ANTERIOR CAROTID ARTERY CIRCULATION EMBOLISM

Main-Stem MCA Territory Ischemia and Infarcts


Among all series, the great majority of emboli are found within the MCAs and their
branches. Large emboli may block the main-stem MCA near its origin, leading to infarc-
tion of the entire territory of the cerebral hemisphere supplied by the MCA. This includes
the basal ganglia (caudate and putamen) and the frontal, temporal, and parietal lobar white
and gray matter supplied by the MCA. The clinical deficits in these patients are very
severe, and most patients die. Rarely, patients survive but remain severely and perma-
nently disabled. These very large infarcts are often referred to as malignant MCA territory
infarcts. Consciousness is reduced. The eyes usually rest conjugately towards the side of
the infarct. The contralateral limbs are paralyzed and insensitive to pin stimulation or
pinch. Although the patient may attend to voices, visual objects, and people situated on
the same side of space as the brain infarct, they often will ignore identical stimuli on
the contralateral side of space. When the left MCA is occluded, patients do not speak
or heed directions or queries. Within the first 24 to 48 hours, stupor deepens, then coma
develops, and the patient often dies without decompressive surgery.
Occasionally, patients with main-stem MCA emboli who have very severe clinical
signs, rapidly, almost miraculously, recover (14). This, so-called “spectacular shrinking
deficit” is due to reperfusion of brain that was reversibly ischemic (“stunned”). CT and
MRI brain scans and vascular imaging tests can be helpful in predicting the prognosis
for recovery. The presence of early signs of infarction bodes poorly for recovery. When
the CT or MRI scan are normal initially, the prognosis is more hopeful.
Occlusion of the MCA proximal to the lenticulostriate branches sometimes produces
an infarct that includes the deep basal ganglionic and capsular territory as well as super-
ficial MCA territory. This pattern of infarction, involvement of superficial and deep MCA
territory, was found in more than half of the patients in the SDB series with cardiac-origin
embolism (27). These patients with large superficial and deep MCA territory infarcts
invariably have a hemiparesis involving the face, arm, and leg on the side contralateral
to the lesion. They also usually have some degree of hemisensory loss. Conjugate eye
deviation and inattention to the contralateral side of visual space are variable findings
68 Caplan

that depend on the size of the infarct and its distribution in the white matter and cerebral
cortex. Cortical function abnormalities, such as aphasia, abnormal drawing and copying,
visual neglect, and lack of awareness of the neurological deficit, depend on the location
and extent of cortical infarction and whether the left or the right cerebral hemisphere
is involved.

Striatocapsular (Deep MCA Territory) Ischemia


Basal ganglia and internal capsule infarction is usually due to embolic occlusion of the
main-stem MCA before its lenticulostriate branches. There is excellent potential for col-
lateral circulation over the convexities but poor collateral circulation in the deep basal gray
nuclei and the internal capsule. For this reason, some patients with MCA occlusion have
selective ischemia of the deep lenticulostriate territory (“striatocapsular infarcts”) (31).
Patients with striatocapsular ischemia are invariably hemiparetic, but the distri-
bution of weakness in face, arm, and leg varies. Sensory loss is usually minor, because
the posterior portion of the internal capsule is spared. When the lesion is in the left hemi-
sphere, after a short period of temporary mutism, speech is sparse and dysarthric, but
repetition of spoken language is preserved. Comprehension of spoken and written
language depends on both the size and the anteroposterior extent of the lesion. When
the right hemisphere is involved, there often is neglect of contralateral visual and tactile
stimuli, usually more transient than with parietal lobe cortical infarction.

Superior Division MCA Ischemia


The superior trunk of the MCA supplies the frontal and superior parietal lobes. Ischemia is
most often due to embolism to the superior division but in situ narrowing does occasion-
ally occur. The neurological signs include hemiplegia, more severe in the face and hand
and upper extremity, with relative sparing of the lower extremity; hemisensory loss,
usually including decreased pinprick and position sense, sometimes sparing the leg; con-
jugate eye deviation, the eyes resting toward the side of the brain lesion; and neglect of the
contralateral side of space, especially to visual stimuli. Visual neglect is usually more
severe in patients with right-hemisphere lesions.
When the lesion is in the left, dominant hemisphere, there is invariably an accom-
panying aphasia. Verbal output is sparse, and the patients do not do what they are
asked with either hand, although they may follow whole-body commands. They may
nod appropriately to “yes/no” questions asked verbally, but comprehension of written
material is poor. With time, a pattern of Broca’s aphasia evolves, with sparse, effortful
speech, poor pronunciation of syllables, and omission of small words (such as preposi-
tions) but preserved comprehension of spoken language. This type of speech has been
called “telegraphic,” as small words were often omitted in telegrams for economy.
In superior-division right-hemisphere MCA infarcts, patients frequently seem
unaware of their deficit (anosognosia) and may not admit that they are hemiplegic or
impaired in any way. Some patients are also “impersistent” (32,33), performing requested
tasks quickly but terminating them prematurely. They may also fail to detect “body
signals” repetitive speech intonations, and accents and so do not pick up the mood and
tone of verbal communications (33,34). These nonlinguistic aspects of speech are often
referred to as “prosody.”

Inferior Divison of the MCA Ischemia


Ischemia is almost entirely due to embolism to this arterial territory. In contrast to patients
with lesions of the superior division, these patients usually have no elementary motor or
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 69

sensory signs. They often have visual field defects, either hemianopia or upper-
quadrantanopia, affecting the contralateral visual field.
When the left hemisphere is involved, patients have a Wernicke-type aphasia.
Speech is fluent and syllables are well pronounced, but patients use wrong or nonexistent
words, and what is said makes little sense. Comprehension and repetition of spoken
language are poor. There may be relative sparing of written comprehension, with the
patient preferring that words be written. When the right hemisphere is affected, patients
draw and copy poorly and may have difficulty finding their way about or reading maps (33).
Behavioral abnormalities often accompany temporal-lobe infarctions. Patients with
Wernicke’s aphasia are often irascible, paranoid, and may become aggressive. Patients
with right temporal infarcts often have an agitated hyperactive state resembling delirium
tremens. The key findings in patients with right inferior MCA division infarcts are a left
visual-field defect, poor drawing and copying, and agitation and restlessness (35).

Anterior Cerebral Artery Ischemia


Intrinsic occlusive disease of the anterior cerebral artery (ACA) is unusual. Most ACA ter-
ritory infarcts are caused by embolism from the heart or the ipsilateral ICA. Most patients
with intrinsic disease of the ACA also have extensive ICA and MCA disease, often with
multiple infarcts. Some ACA-territory infarcts are due to occlusive disease of the ICA and
others are caused by vasospasm-related ischemia in patients with SAH due to anterior
communicating artery aneurysms.
The single most important clue to an ACA-territory infarct is the distribution of
motor weakness (36). Paralysis is usually greatest in the contralateral foot but is also
severe in the proximal thigh. Shoulder shrug is weak on the involved side, but the hand
and face are usually normal if the deep ACA territory is spared. Some patients with
anterior or large ACA territory infarcts have a hemiplegia. Cortical sensory loss is also
present in the weak limbs but is usually slight. A grasp refex is often present in the
hand contralateral to the infarct. When the infarct involves the left ACA territory and
the supplementary motor cortex, a transcortical motor and sensory aphasia often results.
These patients have limited spontaneous speech and may have poor comprehension but
retain the ability to repeat spoken words and phrases.
Occasionally, patients have the sudden development of bilateral ACA territory
infarction explained by hypoplasia or absence of the A1 segment of the ACA on one
side. In that circumstance, the territories of the ACA on both sides are supplied by one
ACA. Occlusion of the ICA or ACA supplying both sides leads to bilateral frontal-lobe
infarction. The resulting clinical picture is that of sudden apathy, abulia, and incontinence.
Patients may become relatively motionless and mute. When the paracentral lobule is
involved, there is weakness on one or both sides, predominantly affecting the lower
extremities.

Anterior Choroidal Artery Territory Ischemia


Many patients with anterior choroidal artery (AChA) territory infarcts are diabetic or
hypertensive. Most often, infarction in AChA territory is due to occlusion of the AChA.
Carotid artery occlusion, vasospasm in patients with carotid artery aneurysms, and
carotid artery-origin and cardiac-origin embolism occasionally cause AChA teritory
infarction, often coupled with MCA territory infarcts. The syndrome of the AChA
includes: (i) hemiparesis affecting face, arm, and leg, (ii) prominent hemisensory loss,
which is often temporary, (iii) homonymous hemianopia, (iv) when the lateral geniculate
body is infarcted, an unusual hemianopia occurs, with sparing of a beak-shaped tongue of
70 Caplan

vision within the center of the hemianopic visual field, and (v) absence of important
persistent neglect, aphasia, or other higher cortical-function abnormalities (37,38).
Hemiparesis is the most consistent finding. Dysarthria and hemisensory abnormal-
ities are less often present and usually do not persist. Hemianopia is the least common
sign. Some patients with bilateral AChA territory capsular infarcts have severe dysarthria
and may even become mute.

POSTERIOR CIRCULATION VERTEBRO-BASILAR


ARTERIES EMBOLISM

About one-fifth of emboli go into one of the vertebral arteries and enter the intracranial
posterior circulation arteries. The most common clinical patterns of symptoms occur in
patients with posterior cerebral arteries (PCA), cerebellar, and top of the basilar territory
infarctions (11 – 13).
Emboli most often go to the most distal portion of the vertebro-basilar system.
Emboli may block one of the intracranial vertebral arteries (ICVAs), causing infarction
in the posterior undersurface of the cerebellum in the territory of the posterior inferior
cerebellar artery (PICA) branch of the ICVA. As the basilar artery is wider at its
origin, having been formed by the confluence of the smaller ICVAs, emboli that pass
through the vertebral arteries do not usually become lodged until they reach the distal
end of the basilar artery and its branches. The resulting infarcts can be localized to:
(i) a unilateral PCA territory in the occipital and temporal lobes, (ii) bilateral PCA
territory, (iii) superior cerebellar artery (SCA) territory, (iv) midbrain and thalamic
territories supplied by penetrating branches arising from the rostral basilar artery, or
(v) combinations of (i) to (iv).

Posterior Cerebral Artery Territory Infarcts


The most common finding in patients with unilateral PCA territory infarction is a hemi-
anopia (39,40). Hemianopia is due to infarction of the striate visual cortex on the banks
of the calcarine fissure, a region supplied by the calcarine branch of the PCA, or is
explained by interruption of the geniculocalcarine tract as it courses toward the visual
cortex. If just the lower bank of the calcarine fissure is involved—the lingual gyrus—a
superior quadrant field defect results. An inferior quadrantanopia results if the lesion
affects the cuneus on the upper bank of the calcarine fissure.
When infarcts are restricted to the striate cortex and do not extend into adjacent par-
ietal lobe cortex, patients are fully aware of the visual defect. Usually described as a void,
a blackness, or limited vision to one side, patients usually recognize that they must give
extra attention to the hemianopic field. When given written material or pictures, patients
with hemianopia due to occipital lobe infarction are able to see and interpret stimuli nor-
mally, although it may take them a bit longer to explore the hemianopic visual field. In
patients with occipital lobe infarcts, physicians can reliably map out the visual fields by
confrontation. At times, the central or medial part of the field is spared—a so-called
macular sparing. Optokinetic nystagmus is normal. Although they accurately report
motion or the presence of objects in their hemianopic field, some patients cannot identify
the nature, location, or color of that object. When the full PCA territory is involved, visual
neglect can accompany the hemianopia.
Some patients with PCA territory embolic infarcts also have sensory symptoms on
the same side of the body as the visual field defect. This is explained by ischemia to the
major somatosensory relay nuclei, the ventral posteromedial and -lateral (VPM and VPL)
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 71

nuclei that are located in the ventrolateral portion of the thalamus. Occlusion of the prox-
imal PCA interupts flows to this portion of the thalamus supplied by the thalamogeniculate
branches (41). Ischemia to these nuclei or to the white matter tracts carrying fibers from
the thalamus to somatosensory cortex (postcentral gyrus and the Sensory 2 region in the
parietal operculum) produces changes in sensation, usually without paralysis. Patients
report paresthesias or numbness in the face, limbs, and the trunk. On examination, their
touch, pinprick, and position senses are reduced. The combination of hemisensory loss
with hemianopia without paralysis is virtually diagnostic of infarction in the PCA territory.
The occlusive lesion is within the PCA before the thalamogeniculate branches to the
lateral thalamus.
Rarely, occlusion of the proximal portion of the PCA can cause a hemiplegia
(13,42). Penetrating branches from the most proximal portion of the PCA penetrate into
the midbrain to supply the cerebral peduncle. Proximal PCA occlusions cause hemiplegia
because of midbrain peduncular infarction, accompanied by a hemisensory loss owing to
lateral thalamic infarction and hemianopia owing to occipital lobe infarction. The resultant
neurological deficit is not easily distinguished clinically from MCA and AChA territory
infarcts, but separation is made readily by CT and MRI results.
When the left PCA territory is infarcted, several additional findings may occur
(13,43 –45).

Alexia Without Agraphia


Infarction of the left occipital lobe and splenium of the corpus callosum are associated
with a remarkable clinical syndrome first described by Dejerine in 1892 (46). Because
the left visual cortex is infarcted, patients see with their right occipital lobe and their
left visual field. In order to name what they see, the information must be communicated
from the right occipital cortex to the language region in the left temporal and parietal
lobes. Infarction of the corpus callosum or adjacent white matter pathways interrupts com-
munication between the right occipital cerebral visual cortex and the left cerebral hemi-
sphere. Patients have difficulty naming what they see. The most obvious abnormality is
in reading. Although usually able to name individual letters or numbers, patients cannot
read words or phrases. Because the speech cortex is normal, they retain the ability to
speak, repeat speech, and write. They can spell words aloud and name words spelled to
them. Although they are able to write a paragraph, they often cannot read it back
moments later. Usually accompanying the dyslexia is a defect in naming colors. Patients
can match colors and shades, proving that their perception of colors is normal. They can
also describe the usual color of familiar objects and can even color correctly when given
an array of crayons. Nonetheless, when shown a colored object, they cannot name the
color (13,44,46 –48).

Anomic and Transcortical Sensory Aphasia


Some patients with left PCA-territory infarction have difficulty naming objects that they
recognize and can identify their use and others can repeat but not understand spoken
language (13,44,49).

Gerstmann’s Syndrome
PCA-territory infarction can undercut the angular gyrus, leading to a number of diverse
findings, usually lumped together as Gerstmann’s syndrome. These abnormalities
include difficulty in distinguishing right from left; difficulty in naming digits on their
own or on others’ hands; difficulty in drawing objects from memory; agraphia; and
72 Caplan

difficulty in calculating. In any single patient, all features may appear together or one or
more may occur in isolation (13).

Altered Memory
A defect in acquisition of new memories is common when both medial temporal lobes are
damaged and also occurs in lesions limited to the left temporal lobe (13,47,48,50,51). The
memory deficit in patients who have unilateral temporal lobe lesions is usually not perma-
nent but has lasted up to six months. Patients cannot recall what has happened recently,
and when given new information, they cannot recall it moments later. They often repeat
statements and questions spoken only a few minutes before.

Other Deficits
Some patients with left PCA-territory infarction have difficulty in understanding the nature
and use of objects presented visually. They can trace with their fingers and copy objects,
showing that visual perception is preserved. They can often name objects if the objects are
presented in their hand exploring by touch or when described verbally, despite not being
able to name or identify objects that they see. The explanation is similar to that of alexia
without agraphia. The patients cannot get the visual information to the speech cortex
(13,44,48).
Infarcts of the right PCA territory are often accompanied by prosopagnosia, diffi-
culty in recognizing familiar faces (13,44,52). At times, patients cannot recognize their
own spouses, their children, or even their own images in a mirror. Disorientation to
place and an inability to recall routes or to read or revisualize the location of places on
maps are also found in some in patients with right PCA-territory infarcts (13,44,53).
Patients with infarcts that involve the right occipital and temporal lobes also may have dif-
ficulty revisualizing a given object or a person. Dreams may also be devoid of visual
imagery. Neglect of visual objects located in the opposite side of space is much more
common after lesions of the right than of the left PCA territory.
When the PCA territory is infarcted bilaterally, the commonest findings are cortical
blindness, amnesia, and agitated delirium (13,44). Most often, bilateral PCA territory
infarction is due to embolism, with blockage of the distal basilar artery bifurcation. Cor-
tically blind patients cannot see or identify objects in either visual field but have preserved
pupillary light reflexes. Some patients with cortical blindness do not volunteer or admit
that they cannot see and seem to avoid barriers in their way. Amnesia due to bilateral
medial temporal-lobe infarction may be permanent and closely resembles Korsakoff’s
syndrome. Also, infarcting the hippocampus, fusiform, and lingual gyri, usually bilater-
ally, leads to an agitated hyperactive state that can be confused with delirium tremens
(13,54). When infarction is limited to the lower banks of the calcarine fissures bilaterally,
the major findings are prosopagnosia and defective color vision (13,44,55,56).

“Top-Of-The-Basilar” Ischemia
Occlusion of the rostral portion of the basilar artery can cause ischemia of the midbrain
and thalami as well as the temporal and occipital lobe cerebral hemispheral territories sup-
plied by the PCAs. In most patients, infarction is limited to either brainstem or hemi-
spheral structures. The major abnormalities associated with rostral brainstem infarction
relate to abnormalities of alertness, behavior, memory, and oculomotor and pupillary
functions (11– 13).
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 73

The most common abnormalities of eye position and movement involve vertical
gaze and convergence. Patients may be unable to look up and down. Voluntary eye
movements in the vertical plane are generated by simultaneous activation of the cerebral
hemispheral gaze centers. Vertical gaze pathways converge on the periaqueductal gray
region of the midbrain that contains a group of nerve cells referred to as the rostral
interstitial nucleus of the medial longitudinal fasciculus (RIMLF). In some patients,
who cannot look up or down on command, vertical eye movements can be obtained by
passive movement of the neck up and down or by simultaneous instillation of warm or
cold water into both ear canals. The pathways that control up and down gaze are not iden-
tical. Either up gaze or down gaze can be selectively involved, but in most patients, both
directions of vertical gaze are involved together. Occasionally, only one eye fails to move
up and/or down.
Asymetric or unilateral lesions in the midbrain tegmentum and posterior thalami can
cause ocular tilt reactions that are contraversive, that is, the contralateral eye and ear are
displaced below their opposite counterparts. The abnormalities include skew deviation,
ocular torsion, and abnormalities of the estimation of the visual vertical (57 –59). At
times, very small amplitude lightening-like movements occur spontaneously and on
attempted horizontal and vertical gaze.
Convergence abnormalities are also very common in patients with rostral midbrain
lesions. Usually, one or both eyes are hyperconverged, as if there was increased tone or
overactivity of structures that control the coordination of bilateral ocular adduction that
we call convergence. The hyperconvergence may be unilateral or bilateral, so that one
or both eyes may rest inward or down and inward at rest. When patients tried to gaze
up, their eyes may show adductor contractions causing convergence movements.
Asking patients to peer inward at the tip of their nose or at the examiner’s finger placed
at a near fixation site often leads to a further increase in the convergence and may
provoke some bilateral synchronous adductor movements of the eyes. Having the
patient watch an upwardly directed optokinetic striped tape also stimulates convergence
movements. Some call the bilateral convergence movements “retractory nystagmus,”
but the movements are not true nystagmus and do not usually cause significant retraction
of the globe, although observation of the eyes superficially gives that impression.
The increased tone and activity of adductor movements are probably responsible for
the so-called pseudosixth phenomenon (11,13,43). This term has been used to describe
failure of full abduction on lateral gaze in patients with upper brainstem lesions in the
absence of a lesion that could affect the sixth nerve whose nucleus and fibers are
located much lower in the brainstem in the pons. Pseudosixth palsy can be unilateral or
bilateral. A close inspection of the eye movements in the abducting eye shows that
there are often inward-directed small movements of the eye as it abducts. Often the
contralateral eye is hyperadducted. Covering the contralateral hyperadducted eye and
asking the patient to look further laterally sometimes enable further abduction excursion
of the open eye. There are two different phenomena that explain the failure of the ocular
abduction in this syndrome: (i) dysconjugate gaze with fixation by the hyperadducted
eye. When the patient looks laterally, they first fixate with the hyperadducted eye. This
fixation will stop any further lateral eye movement as the patient has already fixated on
the object with the adducted eye. Covering the hyperadducted eye then encourages fixation
with the abducting eye. And (ii) convergence vectors counter and neutralize the lateral
excursion of the eye. The sum of the laterally directed gaze vector and the inwardly
directed convergence vector is less than full abduction.
Retraction of the upper eyelid to widen the palpebral fissure has been called Collier’s
sign, when the abnormality is due to a rostral mesencephalic lesion near the level of the
74 Caplan

posterior commissure (60). In some patients, both lids are retracted but one side may have
normal lid position or ptosis.
Lesions in the rostral brainstem often affect the pupillary light reflex so that the
pupils react slowly and incompletely, or not at all to light. The pupils are often small at
rest in patients with diencephalic lesions and may be fixed and dilated if the lesions
involve the third nerve nuclei. A combination of diencephalic and midbrain lesions
cause midposition fixed pupils. In midbrain lesions, the pupil may become eccentric
(“corectopia”) (11,13,61) or assume an oval position (11,13,62). Eccentricity can be tran-
sient and fluctuate from minute to minute.
Abnormalities of alertness and behavior are common in patients with rostral brain-
stem infarcts. Lesions that include the reticular activating system in the rostral brainstem
most often produce hypersomnolence rather than coma. The reticular-activating system
courses through the tegmental regions on both sides of the sylvan aqueduct and the
banks of the third ventricle. This region is perfused by the thalamic subthalamic arteries
(also called the thalamoperforating arteries) and the paramedian mesencephalic arteries
that branch from the apex of the basilar artery and the initial portion of the basilar-
communicating artery (mesencephalic artery). Butterfly-shaped bilateral rostral midbrain
periaqueductal lesions as shown in Fig. 28 in Chapter 3 caused by the top-of-the-basilar
artery embolism can cause both prolonged hypersomnolence and third nerve palsies
(11,13,63,64). Apathy and inertia are also commonly found (65). Some patients show
very little spontaneity and activity.
Abnormal reports and hallucinations probably relate to the altered sleep – wake
dreaming cycle present in patients with rostral basilar artery territory infarction (11,13).
Reports often consist of replies to queries that have no relation to reality. The patients
may mislocate themselves, giving the names of distant geographical locations, and in
the personal time dimension, saying that they were presently performing activities that
they only had done in their childhood, adolescence, or much earlier in their adult life.
Some patients act as if they are performing an activity, for example, talking on the tele-
phone when there is no phone nearby. These reports and behaviors probably represent
what they were daydreaming about at the time. Some may recall nocturnal dreaming.
The reticular activating system and the neural substrates that control the sleep –wake
cycle and dreaming are all intimately related. Clouding of the distinction between
dreams and reality may explain some of the unusual reports and behaviors in patients
with rostral brainstem infarction.
So-called peduncular hallucinations have long been recognized and described in
patients with rostral brainstem lesions (11,13). The term pedonculaire was used by the
French to refer to the general region of the midbrain and not just the cerebral peduncle.
Hallucinations can also occur in patients with thalamic lesions. The hallucinations are
predominantly visual but there may be some minor tactile and auditory components.
The visual hallucinations are often quite vivid and contain multiple colors, objects, and
scenes. The hallucinations occur predominantly after sundown and are sometimes quite
frightening to the patient.
Some patients with rostral brainstem infarcts that include the thalamus have promi-
nent and sometimes persistent memory deficits. The amnesia involves both anterograde
and retrograde memory and usually includes both verbal and nonverbal memory.
Amnesia has developed in patients with infarction in the antero-lateral thalamic territory
supplied by the polar (tubero-thalamic) artery as well as in the territory of the thalamic-
subthalamic artery (13,36,66,67). Patients with left thalamic infarcts may have more dif-
ficulty with memory for language-related activities, whereas patients with right thalamic
lesions may have more difficulty with visual-spatial memory tasks. In patients with top-of-
the-basilar embolism, both territories in the medial thalamus are often infarcted. Patients
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 75

with polar territory infarcts show more decrease in spontaneity and abulia. They have dif-
ficulty generating lists of common objects, for example, colors, items of clothing, fruits,
vegetables, cities in their state, etc. Patients with infarction of the thalamic-subthalamic
artery territory, especially when bilateral, have severe deficits in anterograde memory
formation and some retrograde amnesia.
Sensory and motor abnormalities are usually absent in patients with top-of-the-
basilar territory infarction unless the proximal PCAs are also occluded. Movement dis-
orders, especially, hemiballism have been described in some patients with small infarcts
and hemorrhages involving the subthalamic nuclei, but hemiballism is extremely rare in
patients with well documented top-of-the-basilar territory infarcts.

Cerebellar Infarcts
Large cerebellar infarcts are predominantly caused by embolism. Emboli often reach the
SCA, which lies very near the top-of-the-basilar artery. These emboli arise from the heart,
aorta, or the extracranial or ICVAs. Emboli from the heart, aorta, and vertebral artery in
the neck often block the intracranial vertebral artery leading to an infarct in the territory of
the PICA, which is the largest branch of the intracranial vertebral artery on each side.
Occasional patients have both PICA and SCA territory cerebellar infarcts, an embolus
having rested first at the level of the intracranial vertebral artery, causing a PICA territory
infarct, and then traveled distally to the SCA. Alternatively, a thrombus or occlusive lesion
in the intracranial vertebral artery could have caused the PICA territory infarct and then
been the donor source of an SCA embolus.

Superior Cerebellar Artery Territory Infarction


Isolated SCA territory infarcts are not common; most often SCA territory infarcts are
accompanied by other infarcts in regions supplied by other arteries that arise at the
rostral end of the basilar artery. The symptoms and signs in patients with partial SCA ter-
ritory infarcts are less severe and disabling than those in other cerebellar artery territories
and can easily be overlooked clinically.
The classic SCA syndrome is said to consist of: ipsilateral limb ataxia; ipsilateral
Horner’s syndrome; contralateral loss of pain and temperature sensibility of the face,
arm, leg, and trunk; contralateral fourth nerve palsy (13,68 –70). Abnormal spontaneous
involuntary movements of the limbs on the ipsilateral side also occur. The classic syn-
drome is present when the pontine and midbrain tegmentum and superior cerebellar
surface are both infarcted. The full syndrome is rare.
Some patients with SCA territory cerebellar infarcts have relatively minor symp-
toms of sudden onset with rapid improvement. Slight dizziness, vomiting, ipsilateral
limb dysmetria, gait ataxia, and dysarthria are common. Vertigo is usually not promi-
nent in patients with isolated SCA territory infarcts. Limb incoordination, limb ataxia,
intention tremor, and dysarthria are more common in SCA territory cerebellar infarcts
than in PICA territory cerebellar infarcts. The lateral cerebellar hemispheres are related
predominantly to limb movements under voluntary control, whereas the vermis relates
more to posture, stance, trunk movements, and gait. The dentate nucleus is the major
outflow tract of the cerebellum for modulating voluntary limb movements. The dentate
nucleus and surrounding cerebellar white matter are supplied by SCA branches. SCA
territory infarcts may involve the superior vermis and a sizable portion of the hemi-
sphere, in addition to the dentate nuclei explaining the frequent occurrence of both
limb and gait ataxia in patients with SCA territory infarcts.
76 Caplan

SCA territory infarcts can involve the entire SCA territory, including the rostral
pontine and midbrain tegmentum and the SCA supplied cerebellum, or can involve the
full cerebellar territory but spare the brain stem or be limited to territory supplied by
the medial (mSCA) or lateral (lSCA) branches of the SCA. The bilateral SCA territories
may be involved. SCA territory infarcts are often accompanied by PCA and midbrain and
thalamic infarcts in territories supplied by other branches of the rostral basilar artery.
Branch infarcts are much more common than full SCA territory infarcts (69 –72).
The clinical findings depend very much on whether the brainstem territory of the
SCA is involved and whether infarction is limited to SCA teritory or also includes struc-
tures supplied by other rostral basilar artery branches. Large, full SCA cerebellar infarcts
can produce a pseudotumoral syndrome but do so less often than full PICA territory
infarcts. Stupor and symptoms of hydrocephalus are only rarely found in patients with
infarcts limited to the SCA cerebellar territory.
Branch infarcts have been less often analyzed in the SCA territory, compared to
PICA territory. Isolated lSCA territory infarcts are located predominantly in the rostral
anterior cerebellum and sometimes include the dorsolateral pontine tegmentum. Nearly
all patients have prominent limb ataxia, varying from slight clumsiness to severe incoor-
dination and dysmetria (68). Dysarthria is also a frequent and prominent finding. Cerebel-
lar gait ataxia and severe veering and pulling of the trunk to the ipsilateral side, so-called
axial lateropulsion, also occur. Axial lateropulsion can be the only main finding in patients
with lSCA territory infarction. Edema and mass effect do not occur, and recovery is
usually excellent.
Infarcts limited to the mSCA territory are less frequent than lSCA territory infarc-
tion. One patient with an isolated paravermal infarct in the territory of the mSCA had
atrial fibrillation and presented with the acute onset of severe isolated dysarthria (68).

Cerebellar Infarction in PICA Distribution


PICA cerebellar infarcts can be divided into: (i) infarction in the territory of the mPICA,
affecting mostly the inferior cerebellar vermis, (ii) infarction limited to the lPICA, affect-
ing mostly the lateral surface of the posterior inferior cerebellar hemisphere, and (iii) full
PICA territory infarcts, involving both the mPICA and lPICA territories (13,69 –73).
Full PICA territory infarcts are often accompanied by edema formation and mass
effect— so-called pseudotumoral cerebellar infarcts. About one fifth of PICA territory cer-
ebellar infarcts are accompanied by infarction in the dorsal or dorsolateral medulla (13).
The combination of lateral medullary and PICA territory cerebellar infarction occurs when
the ICVA is occluded and blocks the orifice of both PICA, and the lateral medullary pen-
etrators. PICA usually originates more caudally, but in some patients, these branches arise
near each other. Most often, mPICA territory infarcts are accompanied by dorsal medul-
lary infarcts as the mPICA branch has some supply to the dorsal medulla. Infarcts in the
cerebellum limited to lPICA distribution are rarely accompanied by medullary infarction.
Infarcts limited to the medial vermis in the territory of mPICA usually cause a
vertiginous labyrithian syndrome that closely mimics a peripheral vestibulopathy
(13, 69 –73). Severe vertigo with prominent nystagmus is the major finding. Some patients
also have truncal lateropulsion characterized by feelings of magnetic pulling of the trunk
to the ipsilateral side. Ocular lateropulsion may also be present. Lateral cerebellar hemi-
sphere PICA territory infarcts are usually characterized by minor degrees of dizziness and
gait incoordination with veering to the side of the lesion. Minor limb hypotonia
and incoordination are found. A common syndrome is acute unsteadiness with ataxia
Recipient Artery: Clinical Symptoms and Signs of Brain Ischemia 77

but without vertigo or dysarthria. Body sway towards the side of the lesion, ipsilateral limb
ataxia, and abnormal rapid alternating movements are also common.
When the full PICA cerebellar territory is involved, headache is usually present in
the occiput or high neck on the ipsilateral side. The head may also be tilted with the
occiput lying more ipsilaterally. Vomiting, gait ataxia, truncal lateropulsion, and limb
incoordination are other common findings. The truncal dysfunction is similar to that
found in the lateral medullary syndrome; the body is often tilted or pulled ipsilaterally
upon sitting or standing. The limb incoordination consists mostly of hypotonia rather
than a rhythmic intention tremor as would be found in the involvement of the dentate
nucleus or its superior cerebellar peduncle efferent pathways.
The syndrome of pseudotumoral cerebellar infarction is most often found in patients
with large full PICA territory infarcts. After the first day or so, patients develop increased
headache, vomiting, and decreased consciousness. At first, they become drowsy and later
stuporous. Bilateral Babinski signs are early signs of cerebellar mass effect. Most charac-
teristic of large cerebellar space taking infarcts are the oculomotor abnormalities, which
develop because of brainstem compression. Most common are a conjugate gaze paresis
to the side of the lesion or a paresis of abduction limited to the ipsilateral eye. Bilateral
sixth nerve paresis may occur. Later bilateral horizontal gaze palsies may develop,
often accompanied by ocular bobbing. These signs are due to compression of the
pontine tegmentum by the swollen cerebellar infarct. Stupor is followed by deep coma
when the oculomotor abnormalities become bilateral. Once coma has intervened, the
mortality rate is extremely high. Neuroimaging tests help confirm the compression of
the posterior fossa cisterns and the fourth ventricle and the development of hydrocephalus.

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5
The Eye as the Recipient Artery
Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Readers might ask why include the eye in a monograph about brain embolism. Many
reasons come to mind. The eye is really an outpouching from the brain, and the optic
nerve is really a brain tract. The eye is fed, like the brain, by the carotid arteries. The
eye is delivered and uses more blood than is accounted for by its size and many emboli
headed cranially wind up in the arteries that supply the eye. The human brain is dominated
by visual functions—looking, seeing, and revisualizing things, scenes, and people in our
mind’s eye. The visual loss related to eye ischemia is quite different than that related to
brain ischemia. The two syndromes are different, and it is important that they are separ-
ated. Clinicians should become aware of the signs and symptoms related to embolism
to the eye.

ANATOMY OF THE ARTERIES THAT SUPPLY THE EYE

The eyes are supplied by the ophthalmic artery branches of the internal carotid arteries
(ICAs). The ophthalmic arteries originate just after the ICAs penetrate the dura to enter
the cranial cavity; occasionally, they arise from the ICA within the cavernous sinus
before dural penetration. Rarely, the ophthalmic artery arises from the middle meningeal
branch of the external carotid artery or the middle cerebral or posterior communicating
artery branches of the ICA.
After a very short course within the cranial cavity (2 – 7 mm in length), the ophthal-
mic arteries again penetrate through the dura and enter the optic canals where the arteries
run alongside the optic nerves. Just before the ophthalmic arteries cross the optic nerves,
the central retinal arteries branch out. The central retinal arteries penetrate the optic
nerve, enter the globe, and then divide into superior and inferior branches that supply
the inner two-thirds of the retina (1,2).
Whereas the central retinal arteries supply the major blood flow to the retina,
the posterior ciliary arteries provide the major blood supply to the optic nerves. Two or
three short posterior ciliary arteries originate from the ophthalmic arteries when the
latter cross the optic nerves about 15– 20 mm behind the globes. One or two long posterior
ciliary arteries originate from the proximal ophthalmic artery to supply the inferior portion
81
82 Caplan

of the choroidal supply, whereas the superior ciliary arteries arise more distally from the
ophthalmic artery and supply the superior portion of the choroidal supply (3). The short
posterior ciliary artery branches penetrate the sclera of the eye where the dural sheath
of the optic nerve joins the globe. The major portions of the anterior optic nerve
receive their blood supply from these ciliary arteries. One short posterior ciliary artery
supplies the superior portion of the optic nerve, and another short ciliary artery supplies
the inferior portion of the nerve (1 – 4). This anatomical supply explains the altitudinal
nature of visual field defects related to optic nerve infarction. The posterior ciliary arteries
also supply the choroid, a portion of the retina, and structures within the anterior segment
of the eye.
The arterial supply of the eye is shown in Figure 1.

Figure 1 Blood vessels of the orbit. Source: From Ref. 1.


The Eye as the Recipient Artery 83

CLINICAL SYMPTOMS AND SIGNS OF EYE ISCHEMIA

There are four major syndromes of acute eye ischemia. Embolism to the eye most often
causes temporary loss of vision. This syndrome has been variously referred to as transient
monocular blindness (TMB), transient monocular visual loss (TMVL), and amaurosis
fugax (AF). Because the visual symptoms are often partial and do not qualify as blindness,
and because AF is used variously to incorporate bilateral visual loss and loss of vision
related to brain lesions, I prefer to use TMVL. Persistent loss of vision in one eye is
usually caused by a central retinal artery occlusion (CRAO). When an embolus blocks
a branch of a retinal artery, the term central retinal artery branch occlusions (CRABO)
is most often used.

Transient Monocular Visual Loss


The clinical importance of monocular visual loss was described in detail by Miller Fisher
(5 –7), who emphasized that transient visual loss in one eye often provided a clue to the
presence of severe occlusive disease of the ipsilateral ICA in the neck, especially if
patients with attacks of monocular visual loss also had transient attacks of dysfunction
of the contralateral limbs. Fisher also described and illustrated the fundoscopic findings
in a patient that he observed during an attack of TMVL (8).
The visual loss is usually described by the patient as a graying, blurring, darkening,
fogging, obscuring, or dimming of vision in one eye. It can involve the entire field of
vision in that eye, or an altitudinal, or lateral, or central sector of vision can be obscured
during the attack. Some patients describe a shade, blind, or curtain that descends quickly
over the eye. The arteries that supply the inferior retina are more tortuous, have smaller
diameters, and take a longer course, so that the inferior segments are more vulnerable
to ischemia—explaining why the shade usually descends rather than ascends (3).
Occasionally, the curtain ascends or is drawn laterally across the eye. Sometimes, the
curtain creates a uniform line across the vision, and in other patients there is a step in
the middle. At times, patients with retinal ischemia describe positive phenomena, includ-
ing scintillations: bright, often colored, visual displays, and streaks, lines, and shimmers
(9). Miller Fisher’s original patient, who was examined during an attack of TMVL,
“likened the failure of vision to the snowing up of a television screen . . . colorless snow-
flakes were bright, shining, and jumping. As the cloud took form he could still see through
it, but as the cloud became more dense, a total blackout occurred” (8).
Attacks most often last a few minutes but can range from seconds to hours. In some
patients, the attacks are repeated and can occur from many a day to widely spaced episodes
during a period of months.
Pain in and around the eye is rare in patients with TMVL arising from embolism
but is more common in patients with migraine-related TMVL and when carotid dissection
provided the donor source of embolism. Some patients have ipsilateral facial paresthesias
accompanying the visual loss (10). A warm flush, tingling, and a sensation as if the eye
were twitching can be reported to involve the eye, the eyelid, the periorbital region, or
the cheek. The paresthesias may precede, coincide, or follow the visual loss. Some patients
who have attacks of TMVL also have separate attacks of weakness of the contralateral
limbs or other signs of ischemia affecting the cerebral hemisphere on the same side as
the affected eye (2,11).
The most important and common ophthalmoscopic finding in patients with TMVL
is the presence of embolic particles within retinal arteries (12). The most frequently
detected particles are cholesterol crystals, often called Hollenhorst plaques after the
84 Caplan

Figure 2 A photograph of the ocular fundus in a patient with two visible “Hollenhorst plaques.”
The arrows point to the crystals at arterial bifurcations.

ophthalmologist who first described them (13,14) (Figs. 2 and 3). Hollenhorst recognized
that patients with these plaques often had carotid artery disease (13,14). These cholesterol
crystal emboli are white but may appear bright, often glinting, and yellow-orange. They
are usually small (10 –250 mm in diameter), most often lodge at bifurcations of retinal

Figure 3 An ocular fundus photograph. The arrow points to a large cholesterol crystal blocking a
central retinal artery branch. A white fluffy retinal infarct can be seen in the retina beyond the branch.
The Eye as the Recipient Artery 85

Figure 4 An ocular fundus photograph showing a long partially fragmented white platelet-fibrin
thrombus (arrows).

arteries, and usually do not block blood flow. They can move or disappear rapidly but may
injure the vascular wall leading to sheathing of the artery. Compressing the orbit may
cause crystals to move, flip over, or “flash,” making them more visible with the ophthal-
moscope. Fluorescein angiograms, even when crystals are no longer seen through an oph-
thalmoscope, may show hyperfluorescent crystals or leakage of dye in regions of arteries
damaged by the crystal emboli.
Platelet-fibrin emboli (“white clots”), in contrast to cholesterol crystal emboli, form
longer gray-white columns that gradually progress through small retinal arteries with
distal fragments breaking off as the column moves (Fig. 4). Fisher described and drew
these white clots as they traversed the retina in a patient with episodes of TMVL (8).
Sometimes, the pale plugs are made of fibrin, especially following heart surgery and in
those patients with cardiac donor sources of emboli (15).
The third type of embolic material consists of calcium fragments, which appear
chalky white and usually remain in one location obstructing blood flow. These emboli
do not scintillate and are characteristically somewhat wider than the blood stream (15).
These particles can be dislodged from the aorta and cardiac valves during surgery or
spontaneously embolize from regions of mitral annulus and valvular calcifications.
Talc, cornstarch, and other foreign body emboli have been described in retinal arteries
of patients who inject intravenously mashed up pills intended for oral use after dissolving
the tablets in water (16 – 18).

Central Retinal Artery Occlusion


Most patients with CRAO develop persistent painless blindness in one eye. Von Graefe is
usually credited with the first description of this condition. He noted attenuated arteries
and veins, a pale optic disc, clouding of the retina, and a cherry red spot in the macula
(19). In blind patients, the pupil fails to react to light. At times, perception of hand
86 Caplan

Figure 5 An ocular fundus photograph showing a central retinal artery occlusion. The veins are
visible, but no retinal arteries are seen. The retina is beginning to become edematous and white
regions can be seen along the veins.

movements and light can be retained in portions of the visual field in that eye because the
posterior ciliary arterial system supplies a portion of the retina. If the ophthalmoscopic
examination is performed soon after onset of blindness, the most striking findings relate
to slowing of the retinal circulation (20). Segmentation of the blood column with slow
streaming of flow is seen in the veins. The segmentation has been referred to as box
car – like, resembling the cars that are present on the end of trains that carry cargo. The
blood in the arteries appears dark, and a few areas show segmentation; the segmentation
appears as clear areas alternating with regions where the cells seem clumped together. The
segmentation is always more obvious in the veins than in the retinal arteries. Sometimes,
when the changes in the vessels are not obvious, gentle pressure on the globe during oph-
thalmoscopy can produce segmentation of the blood column, indicating a very low central
retinal artery pressure. If CRAO lasts more than an hour, the retina becomes infarcted.
Cloudy swelling of the ganglion cells causes them to become less transparent, and the
retina develops a milky-white appearance, especially near the macula (20). The cherry
red appearance of the macula is related to accentuation of the normal fovea through
which the choroid coat appears red. Later optic atrophy is evident, and the optic disc
appears chalk white. Figure 5 shows the fundus oculi in a patient with a CRAO.

Central Retinal Artery Branch Occlusions


In patients with central retinal artery branch occlusions (CRABO), branches of the central
retinal artery are occluded. The visual loss is focal and corresponds to the portion of the
retina that is ischemic. The visual defects are usually lateral or altitudinal or form a
scotoma. The ischemic portion of the retina often has a ground glass – like appearance
due to ischemic edema (1). Later, well-delineated retinal infarcts and focal cotton-wool
spots called cytoid bodies that represent retinal microinfarcts are often seen.
The Eye as the Recipient Artery 87

Blockage of the retinal artery branch is often visible with the ophthalmoscope,
especially if ophthalmoscopy is performed relatively soon after the onset of visual loss.
Diagnosis is facilitated with fluorescein angiography that shows a lack of perfusion of
the fluorescein-containing blood in the region of retinal ischemia. The point of occlusion
can often be clarified using fluorescein angiography (21).

Anterior Ischemic Optic Neuropathy


Patients with anterior ischemic optic neuropathy (AION) usually develop painless mon-
ocular visual loss. Most often, the visual loss is noted on awakening in the morning,
and it usually does not worsen later. The severity of the visual loss varies but is usually
not complete. The visual loss is often altitudinal. AION is caused by ischemia to the
optic nerve, usually in the anterior portion of the nerve. The major blood supply of the
optic nerve comes from the posterior ciliary arteries. Ophthalmoscopy soon after
symptom onset usually shows edema of the optic disc, and, at times, small splinter hemor-
rhages are seen at the margins of the optic disc (22). Optic atrophy develops later. When
the ischemia is in the posterior portion of the optic nerve, the fundus can look normal.
Unlike the other syndromes described earlier (TMVL, CRAO, and CRABO), which are
caused predominantly by embolism, AION is thought to be due most often to hypoperfu-
sion of the optic nerve head. Occasionally, infarction of the optic nerve can accompany
ipsilateral cerebral hemisphere infarction. When this occurs, the usual cause is occlusion
of the ICA, with thrombus extension to the carotid siphon blocking flow in the ophthalmic
artery and its branches (23). Carotid dissection can also cause blockage of ophthalmic
artery flow, with resultant hemiparesis and ipsilateral visual loss (24).

METHODS OF INVESTIGATING THE EYE AS A


RECIPIENT SITE OF EMBOLISM

Careful and thorough ophthalmoscopy using either a direct or an indirect ophthalmoscope


is the most important diagnostic maneuver. Often the pupil must be dilated to obtain an
optimal view of the fundus oculi. Embolic particles seen within the eye are tangible
evidence of embolism. Emboli are seen in 11–40% of patients with CRAO and 60 – 70%
of patients with CRABO (1,25,26). In population-based studies, when ophthalmoscopy
is performed by experienced observers, retinal emboli are found in about 1.4% of patients
(27). About one-fifth of patients with acute strokes in the carotid artery territory have
visible emboli in the ipsilateral eye; these are predominantly cholesterol crystal emboli
(27). Often, fluorescein angiography can clarify the presence, location, and nature of
the retinal artery block.
Several techniques have been used in the past to measure retinal artery pressure and
blood flow, but these instrumentations are seldom used clinically today. Ophthalmodyna-
mometry (ODM) is performed using a handheld instrument that looks much like the gauge
that measures pressure in car tires. Pressure is applied to the globe during ophthalmoscopy.
The pressure used to provoke pulsations in retinal arteries is equal to the diastolic pressure
in the central retinal artery (CRA); obliteration of arterial flow occurs at systolic pressure.
Oculoplethysmography (OPG) measures the ocular pulse that can be used to calculate the
systolic pressure of the retinal artery. It is measured by using air-filled cups that are applied
laterally to the sclerae of both eyes. A partial vacuum is applied to the cups to raise
88 Caplan

intraocular pressure. The vacuum is slowly released until a measurable pulse amplitude
appears (1,28).
Transcranial Doppler (TCD) ultrasound has virtually replaced ODM and OPG. TCD
probes placed over the orbit can measure blood flow velocities in the intracranial ICA and
ophthalmic arteries. TCD also allows emboli monitoring. TCD will be discussed
thoroughly in chapter 7.
Color Doppler imaging of the orbit now allows visualization of the ophthalmic,
central retinal, and posterior ciliary arteries. The corresponding veins can also be
imaged. The blood-flow velocities in the arteries supplying the eye can be quantified
using spectral analysis, and a B-mode image is produced that can show occlusion of the
ophthalmic and/or CRA and calcific and other emboli within the major arteries (1,29 – 32).
Techniques used to study the arteries within the cranium (computed tomograph
angiography, magnetic resonance angiography, digital subtraction dye angiography) can
also be used to study the ophthalmic artery but the resolution is not good and branches
are not shown very well.

DIFFERENTIAL DIAGNOSIS OF RETINAL EMBOLISM

Intrinsic disease of the ophthalmic artery can cause TMVL as well as retinal and optic
nerve infarction with persistent monocular visual loss. Atheromatous disease of the
ophthalmic and/or CRA is rare but occasionally occurs in diabetics (33). Severe occlusive
disease of the ICA in the siphon proximal to or at the origin of the ophthalmic artery can
also cause hemodynamic-related monocular visual loss. Sometimes the cause is an aneur-
ysm that harbors a clot. The aneurysm may lie within the cavernous sinus and cause cranial
nerve signs. Most patients with carotid artery siphon stenosis and those with aneurysms
have a high frequency of hypertension.
Giant cell (temporal) arteritis is probably the most frequent cause of ophthalmic
artery disease. Persistent visual loss in one eye followed by visual loss in the other eye
is the commonest clinical pattern in patients with temporal arteritis. TMVL is much
less common.
Occasionally, patients with migraine have attacks of monocular visual loss. These
are usually described as greying or blurring of vision; sometimes a grey or white
curtain covers vision. Descriptions of the visual loss are similar to those used by patients
with carotid artery occlusive disease and eye embolism and are quite distinct from the
bright scintillations of occipital migraine (34 –36). Some have had aching or discomfort
in the eye during attacks. Migrainous vasospastic TMB is most common in relatively
young women but also occurs in men. In some migraine patients, attacks are frequent
and occur more than once a day. Ophthalmoscopy in patients with vasospastic TMVL
usually shows constricted retinal arteries and rouleaux formation in veins in relation to
slowed blood flow. The arteries may appear threadlike, and the optic disc often appears
pale (34 – 36). Hypercalcemia caused by hyperparathyroidism and ingestion of large
amounts of licorice can provoke retinal artery vasospasm and cause transient visual
dysfunction in one or both eyes (37).
Conditions that increase intracranial or intraocular pressure can also cause TMVL.
Patients with pseudotumor cerebri (benign intracranial hypertension) have transient
visual obscurations (38). These are often monocular but can be binocular. The episodes
of visual loss are usually very brief and often are precipitated by coughing, straining, or
other maneuvers that elevate intracranial pressure. The mechanism is presumed to be
insufficient arterial perfusion to surmount the increased intracranial pressure that causes
The Eye as the Recipient Artery 89

increased pressure in retinal veins. The same mechanism probably occurs in patients
with glaucoma and cavernous sinus arteriovenous fistulas.
Systemic disorders that cause hypercoagulability and hyperviscosity, such as poly-
cythemia vera, thrombocytosis, and Waldenstrom’s macroglobulinemia, can cause
sluggish retinal artery blood flow that can give symptomatic transient visual loss.
Detachment of the retina presents rarely as transient loss of vision. Intrinsic disease
of arteries within the eye, including preretinal arterial loops, can cause repeated episodes
of TMVL. These loops arise from the CRA and are often kinked, causing flow to become
temporarily or persistently diminished within the loop, causing transient loss of a portion
of monocular vision (39).

USUAL SOURCES OF RETINAL EMBOLISM

The most important cause of TMVL, CRAO, and CRABO is occlusive disease of the ICA
in the neck. Patients with severe internal carotid occlusive disease with ,1 mm residual
lumen (90% stenosis) often have relatively frequent brief attacks of dimming of vision in
the entire visual field of the eye. Patients with plaque disease that causes less severe
stenosis more often have isolated, infrequent episodes of loss of vision in a part of the
visual field correlated with emboli to branch retinal arteries. When the ICA becomes
completely occluded, patients may show periodic dimming of vision when exposed to
bright light. Occasionally, patients with bilateral internal carotid occlusive disease have
had bilateral dimming of vision on bright light exposure. Some patients who have had
attacks of TMVL when their ICAs were severely stenotic stop having TMVL when the
ICAs fully occlude. Monitoring of the ipsilateral middle cerebral artery using TCD ultra-
sound in patients with TMVL related to severe carotid stenosis shows many high intensity
transient signals (HITS) that represent microemboli emanating from carotid plaques
(40 –42). After the ICA occludes, microemboli diminish and soon are no longer detectable
by TCD. These same patients with carotid artery occlusion may have a recurrence of their
TMVL when the ipsilateral external carotid artery, which provides the main collateral
artery supply of the eye, becomes stenotic or occluded.
Wijman and colleagues used TCD-monitoring to study 45 patients. Thirty-seven had
TMVL, including seven who also had episodes of cerebral ischemia, and seven had retinal
infarcts (CRA or CRABO) (42). Microembolic signals (MES) were detected in 40% of the
patients with retinal ischemia and were more commonly detected when monitoring was
done soon after symptoms manifested. The frequency of signals correlated with ICA
disease in this study, in which cardiac origin embolic sources were excluded. Severe
ICA stenosis or occlusion was present in 33 of 45 (73%) patients (42).
Most patients with retinal strokes (CRAO and CRABO) have embolic occlusions
emanating from the ICA (1,43). Branch retinal artery occlusions are more often attribu-
table to severe ICA disease than CRAOs (1,25,43 –47). In a series of patients with
CRAO and CRABO, 29 of 34 patients (85%) had abnormal ICAs on angiography;
among these 12 had ICA occlusion or severe stenosis, and 17 had plaques, ulcers, or mod-
erate stenosis (43). The aorta can also be an important source of cholesterol crystal
embolism.
Cardiac conditions that promote systemic and brain embolism also cause retinal
infarcts and TMVL. Cardiac-origin embolic sources were found in 29 of 103 (28%)
patients with retinal artery occlusions in one series (26). In this same series, among 18
patients who had angiography, 12 had ICA stenosis or irregularity (26). Repeated
attacks of TMVL are very rarely attributable to cardiac-origin embolism.
90 Caplan

TREATMENT

Treatment depends very much on the cause. Ocular massage, carbon dioxide inhalation,
acetazolamide, inhaled isuprel, and sublingual nitroglycerine all have been advocated
with variable success. In some patients with ophthalmic artery occlusion, intra-arterial
thrombolysis has been used.

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6
Imaging Evaluation: Recipient Artery Sites
Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Brain imaging and vascular investigations play a very important role in the diagnosis and
management of patients suspected of having brain embolism. This chapter concentrates on
the recipient artery and its brain supply and covers donor arterial sites as well. The key
questions that physicians should ask are enumerated in Table 1. The essential issues are
whether or not the patient has a brain infarct, and if so, where, how large, and whether
or not intracranial arteries are occluded by emboli. The advent of thrombolytic
treatment and the potential for mechanical opening of occluded arteries have made it
very important to obtain accurate diagnoses quickly and safely in patients seen soon
after the onset of symptom.

BRAIN NEUROIMAGING

Computed tomography (CT) and magnetic resonance imaging (MRI) are indispensable in
the diagnosis of brain embolism. The first question to be answered is: is there a lesion
caused by cerebrovascular disease present, and if so, is the lesion an infarct or a hemor-
rhage? Brain neuroimaging tests are now able to answer this query very well. CT and
MRI are able to separate brain infarcts from hemorrhages. CT scans have been tradition-
ally used to exclude hemorrhage as hematomas are nearly always visible immediately after
the onset of stroke and are easily seen as hyperdense, well-circumscribed lesions on the
CT. In rare instances, CT scans fail to show hemorrhages, especially, if the hemorrhagic
lesions are near the bony surfaces, for example in the orbital frontal region, or if the patient
is severely anemic (1 – 3). T2-weighted (also called susceptibility-weighted images) MRI
scans also can detect hemorrhages early after the onset of symptom (4 – 7). Figure 1 shows
CT and T2-weighted MRI scans on the same patient with a putaminal hemorrhage. MRI
can also show tiny old hemorrhages, usually called “micro-bleeds,” that represent a risk
for treatment with thrombolytic and anticoagulant drugs (8 –11). Subarachnoid hemor-
rhages can also be detected on MRI scans if proper techniques are performed (6,12).
Recent studies have shown that these MRI studies can show hemorrhages even earlier
and better than CT scans (13,14).
CT scans are not good at detecting very early acute brain infarcts, whereas MRI is
more sensitive in detecting early infarction, especially if diffusion-weighted scans are
93
94 Caplan

Table 1 Questions to Be Answered by Imaging

1. Is there a nonischemic process present in the brain, such as a brain


hemorrhage, brain tumor, subdural hematoma, etc.?
2. Is a brain infarct present? If so, where is it? How large is it? What is the
arterial supply of the infarcted brain region?
3. Are there other older infarcts visible? If so, are they in the same vascular
territory or in other supply zones?
4. Is the intracranial artery supplying the infarcted zone patent or occluded?
Are other intracranial arteries occluded?
5. Are there brain regions that are underperfused and ischemic but not yet
infarcted?

performed. Diffusion-weighted (DWI) MRI scans show regions of increased brain water
content that usually represent regions that will become infarcted. MRI is clearly superior
to CT in detecting and showing infarcts in the cerebellum, brainstem, and inferior tem-
poral lobes. When infarcts are present, their location, size, and multiplicity can help
predict the mechanism of infarction (15). As described in chapter 3, infarcts caused by
embolism are most likely to be cortical, or subcortical and cortical (Fig. 9 of chap. 3).
Embolic infarcts are often confined to a pial arterial branch territory or to the upper or
lower division of one middle cerebral artery (MCA). Infarcts that involve the territories
of the superior cerebellar, posterior cerebral, and posterior inferior cerebellar arteries
are most often embolic—either cardiogenic or intra-arterial, especially if the infarcts
are large (15 –17). Infarcts that are supplied by the arteries emanating from the distal
basilar artery (“top-of-the-basilar”) are also predominantly embolic (15 – 20). Large
infarcts (as shown in Figs. 10 and 11 of chap. 3) are most often caused by embolism,
and cardiac-origin emboli usually produce larger infarcts than artery-to-artery emboli.
Infarcts that are initially hemorrhagic or later become hemorrhagic are most often attribu-
table to embolism. Multiple superficial infarcts, especially in different arterial territories,
are also usually explained by multiple emboli of cardiac or aortic origin. The presence of
multiple infarcts in one vascular territory, such as the right internal carotid artery (ICA)
territory, most often indicates disease in that artery, in this case the right ICA or MCA.
The mechanism of these infarcts is artery-to-artery emboli often admixed with hypoperfu-
sion (21). Infarcts that are very small and deep and conform to the territory of one
penetrating artery are rarely embolic.
CT and MRI brain imaging are useful even when the neurological symptoms
reported by the patient or the family are transient. Scans in that circumstance may show
unexpected infarcts despite the negativity of the history and neurological examinations.
Such so-called “silent infarcts” are common. Neurological symptoms may have been
present but forgotten by the patient. In other instances, the symptoms may have been
trivial, for example, the patient may ignore a temporary limp, a short period of less
precise articulation, or word-finding difficulty, or transient numbness in a limb. Often
the neurological symptoms are misinterpreted as representing transient compression of
a nerve in a limb or other relatively minor nonstroke causes.
Careful inspection of CT scans performed soon after the onset of stroke sometimes
shows subtle signs of early infarction. These so-called early signs are listed in Table 2.
Loss of definition of the gray – white matter junction in ischemic regions, edema that
causes effacement of sulci in one cerebral hemisphere or one arterial vascular territory,
and loss of definition of the basal ganglia and the insular region are all early signs of
infarction. Frank hypodensity usually indicates an established brain infarct. Another
Imaging Evaluation: Recipient Artery Sites 95

Figure 1 A patient with a recent left putaminal hemorrhage: (A) Computed tomography scan. The
hemorrhage on the right of the figure is shown as a well-demarcated white lesion. (B) T2-weighted
magnetic resonance imaging scan of the same patient showing the hemorrhage as a black lesion.

common finding on noncontrast CT scans is opacification of the middle cerebral or other


arteries—the so-called hyperdense MCA sign. Figure 2 shows two examples of this sign.
The hyperdensity is caused by a thrombus or very slow flow within the artery. Sometimes
hyperdense intracranial internal carotid, basilar, and posterior cerebral arteries are found in
96 Caplan

Table 2 Early Computed Tomography Signs of Infarction

1. Loss of definition of the basal ganglia-lenticular nucleus.


2. Loss of definition of the insular ribbon.
3. Poor demarcation of the gray-white cortical ribbon.
4. Effacement of gyral markings.
5. Low-density areas.
6. Hyperdense arteries, especially, the MCA.

Abbreviation: MCA, middle cerebral artery.

Figure 2 Computed tomography scans showing hyperdense middle cerebral artery (MCA). (A)
Double-white arrows point to white curvilinear vascular structures, representing the left internal
carotid artery, anterior cerebral artery, and MCA. (B) A black arrow points to a hyperdense left MCA.
Imaging Evaluation: Recipient Artery Sites 97

patients with ischemia in those vascular territories. Hyperdense arteries on noncontrast


scans were found in 10% of acute strokes in one study (22), in 21% (23) and 22% (24)
of acute embolic MCA occlusions in other studies, and in 31% of acute anterior circulation
brain infarcts in another study (25). The hyperdense MCA sign has a relatively low sen-
sitivity (about 50%) but a very high specificity (about 90%). Occasionally, a hypodense
artery that appears black on CT scans can indicate a fat embolus within an intracranial
artery (26).
Occasionally, CT and MRI can show arterial lesions that can be the source of artery-
to-artery embolism. Aneurysms, either dolichoectatic fusiform expansions, or large berry-
type aneurysms can harbor clots and cause ischemia by embolization of clot material or
blockage of branches by thrombus that remains within the aneurysm. Fusiform and
large berry-type aneurysms are often visible on enhanced CT scans and on MRI. The
appearance of the aneurysm on MRI with heterogeneous shadows can suggest the presence
of thrombus within the lumen. The absence of normal vascular flow voids on MRI scans
can also suggest the presence of occlusive arterial lesions. On gradient echo T2-weighted
MRI scans (also referred to as susceptibility images), thrombosed arteries and veins can
sometimes be seen as dark, hypodense, and curvilinear vascular structures (27,28).
Dissected arteries, another important source of artery-to-artery embolism, often
have a characteristic appearance on MRI. Dissection of an artery can be detected on
MRI by the presence of intramural blood. The clot within the vascular wall has the
same characteristics as hematomas. Typically, the intramural thrombus appears highly
intense on an axial T1-weighted image and remains hyperintense on a T2-weighted
image. Figure 3 illustrates two examples of vertebral artery dissections shown by MRI.
Often, the lumen of the artery is eccentrically narrowed and may be thrombosed.
CT and MRI can also be useful in helping to decide on treatment and in rendering a
prognosis. Patients who have embolic brain ischemia are candidates for thrombolytic
treatment if seen early enough in their course. If a patient with a suspected MCA territory
embolus has a large infarct already visible on CT or MRI at the time that thrombolytic
treatment is considered, the likelihood of a good outcome would be small as much
brain was likely to have been infarcted already and would be unlikely to recover after
reperfusion. The risk of hemorrhage after thrombolytic treatment is also considerably
higher when sizable infarction is present before treatment (29). Decisions on the timing
of anticoagulation also depend on the imaging results. When large infarcts are present,
the risk of hemorrhage after heparin anticoagulation is higher.

INTRACRANIAL VASCULAR IMAGING


Dye Contrast Catheter Angiography
Vascular studies have a dual purpose: to define the lesion within recipient arteries and to
image any possible arterial sources of embolism. As angiography was the first vascular
imaging test used to detect emboli and to define vascular lesions, knowledge of the diag-
nostic angiographic findings will help physicians interpret the results of less invasive vas-
cular tests. Angiographic findings that suggest embolism are enumerated in Table 3. The
presence of blocked superficial branches of intracranial arteries is highly suggestive of
embolism as atherosclerosis rarely affects branch arteries but is much more common in
the major extracranial and basal intracranial arteries. The absence of any vascular occlu-
sive lesion in the artery supplying an infarcted zone usually means that an embolus has
temporarily blocked that artery and then passed. For example, if a patient has a sizable
acute right MCA territory infarct and the right ICA and MCA are normal angiographically,
98 Caplan

Figure 3 Vertebral artery dissections. (A) Axial T1-weighted magnetic resonance imaging (MRI)
showing hyperdense arterial expanded wall (black arrows) on the right of the figure. The lumen is
narrowed compared to the contralateral vertebral artery. (B) Axial T1-weighted MRI scans showing a
right vertebral artery dissection. The image on the left shows a hyperintense hematoma within the
wall of the artery with an eccentric compromised lumen. In the right, more rostral figure of the
medulla, the black lumenal flow void, is larger and the wall is the normal size.

Table 3 Angiographic Signs Indicating Embolism

1. Blockage of superficial branches of intracranial arteries.


2. Absence of any vascular occlusive lesion in the artery, supplying a cortical
or subcortical/cortical infarct.
3. Movement or disappearance of a vascular obstructing lesion on sequential
angiographic films.
4. Sudden sharply demarcated occlusion of major intracranial arteries,
especially the MCAs, PCAs, and cerebellar arteries in the absence of
atherosclerosis in those vessels.
5. A filling defect within a symptomatic intracranial artery.

Abbreviations: MCA, middle cerebral artery; PCA, posterior cerebral artery.


Imaging Evaluation: Recipient Artery Sites 99

then one can conclude that there must have been temporary blockage of the right MCA
by an embolus that remained long enough to cause infarction and later passed. Movement
or disappearance of a vascular obstructing lesion on sequential angiographic films is
diagnostic of embolism, as in situ occlusions are adherent and do not move quickly.
Emboli usually produce sudden sharply demarcated occlusions of major intracranial
arteries, especially, the MCAs, posterior cerebral arteries (PCAs), and cerebellar arteries
in the absence of atherosclerosis in those vessels. Patients who have in situ thrombi
formed at the sites of previous atherosclerosis usually have had prior transient ischemic
attacks, and the occlusion is tapered. The in situ –occluded artery shows some signs of
prior atherosclerotic stenosis. A filling defect within a symptomatic intracranial artery is
also highly suggestive of embolism. Angiography also gives information about possible
proximal arterial sources of embolism. In a patient with a right MCA territory infarct,
severe stenosis of the right ICA in the neck is highly suggestive of intra-arterial embolism
arising from the right ICA.
Newer, less-invasive vascular imaging tests are now used instead of angiography in
most patients. CT angiography (CTA), magnetic resonance angiography (MRA), and tran-
scranial Doppler ultrasound are excellent screening tests that often give enough infor-
mation to guide treatment, although their accuracy is less than catheter dye
angiography. Noninvasive imaging should always precede angiography, even when it
has already been decided that angiography is needed (30). The results of noninvasive vas-
cular tests can help better target angiography and limit the number of arteries that require
study, thus reducing the amount of contrast media needed and the length of the procedure.
CTA and MRA can generate accurate images of the major extracranial and intracranial
arteries but do not show branches very well. Clinicians should view MRA and CTA,
using the same criteria for embolism that were discussed for catheter dye contrast
angiography.

Magnetic Resonance Angiography


MRA is a very important investigation that promises to yield a great deal of information
about vascular occlusive lesions. MRA can be performed at the same time that MRI brain
images are generated. MRA does not require injection of any substance, although gadoli-
nium injection can yield better images of the arteries in some patients with reduced flow. It
is noninvasive and quite safe. MRA can be performed using a variety of different tech-
niques including, two-dimentional and three-dimensional time-of-flight and phase contrast
imaging (31 – 34). MRA is a functional technique that creates an image of flow in the
artery. Unlike the contrast injection angiograms, the images do not reflect anatomy. The
changing angles and curvature of the ICA in the siphon often makes interpretation of
this region more difficult as compared to the straight portions of the artery. The horizontal
segment of the MCA is usually well shown. The intracranial vertebral, basilar, and pos-
terior cerebral arteries are also imaged quite well with MRA. MRA is not as accurate
as digital subtraction catheter angiography in estimating the severity of arterial stenosis,
but complete occlusions of large arteries are usually well shown.

Computed Tomography Angiography


Infusions and bolus injections of contrast in conjunction with CT scanning yield diagnostic
images of neck and intracranial arteries. CTA can be performed at the same time as CT
100 Caplan

brain images. The development of more rapid spiral (helical) CT scanners has enabled the
development of CTA. This technique involves intravenous injection of a bolus of dye fol-
lowed by helical scanning. Volumetric data acquisition and improved computerized image
manipulation have improved the CTA image display into three-dimensional reformations.
CTA is based on anatomical imaging, and, when blood flow is severely reduced, CTA has
theoretical advantages over MRA, which is a functional imaging technique. CTA provides
useful images of intracranial arteries and can show regions of extracranial and intracranial
stenosis, dolichoectasia, and aneurysms (35 – 39). Figure 4 is a CTA that shows a
vertebral-posterior inferior cerebellar artery aneurysm.
In one study, among 40 patients who were considered potential candidates
for thrombolytic therapy, CTA showed that 34 had a recent arterial occlusion (40). Inter-
observer variability for both CTA and MRA are good, but different observers interpret
CTA more variably than MRA (41). Arterial enhancement of branches beyond the
occluded arteries can give information about collateral blood supply to ischemic
regions (38).
Bolus injection of contrast followed by sequential imaging at specific time intervals
(“triphasic perfusion computed tomography”) using helical CT can yield rapid infor-
mation about regions of brain ischemia and blockage of intracranial arteries (42,43).
The technique involves giving a bolus injection using a power injector of contrast into
an antecubital vein after a noncontrast CT has been performed. Early, middle, and late
phase images are obtained 18, 30, and 80 seconds, respectively, after the contrast has
been injected (42,43). Occlusion of the MCA or its branches can be detected from the
images even without reformation, allowing rapid decision about thrombolysis.
However, only limited CT scan cuts, usually taken along the plane of the MCAs, are

Figure 4 Computed tomography angiography showing a large aneurysm at the junction of the
right vertebral and posterior inferior cerebellar arteries.
Imaging Evaluation: Recipient Artery Sites 101

Figure 5 Triphasic computed tomography (CT) perfusion scans in a patient with a right middle
cerebral artery (MCA) occlusion. The four images on the left of each row are from the CT study,
whereas the five images in each row are from diffusion-weighted magnetic resonance imaging
scans at the same levels. The top row represents scans taken 18 seconds after a bolus injection of
contrast. The white arrow in the fourth image in that row points to the failure of filling of the
right MCA. In the second row are scans taken 30 seconds after contrast injection. The right MCA
territory is darker than the left and has much less vascularity indicating less dye delivery. In the
third row are scans taken 80 seconds after contrast injection. Now, the right MCA territory hypoper-
fusion is very well delineated. Source: Photo courtesy of Dr. Soo Joo Lee and his colleagues from the
Samsung Medical Center in Seoul, Korea.

imaged. The contrast dye infusion, also enhances the brain CT images, yielding a per-
fusion CT scan, which is somewhat comparable to a perfusion image MR scan.
Figure 5 is an example of a triphasic CT perfusion study in a patient with a right MCA
occlusion.

MAGNETIC RESONANCE PERFUSION IMAGING AND


COMPLETE MAGNETIC RESONANCE PROTOCOLS

Brain perfusion can also be imaged using dynamic contrast-enhanced MR scans


(31,44 –47). Ultrafast imaging after Gd-DTPA injection is used to calculate regional
cerebral blood volume (rCBV) and regional cerebral blood flow (rCBF) and to produce
the so-called perfusion-weighted images (31,44 – 49). These images show regions of
reduced blood flow when compared to comparable portions of the brain. Perfusion is
however quite complex. There are multiple possible measurements, such as the relative
102 Caplan

Figure 6 Perfusion magnetic resonance imaging, using bolus tracking of contrast in a patient with
an acute right middle cerebral artery territory infarct. (A) Four T2-weighted images are shown
selected from 40 images acquired every two seconds (s). The seconds after injection are noted
above the images. The contrast agent arrives about 20 seconds after the beginning of the series
and causes a transient decrease in the signal. The graph shows the signal drop during time in the
various regions labeled 1, 2, and 3 in the figure on the left. 1 is in normal brain, 2 is in hypoperfused
but not infracted brain, and 3 is in the core of the infarct. The signal decrease is more pronounced in
normal brain. No signal decrease is seen in the core of the infarct. The signal drop is delayed in
underperfused tissue. (B) The images were processed pixel by pixel and time to peak, mean
transit time, relative cerebral blood flow, and relative cerebral blood volume maps were generated.
The diffusion-weighted scan is on the left for comparison. Abbreviations: DWI, diffusion-weighted;
MTT, mean transit time; rCBF, relative cerebral blood flow; rCBV, relative cerebral blood volume;
TTP, time to peak. Source: From Ref. 49.

mean transit time that analyzes the rate of passage of the bolus of gadolinium through the
ischemic region, the time to peak, that is, the time it takes for the maximum perfusion, and
the relative cerebral blood flow and cerebral blood volumes in the ischemic area. Figure 6
(49) shows data available from DWI and perfusion MRI. The various blood flow measure-
ments sometimes vary; some may be abnormal, whereas other measurements are within
the normal range (49). Within an ischemic zone, perfusion may be quite heterogeneous,
showing severe hypoperfusion in one area and minor hypoperfusion in another region
(50,51).
In some centers, it takes additional time to calculate and display perfusion scans,
delaying comparison of the diffusion-weighted scan abnormalities with the perfusion
scan. Perhaps, just as useful information can be gleaned from the diffusion-weighted
scan and the MRA, as in most patients, prediction of the hypoperfused region can
be estimated by the severity of the clinical signs and the location of the occluded
artery.
Comparison of the region of probable infarction on diffusion-weighted scans with
the region of reduced perfusion (either from perfusion-weighted scans or estimated by
Imaging Evaluation: Recipient Artery Sites 103

Figure 7 A drawing showing information obtained using stroke magnetic resonance imaging
(MRI) protocols. The upper left image is an magnetic resonance angiography, showing no
flow in the left middle cerebral artery. The adjacent figure in the upper row is a diffusion-
weighted scan showing the area of infarction. The figure just below it is a perfusion scan that
shows the region of reduced perfusion. In the right figure, the area of cell damage (infarction)
is subtracted from the area of underperfusion to yield a zone of at risk tissue. The figure on
the lower left is a brain tumor studied by MRI. Source: Courtesy of Dr. Peter Schellinger of Hei-
delberg, Germany.

the MRA results) gives an indication of the part of the brain that is underperfused but
not yet infarcted (the presumed ischemic penumbra) (47,48). When the region of
reduced perfusion matches the zone of infarction, progression of infarction and
progression of neurological signs are rare. When this information is supplemented
by vascular imaging, usually MRA, which is acquired at the same time as the
diffusion-weighted and perfusion MRI scans, the treating physician has all the useful
information needed to assess brain perfusion and to allow a logical decision about
the likely utility of acute treatments such as thrombolysis. The drawing in Figure 7
illustrates the information gained from the MRI protocols often used to evaluate
acute stroke patients. A patient with an occluded MCA shown by MRA who has a
large zone of reduced perfusion within the MCA territory shown by perfusion MRI,
and a relatively small region of infarction shown by DWI MRI represents the ideal can-
didate for thrombolysis. On the other hand, a large zone of infarction on DWI MRI,
open ICA and MCA on MRA, and perfusion deficits that match or are less than the
zone of infarction on diffusion-weighted scans are characteristics of candidates in
whom thrombolysis has little likely utility. In patients who show a large perfusion
greater than diffusion mismatch, in whom MRA shows that the artery supplying the
ischemia zone is occluded, the infarct invariably enlarges if the artery is not opened
quickly (48). When MRA shows patency of the intracranial artery leading to an
ischemic zone, usually, no added infarction occurs (48). All of these clinically relevant
data can be acquired rapidly without risk on one machine, making modern MRI
imaging using the new technology far and away the best method for studying
acute stroke patients. Figures 8 – 10 show results of acute MRI stroke protocols to
illustrate their utility. Figure 11 shows MRI studies before and after tissue
104 Caplan

Figure 8 Acute magnetic resonance imaging stroke protocol in a patient with an internal carotid
artery occlusion. Diffusion-weighted (DWI) scan in the upper left shows a striato-capsular zone of
hyperdensity representing infarction. This area of abnormality is faintly shown on the T2-weighted
image below. The upper right image is a perfusion scan showing a large area of hypoperfusion (B),
larger than the infarct shown on DWI. The lower right magnetic resonance angiography image shows
an occlusion of the right internal carotid artery (C arrow). Abbreviation: MRA, magnetic resonance
angiography.

plaminogen activator (tPA) thrombolysis in a patient with an acute embolic occlusion


of the MCA.

COMPUTED TOMOGRAPHY PERFUSION AND COMPLETE


COMPUTED TOMOGRAPHY PROTOCOLS

Brain perfusion can also be studied using contrast-enhanced CT techniques (52 –55). CT
perfusion involves continuous CT acquisition, using a helical scanner during the
Imaging Evaluation: Recipient Artery Sites 105

Figure 9 Acute magnetic resonance imaging stroke protocol in a patient with a vertebral artery
occlusion. The sagittal and axial diffusion-weighted sections in the upper row show a small right
medullary infarct. The T2-weighted image below taken at the same time is normal. The right intra-
cranial vertebral artery is not seen on the magnetic resonance angiography below (white arrow).
Abbreviations: DWI, diffussion-weighted; MRA, magnetic resonance angiography.

administration of iodinated dye. The dye increases the intensity in brain regions that are
normally perfused but is not as visible in regions that are underperfused. Transit times,
cerebral blood flow, and cerebral blood volumes can be calculated using relevant software.
The contrast enhancement in each pixel is compared to the contralateral mirror cerebral
region. The values for mean transit time (MTT), rCBF, and rCBV are compared to
normal values and known ischemic thresholds, and are used to characterize hypoperfused
brain regions as being in the core of an infarct and penumbra (51). Within an established
infarct (usually the core of an infarct), both rCBF and rCBV are reduced; within penum-
bral zones, vascular dilatation usually leads to an increase in rCBV so that rCBF is
decreased but rCBV is increased (53).
When perfusion CT is combined with CTA and noncontrast CT scans, comparable
information to MRI protocols can be obtained (52 –55). Figure 12 (53) shows an acute and
delayed stroke CT perfusion protocol in a patient with a persistent MCA occlusion. The
penumbral zone in the initial scan progressed to infarction during the 28 hours between
scans because the MCA did not open. The major difference between acute CT and MRI
106 Caplan

Figure 10 Acute magnetic resonance imaging stroke protocol in a patient with a posterior cerebral
artery occlusion. The upper row shows axial and sagittal diffusion-weighted sections showing a left
occipital infarct. The T2-weighted image at the same time is normal. The magnetic resonance angio-
graphy shows an embolic occlusion of the left posterior cerebral artery (white arrow). Abbreviations:
DWI, diffusion-weighted; MRA, magnetic resonance angiography.

protocols is that CT does not show the acute area of infarction as well as DWI MRI. A
limited number of CT sections can be shown so that some underperfused regions not
included in the sections taken are missed, whereas MRI is able to show a much larger
area of the brain. Posterior circulation thromboembolism is presently not well studied
by CT perfusion protocols.

OTHER TECHNIQUES FOR STUDYING PERFUSION

Inhalation of xenon, an inert gas that is not metabolized, has been used for decades to study
cerebral blood flow. The development of xenon inhalation combined with CT scanning
(XeCT) has allowed the imaging of rCBF changes on sequential standard CT slices
(56,57). Xenon enhances or modifies the images, allowing visualization of relative
Imaging Evaluation: Recipient Artery Sites 107

Figure 11 Magnetic resonance imaging stroke protocol in a patient with an embolic occlusion of
the left middle cerebral artery (MCA) given tissue plasminogen activator (tPA) 130 minutes after the
onset of symptom. In the upper row, the diffusion-weighted (DWI) shows a faint left capsular infarct,
and the magnetic resonance angiography shows the left MCA occlusion (small white arrow). The
bottom row of scan images is taken 18 hours after tPA. The infarct (identical to that in the upper
row) is shown now in both the DWI and T2-weighted images. The left MCA is partially reperfused,
but there is still a region of underperfusion seen on the perfusion image on the bottom right.
Abbreviations: MRA, magnetic resonance angiography; DWI, diffusion-weighted; PI, perfusion
image; tPA, tissue plasminogen activator.

rCBF in regions of interest. This technique facilitates comparison of the zone of infarction
on CT with regions of reduced cerebral blood flow (CBF).
Single photon emission computed tomography (SPECT) uses ordinary radionuclear
camera equipment and does not require a cyclotron to generate radionuclides. The
most common radioisotopes used now are Technetium-99M-labeled hexamethyl-
propylene amineoxime and Technetium-99m labeled ethyl cysteinate dimer (Tc ECD)
(58,59). Regional radiotracer uptake can be imaged in three planes. The isotopes
measure rCBF rather than metabolic activity. SPECT and XeCT contain no important
metabolic information.
A major advantage of SPECT scanning is that imaging does not have to be per-
formed immediately after the injection of the radionuclide. The findings on SPECT
imaging represent those that were present at the time of injection. Acute treatment
could be initiated immediately after the injection, even before imaging. SPECT
does not show the region of infarction but can be used with CT, and can be helpful in
the diagnosis and management of stroke patients, when the proper questions are asked
(60,61).
Positron-emission tomography (PET scanning) uses rapidly metabolized radioiso-
topes and is not practical in the management of patients with acute stroke.
108 Caplan

Figure 12 Computed tomography (CT) perfusion scans in a patient with a persistent left middle
cerebral artery (MCA) occlusion taken seven hours (left column) and 35 hours (right column) after
the onset of symptom. The upper row shows native CT scans before contrast that show an old right
frontal infarct. A new left parasylvian infarct is visible after 35 hours. The mean transit time maps are
shown in the second row. The dark area of prolonged transit times has enlarged between the scans.
Similarly, the regional cerebral blood flow maps in row 3 and the regional cerebral blood volume
maps in row 4 were also changed during the 28 hours between scans. In the fifth row on the left
is a prognostic map that shows the area of infarction in darker grey and the area of penumbra
(at-risk, underperfused but not yet infarcted brain in lighter grey). On the right in the fifth row,
the previously lighter grey area is now darker, indicating an increase in the area of infarction (as mir-
rored in the native CT scan taken at that time). In the bottom row are CT angiography films that show
the persistent MCA occlusion (white arrows). Source: From Ref. 53.
Imaging Evaluation: Recipient Artery Sites 109

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7
Transcranial Doppler Ultrasound
Carlos A. Molina
Neurovascular Unit, Vall d’Hebron Hospital, University of Barcelona, Barcelona, Spain
Andrei V. Alexandrov
Departments of Neurology and Radiology, University of Texas Health Sciences Center,
Houston, Texas, U.S.A.

INTRODUCTION

Ultrasound offers a clinical tool that can detect embolism in real time (1), particularly
in the form of transcranial Doppler (TCD); it can localize embolic occlusion, detect
recanalization or continuing embolization, and define potential sources or pathways of
embolization (2). Given the great heterogeneity in the pathophysiology of ischemic
stroke, emergent noninvasive neurovascular imaging is essential for timely initiation of
established therapies and development of new treatment strategies to prevent reversal of
brain ischemia.
Rapid identification of the location and severity of arterial obstruction can aid triage
of acute stroke patients (1). Systemic thrombolysis is now increasingly used worldwide for
the treatment of acute stroke. The rationale for thrombolysis in acute ischemic stroke is
recanalization of an occluded artery to reestablish brain function by saving tissues at
risk. Because “time is brain,” it is crucial to rapidly identify patients who will benefit
from thrombolityc therapy, likely those who have embolic or atherothrombotic arterial
occlusions, before lytic drug administration (3,4).
Detection of an intracranial artery occlusion in patients with acute ischemic stroke
depends mainly on the stroke subtype and on the time elapsed from stroke onset to the
initial neurovascular evaluation. Angiography shows intracranial large artery occlusions
of mostly embolic origin from cardiac or proximal arterial sources in up to 75 – 80% of
acute stroke patients (5 –9). If left untreated, an acute occlusion slowly resolves over
time, being no longer evident on subsequent angiographic studies or at autopsy. In one
study, during the first week after stroke, the main-stem middle cerebral artery (MCA)
occlusion spontaneously disappeared in 44% of cases, whereas distal MCA occlusions
were no longer present in 67% of patients (10). These observations indicate that
spontaneous recanalization is common after acute stroke but unfortunately often occurs
too late to rescue ischemic brain tissue. The idea that early spontaneous recanalization
infrequently occurs during the first few hours of acute stroke is supported by data from
the placebo arm of the intra-arterial thrombolysis trials (11,12). If the first diagnostic

113
114 Molina and Alexandrov

angiogram was performed 5 hours and the second one 2 hours later, early spontaneous
arterial reopening was seen in no more than 14% of patients on the second angiogram (12).
Although catheter cerebral angiography is the gold standard for diagnosis of arterial
occlusion, it is a costly and invasive procedure not suited for screening unselected patients
for acute arterial lesions or monitoring spontaneous or therapeutically driven recanaliza-
tion. In contrast, TCD is a rapid, noninvasive, and inexpensive technique that provides
information about the presence and location of arterial occlusion and recanalization in
real-time and at the patient’s bedside. Several studies have evaluated digital subtraction
angiography (DSA), contrast-enhanced CT angiography (CTA), magnetic resonance
angiography (MRA), and ultrasound in the acute stroke setting (13 –17). In one study,
DSA showed complete arterial occlusions in 76% of acute stroke patients within six
hours of symptom onset, of which 66% were intracranial (13). Noncontrast-enhanced
TCD, in one study, had a sensitivity of 80% and a specificity of 90%, compared with
DSA in patients presenting within five hours of MCA-territory stroke (17).
TCD may be used as a screening test to determine the need for further angiographic
studies. The bedside availability, convenience to the patient, and continuous monitoring
option make TCD particularly suitable for emergency evaluations. TCD also allows
real-time assessment of blood flow velocity, pulsatility, and embolization of cerebral
vessels, which is not available with angiography. This chapter reviews current diagnostic
criteria and clinical applications of TCD in patients with brain embolization.

TCD DIAGNOSIS OF ARTERIAL OCCLUSIONS

TCD can identify isolated and tandem occlusions in the intracranial circulation. TCD is
highly sensitive for residual flow surrounding an acute occlusion of a major cerebral
artery. Flow patterns of occlusion on TCD are based on the relative relationship
between thrombus location and arterial segment insonated (Fig. 1). Zanette et al.
(10,18) first noted the different patterns of intracranial artery occlusion on TCD.
A proximal MCA occlusion was defined as the absence of flow or a minimal flow
signal throughout the MCA at an insonation depth between 45 and 65 mm accompanied
by flow diversion in the ipsilateral anterior (ACA) and posterior cerebral arteries
(PCA). A diffuse dampening of mean flow velocity in the affected MCA .21% versus
unaffected MCA is regarded as distal MCA occlusion. Recanalization on follow-up
TCD is diagnosed when dampened flow appears in a previously demonstrated proximal
MCA occlusion (partial recanalization) or when a previous absent, minimal, or dampened
flow comes within the normal range (complete recanalization). No change in the abnormal
waveforms indicates that no recanalization has occurred.
Using these patterns Toni et al. (19) showed that a normal TCD examination within
the first six hours of stroke onset independently predicted spontaneous neurological
improvement and good long-term outcome. Conversely, persistent occlusion at six
hours was an independent predictor of early neurological worsening and poor clinical
outcome.
TCD patterns of occlusion and recanalization described by Zanette et al. (20 – 23)
have been further refined for use in patients undergoing thrombolysis. The thrombolysis
in brain ischemia (TIBI) grading system addresses the dynamic nature of acute occlusion
and recanalization processes (21). This grading system had a good correlation with angio-
graphy with a sensitivity and specificity values .90% for the MCA territory and .86%
for the vertebrobasilar territory (22,23).
Transcranial Doppler Ultrasound 115

Figure 1 Embolic MCA occlusion. Angiography shows an acute embolic occlusion of the MCA
with residual flow around a “sausage-shaped” thrombus. The drawing shows representative
abnormal thrombolysis in brain ischemia waveforms that can be obtained along the middle cerebral
artery stem obstructed by an embolus. Abbreviations: MCA, middle cerebral artery; TIBI, thrombo-
lysis in brain ischemia.

Complete MCA occlusion is defined by absent (TIBI 0) or minimal (TIBI 1) signals


(Fig. 2) at one or more depths (range, 40 –65 mm). MCA occlusion is often accompanied
by flow diversion to the ACA or PCA (mean flow velocity ACA . contralateral MCA, or
PCA . contralateral MCA). Detection of a short systolic spike with no end-diastolic flow
is regarded as a minimal flow signal. In this case, either terminal internal carotid artery
(ICA) or PCA flow signals had to be identified from the ipsilateral temporal window to
exclude suboptimal ultrasound penetration through the bone. Absent or minimal flow
signals may be confirmed by insonation from the contra-lateral temporal window.
Partial MCA occlusion is diagnosed when blunted (TIBI 2) or dampened (TIBI 3)
signals (Fig. 2) at 40 –65 mm depths with potential flow diversion signs to the ACA or

Figure 2 The TIBI flow grades. Abbreviation: TIBI, thrombolysis in brain ischemia.
116 Molina and Alexandrov

PCA. A blunted flow signal is characterized by delayed (0.2 seconds) systolic flow accel-
eration with a pulsatility index (PI) ,1.2. The PI [Gosling-King] is determined by the
formula peak systolic velocity-end diastolic velocity/mean flow velocity. A PI ,1.2
indicates low-resistance flow diversion to branching vessels or a residual positive end-
diastolic flow at the site of occlusion MCA. A dampened (TIBI 3) flow signal is identified
when normal systolic flow acceleration is present in the pulsatile MCA waveform with
mean flow velocities ,70% of the contralateral MCA and positive end-diastolic flow
with variable PI values.
Complete recanalization is diagnosed if low-resistance stenotic (TIBI 4) or normal
(TIBI 5) signals appear throughout the MCA stem (depths 40 to 65 mm), with no other
signs of persisting distal occlusion (i.e., dampened distal signal or flow diversion). In
cases with residual stenosis on TCD, low-resistance flow indicates patency and perfusion
of the distal vasculature.
The TIBI flow grading system has a good correlation with the thrombolysis in myo-
cardial infarction (TIMI) criteria (24). The TIMI score is an angiography-based grading
system, that was originally developed and used to describe flow in the coronary arteries
(24). Its clinical use has been extended to the cerebral circulation (12). TIMI is based
on the degree of opacification of the distal vessels on DSA. Complete occlusion (TIMI
grade 0 or I) is defined as no or minimal perfusion with no opacification of the distal
vessels on DSA and no reconstitution of distal flow on MRA or CTA. Partial occlusion
(TIMI grade II) is defined as an obstruction that results in delayed opacification of the
distal vessels on DSA and appearance of distal slow-flow filling of decreased intensity
on MRA or CTA. Complete recanalization (TIMI grade III) is defined as unimpeded per-
fusion of the distal vasculature regardless of whether a residual stenosis or a focal flow gap
is present. However, the TIMI grading system has limitations when applied to assess reca-
nalization of intracranial arteries. The TIMI system evaluates local recanalization, and,
therefore, it does not accurately reflect the dynamic nature of the recanalization process
during stroke thrombolysis. For instance, the phenomenon of proximal clot fragmentation,
followed by downstream embolization occluding smaller arteries, cannot be adequately
represented by the TIMI system.
Identification of a severe carotid obstruction ipsilateral to an MCA occlusion, the
so-called tandem ICA/MCA occlusion, requires a battery of flow findings on TCD.
This battery was described by Wilterdink et al. and further expanded by Christou et al.
(25,26). A broad TCD battery includes three major and three minor criteria (26). Major
criteria are:

1. Collateral flow signals (anterior, posterior communicating, or ophthalmic


arteries).
2. Abnormal ICA siphon or terminal ICA signals (absent, minimal, blunted, dam-
pened, or stenotic waveforms).
3. Delayed systolic flow acceleration in the MCA (arrival of maximum frequen-
cies in late systole)

Minor criteria are:

1. Decreased pulsatility index (0.6 or interhemispheric difference .30%).


2. Flow diversion signs (velocity: PCA . MCA, PCA . ICA, and contralateral
ACA . MCA).
3. Compensatory velocity increase (.20% increase in the contralateral hemi-
spheric vessels or vertebrobasilar arteries).
Transcranial Doppler Ultrasound 117

In acute stroke patients, this broad TCD battery has shown a sensitivity of 79% and
specificity of 86% against angiography to detect severe ICA stenoses or occlusion (26).
Acute tandem ICA/MCA occlusion is diagnosed with TCD if abnormal TIBI MCA
waveforms or an asonic MCA segment is present with one major or two minor findings
according to the broad TCD battery for an ICA obstruction (27). In other words, an abnor-
mal TIBI waveform indicates the presence of an MCA occlusion, whereas an additional
finding of at least one collateral channel indicates a proximal hemodynamically significant
lesion in the feeding vessel.
TCD can identify not only residual flow signals in the acutely occluded artery but
also major collateral channels in both the anterior and posterior circulations. In patients
with tandem ICA/MCA occlusions, the number and extent of collateral flow through
the ipsilateral ACA and PCA are associated with less severe stroke symptoms as measured
by the National Institute of Health Stroke Scale (NIHSS) score (27). In fact, fluctuations of
neurological signs in the absence of recanalization or reocclusion on TCD may reflect
changes in perfusion through collateral channels. Similarly, in patients with basilar
artery occlusion, the presence of a reversed flow in the distal basilar artery has been
shown to be associated with a lower NIHSS score and good short- and long-term
outcome (28).

TCD MONITORING DURING THROMBOLYSIS

The National Institutes of Neurological Disorders (NINDS) rtPA stroke study showed a
beneficial effect of intravenous recombinant tissue plasminogen activator (tPA), when
given ,3 hours after symptom onset (29). However, the NINDS trial, like other random-
ized clinical trials of intravenous thrombolysis, did not monitor presence and location of
arterial occlusion and recanalization at different times after stroke (30 – 34).
General agreement exists that clinical benefit of tPA in ischemic stroke is linked to
accelerated clot lysis and early recanalization (29,30). However, trials of intravenous
thromblytic therapies did not evaluate whether clinical efficacy was dependent on the pre-
sence of arterial occlusion and whether clinical improvement was linked to subsequent
recanalization after thrombolytic therapy or to spontaneous recanalization in patients
receiving placebo (29 – 34). Nonrandomized angiographic studies with intravenous
tPA showed recanalization rates of 25 –50% (11,35,36). Overall, the rate of early tPA-
induced recanalization (partial or complete) on repeat TCD examinations within the
first six hours of symptom was as high as 66 – 70% (37,38) compared with only 13– 14%
of spontaneous recanalization rates on TCD and angiography (12,13,37). In continuous
TCD-monitoring studies, when intravenous tPA was given within ,3 hours of stroke
onset, the rate of complete and partial recanalization within two hours after tPA bolus
was 30% and 40%, respectively (38). Moreover, a case-control TCD study in patients
with cardioembolic strokes showed that intravenous tPA increased the rates of complete
and partial recanalization 8-fold and 3-fold within six hours of symptom onset (37).
The timing of arterial recanalization after tPA therapy, as determined by TCD, cor-
relates with clinical recovery from stroke. Christou et al. (39) studied 40 stroke patients
who were continuously monitored with TCD for one hour after tPA bolus. In this study,
recanalization on TCD occurred at the mean time of 251 + 171 minutes after stroke
onset, and within 60 minutes of tPA bolus in 75% of patients who were recanalized.
Moreover, the timing of artery reopening inversely correlated with early improvement
in the NIHSS scores within the next hour as well as at 24 hours. Importantly, this
study showed the existence of a 300-minute-after-symptom-onset window for arterial
118 Molina and Alexandrov

recanalization to achieve early complete clinical recovery in human stroke. These findings
parallel animal models of cerebral ischemia, suggesting an S-shaped relationship between
the duration of ischemia and the reversibility of paralysis with subsequent brain infarction
(39,40).
During the last few years, mounting evidence from continuous TCD-monitoring
studies confirmed initial clinical observations in stroke patients, suggesting that spon-
taneous embolus migration with brain reperfusion may lead to a spectacular shrinking
deficit in patients with cardioembolic stroke (41 –43). The dynamic process of thrombus
dissolution during fibrinolytic therapy may be accurately delineated by continuous TCD
monitoring (43). Shortly after tPA administration, TCD can show in real-time the
beginning, duration, amount, and time to maximum completeness of recanalization and
characteristic embolic signals indicating thrombus fragmentation or the presence of
emboligenic surface (43,44) (Fig. 3).
Alexandrov et al. (43) developed a sonographic classification to assess the speed of
intracranial clot lysis during continuous TCD monitoring (43). The beginning and
continuation of recanalization was determined when one of the following flow signal
changes is detected on TCD (Fig. 3):
1. Waveform change by one TIBI residual flow grade (for example, absent to
minimal, minimal to blunted, and minimal to normal).
2. Appearance of embolic signals (transient high-intensity signals of variable
duration).
3. Flow velocity improvement by 30% at a constant angle of insonation.
4. Signal intensity and velocity improvement of variable duration at constant gain/
sample volume/scale settings.
5. Appearance of flow signals with variable (.30%) pulsatility indexes and ampli-
tude of systolic peaks.
The speed of clot lysis during continuous TCD monitoring was categorized into sudden
(abrupt appearance of a normal or low-resistance signal), stepwise (gradual flow improve-
ment over 1 –29 minutes), or slow (flow improvement in 30 minutes) recanalization (43).
Sudden recanalization reflects rapid and complete restoration of flow; stepwise and
slow recanalizations indicate proximal clot fragmentation, downstream embolization,
and continued clot migration (Fig. 4).
These patterns may represent a surrogate measurement of the efficacy of thrombo-
lytic therapy. Although sudden recanalization was observed in only 8– 12% of patients
treated with intravenous tPA, this pattern has been associated with a higher degree of
neurological improvement and better long-term outcome than stepwise and slow recana-
lization, presumably due to faster and more complete embolus dissolution that occurred
closer to stroke symptoms onset (43,45). Moreover, the speed of clot dissolution on
TCD predicts the evolution of the ischemic brain tissue on diffusion-weighted imaging
(DWI) (46). Molina et al. (46) showed that sudden clot lysis produced slower lesion
growth on DWI and greater likelihood of DWI lesion reversal at 48-hour MRI than
slower clot lysis.
Although treatment with tPA is effective across different stroke mechanisms (29),
response to tPA varies, depending on the size, composition, and source of the offending
thrombus. Specific structural aspects of thrombi have received attention with respect to
lytic susceptibility and penetration of thrombolytic agents. Old, platelet-rich, and well-
organized thrombi formed under flow conditions are more resistant to thrombolysis than
fresh, fibrin- and red-cell rich clots formed under conditions of stasis (47 –49). Moreover,
physical structure and biochemical and cellular composition of brain emboli may differ,
Transcranial Doppler Ultrasound 119

Figure 3 Signs of the beginning and continuation of arterial recanalization. (1) Waveform
improvement by one or more TIBI residual flow grade: the first set illustrates flow changes from
a minimal to blunted waveform (appearance of positive end-diastolic flow and rounded systolic
complex); (2) Appearance of embolic signals: the second set of waveforms illustrate dampened
and normal flow signals with multiple transient high intensity signals of variable duration with
characteristic chirp or poplike sounds (arrows); (3,4) Flow velocity improvement by 30% or more
and the signal intensity or improvement: this set shows flow tracing obtained at a constant angle
of insonation with mean flow velocity improvement from 15 cm to 30 cm, preceded by the improve-
ment in the strength (brightness) of the residual flow signal (middle set); (5) Appearance of flow
signals with variable (.30%) amplitude of systolic peaks and pulsatility: a turbulent high
frequency, high resistance stenotic flow signal (bottom left); variable velocities with transient
appearance of flow in a branching vessel below the baseline (arrow, bottom right). Abbreviation:
TIBI, thrombolysis in brain ischemia. Source: From Ref. 43.

depending on whether the embolic source is a thrombus engrafted in a proximal athero-


sclerotic lesion or a clot formed in cardiac cavities.
In a recent study of patients with proximal MCA occlusion treated with intravenous
tPA, early recanalization was shown to be more frequent, faster, and more complete in car-
dioembolic strokes as compared with other stroke subtypes (45). Moreover, cardiac
120 Molina and Alexandrov

Figure 4 Duration of arterial recanalization. (I) Sudden (abrupt appearance of a normal or stenotic
low resistance signal). (a) TCD shows a minimal signal in the MCA at the time of tPA bolus. (b) At
31 minutes after bolus the first improvement in signal intensity was noticed and marked as “beginning”
of recanalization. (c) In less than five seconds, the first low resistance signal was detected with normal
waveform. (d) After 30 seconds, a strong normal flow velocity signal was detected. Recanalization
started at 31 minutes after tPA bolus, its duration was 35 seconds, and timing of complete recanalization
of the distal M1 MCA segment (TIBI grade III equivalent) was 32 minutes after tPA bolus. (II) Stepwise
(flow improvement over 1–29 minutes). (a) TCD shows a minimal signal in the mid-to-distal M1 MCA
at the time of tPA bolus. (b) After nine minutes, TCD shows the first improvement in the amplitude of
systolic velocities (beginning of recanalization). The absence of end-diastolic velocities still indicates
minimal TIBI flow signal and persisting occlusion. (c) At 14 minutes, positive end-diastolic flow is
detected with rounded systolic shape of the waveform (TIBI blunted signal) with flow improvement
by TIBI-1 grade. Note high-intensity bruits during each cardiac cycle with possible embolic signals.
(d) At 16 minutes, TCD shows high resistance turbulent stenotic signals with elevated and variable sys-
tolic velocities, which are replaced by normal waveforms at 18 minutes. (e) At this point, TCD findings
indicate that the M1 MCA patency at the site of insonation is restored. Further improvement in flow
velocity, pulsatility, and strength of the signal was detected 18–20 minutes after bolus (f) indicating
continuous flow recovery presumably due to distal clot migration beyond M2 MCA, bifurcation
TCD shows the beginning of recanalization at nine minutes, duration of 11 minutes, and timing of com-
plete (TIMI grade III equivalent) recanalization at 20 minutes after tPA bolus. (III) Slow (30–60
minutes). (a) At the time of tPA bolus, TCD shows a minimal flow signal at the M1 MCA origin
(above baseline) and a flow signal below baseline from the proximal A1 ACA with mean flow velocity
of 24 cm. (b) At 12 minutes after bolus, slow positive end-diastolic flow appears in the proximal M1
MCA indicating the beginning of recanalization. A decrease in the ACA flow signal may indicate
clot movement or breakup at its proximal part. Variable M1 MCA and A1 ACA flow velocities with
dampened TIBI flow grade are seen during the next 40 minutes (c) with arrival of the dampened
flow signal with the highest mean flow velocity of 28 cm and improved A1 ACA velocities of 54 cm
at 54 minutes after tPA bolus. (d) TCD findings indicate the beginning of recanalization at 12
minutes, duration of 42 minutes, and timing of partial (TIBI grade II equivalent) recanalization with
continuing flow diversion to ACA at 54 minutes after tPA bolus. Abbreviations: TCD, transcranial
doppler; MCA, middle cerebral artery; tPA, tissue plasminogen activator; ACA, anterior cerebral
artery. Source: From Ref. 43.

sources of emboli were identified in 81% of patients who showed a sudden clot breakup
during tPA infusion (45). On the other hand, the presence of concomitant ipsilateral
severe ICA disease was associated with lower MCA recanalization rates and poorer
clinical outcomes, as shown in another study (50).
Transcranial Doppler Ultrasound 121

Faster recanalization rates point to the likelihood that cardioembolic strokes may be
caused by emboli that are more uniform fibrin-rich red clots (45). Given the high binding
affinity of tPA for fibrin, tPA penetrates and distributes more homogeneously in fibrin-rich
clots, leading to more rapid and complete clot dissolution (greater likelihood of sudden
and stepwise recanalizations). In contrast, in well-organized and platelet-rich clots, pen-
etration and distribution of tPA are limited, which may result in nonuniform clot softening
and degradation, mostly from the outside of the clot. As a result, the clot shrinks and
moves distally, lodging in smaller arteries, which can prolong ischemia (tendency to
slow and frequently incomplete recanalizations). This may explain the observation that
slower speed of recanalization is associated with less neurological improvement and
worse long-term outcomes compared to faster recanalizations after initiation of tPA
therapy (43,45).
Slow and incomplete recanalization is often reflected by dampened flow signals
(TIBI grade III). This waveform indicates embolus location in the distal branches and
increased resistance to flow in the distal circulatory bed affected by ischemia (21). This
hemodynamic observation reflects impaired ability to washout or clear embolic debris
through the circulatory bed. Caplan and Hennerici (51) posit that impaired washout inter-
twines embolization with delayed emboli clearance in hypoperfused brain tissues and the
two together (emboli and hypoperfusion) contribute to the development of brain infarc-
tion. On TCD, this impaired washout of proximal emboli is also reflected by abnormal
TIBI waveforms (0 – 2) that indicate persistent proximal arterial occlusion.
Large emboli can cause hypoperfusion that is strongly linked to brain ischemia
and infarction as there is a close correlation of (i) the severity of arterial stenosis
with brain infarction, (ii) impaired functional blood flow reserve in patients with
carotid artery disease and subsequent brain infarction, (iii) reduced collateral blood
flow with poor prognosis after thrombolysis, and (iv) stroke-related neurologic deficits
after cardiac and carotid surgery to hypoperfusion during surgery (51). Furthermore,
microembolization is common in patients with severe symptomatic carotid artery steno-
sis and during and after cardiac/carotid surgery. All these factors predispose to
decreased ability of brain circulation to effectively clear emboli. Ultrasound testing
can directly identify severe stenoses, impaired vasomotor reactivity, poor collaterals,
and hypoperfusion states (2,21,52). Continuous TCD monitoring also shows the
dynamic process of brain embolization and its impact on flow waveforms and velocities
in real time (53).

DETECTION OF INTRACRANIAL ARTERY STENOSIS AND


ARTERY-TO-ARTERY EMBOLISM

Intracranial atherosclerosis is the leading cause of approximately 8% of all strokes in


Caucasian patients and is the most commonly found vascular lesion in Asian stroke
patients (54,55). The traditional dependence on invasive vascular-imaging techniques to
diagnose intracranial artery stenosis has probably underestimated its real prevalence.
TCD represents a reliable noninvasive tool for the diagnosis and follow-up of
intracranial stenosis (2,51 –61). TCD criteria for intracranial stenosis have been validated
with conventional angiography. Sensitivity and specificity values vary depending on the
intracranial artery studied, severity of arterial stenosis, and arterial segment insonated.
The highest sensitivity and specificity values correspond to moderate and severe stenosis
located in the proximal MCA, PCA, and basilar artery.
122 Molina and Alexandrov

TCD diagnosis of intracranial stenoses is based on the following criteria (49): (i)
local flow acceleration, (ii) disturbed flow with spectral broadening in the region of steno-
sis, and (iii) reduced maximum and mean flow velocities distal to the stenosis (49).
MCA stenosis is diagnosed if the mean blood flow velocity (MFV) exceeds 100 cm/s
or peak systolic flow velocities exceed 140– 160 cm/s, with side-to-side differences more
than 30%. In a study with angiographic control, MFV threshold of 100 cm/s is better
differentiated (50%) than MCA stenosis (,50%) with sensitivity 100%, specificity
98%, positive predictive value (PPV) 88%, and negative predictive value (NPV)
95% (60). Regardless of using peak or mean velocities for the maximum flow acceleration
thresholds, the ratio to a nonaffected MCA should be used to decide on the severity of the
stenosis. Mild (,50%) lesions will produce normal stenotic flow velocity ratio 1:,2, mod-
erate (50 –69%) lesions have 1:2, and severe (.70%) lesions have 1:3 ratios (60,62).
Increasing velocity is associated with stenosis progression that occurs more frequently in
symptomatic patients (55,63).
Intracranial arterial stenoses may have emboligenic surfaces, and TCD can detect
embolic signals originating in the M1 MCA and insonation along the distal artery can
show artery-to-artery embolization from isolated intracranial lesions (63 – 66). These
emboli, which appear in clusters or even individually, may change the flow velocity,
indicating that their size is comparable to the residual lumen (65,66). TCD detection
of embolic signals has been shown to be linked to MCA stenoses with higher stroke
recurrence (63 –67a).

EMBOLI MONITORING

Detection of emboli with TCD is based on the definition of microembolic signals (MES)
provided by the International Cerebral Hemodynamics Society consensus (67). MES, as
shown in Figure 3, have the following characteristics on spectral Doppler analysis: (i)
random occurrence during the cardiac cycle, (ii) brief duration (usually ,0.1 sec),
(iii) high intensity (.3 dB over background), (iv) primarily unidirectional signals
(if fast Fourier transformation is used), and (v) audible component (chirp, pop).
The power motion-mode Doppler adds extra dimensions to the process of emboli
detection (68). It shows tracks of emboli in time and space and provides simultaneous
real-time assessment of emboli passing through different vessels (Fig. 5), thereby increas-
ing the yield of emboli detection with a single transducer (68 – 70). A new definition is
proposed to identify emboli using power m-mode Doppler that takes into account
embolus motion in one direction on m-mode display at a minimum spatial extent of
7.5 mm and temporal extent of 30 ms (70).
Practically all MES detected by TCD are asymptomatic as the size of the particles
producing them is usually comparable to or even smaller than the diameter of brain
capillaries (71). However, their cumulative count is related to the incidence of
neuropsychological deficits after cardiopulmonary bypass and (72,73), stroke after
carotid endarterectomy (52,74 – 77). The significance of MES as a risk factor for ischemic
stroke and parameter platelet inhibition efficacy is emerging (78).
Strict standards should be followed when an interpreter documents and reports
microemboli on TCD (78). The gold standard for MES identification still remains the
on- or off-line interpretation of real-time, videotaped, or digitally taped flow signals
(78 –80). If spectral TCD is used, recordings should be obtained with minimal gain at a
fixed angle of insonation with a small (,10 mm) sample volume. The probe should be
maintained with a fixation device for at least 0.5– 1 hour while monitoring for detection
of spontaneous embolization. Prolonged monitoring times, two-channel simultaneous
Transcranial Doppler Ultrasound 123

Figure 5 Power m-mode display of embolic signals. (A) A single embolus (arrow) originating in a
dissolving thrombus in the MCA in an acute stroke patient treated with intravenous tPA for a
cardioembolic MCA occlusion. Note that m-mode tracks embolic path in time and space along
the distal M1 segment. (B) Bilateral simultaneous insonation of both MCAs in a patient
undergoing cardiothoracic surgery experiencing massive air embolization due to perforated pulmon-
ary artery. (C) Positive “bubble” testing for the right-to-left shunt in a patient with paradoxical
embolism due to deep venous thrombosis and a large and functional patent foramen ovale.
Abbreviations: MCA, middle cerebral artery; tPA, tissue plasminogen activator.

registration, and the use of power m-mode can improve the yield of emboli detection.
Differentiation of embolic signals from artifacts is possible with commercially available
software.

DETECTION OF RIGHT-TO-LEFT SHUNTS

Testing for right-to-left shunt is essential in patients with stroke or transient ischemic
attack due to suspected paradoxical embolism (81). Although TCD cannot localize the
shunt, that is, patent foramen ovale (PFO) or anterior septal defect, it provides comp-
lementary information to transesophageal echocardiography (TEE). For instance,
“bubble” testing with TCD can be done in a matter of minutes at the bedside with
minimal or no discomfort to the patient. TCD can offer results of shunt detection with
accuracy equal to TEE for detection of functional PFO’s and detect shunt presence
even after TEE is negative, that is, in case of pulmonary arteriovenous malformation or
inability of patient to perform Valsalva maneuver during TEE (82,83).
To optimize TCD performance, the following protocol should be followed:
1. The patient is in the supine position, and an 18-gauge needle is inserted into the
cubital vein.
124 Molina and Alexandrov

2. A 3-way stop-cock connector with two 10 mL syringes is connected to iv


access.
3. Nine milliliter of isotonic (preferably bacteriostatic) saline is forcefully mixed
with 1 cc of air.
4. Less than 1 mL of the patient’s blood may be suctioned into the syringe for
better bubble formation with agitation.
5. At least one MCA is monitored with TCD.
6. The first bolus injection of agitated saline is made with the patient breathing
normally.
7. A second bolus injection of similarly prepared agitated saline is made with
10 sec Valsalva maneuver initiated five seconds after beginning of saline
injection.
8. If negative, TCD-monitoring is extended up to one minute in order to detect
potentially late-arriving bubbles, suggesting a pulmonary arteriovenous shunt.
At times, a so-called curtain of almost continuous signals develops. A four-level categor-
ization is proposed by the International Consensus criteria (83):
1. No microembolic signals were detected (negative “bubble” test).
2. From one to ten MES detected (positive “bubble” test).
3. More than 10 MES detected with no curtain.
4. A curtain test indicates the presence of a large and functional shunt (Fig. 5).
The report of the findings should comment on whether or not MES or bubbles were
detected at rest or provoked by Valsalva maneuver. If few single bubbles were detected
at rest and curtain appeared with Valsalva, this also needs to be reflected in the report.
Interest in shunt-testing with TCD is increasing. Besides stroke with paradoxical
embolism, functional PFO may play a significant negative role in altitude decompression
of patients undergoing hip replacement and patients who have migraine with aura (84 –
87). Noninvasive shunt detection, functional assessment, and percutaneous closure open
new possibilities in management of these patients.

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PART III: DONOR SOURCES—NATURE, FREQUENCY, RECOGNITION

8
Cardiac Sources of Embolism:
The Usual Suspects
Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.
Warren J. Manning
Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Our understanding of cardiac sources of embolism has expanded greatly over the past
50 years. During the 1950s, the only two cardiac disorders that were accepted as risk
factors for embolism were rheumatic mitral stenosis in combination with atrial fibrillation
and recent myocardial infarction. We now know that many cardiac conditions increase
risk of cardiac thrombosis and embolism (1,2). Advances in cardiac imaging [echocardiogra-
phy and, more recently, cardiovascular magnetic resonance and cardiac computed tomo-
graphy (CT)] and the expanding data derived from large epidemiologic studies (e.g., the
Framingham Heart Study) and large prospective clinical trials have made it possible
during the past three decades to noninvasively diagnose cardiac disorders more definitively
and to attempt to estimate the risk of embolism and benefit of specific therapies.
Cardiac disorders that carry a risk of brain embolism can be divided into seven
groups: (i) arrhythmias, especially atrial fibrillation and atrial flutter, (ii) valvular heart dis-
eases, including mitral stenosis, prosthetic heart valves, infective endocarditis, and maran-
tic endocarditis, (iii) ventricular myocardial abnormalities leading to dilated ventricles,
especially those related to coronary artery disease, and myocarditis, (iv) intracardiac
masses, especially tumors, such as myxomas and thrombi, (v) intracardiac shunts,
especially intra-atrial septal defects and patent foramen ovale (PFO), that allow emboli
forming in the peripheral veins to gain access to the systemic circulation (rather than
being filtered by the lungs) leading to so-called paradoxical embolism, (vi) atrial lesions,
such as dilated atria, thrombi, tumors (e.g., myxomas and fibroelastomas), and atrial septal
aneurysms, and (vii) aortic lesions, such as aortic atherosclerosis.
In 1856, Virchow (3,4) described three requirements for the development of
thrombi: a region of circulatory stasis, injury to endothelial surfaces, and increased
blood coagulability. In areas of stasis, a low shear rate and other factors activate the
classical coagulation cascade, leading to the formation of erythrocyte-fibrin thrombi.
Stasis occurs most often in the atria and atrial appendages in patients with atrial

129
130 Caplan and Manning

fibrillation and dilated cardiomyopathy, in the ventricular chambers in patients with global
dysfunction, and in regions of akinesis, dyskinesis, and aneurysm. Abnormal myocardial
endothelium occurs in patients with myocardial infarcts, ventricular aneurysms, and
inflammatory and other myocardopathies and endocardial disorders. Valvular endo-
thelium can be damaged by many different conditions. Loss of a protective endothelial
surface exposes circulating blood to the underlying tissues and causes platelet activation,
adhesion, and secretion, and also activates the coagulation cascade (4,5). Recent studies
have shown increased platelet activation and blood coagulability in patients with
cardiac-origin embolism (6,7).
In this chapter, we describe the cardiac disorders known to predispose patients to
brain embolism. We emphasize some of the sources that are less well known. In the
succeeding chapters, we will discuss diagnosis and treatment.

ARRHYTHMIAS
Atrial Fibrillation
Atrial fibrillation is characterized by disorganized atrial electrical activation, and, as a
result, atrial contractions are disorganized and ineffective (8). Atrial fibrillation is the
most common arrhythmia, afflicting more than 2.5 million (about 0.4% of the adult popu-
lation) in the United States alone. Atrial fibrillation becomes much more common after 60
years of age. An analysis of the Framingham Heart Study population showed that at age 40
the lifetime risk of developing atrial fibrillation was 26% for men and 23% for women (9).
It is estimated that almost six million adults will have atrial fibrillation in the year 2050
(10). Perhaps as many as 5% of individuals over age 60 have atrial fibrillation (8 – 11).
Epidemiological studies during the past three decades have firmly established that atrial
fibrillation is a major risk factor in stroke, that strokes in patients with atrial fibrillation
are most often due to cardiogenic embolism, and that in moderate- and high-risk patients,
antithrombotic treatment substantially reduces the frequency of clinical brain embolism in
these patients (8 – 12).
The etiology of atrial fibrillation and associated cardiac and other medical factors
affect the risk of stroke in patients with atrial fibrillation. In the Framingham Heart
Study, rheumatic heart disease and atrial fibrillation conveyed a 17.6-fold increased risk
of clinical stroke compared with subjects with no history of atrial fibrillation (12).
For those patients who do not have valve disease, atrial fibrillation increases the risk
5.6-fold compared with nonfibrillation (12). Other clinical risk factors that increase risk
of embolism in the atrial fibrillation population include advanced age, congestive heart
failure, a history of systemic hypertension, and prior thromboembolism (13,14).
In patients with atrial fibrillation who do not have valvular disease, thrombi often
form in the left atrial appendage, whereas patients with atrial fibrillation and valvular
disease have thrombi in the left atrial appendage and the body of the left atrium (15,16).
Figure 1 shows a thrombus in the left atrial appendage. Echocardiographic findings that
identify patients at increased risk for embolism include left atrial enlargement (17,18),
abnormal left atrial appendage function (15,19 – 21), mitral annulus calcification (MAC),
and left ventricular dysfunction (15,18). For the atrial fibrillation population, mitral
regurgitation appears to be somewhat protective against clinical thromboembolism (22).
After atrial thrombus, transesophageal echocardiography (TEE) evidence of spon-
taneous echo contrast (also called “smoke”) is the most important factor that predicts
the likelihood of cardiogenic embolism in patients with atrial fibrillation. First described
in patients with mitral valve disease (23), spontaneous echo contrast refers to swirling
hazes of echogenicity within the atria and in left ventricular aneurysms. Spontaneous
Cardiac Sources of Embolism: The Usual Suspects 131

Figure 1 A thrombus in the left atrial appendage (black arrows) in a patient with atrial fibrillation.

echo contrast can vary from a faint, cloudlike appearance to bright contrast that often may
make it difficult to exclude an atrial thrombus. Spontaneous echo contrast is probably due
to the interaction between plasma proteins and erythrocytes at low shear rates (15,24). The
major determinants of spontaneous echogenicity are the fibrinogen levels and slow intra-
cardiac flow (25). Antithrombotic therapy has no impact on the severity of spontaneous
echo contrast.

Atrial Flutter
Knowledge of the clinical risk attributable to atrial flutter is far less than its more common
cousin, atrial fibrillation. This is because atrial flutter is far less common in the general
population and often degenerates to atrial fibrillation or patients have periods of both
atrial fibrillation and atrial flutter (26). For this reason, many epidemiologic and clinical
studies of patients with atrial fibrillation have included patients with atrial flutter.
Although atrial flutter is associated with a more organized atrial contraction pattern,
atrial appendage function is depressed and spontaneous echo contrast may be found.
Clinical and echocardiographic risk factors for embolism in atrial flutter are not well
defined but are presumed to be similar to atrial fibrillation (27).

CARDIAC VALVE DISEASE

Cardioembolic strokes are common among those with valvular heart disease (28).
Abnormalities of valve surfaces and changes in valve function and cardiac physiology
that result from valve disease promote the formation of both white platelet – fibrin
thrombi and red clots on valve surfaces and in the adjacent cardiac chambers. Pieces of
calcium associated with chronic valvular disease may also embolize. Stenotic valves
have decreased pliability and irregular surfaces; progressive commisural adhesions and
valve leaflet dystrophic calcifications develop, leading to progressive narrowing of the
cross-sectional area of valve orifices. Valvular outlet obstruction causes increased turbu-
lence of blood flow. The intensity of turbulence is markedly increased in the jet stream of
blood distal to stenotic valves (29). Platelets are activated in regions of increased turbu-
lence; the amount of thrombus formed is directly related to valve orifice turbulence (30).
132 Caplan and Manning

Distal to stenotic valves, blood flow consists of a central jet stream surrounded by
annular eddies that course between the outflow tract walls and the mainstream (31).
These eddies permit blood to remain more in close contact with the irregular valve sur-
faces than in regions of normal laminar flow. Platelets activated by the turbulent jet
stream have prolonged contact with dystrophic irregular valve surfaces, causing adhesion
of platelet-fibrin thrombi to valve surfaces, further platelet activation, and formation of
thrombi. Valve incompetence prolongs the time that blood is in contact with abnormal
valve surfaces and also promotes thrombus formation. Valve disease often leads to
atrial and ventricular cavity enlargement. Left atrial enlargement is especially common
in patients with mitral stenosis and mitral insufficiency. In patients with mitral stenosis,
enlargement of the left atrium is associated with stasis and thrombus formation when
atrial fibrillation develops, but thromboembolic risk among those with mitral stenosis is
increased even in the absence of atrial fibrillation.

Rheumatic Mitral Valve Disease


Although the incidence of rheumatic fever and rheumatic heart disease has dramatically
declined during the past decades, rheumatic heart disease is still an important cause of
brain embolism worldwide. The mitral valve is most often involved in women, whereas
the aortic valve is more commonly involved in men. Second in frequency is involvement
of both the mitral and aortic valves. The pulmonic and tricuspid valves are seldom the site
of important clinical rheumatic valvulitis.
Clinicians have long emphasized that embolization, especially to the brain, may be
the earliest clinical indication of rheumatic mitral stenosis. Harris and Levine (33,34) com-
mented in 1941, “It seemed that the typical case was one in which paralysis occurred sud-
denly at a time when there was no complaint of dyspnea and the patient was able to lie flat
in bed and had been ambulatory” (32). They studied 72 patients with mitral stenosis and
brain embolism. In 17 (24%) patients, the heart rhythm was regular at the time of the brain
embolism, and, as far as could be ascertained, the patients never had atrial fibrillation (32).
Atrial fibrillation was present in 55 (76%) patients. The initial stroke was often very
severe, leading to persistent hemiplegia. The case fatality rate was high: 24 (33%) patients
died within a few days or a few weeks after their cardioembolic stroke (32).
The frequency of clinical embolism in patients with mitral stenosis ranges in various
series between 10% (34) and 20% (35,36) and is likely skewed by referral bias. Fifty to
seventy-five percent of clinical emboli involve the brain. Although embolism does
occur in patients with mitral stenosis who are in normal sinus rhythm, the development
of atrial fibrillation greatly increases the risk. In a large study of 754 patients with
chronic rheumatic heart disease followed for more than 5000 patient-years, the incidence
of embolism was 1.5% per patient-year (34). The incidence of embolism was seven times
higher in patients with atrial fibrillation than in those who had sinus rhythm. One-third of
recurrences of embolism occurred during the first month and two-thirds during the first
year after the onset of atrial fibrillation (34).
Rheumatic mitral regurgitation is a less frequent cause of brain embolism than
mitral stenosis. Among individuals with embolism in one series, 93% had predominant
mitral stenosis, and only 7% had mitral insufficiency (37). Mitral insufficiency is often
accompanied by progressive left ventricular hypertrophy.

AORTIC VALVE DISEASE

Progressive calcific aortic stenosis and/or aortic regurgitation often develop between the
ages of 20 and 60 in patients with congenital bicuspid aortic valves and can also follow
Cardiac Sources of Embolism: The Usual Suspects 133

rheumatic valvulitis. Calcific degenerative changes usually are well developed during the
fourth and fifth decades of life in patients with bicuspid valves, whereas idiopathic calcific
aortic stenosis is more prevalent in the sixth through eighth decades (38). Some observers
believe that idiopathic calcific aortic valve disease of the elderly is due to inflammation
and atherosclerosis, but proof of this hypothesis is not yet available. Microthrombi with
evidence of organization have been found at necropsy in 53% of stenotic aortic valves
(39). Changes in the aortic valve are progressive. Thickening of previously diseased
valves is thought to result from the deposition of fibrin. Fibrin deposits become organized
and calcified with resultant distortion of the normal valve architecture. Bicuspid and cal-
cific aortic valves are not able to open freely. Narrowing and irregularity of the valve
orifice contributes to turbulent blood flow. Eddies form in the region of the sinus of Val-
salva and also adjacent to any regurgitant jet stream that flows into the left ventricle
(40). Abnormal flow and abnormal valve surfaces activate platelets and induce fibrin depo-
sition, accounting for the prevalence of microthrombi along valve surfaces.
Embolism has been considered a much less common occurrence in patients with
aortic valve disease when compared to those with mitral valve disease. Pleet et al. (41)
reported four patients who had bicuspid aortic valves and cerebrovascular events: three
had sudden onset strokes, and the other patient had recurrent stereotyped transient neuro-
logical symptoms. Full evaluation showed no cause for the brain infarcts except for the
bicuspid valve, and the authors attributed the strokes to brain embolism from the conge-
nitally abnormal valves. The fourth patient, who had repeated transient ischemic events,
had a chronic hematological disorder and may not have had brain embolism. Others
have reported instances of spontaneous brain embolism from calcific aortic valves
(42 –44). In each patient the calcific embolus was seen on noncontrast CT as a dense
calcified region, and vascular studies showed that the calcific density was within intracra-
nial arteries.
Clinical and necropsy studies show that embolism from calcific aortic valves is
probably not rare. Soulie et al. (45) found emboli in 33% of 81 patients with calcific
aortic stenosis. Holley et al. (46) in another autopsy study, found calcific emboli in 37
of 165 (22%) patients with calcific aortic stenosis. Thirty-two emboli were found in the
coronary arteries, eleven in the renal vessels, one in the central retinal artery, and one
in the middle cerebral artery (MCA) (46). Although the MCA was occluded by a calcific
embolus in one patient, no neurologic signs were recorded and no infarct was found (46).
During life, calcific emboli have often been identified in the eye because of their typical
morphology on fundoscopic examination of the retina (47,48). Calcific retinal emboli
appear as white, irregular, immovable densities and are usually distinguishable from
bright cholesterol crystals and fibrin-platelet plugs. Among 103 patients with retinal
artery occlusions and cardiovascular disease, aortic stenosis was present in 11 patients
and was the most common cardiac lesion (48).
In all clinical studies, symptoms that reflect embolization occur more often after
cardiac procedures (catheterization and surgery) than occur spontaneously. Kapila and
Hart (49) described a patient with calcific aortic stenosis who developed a left hemiparesis
two days after cardiac catheterization, and a calcific embolus was seen on CT scan occlud-
ing the right MCA. The risk of stroke from cardiac catheterization among patients with
aortic stenosis is likely underestimated. Omran et al. (50) reported on 152 patients with
aortic valve stenosis referred for cardiac catheterization. Among the 101 patients random-
ized to retrograde crossing of the aortic valve, three (3%) patients had a clinical stroke, and
an additional 19% had evidence of silent brain infarcts when comparing head MRI
performed prior to and 48 hours after catheterization. This compared with no clinical
or silent events among patients who did not have catheter crossing of their valve.
Aortic valve surgery is especially associated with a high frequency of embolism.
134 Caplan and Manning

Holley et al. (51) found 82 instances of embolization among 38 of the 62 patients (61%)
who had closed valvulotomy or aortic valve replacement and died at various intervals after
surgery. As might be expected, embolization is even more common in patients with endo-
carditis superimposed upon bicuspid or calcific aortic valves than it is in noninfected
valves. The discrepancy between the relatively high frequency of calcific emboli found
at necropsy and in the eye and the low frequency of clinically symptomatic brain and visc-
eral organ ischemic events may be explained by the small size of the embolic particles and
the fact that visceral emboli are much harder to diagnose than brain emboli.
Not much data are available regarding embolism in patients with isolated aortic
insufficiency. Aortic regurgitation is caused by the dysfunction of the aortic valve leaflets
or aortic root dilation. Bicuspid aortic valve, rheumatic valvulitis, and infective endocar-
ditis are probably the most common causes of aortic leaflet disease, whereas Marfans,
aortic dissection, and annulo-aortic ectasia due to hypertension are the common causes
of aortic root dilation (38). Syphillis leading to aortic root dilation was formerly a
common cause of aortic valve insufficiency, but it is now quite rare.

Mitral Valve Prolapse


The topic of embolism in patients with mitral valve prolapse (MVP) has always been con-
troversial. Barlow and Bosman (52), in an early report of the mid-systolic click-MVP syn-
drome, described a 23-year-old woman who had transient left-arm weakness, and
evaluation showed MVP. No details of the neurological symptoms or signs were included
and the relationship of the neurological event to her heart condition was not considered
(52,53). Subsequent reports of a possible relation between MVP and brain ischemia by
Barnett et al. (53 –56) occurred during 1974– 1980. The initial report was of four patients,
but Barnett et al. (54,57) later expanded the number of cases to 14 patients. All patients
were relatively young (10 – 48 year), and none had cardiovascular risk factors or
occlusive vascular lesions. Since then, a number of case-control and necropsy studies
have shown that patients with MVP do have cardiogenic embolism but not very often. Cer-
ebrovascular events in patients with MVP have a relatively low recurrence rate even
without treatment and with no attributable risk for those under the age of 45 years (58).
MVP is a common cardiac valvular abnormality among young and middle-aged
adults (59). Estimates of prevalence range from ,1% in men to up to 5% in women
(60). Systolic prolapse of the posterior leaflet is most common but can be bileaflet or
rarely isolated anterior leaflet prolapse. The pathological process is the disruption of col-
lagen and infiltration by a myxomatous substance rich in mucopolysaccharide. The mitral
valve leaflets are often thickened. The chordae tendinae and the mitral annulus may also
contain myxomatous deposits with elongation of the chordae, which sometimes rupture,
and dilatation of the mitral valve annulus (61). Mitral regurgitation develops when the
mitral leaflets fail to coapt. At necropsy, thrombi have been found, especially in the
angle between the posterior leaflet of the mitral valve and the left atrial wall (57,62).
The development of an adherent thrombus in the cul-de-sac created between the prolap-
sing posterior mitral valve leaflet and the atrial wall may be attributed to an irregular
surface caused by a jet of mitral regurgitant (53). A friable, granular, yellow thrombus
composed of fibrin and platelets was found at necropsy in a 21-year-old patient who
died after the sudden onset of a left hemiplegia (63). Fibrin emboli were found in the
coronary and renal arteries as well as in the frontal MCA branches in the brain (63).
MVP is diagnosed by echocardiography when there is abnormal posterior systolic
motion of the coapted posterior and/or anterior leaflets of at least 2 mm in the parasternal,
long-axis view (59). Mitral valve thickening and redundancy and the presence of mitral
Cardiac Sources of Embolism: The Usual Suspects 135

regurgitation, especially late systolic mitral regurgitation, are important additional criteria
for the presence of important myxomatous mitral valve changes (64–66). About 8% of
patients with MVP develop severe mitral regurgitation, leading to congestive heart failure
and necessitating mitral valve replacement. Atrial fibrillation can occur at any time but is
more common in older patients, especially those with mitral regurgitation and large left
atria. Myxomatous valves can become infected during bacteremia. Antibiotic prophylaxis
is indicated in the presence of mitral regurgitation, but the frequency of infective endocar-
ditis is quite low (67). MVP most often occurs in isolation but is more common in patients
with inherited connective tissue disorders, such as Marfans, Ehlers-Danlos, osteogenesis
imperfecta and bicuspid aortic valves (56).
Abnormalities of platelet function have been shown in patients with MVP and throm-
boembolism. Shortened platelet survival time, an increase in circulating platelet aggregates,
and increased levels of b-thromboglobulin and platelet factor-4 have been reported in
patients with MVP (53). Interaction of circulating platelets with abnormal endocardial
and valve structures found in patients with myxomatous valve degeneration causes increased
platelet aggregation, adhesion, and secretion. Platelet fibrin aggregates adhere to abnormal
valve surfaces and later embolize or promote formation of erythrocyte-fibrin clots.

Mitral Annulus Calcification


Mitral Annulus Calcification (MAC) is a degenerative disorder of the fibrous support
structure of the mitral valve that occurs rather commonly in the elderly, especially in
women. MAC is also associated with hypertension, coronary atherosclerotic heart
disease, and occlusive cerebrovascular disease. Posterior mitral annular calcification is
most common and is easily recognized on transthoracic echocardiography. McKeown
(53,68) found MAC at necropsy in 27% of 100 elderly patients. Among 5694 individuals
in the Framingham Heart Study, 2.8% had posterior submitral calcification; 95% of those
patients who had MAC came from the 40% of subjects who were more than 59 years of
age, and twice as many women as men had MAC (69). In the original autopsy description
of MAC, which appeared in the New England Journal of Medicine in 1962, four of the 14
patients described by Korn et al. (70) had brain infarcts, multiple in three. The first import-
ant clinical premortem description of MAC as a potential cause of stroke was in 1979 by
DeBono and Warlow (71), who studied 151 consecutive patients with retinal or brain
ischemia. They found MAC in eight patients, compared to no instances of MAC in age-
and sex-matched controls who did not have brain or eye ischemia (71).
Perhaps, the best epidemiological study of the relationship of MAC with stroke was
the Framingham Heart Study (72). Between 1979 and 1981, 426 men and 733 women in
the Framingham Heart Study cohort (average age of 70) who had no prior clinical strokes
had m-mode echocardiograms. Among these 1159 patients, 44 (10.3%) men and 116
(15.8%) women had MAC. During eighth year of follow-up, 51 (5.1%) patients without
MAC had strokes compared with 22 (13.8%) patients with MAC; MAC was associated
with a 2.10 relative risk of stroke (95% confidence interval 1.24 –3.57, P ¼ 0.006) (72).
There was a continuous relation in this study between frequency of stroke and severity
of MAC; each millimeter of thickening on the M-mode echocardiogram represented a
relative risk of stroke of 1.24. Even when patients with atherosclerotic heart disease
and congestive heart failure were excluded, patients with MAC still had twice the
stroke risk as those without MAC (72).
Pathological data is more convincing, in our opinion, in linking MAC to brain embo-
lism. Korn et al. (70) reported the clinical and necropsy data on 14 patients with MAC.
They noted that calcification has a predilection for the posterior portion of the mitral
136 Caplan and Manning

annulus ring. Calcific masses often projected superiorly toward the atrium and centrally
into the cavity of the left ventricle (70). Pomerance later noted ulceration and extrusion
of the calcium through the overlying cusp into the ventricular cavity in some patients
with MAC studied at necropsy, and thrombi were attached to the ulcerated regions in
four patients (73). The embolic material can be either calcium (as has also been shown
in calcific aortic stenosis) or thrombus.
Thrombi attached to calcified mitral annuli have also been shown by echocardiogra-
phy. Stein and Soble (74) reported two such patients. TEE showed a 2 mm mobile throm-
bus attached to the atrial surface of the calcified posterior portion of the mitral annulus in a
74-year-old woman who had developed a sudden onset right hemiparesis and aphasia.
There were no other cardiac sources of emboli. In a second patient who had a parietal
lobe brain infarct, TEE showed a 5 mm mobile thrombus attached to an 8 mm calcified
nodule on the posterior mitral valve leaflet (74). Eicher et al. (75) reported on ten
patients with MAC who underwent TEE in which thombus assocated with MAC was
identified in three (30%) patients. Thrombus resolved with antithrombotic therapy.

Prosthetic Cardiac Valves


Advances in cardiac diagnosis and cardiac surgery have led to increasingly frequent repla-
cement of heart valves. More than 60,000 valve replacements are performed annually in
the United States alone (76). Mechanical valves are made primarily with metal and
carbon alloys and are inherently quite thrombogenic. Thrombogenic potential is highest
with caged-ball prostheses (e.g., Starr-Edwards valve), lowest in individuals with bileaf-
let-tilting-disk prostheses (e.g., St. Jude Medical), and intermediate with single-tilting-
disk valves (e.g., Bjork-Shiley) (76). Bioprosthetic valves are most commonly heterografts
derived from pig or cow pericardial or valve tissues mounted on metal supports and are
currently the most common choice for valvular prosthesis, especially among older
patients. Homografts in the form of preserved human cadaveric valves are occasionally
used for valve replacements in middle-aged adults. Bioprosthetic valves have low throm-
bogenic tendencies (but still higher than native valves), and so long-term anticoagulation
is ordinarily not prescribed. Older bioprosthetic valves were less durable than mechanical
valves, but newer valves demonstrate excellent durability (76).
Valve thrombosis and endocarditis are important complications in patients with
mechanical and occasionally bioprosthetic valve prostheses. Important valve thrombosis
causes pulmonary congestion, reduced cardiac output, and brain and systemic embolism.
The frequency of prosthetic-valve thrombosis is estimated to be between 0.1% and 5.7%
per year (77,78). Alteration of blood flow related to mechanical valves, as well as the
inherent thrombogenicity of the materials used, promote thrombosis and thromboembo-
lism. Flow velocity studies show turbulent flow patterns that contribute to vascular
stasis and thrombus formation around mechanical valve prostheses (79). Hematological
studies in patients with mechanical valves show elevation of platelet-specific proteins
that indicate platelet activation and decreased platelet survival in patients with artificial
heart valves (80 – 82).
The pathophysiological events that promote thromboembolism begin during heart
surgery. Prosthetic materials and injured perivalvular tissues cause platelet activation as
soon as circulation is restored. Dacron sewing rings common to all prosthetic valves
form a fertile nidus for platelet activation and adhesion (2). Prosthetic materials also acti-
vate the intrinsic pathway of the coagulation cascade (83). Both platelet activation and
activation of the coagulation cascade promote the formation of red erythrocyte-fibrin
thrombi. Degenerative changes in bioprosthetic valves also can lead to the deposition of
Cardiac Sources of Embolism: The Usual Suspects 137

white platelet-fibrin thrombi (84). Late thrombosis has also been shown in the cusp sinuses
of bioprosthetic mitral valves that have undergone fibrosis and calcification (85,86).
Embolism is an important complication in patients with both mechanical and bio-
prosthetic valves. Most symptomatic emboli go to the brain. Patients with mitral mechan-
ical valves have a higher frequency of embolization than those with aortic valves,
especially patients with coexistant atrial fibrillation. This is probably related to the
lower velocities across the mitral valve and large left atria in patients with mitral valve
prostheses.

INFECTIVE ENDOCARDITIS

Although neurological complications of infective endocarditis have been well recognized


since the time of Osler (87), the clinical spectrum of endocarditis has changed dramatically
during the past decades. Compared with endocarditis patients three decades ago, present
day series of patients with infective endocarditis are on average older, use illicit drugs
more often, more commonly are on hemodialysis, more often have tricuspid and prosthetic
valve infections, and have more infections with staphylococcus aureus (88 –90).
Valvular vegetations in patients with infective endocarditis are composed of plate-
lets, fibrin, erythrocytes, and inflammatory cells attached to the damaged endothelium of
native and prosthetic valves. Organisms are enmeshed, often deep within the fibrinous
material, explaining why antibiotics may have difficulty sterilizing the lesions. Veg-
etations range in size from a few millimeters to several centimeters, and their potential
for embolization is directly related to size, mobility, and friability (91). Larger vegetations
are seen among those with staphylococcus aureus and fungal endocarditis. Figure 2 shows
vegetations in a patient with infective endocarditis.
Salgado et al. (92) compared valve involvement in patients with and without
neurologic complications of endocarditis. Aortic valve disease was present in 38
(59.4%) of 64 patients with neurologic complications, as compared to 65 (59.6%) of
111 patients without neurologic complications. Mitral involvement ocurred in 22
(34.4%) of 64 patients with neurologic complications, as compared to 34 (31.5%) who

Figure 2 Bacterial vegetations (black arrows) found at necropsy in a patient with infective
endocarditis.
138 Caplan and Manning

did not have neurologic problems (92). The frequency of tricuspid valve endocarditis is
quite variable, possibly related to the underlying population served by the facility (e.g.,
intravenous drug abusers). Although the predominant underlying valve disease was for-
merly rheumatic, now calcified valves, MVP, and prosthetic valves make up a higher pro-
portion of endocarditis cases than in the past. In the Salgado et al. (92) series, among
patients with prosthetic valve infections, mechanical valve endocarditis was more often
associated with neurologic complications than bioprosthetic valve endocarditis.
In 1969, Mayo Clinic neurologists reported their experience accumulated during the
period 1950 – 1964 (93). Among 385 patients with endocarditis, 110 (29%) patients had
neurologic complications, including 55 (50%) with cerebrovascular disease. Forty-four
(80%) of the 55 individuals with cerebrovascular complications had brain infarcts (38
carotid system, 6 vertebrobasilar). Among the 11 patients with brain hemorrhages, eight
hemorrhages were into the brain substance (intracerebral), and three were subarachnoid
(93). Twenty-one patients in the Mayo Clinic series had acute encephalopathy and
seven had meningitis. These syndromes, brain ischemia, intracerebral hemorrhage, subar-
achnoid hemorrhage, encephalopathy, and meningitis, remain the major neurological
complications found in recent series of patients with both native valve and prosthetic
valve endocarditis (92,94 – 97).
Brain ischemia in patients with endocarditis is invariably due to embolism. Ischemia
can take the form of transient ischemic attacks that involve the brain or the retina.
About one-fifth of patients with endocarditis develop brain infarcts: Brain ischemia is
reported in 17% (92), 19% (94), and 15% (97) of patients in various infective endocarditis
series. At necropsy, small cortical or subcortical bland infarcts are found, usually multiple.
In one series, 19 (58%) of 33 infarcts were small, 11 (33%) were moderate in size, and
three (9%) were large (94). Larger infarcts were found in patients with staphylococcus
aureus endocarditis. In another series, among 133 episodes of endocarditis, three patients
had transient monocular visual loss, and one patient had a retinal infarct (95). Brain ische-
mia may be the presenting sign of endocarditis and is most common early in the course of
the disease. Ischemic strokes can also occur in the days after antibiotic treatment is begun.
Transcranial Doppler monitoring of patients with endocarditis shows that microemboli
continue to occur even after antibiotic treatment, although more emboli are detected
before and early after antibiotics are initiated.
Brain hemorrhage is much less frequent than ischemia, but the effects of hemorrhage
can be devastating or mortal. Some patients have bleeding into bland infarcts. This usually
takes the form of hemorrhagic infarction—petechial and larger hemorhagic mottling
within the infarct without formation of a frank discrete hematoma. In some patients,
large hematomas develop. Hematomas are often found in patients with mechanical
valves treated with warfarin anticoagulation. In other patients, intracerebral hemorrhage
results from rupture of a septic arteritis caused by the embolization of infective material
to the artery with necrosis of the arterial wall (98,99). In a small minority of cases, intra-
cerebral hemorrhage is due to rupture of a mycotic aneurysm into the brain substance.
Mycotic aneurysms are caused by the embolization of infected material into the wall
and adventitia of brain arteries. The aneurysms usually occur distally along arteries and
tend to be multiple. The location of aneurysms in patients with infective endocarditis is
similar to those found in patients with atrial myxomas, probably because of similar
embolic etiologies. In contrast, ordinary saccular “berry” aneurysms occur proximally
along the basal arteries of the circle of Willis. Angiography of patients without brain
hemorrhage seldom shows mycotic aneurysms. Many patients who develop brain hemor-
rhage have had an attack of transient or persistent brain ischemia in the hours or days
before the hemorrhage. This prodromal ischemia is explained by an arterial embolus
Cardiac Sources of Embolism: The Usual Suspects 139

causing brain infarction. Hemorrhage into an infarct or rupture of the artery that received
the infected embolus causes the hemorrhage that often proves fatal (98,99).
Diffuse brain-related symptoms, usually referred to as encephalopathy, are very
common in patients with endocarditis. Symptoms include lethargy and decreased
level of consciousness, confusion, agitation, poor concentration, and poor memory.
Encephalopathy has different explanations. Often the encephalopathy is metabolic and
is explained by systemic factors, such as azotemia, pulmonary dysfunction, hyponatre-
mia, and so on. In other patients, the encephalopathy is a toxic effect related to fever
and to the acute infection. Patients with staphylococcus aureus endocarditis are more
often encephalopathic than in endocarditis caused by other organisms. Necropsy and
CT/magnetic resonance imaging studies of patients with encephalopathy often reveal
multiple small, scattered brain infarcts, and/or microabscesses (95,100). Encephalo-
pathy usually develops during uncontrolled infection, with more virulent organisms
supporting the role of microscopic sized septic emboli as the cause (95,101).
Though reported, meningitis is rare in patients with endocarditis. The presentation is
often headache with fever. Meningeal infection is caused by the embolization of infected
vegetations to meningeal arteries.
The infecting organisms have changed during the years; staphylococcus aureus endo-
carditis has become more frequent and the cause of increased morbidity (90). Patients with
staphylococcus aureus endocarditis have larger and more multiple brain infarcts (94),
encephalopathy (95), and intracerebral hemorrhages (92).
Laboratory studies are very helpful in diagnosing endocarditis, but the clinical find-
ings remain most important for recognition. The disease should be suspected in any
patient with unexplained fever and a new heart murmur. Multiple blood cultures should
be obtained prior to the initiation of antibiotics. The spinal fluid in patients with clinical find-
ings suspicious but not diagnostic of endocarditis can be helpful. The cerebrospinal fluid
may be normal or contain slightly increased protein levels and increased numbers of eryth-
rocytes and leukocytes. Usually, the pleocytosis is moderate (,300 cells/cc) and may be
predominantly lymphocytic or polymorphonuclear, unless a clinical picture of meningitis
is present, in which case there may be more white blood cells. The most important treatment
is the rapid introduction of antimicrobial therapy. Most neurologic complications occur
before or soon after the initiation of antibiotic treatment. Recurrent strokes do occur after
bacteriologic cure but rarely. In one series, among 147 patients discharged from the hospital
after treatment of infective endocarditis, 15 developed strokes after discharge; all except one
of the stroke patients had prosthetic valve endocarditis (92). Strokes in this series occurred
long after discharge (median 22 months) and were better explained by recurrence of
endocarditis, complications of anticoagulants, or to noninfective disease of the prosthetic
valves, than to cerebrovascular complications of the original endocarditic episode (92).

NONINFECTIVE FIBROUS AND FIBRINOUS ENDOCARDIAL LESIONS


(INCLUDING VALVE STRANDS)

Fibrous valve thickening, often with grossly visible vegetations that contain mixtures of
blood, platelets, and fibrin are sometimes found on the heart valves and adjacent endocar-
dium in patients who have no evidence of either rheumatic fever or bacterial endocarditis.
The first detailed description of such lesions was in 1924 by Emanuel Libman and
Benjamin Sacks (102), who reported four patients studied clinically and pathologically
of an “atypical verrucous endocarditis.” These patients included three young women
and one 19-year-old man. Necropsy showed fibrous thickening of valves with vegetations,
140 Caplan and Manning

especially along the closure lines of the valves and on the valve leaflets. The vegetations
extended to the papillary muscles and ventricular endocardium. The histopathology was
thought to be unique by the authors. In one patient: “In the mitral valve, there was a
deposit of agglutinated blood platelets over large flat areas, beneath which the endocardial
tissues were densely infiltrated with polymorphonuclear leukocytes and round cells . . .
The valve itself was enormously thickened owing to an old chronic inflammatory pro-
cess . . . The blood platelet masses showed a tendency in places to fibroblastic invasion.
The inflammatory process extended throughout the entire thickness of the valve, and
the vegetative deposit was therefore present on both the auricular and the ventricular
aspects of the valve” (102). Figure 3 is a drawing from the Libman and Sacks paper
illustrating the findings at autopsy in one of their patients.
Fibrinous pericarditis was present in three of the patients, and a skin rash, bleeding,
arthritis, anemia, and glomerulonephritis were common clinical features. The fouth patient
was the only one who had prominent clinical neurological abnormalities that consisted of a
unilateral paralysis and seizures that developed shortly before death. The authors specu-
lated that the neurological findings in this patient might be caused by emboli from the
valvular vegetations (the brain was not available for examination in this patient).
Libman and Sacks were uncertain of the diagnosis but noted that the clinical picture
resembled some of the erythematous diseases that Osler had mentioned in his textbook
of medicine (102). Baehr et al. (103) published a series of 23 patients who had acute

Figure 3 Drawing of a heart at necropsy. The left side of the heart shows a verrucous vegetations
along the line of closure of the mitral valve extending in places to the free edge. There are areas of
endocarditis on the papillary endocardium and adjacent mural endocardium and an isolated patch of
mural endocarditis in the region of the apex of the ventricle. A healing fibrinous pericarditis is also
present. Source: From Ref. 102.
Cardiac Sources of Embolism: The Usual Suspects 141

disseminated lupus erythematosis, among whom 13 had a nonrheumatic verrucous endo-


carditis similar to that described earlier by Libman and Sacks. Pollack et al. (104) reported
the pathological findings in disseminated lupus erythematosis in 1941. These clinical and
pathological reports brought the disease lupus erythematosis, known previously as
predominantly a skin disorder, to the attention of the medical community as an acute
disseminated systemic disease.
Gross, a younger colleague of Libman and Sacks at Mt. Sinai Hospital in New York,
reported a detailed study of 27 hearts, 23 of whom were fatal cases of acute lupus erythe-
matosis (105). Gross pointed out that the patients in the original Mt. Sinai Hospital report
had the typical clinical findings of lupus erythematosis, and Gross suggested that the endo-
carditic lesions be named after Libman –Sacks and that the verrucous endocardial lesions
were disgnostic of lupus erythematosis (105). Libman and Sacks (102), and Gross (105)
knew that similar endocarditic lesions also occurred in terminal or cachectic diseases,
such as carcinoma, tuberculosis and leukemia, and had usually been called nonbacterial
thrombotic endocarditis (NBTE). Since these early reports, we now know that similar
lesions of the cardiac valves and endocardium occur in patients with systemic lupus
erythematosis (SLE), the antiphospholipid antibody (APlA) syndrome, and marantic
NBTE. Presumably all have a similar pathogenesis.
Echocardiographic studies have attempted to define the frequency and importance of
noninfective endocarditic lesions in series of patients with SLE (106 –108). Galve et al.
(106) performed transthoracic echocardiography on 74 patients with SLE on two
occasions approximately five year apart. Clinically important valve disease was found
in 18% of patients, including seven with vegetations mostly on the mitral and aortic
valves. Nine patients had leaflet thickening and stiffness, causing stenosis or regurgitation
in six and calcification in two. Six of the 74 patients required valve surgery during the five
year of follow-up and one developed vegetations not present five year previously (106).
Roldan et al. (107) performed two TEE studies (29 months apart) on 69 SLE patients.
Valvular abnormalities were found on the initial TEE in 61% of patients, including
valve thickening (61%), vegetations (43%), valve regurgitation (25%), and stenosis
(4%). Involvement of the mitral valve was found with involvement of the aortic valve; tri-
cuspid valve disease occurred occasionally, but pulmonic valve involvement was rare. The
second TEE demonstrated valvular disease in 53% of patients (107). The combined inci-
dence of stroke, peripheral embolism, heart failure, and superimposed infective endocar-
ditis was 22% in those with valvular disease on TEE (107). Crozier et al. (108) found a
high frequency of mitral regurgitation (46%) among 50 Chinese women with SLE.
Stroke and microinfarcts were most often attributable to brain embolism from valvular
lesions or coagulopathy. The presence of coagulopathy and thrombocytopenia in SLE
probably correlates with the presence of valvular disease, although this relationship has
not been well reported.
The APlA syndrome has become recognized within the past two decades as a
prothrombotic syndrome separate from the SLE. The APlA syndrome is characterized
by frequent fetal loss, strokes, myocardial infarctions, thrombophlebitis, pulmonary
embolism, and thrombocytopenia. Serological testing reveals positive assays for the
lupus anticoagulant and/or anticardiolipin antibodies. Echocardiographic studies have
shown that there is a relatively high frequency of valvular cardiac lesions in patients
with this syndrome and that the valve lesions are indistinguishable from those found
in patients with SLE. Brenner et al. (109) studied 34 patients with the APlA syndrome
using transthoracic echocardiography. Fourteen (41%) patients had arterial thromboem-
bolism, 6 (18%) had venous thrombosis, and 14 (41%) had recurrent fetal loss.
Valvular lesions (mostly mitral and aortic thickening and vegetations) were found in
142 Caplan and Manning

11 (32%) patients, including 9 (64%) of the 14 with arterial thromboembolism (109).


Barbut et al. (110) studied the prevalence of APlA syndrome among patients in
whom echocardiography showed mitral and/or aortic regurgitation. Among 87 consecu-
tive patients with these valve dysfunctions, 26 (30%) had immunoglobulin G or M
anticardiolipin antibodies. Focal cerebral ischemic events occurred in eight (30%) of
these patients (seven judged embolic), including 7 of the IgG anticardiolipin positive
patients (110). Barbut et al. (111) studied 21 patients with APlA antibodies who had
focal cerebral ischemic events. Twelve (86%) of fourteen stroke patients, and 3
(42%) of seven nonstroke lesion patients had echocardiographic evidence of mitral
or aortic valve abnormalities. Eight (38%) of 21 patients with APlAs had SLE (111).
In a cooperative study performed by the APlAs in Stroke Study Group, among 128
patients who had brain or ocular ischemia and were APlA positive and had echocardio-
graphy, 16 (22.2%) had mitral valve abnormalities, and 2 (1.6%) had aortic valve
abnormalities (112). Figure 4 contains an echocardiogram that shows a vegetation on
the mitral valve in a patient with multiple brain emboli and APlAs and the appearance
of the mitral valve removed at surgery. Phospholipids are important constituents of
cardiac valve endothelium, blood platelets, vascular endothelium, and coagulation pro-
teins. At present, assays for APlAs only include testing for lupus anticoagulant and
anticardiolipin antibodies. Some patients with the clinical features of the APlA syn-
drome have negative antibody assays. Some of these patients also have prominent
valve vegetations and cardiogenic brain embolism.
Both hypercoagulability and NBTE have long been recognized to occur in patients
with cancer and other debilitating chronic diseases. Most often the cancers are mucinous
adenocarcinomas (113). In one study, among 20 cancer patients who had thromboembolic
disease of the brain and other organs, 16 (80%) had NBTE at necropsy (114). Among
those with NBTE, valvular involvement was mitral in eight (50%) patients, aortic in
four (25%), combined mitral and aortic in three (19%), and tricuspid in one (6%) patients.
Large vessel occlusive emboli and multiple infarcts and microvascular occlusions were
found in the brains of these patients (114). In another study, among 18 patients with
cancer and NBTE, 8 (44%) developed a stroke, and in 5 patients, stroke was the initial
clinical manifestation of cancer (115). Edoute et al. (116) performed prospective echocar-
diograms on 200 cancer patients and found a 19% frequency of NBTE. The valve lesions
equally involved the mitral and aortic valves, and elevated plasma D-dimer levels, a marker
for hypercoagulability was also often found in the cancer patients with clinical thromboem-
bolism (116).
NBTE is characterized by friable white or tan vegetations, usually along lines of
valve closure. The vegetations can be large. Microscopy usually shows degenerating plate-
lets interwoven with strands of fibrin and some leukocytes forming eosinophilic masses of
tissue. All three conditions—SLE, APlA syndrome, and NBTE—are associated with
hypercoagulability, strokes, and platelet abnormalities. The cardiac valve and endothelial
lesions in these three conditions are very similar and probably indistinguishable grossly
and microscopically. Platelet deposition, incorporation of fibrin, and the formation of
platelet thrombi on valve and endocardial surfaces are common to all three conditions.
Noninfective NBTE valve lesions are also found in patients with carcinoid tumors
(probably causally related to elevated serotonin levels in the blood), and after the use of
some drugs (ergotamine, methysergide, dexfenfluramine, and the combination fenflura-
mine and phentermine) (117). The valve and endocardial lesions that result are similar
to each other morphologically and consist of fibrotic thickening of the valves with
reduced pliability. To date, embolism has not been reported as a consequence of this
type of valve disease.
Cardiac Sources of Embolism: The Usual Suspects 143

Figure 4 Mitral valve vegetations in a patient with antiphospholipid antibody (APlA) syndrome
and multiple brain emboli. (A) Echocardiography showing a pedunculated, mobile lesion on
the mitral valve (white arrows). (B) Mitral valve removed surgically showing vegetations.
Abbreviations: LA, left atrium; LV, left ventricle; AO, aorta. Source: From Ref. 1.

TEE in older individuals often show strands of mobile tissue attached to valve
surfaces. The cause and significance of these strands remain uncertain. Lambl (118) had
originally described such filamentous outgrowths from the ventricular surfaces of the
aortic valves sometimes found at necropsy, and, therefore, these fibrous strandlike
lesions have often been called Lambl excrescences. Later Magarey (119) found similar
filiform strands on the atrial surface of mitral valves. The strands, which were composed
of a cellular connective tissue core covered by endothelium, were usually ,1 mm thick
and ranged in length from 1 to 10 mm. Magarey (119) related the strands to mitral
valve thickening and posited that they originated from fibrinous deposits on the valve
144 Caplan and Manning

surface. Freedberg et al. (120) reviewed retrospectively an unselected series of 1559


patients who had undergone TEEs during a two year period and found mitral valve
strands in 63 (4%) and aortic valve strands in 26 (1.7%) patients. Strands were found in
10.6% of patients referred because of suspected recent embolic events, compared to
only 2.3% of those referred for other indications (120). In another TEE study, Tice et
al. (121) prospectively sought mitral valve strands among all patients who had echocardio-
graphy during a two-year period at their hospital. Among 968 patients, 22 (2.3%) had
mitral valve strands, including 20 (91%) patients who had TEE because of brain ischemic
events. Overall, 20 (6.3%) of 318 patients having TEE because of brain ischemia had
strands, compared with only two (0.3%) of 650 patients having TEE for other
indications (121).
Nighoghossian et al. (122) reported three patients who had brain ischemic events
presumably related to mitral valve strands who had cardiac surgery. Extensive evaluation
including cerebral angiography and serological testing showed no cause for stroke other
than the valve lesions. The valve lesions were described as: a floating mass 6 mm thick
on the ventricular surface of the mitral valve, a 6 mm lesion on the anterior mitral
valve leaflet, and a sessile 5 mm lesion on the anterior mitral valve leaflet (122). One
patient had immediate cardiac surgery when the valve lesion was found; the other two
patients had surgery when they had subsequent strokes despite anticoagulant therapy.
Histopathological examinations showed that the lesions were composed of an acellular
fibrous core with rings of granular material and endothelial cells. In two patients,
thrombi were attached to the lesions (122).
Roberts et al. (123) compared the frequency of strands among patients referred for
TEE because of brain ischemia and those referred for other indications. An association
between brain ischemia and strands was found (odds ratio 4.4, 95% confidence interval
2.0 – 9.6). The association was maintained for men and women and all racial groups and
was strongest for younger patients and those with both mitral and aortic valve strands.
The effect of strands did not depend on valve thickness (123). Cohen et al. (124)
studied 338 patients referred to their echocardiographic labratory because of brain ische-
mia and compared the findings to 276 patients who had no history of brain ischemia.
Strands were found in 22.5% of brain ischemia patients, compared with only 12.1% of
controls (crude odds ratio of 2.1– 95% confidence interval 1.3– 3.4, P , 0.005). Strands
were often found in patients with mitral valve thickening (124). Homma et al. (125) per-
formed echocardiography on 619 stroke patients and found strands in 244 (39%), 36 (6%)
aortic, 172 (28%) mitral, and 36 (6%) aortic and mitral. These observations and the patho-
logical studies of Magarey (119) suggest that strands probably most often are formed
because of a degenerative process that causes fibrinous deposits on valve surfaces.
Emboli can arise from the abnormal valves, or, on occasion, from the strands, or from
thrombi formed on the surface of the valve or on the strands. Strands may share a patho-
genesis with valve lesions found in some patients with SLE, APlA syndrome, and cancer.
Some patients with strands have APlAs (126).

MYOCARDIAL AND CARDIAC CHAMBER LESIONS


Myocardial Infarction
Myocardial Infarction and Coronary Artery Disease
Systemic embolism is apparent clinically in about 3% (range 0.6 – 6.4%) of patients with
acute myocardial infarction with large anteroapical infarctions with aneurysm formation
Cardiac Sources of Embolism: The Usual Suspects 145

Figure 5 The heart at necropsy in a patient with a massive brain embolus. A large thrombus is
seen overlying a recent myocardial infarct. Source: From Ref. 2.

conveying the highest risk (127 –132). Most clinically symptomatic emboli are those that
involve the brain and present as acute strokes. Most strokes that occur in patients with
acute myocardial infarcts are caused by embolization of thrombi formed in the left
ventricle but some strokes are related to left atrial thrombi and extracranial occlusive
vascular disease. Figure 5 shows a large mural thrombus at necropsy in a patient with a
recent myocardial infarction who died of brain embolism. Vascular occlusions, including
coronary artery thrombosis, are followed by an increase in acute phase reactants, including
serine protease coagulation proteins. Venous thromboses and occlusion of atherostenotic
craniocervical arteries may occur in the days and weeks after myocardial infarction
because of this hypercoagulability.
Left ventricular thrombi have been described in up to 20 –40% of patients with acute
anteroapical myocardial infarcts but are unusual in patients with inferior infarction
(129,133,134). Most thrombi form on the apical wall of the left ventricle probably in
relation to regions of reduced ventricular contractility. Mural thrombi are more likely to
form in patients with transmural and large anterior myocardial infarcts than in those
with small infarcts. Areas of decreased ventricular contractility, low ejection fraction,
and development of a left ventricular aneurysm predispose to thrombus formation.
Large thrombi most often occur within the first three days after myocardial infarction
especially in those patients with large infarcts that carry a poor prognosis (135,136). Sys-
temic embolization occurs on average 14 days after myocardial infarction and is unusual
146 Caplan and Manning

after four to six weeks (137). Pedunculated, mobile thrombi that project into the left ven-
tricular cavity pose the greatest risks for embolization.
Regions of akinesis and dyskinesis and frank ventricular aneurysms often persist
after acute myocardial infarction. In the Coronary Artery Surgery Study, 7.6% of patients
had angiographically defined left ventricular aneurysms (138). Aneurysms are usually
anterior, apical, or anteroapical; posterior aneurysms involving the diaphragmatic wall
occur but are rare. Although aneurysms are relatively common and mural thrombi often
form within aneurysms, the risk of stroke is relatively low, about 5% (137,139). Posited
reasons for a rather low rate of embolization despite aneurysm formation include: mural
thrombi become organized and adherent to the aneurysm walls, thrombi often have a rela-
tively small area of contact with blood flow in the ventricle, and there is a loss of systolic
force generated by the underlying adjacent myocardium (86,140).
Considering all patients who have recovered after myocardial infarction, the risk of
stroke in patients with impaired left ventricular function after myocardial infarction is sub-
stantial. Among 2,231 patients with left ventricular dysfunction after acute myocardial
infarction who were followed for an average of 42 months, 103 (4.6%) patients developed
strokes (141). The estimated five-year stroke rate was 8.1%, and the actual stroke rate was
1.5% per year of follow-up (141). Large size of myocardial infarcts and reduced
left ventricular ejection fraction were the two most important predictors of the
development of stroke in this study. Patients with ejection fractions of ,30 were at
highest risk, and for every absolute decrease of 5% in the left ventricular ejection fraction,
the risk of stroke increased by 18% (141). In the Survival and Ventricular Enlargement
trial, the beneficial effects of anticoagulation in preventing stroke were found in patients
with moderate to severe decreases in left ventricular ejection fraction and also in patients
with better preserved function (ejection fractions .35%) (141).
Some patients with brain embolism are unexpectedly found to have left ventricular
thrombi (142,143). Some of these patients do not have a history of acute myocardial
infarction, and the cardiac cavity lesions are often first thought to represent myxomas
or other cardiac tumors. Sequential echocardiography shows that these thrombi can gradu-
ally regress or suddenly disappear (143 – 145) sometimes without development of neuro-
logical or systemic organ symptoms or signs of embolism. Thrombus formation and
spontaneous endogenous fibrinolysis and fragmentation of thrombi are dynamic processes.

Nonischemic Cardiomyopathies
Conditions that affect the endocardium and underlying myocardium can promote the for-
mation of intracavitary mural thrombi and resultant systemic and brain embolism. Prob-
ably, the three most important factors that determine thrombus formation are extent of
involvement of the endocardial surface, underlying ventricular contractility within the
ventricles, and activation of platelets and the coagulation system. Among the three
categories of cardiomyopathies—dilated, restrictive, and hypertrophic—mural thrombus
formation and embolism are most common among the dilated cardiomyopathies. Intraven-
tricular thrombus formation is enhanced by stasis of blood and by the loss of normal
subendocardial trabeculation. The network of subendocardial trabeculae can act as
many small compartments that produce high levels of force within the ventricle propelling
blood away from the endocardial surface (146). As the left ventricle dilates and systolic
function deteriorates (left ventricular ejection fraction ,40%), thrombi are more likely
to form, and patients have an increased risk of thromboembolism (146).
In one study of patients with idiopathic dilated cardiomyopathy, 60% had mural
thrombi defined by echocardiography, and even more had clinical or necropsy evidence
Cardiac Sources of Embolism: The Usual Suspects 147

of systemic embolism (147). Conditions as diverse as muscular dystrophies (148,149),


cardiac amyloidosis (150), peripartum cardiomyopathy (151,152), cocaine-related cardio-
myopathy (153) noncompaction of the myocardium (154), and cardiac sarcoidosis (155)
have all been reported to cause thromboembolism. Mural thrombi form mostly within the
trabeculae carnae near the cardiac apex. Atrial fibrillation further increases the frequency
of embolism in these groups. Embolism is unusual in patients with hypertrophic cardio-
myopathies unless they develop atrial fibrillation or end-stage dilated cardiomyopathy.

CARDIAC MYXOMAS AND OTHER TUMORS

Although cardiac tumors are rare, they are an important cause of embolism and are very
important to diagnose. The cells of origin for myxomas are endocardial and arise from
multipotential mesenchymal cells that persist as embryonal remnants during septation
of the heart (156). About 75% form in the left atrium and 15 –20% in the right atrium,
and the rest are located in the ventricles and very rarely (,2%) on a heart valve
(156,157). Most myxomas originate from the interatrial septum at the edge of the fossa
ovalis, but some originate from the posterior or anterior atrial walls or the auricular appen-
dage (156,157). Myxomas project from their endocardial attachments into cardiac
chambers. Myxomas are most often found in patients between the ages of 30 and 60;
women are slightly more often affected than men, and 5 –10% of patients have a familial
myxoma syndrome in which multiple myxomas are more common.
Embolism is estimated to occur in 30– 50% of patients with cardiac myxomas and
may be the presenting manifestation (156,158 – 160). Most emboli arise from the left
atrium and go to the brain or systemic organs. Occasional cases of right atrial myxomas
with systemic embolism have been reported in the presence of a PFO (161 –163). The
most common recognized site of embolism is to the brain, embolism to the eye can
cause transient or persistent visual loss, and embolism to the spinal cord has also been
reported (156,164,165). Most often, patients with brain embolism present with a sudden
onset focal neurologic deficit. Transient neurological deficits sometimes occur. Often
there has been more than one brain embolism before atrial myxomas are diagnosed.
Patients may also present with systemic symptoms (e.g., low grade fever, myalgia,
night sweats) or with syncope/presyncope if the myxoma is large enough to obstruct
mitral inflow. Usually the diagnosis of myxomas is made when the patient is referred
for an echocardiogram to evaluate a suspected cardiac source of embolism. Transthoracic
echocardiography is very sensitive for the detection of myxomas, although the frequency
of detection is likely related to tumor size and to residual tumor for those who present with
an acute neurologic event (166). Mobile myxomas on a stalk are more likely to embolise
than sessile tumors with a broad base of attachment. Embolic material may be tumor frag-
ments and/or overlying thrombus. Patients with progressive dementia caused by multiple
small brain infarcts (167), and sudden coma due to a shower of tumor emboli to multiple
brain arteries have been reported (168).
Occasional patients with brain emboli from myxomas have subarachnoid or intra-
cerebral hemorrhage. Bleeding is related to the development of hemorrhagic infarction
or rupture of aneurysms. Embolism of myxoma tissue to the wall of brain arteries
causes aneurysms that are similar to mycotic aneurysms found in patients with bacterial
endocarditis. Usually, the aneurysms are relatively small, multiple, and on peripheral
branches of brain arteries. Some aneurysms are quite large. The peripheral location of
aneurysms in patients with myxomas and endocarditis differs from that usually found in
patients with saccular (berry) aneurysms. Delayed progressive brain ischemia and
148 Caplan and Manning

enlargement of aneurysms can develop after the initial embolic event (169). Although
delayed growth and rupture of aneurysms, and metastatic tumor growth do occur, their fre-
quency is very low. In a review of 35 patients with atrial myxomas followed at the Mayo
Clinic, none had subsequent delayed neurological events attributable to their myxomas
(170). Recurrent cardiac tumors after surgery can be the result of incomplete excision
or reucurrent primary tumor as in the familial myxoma syndrome.
Papillary fibroelastomas are another primary cardiac tumor associated with brain
embolism (171,172). The lesions consist of multiple papillary fronds that radiate from
an avascular fibrocollagenous core attached by a short pedicle to the endothelium. They
most often arise from the valves with a slight predisposition for the aortic valve (173).
Angina and coronary ischemia may be caused by embolism to the coronary arteries or
transient obstruction of flow into the coronary ostia. Multiple brain infarcts usually
occur before the diagnosis is made by echocardiography. Other cardiac tumors are
more rare and also rarely present with neurologic symptoms. Rhabdomyomas are often
multiple, arise from the ventricular myocardium, and project into the ventricular cavity
(173). Tuberose sclerosis is present in about 33% of patients with rhabdomyomas (173).
Other cardiac tumors include lipomas, which often involve the interatrial septum
and can arise from the mitral or aortic valves, rhabdomyosarcomas, angiosarcomas, and
metastatic tumors. These rarely have been associated with brain embolism. Patients
with neurofibromatosis may develop rhabdomyosarcomas that have been reported to
cause brain emboli (174).

PARADOXICAL EMBOLISM AND CARDIAC SEPTAL LESIONS

Although once considered to be rare, emboli entering the systemic circulation through
right-to-left communication of blood are becoming more frequently recognized with the
advent of newer diagnostic technologies. By far, the most common potential intracardiac
shunt is a PFO. Because the nomenclature is confusing, it is worthwhile to review the
embryology of the division of the common atrium into left and right atria. The interatrial
septum begins to form during the fifth week of uterine life (175). The septum primum
grows caudally from the superior portion of the single atrium and fuses with the endocar-
dial cushion, closing the defect called the ostium primum. Another potential defect forms
from partial resorption of the septum primum and is called the ostium secundum. A second
septum, the septum secundum, arises from the superior portion of the atrium and descends
on the right side of the septum primum to cover the ostium secundum. The ostium secun-
dum is not covered completely because of the presence of the foramen ovale. The foramen
ovale consists of the septum primum and septum secundum, which are joined parallel to a
slitlike valve. This valve allows oxygenated blood to bypass the pulmonary circulation of
the fetus during intrauterine life (175). In a significant number of individuals the foramen
ovale remains somewhat patent during adult life.
The relatively high frequency of PFOs in the normal adult population has made it
difficult to be certain in an individual stroke patient with a PFO as to whether paradoxical
embolism through the PFO was the cause of their stroke or whether the PFO was merely an
incidental finding. Autopsy series have shown that about 30% of adults have a PFO (176).
Hagen et al. (176) studied 956 patients with clinically and pathologically normal hearts
and found a PFO in 27.3%. The frequency of PFOs declined with age: 34% during the
first three decades of life, 25% during the fourth to eighth decades, and 20% during the
9th and 10th decades. The average diameter of PFOs was 4.9 mm, and the size tended
to increase with age (176).
Cardiac Sources of Embolism: The Usual Suspects 149

Echocardiographic studies have shown that PFOs are more commonly found in
younger (,45 –55 year) patients with stroke than in controls, and PFOs are more
common in patients with an undetermined cause of stroke (“cryptogenic stroke”) than
in those in whom another etiology has been defined (177). Lechat et al. (178) examined
60 adults ,55 years old with stroke and 100 controls, using transthoracic echocardiogra-
phy with injections of agitated saline to identify PFOs. The frequency of PFOs was higher
in the stroke group (40%) than in controls (10%). Among patients with an identifiable
stroke cause 21% had PFOs, whereas 40% of patients with possible risk factors for
stroke, such as migraine, mitral valve prolapse, or use of oral contraceptives, had PFOs.
The frequency of PFO detection was highest (54%) in those patients with no identifiable
risk factor or cause of stroke (178). DiTullio et al. (179) studied 146 patients among whom
31% had no known cause of stroke and 69% had identifiable causes other than paradoxical
embolism. Among the total group of patients, 26 (18%) patients had PFOs. Patients with
cryptogenic stroke had a higher prevalence of PFOs than those with identifiable causes
both in the group ,55 years (48% compared to 4%) and those .55 years (38% vs.
8%) (179). A meta-analysis showed that among nine case-control studies involving 566
stroke patients and 458 control nonstroke patients, young stroke patients had an odds
ratio of 3.1 for having a PFO (180).
Review of series of patients with paradoxical embolism (181 – 183) through a PFO
and our own experience allows us to arrive at five criteria that, when four or more are met,
establishes with a high degree of certainty the presence of paradoxical embolism. The find-
ings are: (i) a situation that promotes thrombosis of leg or pelvic veins, for example long
sitting in one position, recent surgery, and so on, (ii) increased coagulability, for example
the use of oral contraceptives, presence of factor V Leiden with resistance to activated
protein C, dehydration, (iii) the sudden onset of stroke during sexual intercourse, straining
during bowel movements, coughing or other activity that includes a Valsalva maneuver or
that promotes right-to-left shunting of blood, (iv) pulmonary embolism within a short time
before or after the neurological ischemic event, and (v) the absence of other putative
causes of stroke after thorough evaluation.
The most common territory of stroke is the MCA, but the vertebrobasilar territory is
involved more than explained by chance (183,184). The 37.5% of posterior circulation
infarction in one study (182) is more than expected, as only 20% of blood flow to the
brain goes through the posterior circulation.
Paradoxical embolism has also been described through ventricular septal defects
(VSDs) (185), atrial septal defects (ASDs) (186), and pulmonary arteriovenous fistulas
(187). Among these, atrial septal defects are the most important and most frequent sites
after PFOs among patients with paradoxical embolism. There are three types of atrial
septal defects: primum ASDs (about 15% of ASDs) when the septum primum does not
fuse with the endocardial cushion leaving a defect; secundum ASDs (about 75% of
ASDs) when the fossa ovalis is not completely covered by the septum secundum; and
Sinus Venosus ASDs (5 –10% of ASDs) when there is an abnormal insertion of the
superior or inferior vena cava that overrides the interatrial septum leaving a defect at
the mouth of the vein insertion (175). Venous thrombosis can be detected if studies are
performed early in the course (188). Some venous thrombi involve the pelvic veins and
might be detected by abdominal and pelvic imaging techniques (189).
Predictors for the likelihood of paradoxical embolism through PFOs have been
sought using TEE (179,190 –192). In one study, the presence of an atrial septal aneurysm
accompanying the PFO was an important finding favoring the presence of paradoxical
embolism (190). In another study, PFOs were significantly larger (2.1 þ 1.7 vs.
0.6 þ 0.8 mm), and there were more microbubbles (14 + 11 vs. 1.6 + 0.8 per mm3) in
150 Caplan and Manning

patients with cryptogenic stroke than in those with identified causes of stroke (191).
Occasionally a thrombus can be seen during echocardiography traversing the foramen
ovale (193). Figure 6 from (193) shows such an embolus intransit through a PFO.
Atrial septal aneurysms have recently received increased attention in relation to their
possible role in contributing to brain embolism (177,194). Fusion of the septum primum
closes the foramen ovale and leads to a depression on the right side of the interatrial septal
wall. Bulging of the septum primum tissue of the atrial septum through the fossa ovalis
into either the right or the left atrial cavity is called an atrial septal aneurysm. Atrial
septal aneurysms were first reported in 1934 (195); they were found in 1% of necropsies
by Silver and Dorsey (196) and were found in 3 –4% of TEEs (197). The majority of

Figure 6 Thrombus traversing a patent foramen ovale (PFO). (A) An echocardiographic image of
the heart in the oblique plane (508) at the level of the aortic root. A large thrombus is in transit from
the right atrium to the left atrium through a PFO. (B) The large 13 by 1.5 cm thrombus removed at
surgery. Abbreviations: T, thrombus; RA, right atrium; LA, left atrium; AO, aorta; IAS, intraatrial
septum; TV, tricuspid valve. Source: From Ref. 193.
Cardiac Sources of Embolism: The Usual Suspects 151

patients with an atrial septal aneurysm have a PFO, and there is a strong association
between atrial septal aneurysms and interatrial shunts. The presence of either atrial
septal aneurysms and/or PFOs is strongly associated with the presence of cryptogenic
stroke especially among young stroke patients (177,194,197 –199). The exact independent
mechanism by which atrial septal aneurysms may contribute to brain embolism has not
been clarified. The atrial septal aneurysm might alter flow through the PFO or serve as
a nidus for local thrombosis due to abnormal endothelial surface (177). Thrombus has
been reported within the neck of an atrial septal aneurysm in one patient (200) and has
been found within the base of atrial septal aneurysms at necropsy (198).

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9
Cardiac Source of Embolism:
Pathophysiology and Identification

Warren J. Manning
Department of Medicine, Cardiovascular Division, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Cardiac sources of cerebrovascular ischemic events are increasingly being recognized and
may account for 20– 30% of the 500,000 strokes that occur annually in the United States
(1). Conventional transthoracic echocardiography (TTE) remains the cornerstone of
noninvasive cardiac imaging and has been extensively used in numerous studies during
the past three decades to identify both clinical and imaging risk factors for cardiogenic
thromboembolism. Subsequently, moderately invasive transesophageal echocardiography
(TEE) has been shown to be a superior method for the identification of most cardiac
sources of emboli (2,3) and to be more cost effective (4). Clinical paradigms for the use
of these primary imaging modalities continue to evolve. In addition, preliminary data
suggest that newer imaging methods, such as magnetic resonance imaging (MRI), may
also have an important role in identifying cardiogenic sources of embolism, but the
impact of these newer imaging methods on treatment and prognosis remains to be defined.

MAJOR SOURCES OF EMBOLI

Potential cardiac sources of thromboembolism are summarized in Table 1 and can be


broadly categorized into masses (e.g., thrombi, aortic atherosclerotic plaques, valvular
vegetations, and intracardiac tumors) that migrate/embolize, an increased propensity
for thrombus formation identified on imaging studies [e.g., left atrial (LA) spontaneous
echo contrast, prominent mitral annular calcification, left ventricular (LV) aneurysms],
and “passageways” for paradoxical thromboembolism, for example, patent foramen
ovale (PFO) and atrial septal defects, often accompanied by atrial septal aneurysms
(ASAs). The most common cardiac sources are LA thrombi, LV thrombi, aortic athero-
sclerosis, and PFO.

LEFT ATRIAL ANATOMY AND IMAGING

The body of the left atrium is a thin-walled, ovoid chamber that lies immediately posterior to
the ascending aorta. The endocardial surface of the LA is generally smooth and continuous,
161
162 Manning

Table 1 Sources of Cardioembolic Thromboembolism

Masses
Left atrial thrombi
Rheumatic mitral stenosis
Atrial fibrillation
Left atrial tumors
Intracardiac tumors, e.g., myxoma, fibroelastoma
Left ventricular thrombi
Anteroapical infarction/aneurysm
Aortic atherosclerosis
Hypertension
Hypercholesterolemia
Valvular heart disease
Endocarditis
Calcific aortic stenosis
Dysfunctional prosthetic valve
Propensity for thrombus formation
Spontaneous echo contrast
Left ventricular cavity enlargement/systolic dysfunction
Interatrial septal aneurysm
“Passageways” for paradoxical embolism
Patent foramen ovale
Atrial septal defect

as it developed from the fetal common pulmonary vein (5). Gender-specific and body-size
normograms for transthoracic LA measurements have been published, but absolute LA
dimension and length value are reported by most clinical echocardiographic laboratories.
With normal aging, the LA cavity dimensions increase. The body of the LA is well visual-
ized from multiple perspectives on TTE (Fig. 1). In contrast, the left atrial appendage (LAA)
is a highly trabeculated and often multilobulated cul-de-sac arising from the midportion of
the lateral wall of the LA near the entrance of the left upper pulmonary vein (Fig. 2).
Although the LAA is often not visualized on TTE, the close proximity of the esophagus
to the posterior LA (Fig. 3) and the absence of intervening bone or lung makes the TEE
an ideal imaging tool for visualization of both the LA and the LAA. Several studies have
documented the very high accuracy of TEE for the identification of LA and LAA
thrombi when compared with intraoperative series (5a,b).

LEFT ATRIAL THROMBI

LA thrombi are almost exclusively seen in association with atrial fibrillation and/or rheu-
matic mitral stenosis and are thought to account for nearly half of all cardiogenic throm-
boemboli. In the absence of mitral stenosis or atrial fibrillation, the incidental finding of an
LA thrombus is very rare (6), even in the setting of embolic stroke or transient brain ische-
mia (7). A report of almost 3,000 consecutive patients who underwent TEE for various
indications found an LA thrombus in only 0.3% of those in sinus rhythm (6). Another
study of nearly 900 patients presenting with an embolic stroke or a transient ischemic
episode and sinus rhythm identified an LA thrombus in only 1% of those without mitral
valve disease (7). The community-based SPARC (Stroke Prevention: Assessment of
Risk in a Community) study reported no atrial thrombi on initial TEE (8).
Cardiac Source of Embolism: Pathophysiology and Identification 163

MITRAL STENOSIS

The strong association of rheumatic mitral stenosis and stroke has long been recognized,
both in the sinus rhythm population and particularly among patients with atrial fibrillation.
The normal adult mitral valve cross-sectional area is 4– 6 cm2. There is tremendous
reserve, with clinical symptoms often lacking until the mitral valve area declines to
,2 cm2. The predominant cause of mitral stenosis is rheumatic fever leading to

Figure 1 Transthoracic echocardiogram in a normal subject. (A) Parasternal long-axis view in


which the left atrium (LA) and the anterior septum and inferolateral walls of the left ventricle
(LV) are seen. The anterior (small white arrow) and posterior mitral leaflets as well as the right cor-
onary and noncoronary (thick white arrow) aortic leaflets are also visualized. (B) Parasternal short
axis at the left of the aortic valve. The noncoronary (N) and left (L) coronary leaflets are identified.
The LA, right atrium, and right ventricle (RV) are also depicted. (C) Apical four-chamber view
depicting the right and left atria as well as the RV free wall and the septal and lateral walls of the
LV. The anterior mitral leaflet (white arrow) is also seen. (D) Subcostal view demonstrating the
RV and LV. The anterior mitral leaflet (white arrow) is again seen. Abbreviations: LV, left ventricle;
LA, left atrium; RV, right ventricle; RA, right atrium; N, noncoronary; L, left coronary.
164 Manning

Figure 1 Continued.

predominant mitral stenosis (especially common among women), mixed mitral stenosis
and mitral regurgitation, or predominant mitral regurgitation (more common among
men). With rheumatic valvular disease, the mitral leaflets fuse at their edges with thicken-
ing of the chordae. The stenotic mitral valve is typically funnel shaped (Fig. 4).
Progressive mitral valve obstruction leads to increased intra-atrial pressure and progress-
ive LA dilation. In addition, there may be endocardial fibrosis of the LA walls. Progressive
LA dilation, blood stasis, and endocardial surface abnormalities are thought to promote
thrombus formation, yet the incidence of thromboembolism does not appear to be
related to the severity of mitral stenosis (9). Large thrombi within the body of the LA,
especially “ball” thrombi (Fig. 5), are almost exclusively seen among patient with rheu-
matic mitral stenosis (and those with prosthetic mitral valve thrombosis). Though
unusual, these ball thrombi are often readily appreciated by TTE.
Prior to the availability of anticoagulation, both autopsy and surgical series showed
an increased risk of clinical thromboembolism in the mitral stenosis population (10 – 12).
Atrial fibrillation markedly increases the risk of thromboembolism in mitral stenosis
(9,13), whereas mitral regurgitation appears to be somewhat protective (14). In addition
Cardiac Source of Embolism: Pathophysiology and Identification 165

Figure 2 (A) Transesophageal echocardiogram (TEE) demonstrating a thrombus (white arrow)


within the left atrial appendage (LAA). (B) TEE demonstrating the far less common situation of
mural thrombus (white arrow) along the wall of the body of the left atrium. Note that LAA is
free of thrombus. Abbreviation: LA, left atrium.

to atrial fibrillation, clinical risk factors for stroke for patients with mitral stenosis include
advancing age and progressive LV systolic dysfunction (9,15,16).

ATRIAL FIBRILLATION

With atrial fibrillation, there is loss of organized atrial electrical and mechanical activity
(Fig. 6), resulting in stagnation/stasis of blood within the body of the atria and especially
within the LAA. LAA ejection velocity is markedly depressed (,20 cm/s) in patients
with atrial fibrillation, with the risk of thrombus formation being inversely related to
residual LAA ejection velocity (17). In addition to stasis, hematological studies suggest
that atrial fibrillation is associated with a hypercoagulable state (18).
More than 2.5 million people in the United States have atrial fibrillation, a popu-
lation that greatly exceeds those with rheumatic mitral stenosis (19). As a result, the
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Figure 3 Lateral chest X-ray following a barium swallow, demonstrating close relationship of
esophagus to left atrium.

clinical association of atrial thrombus and atrial fibrillation is far more common, with
stroke rates as high as 20% per year among very-high-risk patients. In the setting of non-
valvular atrial fibrillation, atrial thrombi are most often seen completely within or primar-
ily involving the LAA (20), a structure best imaged with TEE (Fig. 2). Coexistant
spontaneous echo contrast (visualized as “smokelike” echoes), a marker of stasis,
within the LAA and/or body of the LA may be seen in 60% of patients with atrial fibrilla-
tion and .85% of those with atrial fibrillation and LA thrombi (21,22). Prospective TEE
studies show LA thrombi in 14% of patients with new-onset atrial fibrillation (20,23),
increasing to 27% of those with chronic atrial fibrillation (24), and 45% in those presenting
with atrial fibrillation and recent clinical thromboembolism (25). For the latter population,
the frequency of LAA thrombus represents residual thrombus. TEE risk factors for sub-
sequent thromboembolism include increased thrombus size and mobility.
Although patients with atrial fibrillation and mitral stenosis remain at highest risk for
clinical thromboembolism (estimated at 20% per year), several prospective clinical studies
have now identified clinical risk factors for stroke among patients with nonvalvular atrial
fibrillation, including systemic hypertension (systolic blood pressure .160 mmHg),
age .75 years, congestive heart failure/LV systolic dysfunction, diabetes, and prior
stroke/transient ischemic episode. These are best summarized by the CHADS2 criterion
(Table 2) (26), which help guide the use of anticoagulant therapy (chap. 16). TTE- and
Cardiac Source of Embolism: Pathophysiology and Identification 167

Figure 4 Transthoracic echocardiogram in the parasternal long-axis view in a patient with rheu-
matic mitral stenosis. Note the mildly thickened leaflets with fixed posterior leaflet position and
“hockey-stick” appearance (white arrow) of the anterior mitral leaflet. Abbreviation: LA, left atrium.

Figure 5 Transesophageal echocardiogram in a patient with rheumatic mitral stenosis. Note the
free-floating intra-atrial thrombus ( ) within the body of the LA. Abbreviation: LA, left atrium.
168 Manning

Figure 6 Transesophageal echocardiogram with pulsed sample volume in the mouth of the left
atrial appendage in a patient with (A) sinus rhythm. Note the single ejection velocity (solid
arrows) following each p-wave on the echocardiogram (dashed arrows). (B) Atrial flutter. Note
the saw-tooth-like pattern with ejection velocities approaching 0.5 m/s. (C) Atrial fibrillation.
Note the very irregular and low velocity (,0.2 m/s) ejection velocity pattern.

TEE-specific imaging risk factors for thromboembolism include increased LV systolic


dysfunction, more pronounced spontaneous echo contrast, reduced LAA ejection velocity,
and the presence of LAA thrombus and aortic atherosclerosis (22). Interestingly, moderate
or greater mitral regurgitation does not appear to be “protective” for atrial thrombus

Table 2 CHADS2 Stroke Risk Strategy for Nonvalvular Atrial Fibrillation

C, congestive heart failure or left ventricular systolic dysfunction


H, hypertension; SBP . 160 mmHg
A, age . 75 yr
D, diabetes
S2, stroke or transient neurological event
Minimum score ¼ 0
Maximum score ¼ 6 (a stroke or transient neurologic event gets two points)

Abbreviation: SBP, spontaneous bacterial peritonitis.


Cardiac Source of Embolism: Pathophysiology and Identification 169

formation in new-onset atrial fibrillation (20), but moderate or greater mitral regurgitation
is protective against clinical stroke in the chronic atrial fibrillation population (27). This
difference may represent pathophysiologic differences between thrombus formation and
thrombus migration. The LA size is absent from echocardiographic risk factors for
stroke in atrial fibrillation. This is likely because of the confounding impact of LA dilation
promoting stasis with LA dilation due to “protective” mitral regurgitation. Among patients
with atrial thrombi, larger size and increased mobility are risk factors for clinical throm-
boembolism (28). Even among patients without a clinical history of stroke, studies show
subclinical stroke in cranial CT among 15% of patients with atrial fibrillation (28).
Systemic thromboembolism occurs in patients with dilated cardiomyopathy (LV
thrombi) at an annual rate of 4%. LV thrombi had been presumed to be the source of
emboli in these patients (29). However, TEE studies show that LAA thrombi are also a
common culprit (30).

LEFT VENTRICULAR THROMBI

LV thrombi are most often associated with acute myocardial infarction but can also be
seen in patients with dilated (nonischemic) cardiomyopathy. Historically, LV thrombi
are most often detected with TTE, which has a reported sensitivity and specificity
exceeding 90% (Fig. 7) (31 –33a). The use of intravenous echo contrast may assist in
the discrimination between apical trabeculations and thrombus (Fig. 8). Although the
detection of apical LV thrombi has been reported (34), from a practical perspective, the
frequent inability of TEE to visualize the true LV apex makes TEE a less appropriate
imaging test for suspected LV apical thrombi. Moreover, a preliminary intraoperative
validation report has suggested that delayed enhancement cardiac magnetic resonance is
superior to both TTE and TEE for identifying LV thrombi (Fig. 9) (35). Until confirmation
by others/larger series, TTE is considered the noninvasive “clinical gold standard” for
those with suspected LV thrombi.

Figure 7 Transthoracic echocardiogram from the apical four-chamber orientation. Note the apical
thrombus (white arrow) in this patient who had an anteroapical myocardial infarction. Abbreviation:
LV, left ventricle.
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Figure 8 Apical left ventricular thrombus demonstrated by echo contrast. Transthoracic echocar-
diogram from the apical view after intravenous administration of an echo contrast agent. Note that
the left ventricular cavity is now “bright” and the apical thrombus (T) appears dark.

MYOCARDIAL INFARCTION

Among patients with acute infarction, the risk of clinical stroke is reported at up to 3.6%
(36,37). The risk of stroke and thrombus formation is related to infarct location (anterior at
higher risk) and infarct size. In the GISSI-3 trial (38), the incidence of LV thrombus
among those with an anterior infarction increased to almost 18% for patients with an
LV ejection fraction of ,40%, when compared with ,10% for those with a higher
ejection fraction. The corresponding incidence for infarctions at nonanterior sites were
5.4% and 1.8%, respectively (34). Somewhat surprisingly, limited data do not suggest

Figure 9 Delayed enhancement cardiovascular magnetic resonance imaging in the (A) four-
chamber and (B) two-chamber orientation. Note the extensive area of hyperenhancement (white
arrowheads) with a nonenhancing subendocardial thrombus (white arrow). Source: Courtesy of
Dr. Scott Flamm. Abbreviations: RV, right ventricle; LA, left atrium; LV, left ventricle.
Cardiac Source of Embolism: Pathophysiology and Identification 171

an independent benefit with the use of thrombolysis (39). This may be due to the develop-
ment of most thrombi in the days following initial presentation. Using serial TTE, most
thrombi are found to develop within the first two weeks after infarction (median 5 – 6
days) (40 – 42). Although some patients develop a new LV thrombus to a greater extent,
it is most often in association with worsening LV systolic function (42 – 43). Thrombus
mobility and protrusion are also associated with the increased risk of stroke (44).

DILATED CARDIOMYOPATHY

Even in the absence of acute infarction, patients with depressed LV systolic function and
heart failure are at increased risk for stroke (45 – 47). Like the setting of acute infarction,
the risk of clinical stroke appears to be related to the severity of LV systolic dysfunction
(46 –49). For patients with heart failure/low ejection fraction who sustain a stroke, the
recurrence rate may reach 20% in the first year and 45% after five years (50,51).
In addition to identification of LV thrombus and monitoring for thrombus resolution,
TTE-visualized thrombus characteristics can help to identify those patients at high risk of
clinical thromboembolism. The two most important risk factors include thrombus size and
mobility (52 – 54).

PROSTHETIC VALVE THROMBI

Thrombus formation and subsequent embolization may be seen in patients with valve
prostheses, especially mechanical valve prostheses in the mitral or tricuspid position in
the setting of suboptimal anticoagulation (55,56). Anticoagulation strategies are depen-
dent on the type of prosthesis and valve position (Table 3), with patients requiring lifelong
warfarin anticoagulation with a recommended international normalized ratio (INR)
between 2.0 and 3.5 (57).
Evaluation of prosthetic valves, especially prostheses in the mitral position, is best
performed by TEE. It is often assumed clinically that patients with mechanical prostheses
who present with systemic embolization have prosthetic valve thrombi, especially if there
is no other obvious cause and/or the INR is suboptimal. Although TEE can confirm the
diagnosis, it does not usually change the therapy (except for patients with valvular dys-
function due to a massive thrombus). In the setting of thromboembolism and a therapeutic
INR, TEE is often helpful to distinguish valve dysfunction related to pannus ingrowth
versus thrombus (56).

AORTIC ATHEROSCLEROSIS

Among patients with ischemic stroke, TEE evidence of complex (mobile plaque or protru-
sion into the aortic lumen of .4 mm) aortic atherosclerosis is more common in patients
without other known causes of thromboembolism, when compared with those with poss-
ible or likely other causes (58) (chap. 10). Ulcerated plaques in the aortic arch have been
noted in more than 60% of patients without a known cause of cerebral infarction versus
only 22% of those with another cause of brain infarction (59). Aortic atherosclerosis is
most often clinically identified by TEE, though thoracic MRI is also able to identify
and quantify thoracic aortic atherosclerosis (60).
Atherosclerotic plaques on TEE are more likely in patients with a history of transient
ischemic attack, stroke, or peripheral embolism (61), with a higher incidence of clinical
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Table 3 Anticoagulation Guidelines for Native and Prosthetic Valves

Condition Association condition Target INR

Native valve
Rheumatic MVD Atrial fibrillation 2.0 – 3.0
Sinus rhythm, thromboembolism 2.0 – 3.0
Sinus rhythm, LAD ?.5.5 cm 2.0 – 3.0
Sinus rhythm, LAD ?,5.5 cm aspirin
Prosthetic valve
Bileaflet—aortic 2.0 – 3.0
Atrial fibrillation 2.5 – 3.5
Bileaflet—mitral 2.5 – 3.5
Atrial fibrillation 2.5 – 3.5
Poor LV function 2.5 – 3.5
Starr-Edwards—Aortic 3.0 – 4.0
Starr-Edwards—Mitral 3.5 – 4.5
Bioprosthetic—Mitral aspirin
Atrial fibrillation 2.0 – 3.0
Bioprosthetic—Aortic aspirin
Atrial fibrillation 2.0 – 3.0

Abbreviations: MVD, mitral valve disease; LAD, left atrial dimension; LV, left ventricle; INR, international
normalized ratio.

thromboembolism when the plaque is pedunculated and highly mobile (62 – 64), especially
if located within the ascending aorta (65). Patients with complex aortic atherosclerosis and
atrial fibrillation may be at particularly high risk for clinical thromboembolism (22).
Atherosclerotic disease of the aortic arch is also a risk factor for recurrent ischemic
stroke (66). Finally, aortic atherosclerotic “debris” (especially when mobile) on TEE also
identifies patients in whom cardiac catheterization or insertion of an intra-aortic balloon
pump carries a high risk for thromboembolism (67). This increased risk is most frequently
associated with catheterization performed via a femoral approach.

INFECTIVE ENDOCARDITIS

After congestive heart failure, arterial embolism is the most common life-threatening com-
plication in patients with infective endocarditis. Embolization during the first week of anti-
biotic treatment is most common (68) and declines thereafter (69). Late thromboembolism
(after completion of antibiotics) in the absence of recurrent infection is rare. Staphylococci
and streptococcus species account for .80% of native valve endocarditis (70), with an
increased risk of clinical thromboembolism among patients infected with staphylococci
(68,69,71,72). Although one might expect increased clinical thromboembolism from
aortic valve vegetations due to increased shear stress with LV ejection, data suggest
that mitral valve vegetations lead to an increased propensity for thromboembolism
(68,73,74). Although rarely the only clinical manifestations of endocarditis, the acuteness
and magnitude of the event may be the primary cause for the patient to seek urgent care.
TTE has relatively low sensitivity in endocarditis (75). A negative TTE does not preclude
the diagnosis and should be followed by TEE (with superior spatial resolution) if the
clinical suspicion is high or moderate (Fig. 10) (75,76). Consideration of direct TEE
should also be considered for patients in whom a “negative” TTE would lead to a TEE.
Cardiac Source of Embolism: Pathophysiology and Identification 173

Figure 10 (A) Transesophageal echocardiogram demonstrating a large vegetation involving the


posterior mitral leaflet (short arrow) and a much smaller vegetation at the tip of the anterior
mitral leaflet (long arrow). (B) Transthoracic echocardiogram in the parasternal long-axis view.
Note the vegetation (white arrow) on the left ventricular outflow tract side of the aortic valve.
Abbreviations: LA, left atrium; LV, left ventricle.

TEE evidence for larger (.10 mm) vegetations and increased mobility identify patients at
higher risk for clinical thromboembolism (77).

VALVULAR CALCIFICATION

Valvular calcification most often involves the aortic valve and mitral annulus. Case reports
suggest that calcified material can spontaneously embolize from calcified bicuspid valves,
rheumatic aortic stenosis, and senile degenerative aortic valves (78 –80). These events,
however, are quite rare, and other causes for thromboembolism should be sought
among patients with aortic stenosis presenting with thromboembolism. Although spon-
taneous embolism is quite rare, the frequency of clinical and subclinical thromboembolism
may exceed 20% for patients with aortic stenosis undergoing cardiac catheterization
during which the stenotic aortic valve is crossed (81).

VALVE EXCRESCENCES

Valve excrescences are thin, elongated, and mobile echoreflective structures with indepen-
dent, undulating hypermobility seen near the leaflet’s line of closure. They occur on the
174 Manning

atrial side of the mitral valve and the ventricular side of the aortic valve and are increas-
ingly recognized in the elderly. Valve excrescences do not appear to be a primary source of
cardioembolism (82).

MITRAL ANNULAR CALCIFICATION

The most common TTE finding among elderly patients referred for a cardiac source of
embolism is a high reflective area in the posterior portion of the mitral annulus representing
mitral annular calcification (MAC) (Fig. 11) (83,84). MAC is very common in the elderly. A
study of more than 2,000 patients (mean age 81 years) found that 48% had MAC with an
increased prevalence of atrial fibrillation (22% vs. 8% without MAC) (83). In addition to
age, MAC is associated with hypertension and aortic atherosclerosis. During a 44-month
follow-up, MAC was associated with an increased incidence of thromboembolism in
patients both with and without atrial fibrillation. The incidence of stroke and the severity
of calcification appear to be linearly related (84). Case report TEE observations suggest
that the MAC may serve as a nidus for thrombus formation (85,86a,b). Alternatively, the
association of MAC and aortic atheroma (84% vs. 33% without MAC) may partially
explain the association of MAC with stroke (87). A recent study explored the role of
MAC among 2723 American-Indians who did not have known cardiovascular disease
(86a). The presence of MAC but not aortic valve sclerosis proved to be a strong risk
factor for incident stroke, even after adjusting for multiple other risk factors (86a).

INTRACARDIAC TUMORS

Primary cardiac tumors are extremely rare, found in ,0.03% of autopsy studies, with
myxomas constituting almost 60% of these lesions (88). Myxomas are histologically

Figure 11 Transthoracic echocardiogram in a patient with symmetric left ventricular hypertrophy


and prominent echogenic areas along the posterior mitral annulus (black arrow) and extending to the
anterior mitral annulus consistent with extensive mitral annular calcification. Abbreviation: LV, left
ventricle.
Cardiac Source of Embolism: Pathophysiology and Identification 175

Figure 12 Transesophageal echocardiogram in a patient with a large left atrial myxoma (white
arrow) attached to the interatrial septum in the area of the foramen. Abbreviation: RA, right atrium.

benign tumors that are most often found within the body of the LA and attached to the
midportion of the interatrial septum in the area of the foramen (Fig. 12). Myxomas are
more common among women. They are clinically important because more than half
may present with thromboembolism, which may be due to embolization of either tumor
or overlying thrombi. Multiple myxoma may be present in the uncommon (7%) familial
myxoma syndrome.
Another histologically benign tumor associated with emboli is a papillary fibroelas-
toma. These tumors are usually highly spherical, highly mobile pedunculated tumors most
commonly located on the aortic (Fig. 12) or mitral valves. Less often, they may be present
on endocardial surfaces. Echocardiographically, papillary fibroelastomas appear speckled
with echolucencies near the edges (89). These tumors classically are not associated with
valvular dysfunction, but they may be a source of systemic embolization due to migration
of thrombus from the tumor surface (89) or tumor embolization (90).
Both TTE and TEE are highly sensitive in detecting myxomas and papillary fibro-
elastomas, though TEE may provide more accurate anatomical details, such as the site of
attachment and, in selected patients, may help to differentiate these tumors from thrombi.

LEFT ATRIAL SPONTANEOUS ECHO CONTRAST

Spontaneous echo contrast or “smokelike” echoes within the LA and/or LAA (Fig. 13) is a
common TEE finding among patients with atrial fibrillation (91,92) and mitral stenosis.
Spontaneous echo contrast is believed to represent erythrocyte aggregation in low
shear-rate conditions (93), a process mediated by plasma proteins, particularly fibrinogen,
which promote red cell rouleaux formation (94). Spontaneous echo contrast has also been
associated with elevated plasma fibrinogen concentration and a hypercoagulable state
(95), thereby promoting thrombus formation. More than 60% of patients in atrial fibrilla-
tion and more than 80% of patients with LAA thrombi (vs. ,2% of patients with sinus
176 Manning

Figure 13 Transesophageal echocardiogram in a patient with spontaneous echo contrast (swirling


pattern) in the body of the left atrium suggesting slow/stagnant flow. Abbreviation: LA, left atrium.

rhythm) demonstrate spontaneous echo contrast (96). Among patients with atrial fibrillation,
spontaneous echo contrast is associated with reduced peak LAA ejection velocity (95) and
is an independent predictor of thromboembolic risk.
In addition, more than two-thirds of patients with mitral stenosis have TEE evidence
of spontaneous echo contrast, which is thought to indicate a relatively hypercoagulable state
and atrial blood stasis (91). The finding of elevated LA levels of prothrombin fragments
1 and 2 (markers of coagulation activity) among patients with spontaneous echo contrast
and mitral stenosis also supports an association with a hypercoagulable state (97).
From a mechanistic perspective, the previously mentioned abnormalities provide the
necessary pathophysiologic substrate for thromboembolism. In the normal circulatory
system, the pulmonary arteriolar and capillary beds provide a “filtering system” that pre-
vents venous thrombi from gaining access to the arterial system. For some patients, an
abnormal connection between the right and left heart provides a conduit through which
venous thrombi can bypass the pulmonary bed, thereby leading to “paradoxical” throm-
boembolism. The most common sites for “crossing” of these thrombi are at the atrial level.

ABNORMALITIES OF THE INTERATRIAL SEPTUM

Abnormalities of the interatrial septum are associated with thromboembolism via two
pathophysiologic mechanisms: right-to-left shunting and ASA. Patients with an atrial
septal defect or PFO may have intermittent flow of blood from the right atrium to the
LA. This can be induced on a daily basis by maneuvers that transiently increase right
atrial pressure, such as coughing or Valsalva maneuvers during bowel movements
(Fig. 14). A thrombus in the venous system may thereby cross to the left side of the
heart, resulting in systemic thromboembolism (Fig. 15).
A PFO is necessary during fetal development to facilitate shunting of blood from the
right atrium to the LA, thereby bypassing the high-resistance pulmonary circuit. At birth or
Cardiac Source of Embolism: Pathophysiology and Identification 177

Figure 14 Transesophageal echocardiogram in a patient with a patent foramen ovale. After intra-
venous injection of agitated saline, microbubbles can be seen on the left atrial side of the septum
(arrow). Abbreviations: LA, left atrium; RA, right atrium.

shortly thereafter, the septum primum and the septum secundum usually fuse, closing the
interatrial septum to the flow of blood. Ostium secundum atrial septal defects occur when
there is excess resorption of the septum primum or inadequate formation of the septum
secundum. A PFO occurs when fusion of the septum primum with the septum secundum
is inadequate.

Figure 15 Transesophageal echocardiogram in a patient who presented with acute onset of


neurological symptoms. Note the thrombus (arrow) in transit through the intra-atrial septum.
Abbreviation: RA, right atrium.
178 Manning

The prevalence of a PFO varies depending on its definition. In an autopsy study of


nearly 1,000 patients, a PFO was found in 27% of all hearts, declining from 34% among
those ,30 years to 20% after 80 years (98). Thus, more than 50 – 70 million Americans
have a PFO. A PFO may be identified noninvasively with the use of TTE and/or TEE
with intravenous agitated saline contrast, with the appearance of microbubbles in the
LA within three to five beats of full opacification of the right atrium. Imaging is usually
performed at rest and with maneuvers designed to transiently increase the right atrial
pressure, so as to promote right-to-left shunting—including Valsalva maneuver release
and cough. The imaging with cough is felt to provide the highest sensitivity. The size
of the shunt is graded semiqualitatively, with less than 10 bubbles considered “trivial,”
10 – 30 bubbles considered a “small shunt,” and more than 30 bubbles suggesting a
“large shunt” (99). Although both TTE and TEE are considered sensitive, TEE is con-
sidered superior (100). Administration of saline contrast from the groin may be superior
to introduction from the antecupital fossa (101). The relative quantity of contrast (or sever-
ity of right-to-left shunting) appearing in the LA after venous injection appears to be
associated with increased risk (102 –104). Other novel methods to detect PFO include
intravenous saline injection with transmitral Doppler (105) or transcranial Doppler sono-
graphy of the middle cerebral artery (106) and real-time MRI during injection of a
gadolinium-based contrast agent (107). The latter two techniques are less well studied.
An ASA is far less common than a PFO and is usually defined by echocardiography
as a bulging/septal mobility in the region of the fossa ovalis (Fig. 16) due to redundant
atrial septal tissue (108). The amount of septal excursion for an ASA is usually defined

Figure 16 (A) and (B) Transthoracic echocardiogram in a patient with an aneurysm of the intera-
trial septum. Note the wide magnitude of septal motion (arrows). (C) Transesophageal echocardio-
gram in another patient with an interatrial septal aneurysm. Abbreviations: LA, left atrium; RA, right
atrium.
Cardiac Source of Embolism: Pathophysiology and Identification 179

as the sum of the greatest leftward and rightward deflections of at least 10 or 15 mm.
Prevalence in the normal population is estimated to be 0.5% by TTE (109) and up to
5% by TEE (110,111). ASA is commonly associated with a PFO, with more than 50%
of patients with an ASA having a coexistent PFO (112,113). The mechanism for stroke
in ASA has been ascribed to coexistent PFO (paradoxical embolism), propensity for
atrial arrhythmias (114), and direct thrombus formation in the neck of the aneurysm
due to an irregular surface (115). The specific risk of ASA in the absence of PFO is uncer-
tain. One prospective intraoperative study found that the incidence of embolic strokes
associated with an atrial septal defect was quite low (111).
Although a case report in 1930 described a patient who died from a stroke with a large
thrombus across a PFO (116), the pathological role of PFO was largely unrecognized until
Lechat et al. (117) reported a high prevalence of PFO among patients ,55 years with
stroke. TTE evidence of a PFO was found in 40% of the study population, including
54% of patients with cryptogenic stroke, when compared with only 10% of a control
group without stroke. Mas et al. (118) studied 598 patients aged 18– 35 with cryptogenic
stroke. More than 36% had evidence of a PFO, 1.7% had an ASA, and 8.5% had both
abnormalities. A meta-analysis of nine studies showed that the overall risk of stroke was
associated with younger (,55 years) patients with a PFO [odds ratio (OR) 3.1], ASA
(OR 6.1), or both (OR 15.6). As a result, the finding of a PFO has been considered
presumptive evidence of a paradoxical embolus in younger (,55 years) patients with cryp-
togenic stroke. A similar relationship is less certain for patients .65 years (119,120).
Although the primary mechanism of PFO-related stroke is believed to be paradox-
ical embolism of thrombus, documentation of such thrombi is quite limited. The incidence
of deep venous thrombus may be quite low (121,122). A study of 197 patients with an
embolic stroke reported that only 9.5% had a deep vein thrombosis on venography
(122). In contrast, when peripheral lower-extremity venography was performed in 49
patients with systemic thromboembolism and PFO, peripheral venous thrombosis was
seen in 57% (123), with more than half of the thrombi limited to the calf or popliteal veins.

IMAGING PROCEDURES
Transthoracic Vs. Transesophageal Echocardiography
TTE performed with saline contrast is a minimally invasive procedure, whereas TEE is a
moderately invasive procedure during which a modified gastroscope (containing an ultra-
sound crystal at its tip) is positioned within the esophagus. Imaging is performed within
the esophagus and the gastric fundus. The close proximity of the esophagus to the posterior
heart, the lack of intervening lung and bone, and the use of higher frequency imaging
transducers result in enhanced spatial resolution. TEE should not be considered as a
“better” echocardiogram but may be preferred for identification or exclusion of pathology
that is particularly relevant to the patients presenting with history suggestive of throm-
boembolism, including identification of intra-atrial thrombi and tumors, PFO, valvular
vegetations, atheromatous plaques within the aorta, and spontaneous echo contrast. TTE
remains preferred for identification of LV regional systolic function and apical LV
thrombi.

SUMMARY AND RECOMMENDATIONS

Although multiple potential cardiac sources for embolism can be identified by TTE, the
use of this procedure among patients with unexplained stroke has recently come into
180 Manning

question (124). In an unselected population, for example, the prevalence of a highly


probable source of embolism was only 3– 15% (125,126), with the highest yield if the
clinical history suggests a cardiac source (as with atrial fibrillation, rheumatic mitral
stenosis, diffuse atherosclerosis, LV aneurysm, or clinical endocarditis). Aside from
identification of apical LV thrombi and MAC, TEE is superior to TTE with a correspond-
ing yield for cardiac source of 57 – 65% (126,127). Thus, for many patients, direct TEE
(with omission of the TTE) may be the most expeditious route to identify a cardiac
source of embolism.

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10
The Aorta as a Donor Source of
Brain Embolism

Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

EARLY PATHOLOGY-BASED REPORTS OF EMBOLISM


FROM THE AORTA

Although clinicians and pathologists have recognized for more than a century that athero-
sclerotic lesions appear early within the aorta and that aortic atherosclerosis is often
severe, only recently has the relationship between aortic disease and stroke been
studied during life. Studies of patients with stroke and transient ischemic attacks have
now firmly established that the thoracic aorta is a very important source of brain embo-
lism. The first report on this subject was published more than a half a century ago.
Meyer in 1947 described two patients with syphilitic aortic aneurysms that developed
cholesterol crystal embolism considered to have derived from material in the aneurysms
(1). A decade later, Winter described two additional patients with syphilitic aneurysms
of the proximal aorta (2). The ascending aorta of Winter’s first patient was “covered by
innumerable atheromata most of which were eroded and partly calcified. Soft thrombi con-
taining cholesterol crystals were adherent to many” (1). Many brain arteries were blocked
by cholesterol crystal containing thrombi. In another patient who also had multiple brain
cholesterol crystal emboli, the “entire intimal surface of the aorta, but in particular the
aneurysm, was covered by atheromatous plaques, many of which were ulcerated and
covered by soft thrombi” (2).

AORTIC ATHEROSCLEROSIS

In 1965, Fisher et al. (3) examined the aorta and extracranial and intracranial arteries
among 178 patients and found that only 37 aortas were free of ulceration and that the
aorta was two to four times more likely to show severe atherosclerosis than the cervical
carotid and vertebral arteries.
The International Atherosclerosis Project was the first extensive attempt to charac-
terize the distribution and relative severity of atherosclerosis in major systemic and
cervico-cranial arteries (4,5). Sex, race, and geographical differences in severity and

187
188 Caplan

location of atherosclerosis were also studied (5). Pathologists is five countries examined
1,547 sets of aortas, as well as coronary and neck and cranial arteries. Fatty streaks,
yellow lipid deposits that elevate the intima only slightly, were found in all groups of
patients beginning in infancy but reaching a peak at puberty. Raised lesions, including
fibrous plaques, calcified lesions, and lesions complicated by hemorrhage, ulceration,
or thrombosis developed later (4,5). In all groups, fibrous plaques were more prevalent
and more severe in the aorta than in the coronary and cervico-cranial arteries, and the
abdominal aorta was more severely involved than the thoracic aorta. In the age group
of 65 –69, in patients from Oslo, Norway, on average 40% of the surface area of the
thoracic aorta contained raised atherosclerotic lesions (5).
The International Atherosclerosis Project (4,5) and a more recent study showed that
aortic atherosclerosis is more severe in whites compared with Asians and blacks and is
usually more severe in men compared with premenopausal women (6). The aortic arch
and ascending aorta contained significantly more 4 mm or larger plaques in whites com-
pared with American blacks in Alabama (6). Complex plaques were also more common
among whites (6). A study of the location of plaques found in the thoracic aorta using
transesophageal echocardiography (TEE) showed the highest prevalence in the arch
(27.6%) and descending aorta (38.2%) (7). The frequency of aortic atheromas increases
dramatically with age, from 20% in the fifth decade at necropsy to 80% in patients
.75 (8). Tobler et al. (9) studied at necropsy the presence and distribution of atherosclero-
tic plaques in the ascending aorta. Among 97 ascending aortas, 38% had atherosclerotic
plaques .8 mm in diameter; the average diameter of plaques was 19 mm. Most of the
66 plaques were distributed anteriorly or posteriorly on the right side of the ascending
aorta, and the upper and lower halves of the ascending aorta were equally involved (9).
Plaques were also prevalent in the aortic arch, especially at the orifice of the innominate
artery (21% of 48 arch specimens) (9).
The presence and severity of atherosclerotic risk factors (hypertension, diabetes,
hyperlipidemia) and inflammatory markers (C-reactive protein, fibrinogen levels,
plasmin/antiplasmin complexes, and D-dimers) predict the severity of aortic athero-
sclerosis (10).

Clinical, Pathological, and Echocardiographic Analyses of


the Relation between Aortic Atherosclerosis and Stroke
Further mention of aortic atherosclerotic disease as an important cause of stroke began to
appear during the beginning of the last decade of the twentieth century (11). Until that time
in vivo recognition of the presence and severity of aortic atherosclerosis was very limited.
Tunick and his colleagues (12,13) at the New York University Medical Center published
two reports that included four patients with unexplained brain ischemic events in whom
TEE showed large protruding, often mobile atheromas. In one patient who had brain,
leg, and arm emboli, TEE showed “a large mass with smaller mobile components, protrud-
ing into the lumen of the aortic arch” (13). Several aortic masses in this patient were
removed surgically and showed severe atherosclerotic plaques with superimposed
thrombi (13). Tunick et al. (14) later reported TEE results among 122 patients who had
stroke, transient ischemic attacks (TIAs), or peripheral emboli, and 122 age and sex-
matched controls. The presence of protruding atheromas were strongly related to the occur-
rence of embolic events (odds ratio 3.2, 95% confidence interval 1.6– 6.5, P , 0.001), and
atheromas with mobile components were only found in patients with embolic events (14).
Karalis et al. (15) also reported an observational TEE study of their experience with
aortic atheromas. “Intraaortic atherosclerotic debris” was found in 7% of 556 patients
The Aorta as a Donor Source of Brain Embolism 189

studied by TEE; 11 patients with these atheromatous aortic lesions (31%) had embolic
events (15). Embolic events were more often associated with pedunculated and mobile
aortic lesions than those that were layered and immobile (15).
These observational studies and case reports alerted the medical community to the
possible importance of aortic atheromas as a cause of stroke and peripheral embolism. In
1992, Amarenco and his Paris colleagues (16,17) published two reports, which showed defi-
nitively that aortic atheromatous disease was an important cause of stroke and could be
identified clinically during life. Amarenco et al. first published a necropsy study of 500
patients who had stroke or other neurologic diseases. Ulcerated aortic plaques were
found in 26% of 239 patients with cerebrovascular disease, compared with only 5% of
261 patients with other neurological diseases ( P , 0.001) (16). The prevalence of aortic
atheromas was 61% among patients with brain infarcts and no demonstrated cause and
22% among those with other defined causes ( P , 0.001) (16). The presence of ulcerated
plaques in the aortic arch did not correlate with the presence of carotid artery stenosis,
suggesting that aortic and carotid artery diseases were independent risk factors for stroke
and were not necessarily proportionate (16).
Amarenco et al. (17) also reported a study of 12 consecutive patients with crypto-
genic stroke studied by TEE. Six (50%) patients had intraluminal echogenic masses in
the aortic arch most often at the junction of the ascending aorta and the arch. In one
patient, the mass was pedunculated, but in the other five the attachment was broad-
based with a very irregular surface. The masses extended from 3 to 15 mm into the
lumens of the aortas. Cholesterol emboli were found in quadriceps muscle biopsies in
two patients with aortic masses (17).
Amarenco and colleagues (18,19) also studied the risk of brain infarction according to
the thickness of plaques in the ascending aorta or proximal aortic arch (Table 1). The occur-
rence of brain infarction correlated significantly with the thickness of aortic plaques. Other
TEE studies in the United States (20,21), Japan (22), and Australia (23) confirmed the import-
ance of aortic arch atheromas as a source of brain and peripheral embolism.
Jones et al. (23) in an Australian study compared TEE findings in the aorta among
215 patients who had TIAs or brain infarcts with 202 healthy volunteers. They found
simple plaques ,5 mm thick in the ascending aorta and arch in 33% of the brain ischemia
patients and in 22% of controls. Plaques that were .5 mm thick and/or had irregular sur-
faces or mobile components (complex plaques) were found in 22% of patients and only 4%
of controls, a 7.1-fold increase (23). Davila-Roman et al. (24) examined the frequency and
nature of aortic plaques in patients who were to have coronary artery surgery, using
epiaortic ultrasound probes. This technique allows exploration of the entire surface of

Table 1 Risk of Brain Infarction According to Aortic Atherosclerotic Plaque Thickness


(Ascending Aorta or Proximal Arch)

Plaque Patients (%) Controls (%) Crude Adjusted


(mm) n ¼ 250 n ¼ 250 OR (95% CI) OR (95% CI) P-value

,1 99, 39.6% 189, 75.6% 1 1 —


1 – 1.9 28, 11.2% 16, 16.4% 3.3 (1.7– 6.5) 4.4 (2.1– 8.9) ,0.001
2 – 2.9 56, 22.4% 26, 10.4% 4.1 (2.4– 7) 5.0 (2.7– 9) ,0.001
3 – 3.9 31, 12.4% 14, 5.6% 4.2 (2.2– 8.3) 3.4 (1.5– 7.4) ,0.001
.4 36, 14.4% 5, 2% 13.8 (5.2– 36.1) 9.1 (3.3– 25.2) ,0.001

Abbreviations: CI, confidence interval; OR, odds ratio.


Source: From Ref. 18.
190 Caplan

the ascending aorta from the aortic root to the proximal arch, a region difficult to image
with TEE. Among 1,200 patients who had epiaortic ultrasound, 158 patients had a pre-
vious embolic event, and in 1042 no prior event was recognized. Among those with a
prior embolic event, 26.6% had plaques .3 mm, compared to 18.1% of patients
without events (24).
Pathological studies provided further evidence of a relation between aortic
disease and brain embolism. Masuda et al. (25) analyzed the clinical features and
the distribution and pathology among 15 patients with brain atheromatous embolism
studied clinically and at necropsy. Heart surgery, cardiac catheterization, and angiogra-
phy triggered embolism in six (40%) patients in this series (25). Nine (60%) patients
had extensive cortical, often hemorrhagic, infarcts in the regions of the arterial border-
zones between the anterior cerebral arteries and middle cerebral arteries (MCA) and
between the MCA and posterior cerebral arteries. Six (40%) patients had territorial
infarcts of different sizes caused by occlusion of major or branch cerebral arteries
(25). All patients had complicated atheromas in the ascending aorta and the aortic
arch. Calcification, ulcerations, mural thrombi, and aneurysmal dilatations were preva-
lent. Cholesterol crystal emboli were often found in arteries within the borderzone
regions (25).
Two studies investigated the frequency of occurrence of vascular events in patients
who had TEE-documented aortic arch atherosclerosis (26,27). The French Study Group
followed 331 patients who presented with brain infarcts for two to four years (26). The
frequency of subsequent brain infarction and other vascular events was closely correlated
with the thickness of the aortic wall. The frequency of recurrent brain infarcts was
11.9/100 patient-years in those with aortic lesions that had thickness of .4 mm, com-
pared to rates of 3.5/100 patient-years for those with 1– 3.9 mm thick aortic wall
lesions, and 2.8/100 patient-years in those with aortic walls ,1 mm thick. After control-
ling for other confounding factors the relative risk of brain infarction was 3.8 (95%
confidence interval 1.8 –7.8, P ¼ 0.0012) and of all vascular events 3.5 (95% confidence
interval 2.1– 5.9, P , 0.001) in patients with aortic wall plaques .4 mm (26). In a pro-
spective study conducted in two German University hospitals, physicians followed 136
patients with flat plaques ,5 mm in thickness, and 47 patients with either thick
plaques .5 mm thick or complex plaques with mobile components for an average of
16 months (27). Embolic events developed in 15 patients; the incidence was 4.1/100
patient-years in patients with flat plaques versus 13.7/100 patient-years in those with
complex, thick, or mobile plaques (27).

Nonatherosclerotic Disease of the Aorta


Atherosclerosis is not the only disease of the aorta that can serve as a donor source of
embolic material. Syphilitic aortitis and aneurysms have long been known to ulcerate
and cause thromboembolism (1,2). Physicians in Sri Lanka described ten patients who
had an inflammatory aortitis different from Takayasu’s disease that caused brain embolism
and strokes (28). The earliest histological changes in this condition were focal fragmenta-
tion of elastic lamella and an acute inflammatory aortitis in the media of the aortic arch.
The aortic intima was edematous, and mural thrombi often formed on the endothelial
surface of the aorta and embolized intracranially (28). Takayasu’s disease is especially
common in India and Pakistan and in other neighboring countries. Takayasu’s disease,
aortic trauma, and aortic dissection probably are also occasionally complicated by embo-
lism arising from the aorta. In the case of aortic dissection, thrombus formation within the
aorta and subsequent embolism should be separated from obliteration of the orifices of the
The Aorta as a Donor Source of Brain Embolism 191

branches of the arch by the dissection and from concurrent dissection of brachiocephalic
arteries that often accompany aortic dissections (29 –31).

HEART SURGERY AND AORTIC ATHEROSCLEROSIS


Strokes and Mortality after Heart Surgery
Mounting evidence now also links the occurrence of postoperative strokes, encephalopa-
thies, and cognitive dysfunction to ulcerative atherosclerotic lesions of the ascending aorta
(25,32 –40). Yellow aortic plaques are often visible and can be palpated by the surgeon.
They are more readily detected by epiaortic ultrasound probes placed on the aorta.
When the aorta is clamped, an audible crunch is often heard. Cross-clamping of the
aorta or aortotomy to anastomose the vein graft often liberates cholesterol crystals and
calcific plaque debris.
The most important risk factor for stroke after cardiopulmonary bypass surgery is
aortic atheromatosis. The stroke rate after coronary artery bypass graft (CABG) increases
sharply with age, from 1% in patients aged 51 – 60 to 9% in patients aged .80, paralleling
the increase of aortic atheromas with age (8,34). The correlation between aortic atheromas
and stroke after CABG was first shown at necropsy in a study that involved 221 patients
(8). Atheroemboli were found in 37% of patients who had severe atherosclerosis of the
ascending aorta but in only 2% of patients who did not have significant ascending
aortic atheromas (8). In another study, cardiac surgeons retrospectively reviewed the
records of 3279 consecutive patients having CABG at Johns Hopkins, seeking risk
factors for postoperative stroke (40). Severe atherosclerosis of the ascending aorta was
one of the most definitive risk factors found (40).
Embolization can now be detected and quantified before, during, and after surgery
using ultrasound. Transcranial Doppler (TCD) recording over the MCAs detects the
arrival of microemboli in the cranial arteries. Figures 1 and 2 show TCD recordings

Figure 1 Transcranial Doppler recording from the middle cerebral artery during steady state
cardiac bypass surgery at a time when the aorta was being manipulated. The white streaks represent
microemboli. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.
192 Caplan

Figure 2 Transcranial Doppler recording from the middle cerebral artery during cardiac bypass
surgery. A few distinct emboli (white streaks in the left of the figure) are followed by a massive
shower of emboli (whiteout) at the time of the release of aortic clamps. Kindly submitted by
Dr. Denise Barbut. Source: From Ref. 32.

taken during cardiac surgery at various times during the procedure. Figure 2 shows record-
ing just after clamping of the aorta. Intraoperative TEE can be used to detect the passage of
emboli into and through the proximal aorta. Figure 3 is a TEE recorded during cardiac
surgery that shows a shower of emboli entering the aortic lumen. More emboli are detected
during intracardiac surgery than during CABG because these patients often have valve
calcifications, valve vegetations, and intracardiac thrombi. By using TCD monitoring
during closed cardiac operations, the number of microemboli vary from 0 to 1,200
within one MCA (average 130) (34). The numbers of emboli detected in the aorta by
TEE is in thousands, reflecting the fact that only a fraction of the microembolic particles
reach the brain (34,41).
Embolization is not evenly distributed during the various stages of surgery. Maneu-
vers that involve manipulation of the aorta, such as clamping and unclamping, account for
.60% of the total number of emboli (34,41). Flurries of emboli are detected during aortic
cannulation and at the start and ending of cardiopulmonary bypass. During open cardiac
procedures, the number of emboli detected by TCD is especially high during cardiac ejec-
tion after the release of the aortic cross clamps and immediately after bypass (34). Figure 2
is a TCD recording during cardiac surgery that shows a “whiteout” created by a massive
shower of emboli that occurred immediately after release of aortic clamps. Many of the
microemboli are gaseous particles. Aortic clamping and clamp release are followed by
a snowstorm-like appearance of intensely echogenic, well-defined particles within the
aorta and a corresponding flurry of particles within the brain arteries (34). The mean
diameter of these particles is 0.85 mm. These microembolic particles are most likely
atheromatous debris coming from the aorta. They are small enough to enter the brain
circulation, although only a small fraction do so. The quantity of emboli is closely associ-
ated with the presence of atheromas in the ascending aorta and arch (42). Figure 4 shows a
very atherosclerotic aorta found at autopsy.
The Aorta as a Donor Source of Brain Embolism 193

Figure 3 Transesophageal echocardiography recording during cardiac surgery from the aorta at
the level of the origin of the left subclavian artery. A mobile plaque is seen protruding into the
aortic lumen (small black arrow). This recording was taken after the release of aortic clamps and
shows a “shower” of emboli within the aortic lumen beyond where the aorta was previously
clamped. Kindly submitted by Dr. Denise Barbut. Source: From Ref. 32.

The presence and severity of atherosclerosis of the aorta has in the past been quan-
tified by TEE before surgery, intraoperative TEE, or after the chest is opened, by palpation
of the aorta by the surgeon, or by using epiaortic ultrasound probes placed on the surface of
the aorta. The findings when performed before surgery can be used as one of the factors
that gauge the risk of on-pump surgery and so help with the decision on surgery versus
medical treatment. The location and severity of aortic atheromas can also guide the
regions of the aorta to avoid during clamping or to choose between on or off-pump
CABG—the latter not requiring clamping of the aorta. Marshall et al. (43) first reported
the use of an intraoperative B-mode probe placed on the aorta in search of protrud-
ing plaques. Ultrasonic imaging showed plaques better than visual inspection and
palpation. The amount, nature, and location of the plaques often altered the procedure

Figure 4 The aorta at necropsy in a patient with severe aortic atherosclerosis. Source: From
Ref. 32.
194 Caplan

performed (43). Hangler et al. (44) used epiaortic ultrasonography applied before opening
the pericardium among 352 patients undergoing CABG (44). When patients had moderate
atherosclerosis, defined as aortic wall thickness of 3– 5 mm, single aortic cross clamping
was performed. When the maximum wall thickness was .5 mm, a no-touch strategy
was used. The operative technique was modified in 31% of patients with moderate
disease and 91% of those with severe disease (44).
In one study, among 5,737 patients, 913 were found by preoperative TEE to have
severe aortic atheromatous disease. Among these patients, 235 (25.7%) patients had off-
pump CABG, and 678 (74.3%) had conventional on-pump CABG. In-hospital mortality
was less in the off-pump patients—5.1 versus 8.7% (45). The authors compared mortality
and stroke rate of 211 of the off-pump and 211 of the on-pump patients with severe aortic
atheromatous disease matched for age, ejection fraction, stroke history, diabetes, renal
disease, non-elective surgery, cerebrovascular disease, and prior heart surgery (46). Hos-
pital mortality was 11.4% for on-pump, versus 3.8% for off-pump surgery. Ten on-pump
patients had strokes (4.7%), compared with five (2.4% of off-pump strokes) (46).

ENCEPHALOPATHY, COGNITIVE, AND NEUROBEHAVIORAL


ABNORMALITIES AFTER HEART SURGERY

A broad spectrum of neuropsychiatric findings, including delirium, confusion, disorienta-


tion, drowsiness, and altered behavior, without focal neurological abnormalities are often
bundled together under the broad term encephalopathy. In these patients, neuroimaging
tests do not show new large focal brain infarcts. In a Cleveland Clinic series of CABG
operations, 11.6% of patients were considered encephalopathic on the fourth postoperative
day (47).
In another very large series, 57 of 1669 (3.4%) patients who had CABG surgery had
severe postoperative mental changes, including delirium and encephalopathy (48).
Undoubtedly, the causes are multiple. Encephalopathy is especially common among
older patients and those with a history of alcohol abuse and renal disease. Some patients
have a hypoxic-ischemic encephalopathy because of a long surgical time, during which
their brain was poorly perfused. An important number of cases are explained by medi-
cations. Sedatives, analgesics, especially narcotics, and most important haloperidol
are common offenders. Haloperidol very often produces depressed alertness, stiffness,
inertia, and drowsiness, and the drug stays in the body a long time. Haloperidol has
been shown to retard recovery in animals with brain lesions (49,50). This drug should
not be used in older surgical and medical patients, especially those with abnormal brains.
When surgeons first became aware of postoperative changes in behavior after heart
surgery, these abnormalities were attributed to psychological reactions to the milieu of
intensive care units—constant light and stimulation, lack of sleep, and so on. The initial
recognition that the encephalopathy and neurobehavioral changes were not psychiatric
in origin was made by Sid Gilman in 1965 when he prospectively followed a series of
open-heart surgery patients (51). Early researchers posited that the embolization of par-
ticulate matter that was related to the pump and its filters had led to the encephalopathy.
The introduction of membrane rather than bubble oxygenators and in-line filtration led
to a decrease in the risk of macroembolic particles (.25 mm) reaching the systemic
circulation (52).
A 1990 report of the necropsy findings in five patients and six dogs who all had
cardiac surgery awakened new interest in this subject (53). Widely scattered in 10 of
The Aorta as a Donor Source of Brain Embolism 195

these 11 brains were focal small capillary and arteriolar dilations (SCADs). About half of
the SCADs contained birefringent crystalline material within the dilated capillary regions
(53). The vascular lesions affected medium-sized arterioles, terminal arterioles, and
capillaries; they were often distributed in multiples in the same vessels or in clusters
near each other. Two other patients had a small number of SCADs after arteriography.
The authors thought that the findings were most consistent with iatrogenically induced
release into the system of small particles of air or fat (53). Moody’s observations antedated
TCD monitoring of brain arteries during cardiac surgery. Subsequent studies have shown
that the number of microemboli that reach the brain correlates with the occurrence of ence-
phalopathy and cognitive and behavioral abnormalities noted after surgery. Furthermore,
the number of microemboli correlate with the severity of aortic atherosclerosis in patients
who have on-pump cardiac surgery. Microemboli released from the aorta are likely to be
the most important cause of encephalopathy and of persistent cognitive abnormalities
after cardiopulmonary bypass surgery.
Cognitive dysfunction without accompanying obvious focal motor, sensory, or
visual dysfunction is the most common complication of CABG surgery. Some patients
have obvious loss of intellect, whereas others have subtle problems detectable only by
formal neuropsychological evaluation. Estimates of the frequency of cognitive dysfunc-
tion after CABG range from 30% (54) to 88% (55), depending on the timing and extent
of neuropsychological testing.
The most frequent cognitive abnormalities are defective memory, concentration,
attention, and rapidity of response to stimuli (56). Although many patients improve con-
siderably within a few months, studies show that a substantial number of patients have per-
sistent loss of intellectual functions. Cognitive dysfunction was present in 35% of patients
one year postoperatively (56) and in 20% (57) of patients at three years in two different
studies. In a recent well-designed prospective study, 127 patients who had CABG
surgery were tested in eight cognitive domains before surgery and at one month and
one year after surgery. Only 12% of patients had no loss of function after surgery.
Among the 88% of patients who showed cognitive loss in at least one domain, 10% had
persistent decline in the domains of verbal memory, visual memory, attention, and
visual-related construction after one year (55). Depression was also common after CABG.
Advanced age and length of bypass are important risk factors for cognitive dysfunc-
tion after cardiopulmonary bypass (58). Recent prospective studies provide evidence that
microembolism is the most important cause of cognitive deficits after cardiac surgery
using cardiopulmonary bypass. Pugsley et al. (59) studied 100 patients who had cardiopul-
monary bypass, 50 with an arterial line filter and 50 without a filter. TCD was used to
monitor microemboli. All patients were given neuropsychological tests before and after
surgery. Neuropsychological deficits at eight days and eight weeks postoperatively were
more common in patients who had cardiopulmonary bypass without the arterial filter
and neuropsychological abnormalities correlated with the number of microemboli (59).
Pugsley et al. (59) found that 43% of patients with intraoperative embolic counts
.1000 had cognitive abnormalities at eight weeks after cardiac surgery, compared with
only 8% of patients with ,200 emboli. Barbut et al. (60) found that the average
number of microemboli at the time of removal of aortic clamps was 166 in 6 patients
with cognitive abnormalities compared with 73 microemboli in 11 patients who showed
no loss of cognitive function.
Goto et al. (61) in Japan studied 463 patients .60 years old who had CABG surgery.
Aortic atherosclerosis was quantified using an epiaortic ultrasound probe. The 76 patients
with severe aortic atherosclerosis had a rate of 26% of postoperative neuropsychological
findings and a stroke rate of 10%; patients with moderate aortic atherosclerosis and
196 Caplan

Figure 5 Cholesterol crystals and other particulate debris are caught in a filter placed in the
aorta at the time that aortic lamps are removed. Kindly submitted by Dr. Denise Barbut. Source:
From Ref. 32.

those with mild or no atherosclerosis had rates of 7% and 8% for neuropsychological dys-
function and stroke rates of 1.8% and 1.2%, respectively (61). In this study, thickness of the
aorta around the site of aortic manipulation and deformities due to clamp or cannulation
were significantly associated with postoperative neurological dysfunction (61).
Recently, cardiac surgeons have begun to introduce filter devices into the aorta when
aortic clamps are removed during on-pump surgery to catch debris and cholesterol crys-
tals. Figure 5 shows cholesterol crystals and other particulate debris caught in one of
these filters.

IMAGING OF THE PROXIMAL AORTA

TEE has become the standard way to image the aorta. There is good concordance between
TEE images and pathology of the aorta (22,24,62). The limitations of TEE are that it is
invasive and there is an area of the aorta that is obscured because of the bronchus and
is not readily imaged. TEE has often been done before CABG or during the surgery.
TEE can show large plaques and floating mobile thrombi within the lumen of the aorta.
Figures 6 and 7 show various aortic plaques shown by TEE. Vaduganathan et al. (63)
showed a 73% agreement between intraoperative TEE imaging of the thoracic aorta
and histology. TEE did not always detect ulceration but was able to detect complex
atheroma and mobile debris in every case. Epiaortic ultrasound applied at the beginning
of surgery is also a useful method for detecting severe atheromas and intima-medial
thickness of the aorta at various locations (44,61).
The ascending aorta can also be insonated using a duplex ultrasound probe placed in
the right supraclavicular fossa, and the arch and proximal descending thoracic aorta can be
imaged using a left supraclavicular ultrasound probe (64). The results so far are prelimi-
nary but promising. The technique requires training to master and is not used in most
centers. Most plaques are located in the curvature of the arch from the distal ascending
The Aorta as a Donor Source of Brain Embolism 197

Figure 6 Transesophageal echocardiographic image of the aorta showing small and large plaques.

aorta to the proximal descending aorta, regions well shown using B-mode ultrasound (64).
The aorta has also been imaged by a suprasternal approach during transthoracic echocar-
diography using harmonic imaging; in one study large protruding plaques were found with
a 91% positive predictive value, and negative findings had a 98% predictive value, but
unfortunately adequate image quality for interpretation could only be obtained in 89%
of patients studied (65).

Figure 7 Transesophageal echocardiographic image of the aorta showing a protruding large


plaque that was highly mobile.
198 Caplan

Magnetic resonance angiography (MRA) and Magnetic resonance imaging (MRI)


have also been used to image the proximal aorta. Kutz et al. (66) compared the sensitivity
of detection of large plaques (.5 mm) using gadolinium enhanced MRA during breath-
holding versus TEE. The sensitivity was 54% with MRA versus 92% with TEE. Techniques
that show the lumen of the aorta, such as MRA and standard angiography, usually do not
show the wall of the aorta and so underestimate atherosclerotic plaques. Some researchers
have experimented with techniques that enhance atherosclerotic plaques and the vascular
endothelium. In a rabbit model, gadofluorine enhances plaques and allows for the detection
of early atherosclerotic lesions (67). High-resolution MRI using plaque and endothelial
enhancing agents has great promise for becoming the preferred imaging technique for detect-
ing and quantifying aortic atherosclerosis in near future.

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11
Arterial Sources of Embolism
Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

The extracranial and intracranial large arteries often act as donor sources for embolism to
the brain. Arterial-source embolism is also referred to as artery-to-artery, intra-arterial,
and “local” embolism.

DISEASES, PATHOLOGY, AND PATHOPHYSIOLOGY

Although atherosclerosis is by far the commonest condition that serves as a donor source
of intra-arterial embolism, other vascular diseases also can release embolic materials.
Trauma and dissections of arteries lead to local thrombus formation and embolism.
Occasionally, inflammatory diseases of the brachiocephalic branches of the aortic arch,
such as temporal arteritis and Takayasu’s disease, can lead to intra-arterial embolism.
Thrombi sometimes form within arterial aneurysms, both saccular (1,2) and fusiform doli-
cocephalic aneurysms (3), and can then break off and embolize to distal branch arteries.
Fibromuscular dysplasia (FMD) is an important but relatively uncommon vascular
disease that affects the pharyngeal and occasionally the intracranial portions of the
carotid, and vertebral arteries that also can become a source of distal intra-arterial embo-
lism. Thrombi can, on occasion, form within large arteries in the absence of important
arterial disease in patients with cancer and other causes of hypercoagulability (4).
Figure 1 is an angiogram showing a large thrombus within an internal carotid artery
caused by hypercoagulability in a patient with cancer. These luminal thrombi then can
embolize to intracranial arteries causing strokes.

ATHEROSCLEROSIS

Atherosclerosis is the predominant cause of intra-arterial embolism. The initial arterial


lesion is a fatty streak that develops during the first three decades of life on the surface
of the intima and then enlarges, usually during a period of decades, into a raised athero-
sclerotic plaque. Plaques contain a mixture of lipid, smooth muscle, fibrous and collagen
tissues, macrophages, and inflammatory cells (5 – 8). Plaques can enlarge quickly when
203
204 Caplan

Figure 1 Carotid angiogram lateral view. Dark filling defects (white arrowheads) represent
thrombi within the internal carotid artery. The insert on the left shows the location of the
thrombi.

hemorrhages occur within the plaques. When a critical plaque size and encroachment on
the lumen are reached, the atherosclerotic process often accelerates. Reduced luminal area
and the bulk of the protruding plaque alter the physical and mechanical properties of blood
flow and create regions of local turbulence and stasis. Platelets often adhere to irregular
surfaces of plaques. Secretion of chemical mediators within platelets and within the under-
lying vascular endothelium causes aggregation and further adherence of platelets to
the endothelium. Platelets begin to stick together and adhere to the endothelial lining of
the plaque. A “white clot” composed of platelets and fibrin develops. Plaques often inter-
rupt the endothelial lining of arteries and ulcerate. Figure 2 shows an ulcerated, irregular
plaque within a specimen of a carotid artery removed at surgery. Breaches in the
endothelium allow cracks and fissures to form, allowing contact of the constituents of
the plaque with the blood within the lumen. Tissue factor, an important stimulator of
the bodies coagulation system, is released. The coagulation cascade is activated by
this contact, and a “red thrombus” composed of erythrocytes and fibrin forms within
the lumen. Platelet secretion can also activate the serine proteases that form the body’s
coagulation system and also promote the formation of red clots. When white or red
thrombi first form, they are poorly organized and only loosely adherent. They often
propagate and embolize. Figure 3 shows an occluded carotid artery found at necropsy.
The specimen contains a large, mobile, red thrombus, a part of which had embolized
to the brain. Within a period of 1– 2 weeks, thrombi organize and become more adherent,
and fragments are less likely to break off and embolize. A variety of different materials—
cholesterol crystals, calcified plaque fragments, white clots, and red thrombi—can form
the substance of intra-arterial emboli.
Arterial Sources of Embolism 205

Figure 2 A carotid endarterectomy specimen that shows an irregular ulcerated plaque.

ARTERIAL DISSECTIONS

Arterial dissections are probably the second most common disease that leads to artery-to-
artery brain embolism. Stretching or tearing within the arterial media causes the formation
of an intramural hematoma. Blood within the media dissects longitudinally along the arter-
ial wall. Expansion of the arterial wall often impinges on the lumen, narrowing it. Figure 4
shows a vertebral artery dissection containing a large intramural hematoma. The expand-
ing intramural hematoma can break through the intima and release fresh red congealed
hematoma containing thrombus-like material into the arterial lumen. This red clot is, at
first, not adherent to the endothelium and thus often embolizes. The intimal tear and the
underlying intramural hematoma cause perturbation of the arterial endothelium that, in
turn, causes the activation of platelets and the coagulation cascade, promoting the for-
mation of a thrombus in situ within the lumen. Compromise of the lumen by expanding
intramural lesion alters blood flow within the lumen, which also promotes thrombus for-
mation. Thrombus can form in situ within the dissected artery or reach the lumen by the
introduction of the intramural contents. In either case, the acute luminal thrombus is
poorly organized and nonadherent and readily embolizes intracranially (9 – 12).
Marfans, Ehlers-Danlos, Pseudoxanthoma elasticum, cystic medial necrosis, and FMD
predispose to arterial dissection.

FIBROMUSCULAR DYSPLASIA

First recognized in the renal arteries as a cause of hypertension in young women, FMD also
affects other systemic arteries, including extracranial and intracranial arteries. FMD is a
206 Caplan

Figure 3 Autopsy specimen showing an occluded carotid artery. A large red thrombus is project-
ing into the lumen of the artery (white arrow).

nonatheromatous multifocal disease that can involve any or all layers of arterial walls.
The major pathology is fibroblast-like transformation of smooth muscle cells (13,14).
The major morphological abnormalities include: (i) severe elastic tissue destruction,
(ii) thinning of the media, (iii) medial smooth muscle hyperplasia and fibrosis, and

Figure 4 Cut sections of a vertebral artery removed at surgery. The proximal portion of the artery
is to the left of the figure. A large brown-appearing intramural hematoma is present, severely narrow-
ing the arterial lumen.
Arterial Sources of Embolism 207

(iv) adventitial fibrosis (15). The most common type of FMD predominantly affects the
arterial media. Constricting bands made up of fibrous dysplastic tissue and proliferating
medial smooth muscle cells alternate with regions of luminal dilatation related to thinning
of the media and disruption of the elastic membranes (16,17). These pathological changes
explain the characteristic string-of-beads appearance found on cervicocranial cerebral angio-
graphy. Figure 5 is an angiogram that shows characteristic changes of FMD within the
pharyngeal portion of an internal carotid artery. Focal regions of hypertrophy of fibrous
tissues in the adventitia or intima cause segmental areas of stenosis. The severity of stenosis
can vary on different vascular imaging studies because some of the luminal narrowing is due
to reversible vasoconstriction.
Patients with FMD have a much higher than normal frequency of intracranial aneur-
ysms (13,15,18). Pathological examination of arteries with FMD often shows dissections,
and evaluation of patients presenting with arterial dissections shows an increased
frequency of FMD. The cause of FMD is unknown. The pathological abnormalities
could result from a number of different disorders, all sharing the tendency for proliferation
of fibrous tissue or smooth muscle. Hereditary and genetic factors are likely to be very
important (13,18).
About two-thirds of patients with FMD are women, and the mean age at presentation
is 50 (18). Among 1,100 patients reported with FMD, 300 (27%) patients had involvement
of aortocranial arteries (18). Among reports of patients with cerebrovascular FMD,
12 – 43% of patients have involvement of the pharyngeal portion of the internal carotid
artery often accompanied by involvement of the cervical vertebral artery (19). The phar-
yngeal portion of the extracranial vertebral arteries is most often involved usually opposite
the second cervical vertebrae; the lesions usually extend for about 1– 2 cm. Most reported
patients with intracranial FMD have also had extracranial involvement of the vertebral or
carotid arteries or both (19).

Figure 5 A carotid angiogram shows characteristic string-of-beads appearance (black arrows)


characteristic of fibromuscular dysplasia within the pharyngeal portion of the artery.
208 Caplan

The mechanisms by which FMD causes brain ischemia are not very well understood.
Luminal irregularity and endothelial abnormalities could promote the formation of white
platelet fibrin or red fibrin-dependent thrombi with subsequent intra-arterial embolism.
Undoubtedly, some brain infarcts are caused by dissections often unrecognized in the
presence of FMD.

ARTERIAL ANEURYSMS AND DOLICHOECTATIC ARTERIES

Saccular aneurysms are localized outpouchings along arterial walls. About 4 –6% of the
population have aneurysms at necropsy (18,20,21), and as many as 10% of adults more
than 20 years old may harbor aneurysms, and saccular aneurysms are more common in
women. Among 7,010 patients with aneurysms in one large series, 56% were women
(21,22). Saccular aneurysms are most often located at branch points and forks along the
intracranial large arteries along the circle of Willis and in the basal cisterns. Conditions pre-
disposing to aneurysm formation include FMD, polycystic kidney disease, and congenital
disorders of connective tissue, such as the Ehlers-Danlos syndrome. Both congenital and
acquired factors contribute to the formation and growth of saccular aneurysms. Figure 6
shows a large saccular basilar artery aneurysm shown at dye contrast cerebral angiography.
Figure 7 is a CT angiogram that shows a large vertebral artery–posterior inferior cerebellar
artery aneurysm. Each harbored thrombi. Large aneurysms have been shown to harbor
thrombi that can embolize distally (1,2).
Some patients are prone to elongated, ectatic, tortuous intracranial arteries. The intra-
cranial arteries in these patients often contain regions of marked vascular dilatation variously
referred to as dolichoectasia, dilatative arteriopathy, or fusiform aneurysm formation. The
basilar artery is most often affected, but the intracranial vertebral arteries are also often
involved (23). Some patients also often have similar dilatation of the petrosal, cavernous,

Figure 6 A cerebral dye contrast angiogram showing a very large basilar artery aneurysm (black
arrow) that harbored a thrombus.
Arterial Sources of Embolism 209

Figure 7 A computed tomography angiogram showing an aneurysm at the vertebral-posterior


inferior cerebellar artery junction (small white arrows). Thrombus material was present within the
lumen.

and intradural segments of the internal carotid arteries and the middle cerebral arteries.
Although usually found in older patients, especially those with hypertension and diabetes,
dolichoectasia is also occasionally found in the very young and also occurs in children
with AIDS (24–27). Hereditary factors probably play an important role especially in the
young. Hypertension and diabetes may cause progressive vascular wall damage in patients
with dilatative arteriopathy. Extensive atherosclerotic plaques—often with calcification,
encroachment on the lumen, and thrombus formation—are often found at necropsy. Flow
within dilated segments is sometimes abnormal. Recent studies using transcranial Doppler
(TCD) ultrasound show reduced velocity, to-and-fro flow, and even zero flow near the arter-
ial walls (28,29). As a result, thrombi often form within dilated segments (30–32). Figure 8 is
a dye contrast angiogram that shows a large filling defect (thrombus) within a dolichoectatic
basilar artery. Clots within the arteries can embolize distally, and plaques and thrombi can
block the orifices of penetrating and circumferential artery branches thus causing ischemia
in the territory of these branches (30–32).

DISTRIBUTION OF ARTERIAL LESIONS

The distribution of arteriosclerotic occlusive lesions varies depending on race, sex, and
risk factors (9,10,33 – 36). In white men, the predominant cervicocranial occlusive
lesions are in the carotid and vertebral arteries in the neck at or near the origins of
these arteries. Blacks, individuals of Asian origin, and women more often have occlusive
lesions in the large intracranial arteries and their main branches and less often have severe
occlusive vascular lesions in the neck. White men who have carotid artery disease also
have a high frequency of co-existing coronary artery and occlusive lower limb artery
disease, as well as hypertension, and hypercholesterolemia. Smoking also promotes the
development and progression of atherosclerotic lesions within the proximal carotid and
210 Caplan

Figure 8 A dye-contrast cerebral angiogram that shows a large filling defect representing throm-
bus (small black arrows) within a dolichoectatic basilar artery. Note that the posterior cerebral artery
does not fill. After intravenous recombinant tissue plasminogen activator, the thrombus lysed, and
the posterior cerebral arteries and distal basilar artery recanalized fully.

vertebral arteries. After the menopause, the frequency of extracranial occlusive disease
increases in women.
Within the anterior circulation, the most frequent and most important occlusive
lesion in white men is within the internal carotid artery in the neck. Atherosclerotic
lesions usually begin along the posterior wall of the common carotid artery opposite the
flow-divider between the internal and the external carotid arteries (6,7,37). Figure 9 illus-
trates this localization of plaque, and Figure 10 is a carotid angiogram showing a very
severe stenosis at this location within the initial portion of the right internal carotid artery.
Atherosclerotic plaques grow and begin to intrude on the lumen and spread cranially
within the common carotid artery and the proximal portion of the internal and sometimes
the external carotid arteries. The next most common atherosclerotic lesions in white men
within the anterior (carotid) circulation are found within the intracranial internal carotid
artery, in the proximal intracranial portion of the artery called the carotid siphon
because of its S shape, and within the proximal portions of the middle cerebral arteries.
These lesions all most often produce symptoms by embolism of fragments of clots that
form upon the vascular endothelium of plaques or of particles of the plaques themselves.
Women, blacks, and Asians often develop occlusive lesions within the middle
cerebral arteries and their branches. ICA siphon and neck lesions are less often found.
Blacks, Asians, and women who develop occlusive neck lesions often smoke and have
important coexisting atherosclerotic risk factors, such as hypertension, diabetes, and
hypercholesterolemia.
Within the posterior (vertebro-basilar) circulation, the most common occlusive
lesion among white men is at the vertebral artery origin in the neck and within the adjacent
subclavian artery. Plaques usually begin within the subclavian arteries and extend into the
Arterial Sources of Embolism 211

Figure 9 A diagram generated from ultrasound reconstructions showing the location of an ather-
osclerotic plaque (single black arrow) opposite the flow divider (double arrows) and between the
internal carotid artery to the left and the external carotid artery to the right.

vertebral arteries at their origins or begin at the origins or within the first few centimeters of
the vertebral arteries. Figures 11 and 12 are dye contrast angiograms that show severe
atherosclerotic stenosis at and near the vertebral artery origins. The next most common
lesions are within the intracranial vertebral arteries and the basilar artery (38). White
men with occlusive atherosclerotic lesions at the origins of the vertebral arteries also
have a high frequency of coexisting carotid artery disease (37 – 40), as well as hypertension
and hypercholesterolemia. Intracranial lesions are also very common both in white men
and in women, blacks, and Asians. The predominant lesions are within the intracranial
vertebral arteries. Atherosclerotic lesions within the ICVAs are often bilateral (38).
Atherosclerotic lesions involving the posterior cerebral arteries are more common in
women, blacks, and Asians (10). The predominant mechanism of brain ischemia within
the posterior circulation, as within the anterior circulation, is embolism (10,38,41,42).
Intra-arterial embolism is just as common and important a mechanism of stroke within
the vertebrobasilar arterial system as it is within the carotid artery system.
Arterial dissections most often involve the pharyngeal portions of the extracranial
carotid and vertebral arteries (9,10). The pharyngeal portions of the neck arteries are rela-
tively mobile, whereas the origins of the arteries and their penetrations into the cranial
cavity are anchored and much less mobile. Tearing occurs in portions of arteries that
are flexible and stretch with motion. Within the extracranial vertebral arteries, the most
common site of dissection is the most distal portion of the artery that emerges from the
intervertebral foramina and courses around the atlas to penetrate the dura mater and
enter the foramen magnum (10,43,44). Dissections also occur in the mobile part of the
212 Caplan

Figure 10 A carotid angiogram showing a very severe stenosis within the initial portion of the
right internal carotid artery (white arrowhead ).

Figure 11 A dye-contrast angiogram showing stenosis at the origin of the vertebral artery (white
arrow) from the subclavian artery. The artery is dilated after the region of stenosis (poststenotic
dilatation).
Arterial Sources of Embolism 213

Figure 12 A dye contrast angiogram showing stenosis a few centimeters beyond the origin of
the vertebral artery (white arrow) from the subclavian artery.

proximal portion of the extracranial vertebral arteries above their origin from the
subclavian arteries but before the arteries enter the vertebral column at the intervertebral
foramen of the sixth or fifth cervical vertebrae (10). Figure 13 is an artist’s drawing of the
locations within the vertebral artery that are predilection sites for atherosclerosis and
dissections.
Figure 14 contains arteriograms that show the findings in patients with dissections of
the carotid and vertebral arteries in the neck.
Intracranial dissections are much less common than extracranial dissections. In the
anterior circulation, intracranial dissections most often affect the intracranial internal
carotid arteries and extend into the middle and anterior cerebral arteries (45). Within
the posterior circulation, the most common site is the intracranial vertebral arteries
(10,43,46). Dissections within the ICVAs often spread into the basilar artery. Occasion-
ally, the basilar artery is the primary site of dissection (46). Dissecting aneurysms as
well as large saccular and dolicocephalic fusiform aneurysms can serve as a source of
thrombus formation with subsequent distal embolization (46).

RELATION OF SYMPTOMS TO SEVERITY OF


ATHEROSCLEROTIC ARTERIAL STENOSIS

Unlike the situation within the coronary arteries, brain ischemia is closely related to the
severity of arterial stenosis. Transient or persistent brain ischemia is far more likely to
214 Caplan

Figure 13 An artist’s drawing of the vertebral artery. The open arrowheads show the areas of pre-
dilection for atherosclerosis, and the black arrowheads show the areas predisposed to dissections.

develop, when arterial lumens are severely narrowed. The arterial lesions cause brain
ischemia either by substantially reducing blood flow to a region of the brain supplied
by the artery (hypoperfusion) or by providing the donor source for intra-arterial embolism.
Most sizable brain infarcts in patients with arterial stenoses and occlusions are embolic.
TCD studies show an increased rate of high intensity transient microembolic signals in
patients with severe ICA stenosis, supporting the key role of embolization (47 – 50). Hypo-
perfusion and embolism may complement each other (51). Normal blood flow allows effi-
cient clearance (washout) of microemboli. When blood flow is importantly diminished,
emboli may not washout and so remain to obstruct intracranial arteries causing brain
infarction (51).
Severity of stenosis is widely accepted as the most important prognostic risk factor
that indicates the likelihood of future development of stroke in patients with symptomatic
and asymptomatic carotid artery disease in the neck (52 – 55). Norris et al. (56) found
increasing cumulative rates of transient ischemia and stroke in relation to increasing
grades of arterial stenosis. The incidence of ischemic events also correlated very
closely with the progression of the luminal compromise.
In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the
risk of stroke correlated highly with the degree of ICA stenosis in all patients with transient
monocular blindness, transient hemispheral ischemic attacks, and minor strokes (52,54).
The presence of “silent infarcts” on magnetic resonance imaging (MRI) (57), and even
Arterial Sources of Embolism 215

Figure 14 (A) A dye-contrast arteriogram showing a carotid artery dissection. There is a long area
of narrowing—a so-called “string sign” (small black arrows). (B) A dye-contrast angiogram
showing a dissecting aneurysm (black arrow) in the pharyngeal portion of a carotid artery. (C) A
dye-contrast angiogram of a vertebral artery showing irregular regions of narrowing and dilatation
in the rostral extracranial portion of the artery ( paired black arrows) and an aneurysmal outpouching
in the intervertebral portion of the artery (lower single black arrow).

the size of brain infarcts (58), has been shown to depend on the severity of ICA stenosis in
the neck. The severity of intracranial arterial stenosis also has been shown to correlate
highly with the occurrence of symptoms of brain ischemia (59 – 61). When stenosis is
severe, the altered physical characteristics of blood flow strongly promote thrombus
formation within the lumen, and thromboembolism develops.
216 Caplan

Some patients with lesser degrees of arterial stenosis do develop intra-


arterial embolism. Most often these emboli are white clots that cause transient ischemia
or minor strokes—a phenomenon that Miller Fisher calls acceptable minor embolism.
The morphological characteristics of plaques from specimens removed at endarterectomy
correlate with symptoms (11,62). Some features of plaques as they appear on B-mode
images of the cervical arteries—their degree of surface irregularity, heterogenicity, and
echogenicity—are helpful in predicting the likelihood of related stroke. Echolucent
plaques are rich in lipids and are associated with elevated levels of triglyceride-rich lipo-
proteins (63,64). Soft, heterogeneous plaques with irregular surfaces are more often asso-
ciated with symptoms compared to calcified, dense plaques with regular surfaces (64,65).

IMAGING AND LABORATORY EVALUATION OF


POTENTIAL DONOR SOURCES OF EMBOLISM

In patients suspected of having brain embolic events, a thorough evaluation of all potential
sources—cardiac, aortic, and cerebrovascular—is usually indicated. Atherosclerotic
plaques and occlusive lesions often coexist in the heart, aorta, and brachiocephalic
arteries. Furthermore, patients with cerebrovascular occlusive lesions have a very high fre-
quency of coronary atherosclerotic heart disease, and their coronary artery disease often is
a more serious threat for mortality and disability than their cerebrovascular disease.
Patients with myocardial infarcts and coronary atherosclerotic heart disease have a high
frequency of occlusive lesions within their extracranial and intracranial vascular beds.
Prophylactic treatment to prevent subsequent thromboembolism should optimally con-
sider measures to prevent embolism from all potential donor sources, not only the one
that caused the present embolism.
The extracranial and intracranial arteries should be studied to define potential
arterial donor sources of embolism. The four most common and effective means of study-
ing the brachiocephalic arteries are by magnetic resonance angiography (MRA), computed
tomographic angiography (CTA), extracranial duplex ultrasound, and cerebral catheter-
dye angiography. Brain imaging always should precede or accompany the vascular
studies to show the location, severity, and distribution of related brain ischemia.
Imaging of the brain and intracranial recipient arteries has been thoroughly dis-
cussed in Chapter 6. Optimal information is provided by thorough magnetic resonance
imaging. MRI scans of the brain, including fluid-attenuated inversion recovery images
and T1- and T2-weighted images show the extent of brain infarction and adequately
show hemorrhages and hemorrhagic infarction. These studies can be accompanied by
MRA of the extracranial and intracranial arteries. MRA provides a good image of the
extracranial carotid arteries but can overestimate the severity of the stenosis (66 –68).
When the arterial stenosis is very severe, there is often a gap in the arterial images indi-
cating an impediment to flow, but gaps do not allow accurate quantification of the sever-
ity of the stenosis or the presence of thrombi. MRA of the intracranial anterior
circulation arteries is a good screening test for occlusion or severe stenosis of the
major arterial branches of the intracranial carotid arteries (69,70). Tortuous regions
within the carotid artery in the siphon often are not imaged well, and MRA does not
show distal branch artery occlusions. When the carotid artery is occluded in the neck,
there may be too little flow to provide good images of the intracranial carotid artery
and its major branches, although often these vessels are filled well by collaterals.
MRA can also be used to screen for occlusive lesions within the vertebrobasilar circula-
tion (10,71,72). Unfortunately, the origins of the vertebral arteries from the subclavian
Arterial Sources of Embolism 217

arteries are difficult to image unless a proximal view of the aortic arch arteries is
included in the imaging. The extracranial and intracranial vertebral arteries are some-
times imaged using two different views—a neck and a head studies. Sometimes the
neck view is cut off too high missing the origin of the artery, and the head view is
cut off too high failing to include the proximal intracranial vertebral artery after its
dural penetration. Care must be taken to ensure that the entire vertebral artery is seen.
The basilar and posterior cerebral arteries are imaged well using MRA (10,71,72).
The extracranial and intracranial arteries also can be accurately imaged by CTA
(73,74). This technique employs rapid filming using a spiral (helical) CT scanner after
the intravenous injection of a dye load. Reformatting of the CT images yields good recon-
structions of the extracranial and intracranial arteries. The CT source films can be
reviewed quickly to detect arterial occlusions, but time is sometimes needed to reproduce
reformatted arterial images depending on the available software. CT scans of the brain are
also acquired so that both brain and vascular images are created using the same technology
and at one sitting. CTA is accurate in showing large artery occlusions, severe stenosis, and
aneurysmal changes in both the anterior and posterior circulations (73,74).
Ultrasound capabilities have dramatically improved and are now an integral part of
the evaluation of patients with brain embolism. Ultrasound has the advantages of being
portable, noninvasive, and relatively inexpensive when compared with MR and CT.
Ultrasound can be repeated sequentially to study the effects of spontaneous or therapeutic
reperfusion. In some centers, ultrasound equipment is available in the emergency room
and at the bedside and can be used by examining physicians as an extension of the physical
examination of the arteries. At present, Doppler ultrasound is available in almost all
intensive care units to follow blood flow in various peripheral arteries. Duplex scanning
(combined B-mode and multigated pulsed-Doppler) is used to image the extracranial
carotid and vertebral arteries. Both duplex scans and C-W Doppler give accurate infor-
mation about the ICA in the neck (67,75,76). Figure 15 shows a B-mode ultrasound of

Figure 15 (A) B-mode ultrasound showing echoes representing plaques. (B) (small white arrows)
protruding into the lumen of the internal carotid artery from both the anterior and posterior walls of
the artery. (C) Artists diagram of B-mode findings in a patient with a large plaque in the internal
carotid artery. Abbreviations: ICA, internal carotid artery; ECA, external carotid artery; CCA,
common carotid artery.
218 Caplan

Figure 16 Composite B-mode ultrasound showing clearly the innominate, right common, internal
and external carotid arteries and the right subclavian and vertebral arteries. Abbreviations: IA,
innominate artery; SA, subclavian artery; VA, vertebral artery; CCA, common carotid artery; ICA,
internal carotid artery; ECA, external carotid artery.

plaques within the internal carotid artery and also an artists drawing of the findings from a
B-mode ultrasound of a patient with an atherosclerotic plaque that extends from the
common carotid artery along the posterior wall of the internal carotid artery. Color-flow
Doppler imaging is probably even more effective in grading the severity of ICA stenosis
and depicts flow abnormalities and regions of turbulence (77 –79).
The innominate, subclavian, and vertebral arteries can also be studied using duplex
and color-flow ultrasound (10,75,80,81). Ultrasound of the carotid and vertebral arteries is
also useful in suggesting dissections (82 – 84). Figure 16 is a composite B-mode ultrasound
picture that shows the extracranial arteries quite well.
TCD ultrasound yields very important information about flow in the intracranial
arteries (10,75,85,86). TCD has been thoroughly discussed in Chapter 7. Angiography
of the extracranial and intracranial arteries is still important. Angiography is performed
in patients: (1) in whom noninvasive vascular tests (CTA, MRA, extracranial and
transcranial ultrasound) show lesions but not sufficiently to guide treatment, (2) when non-
invasive testing shows a lesion that would be best treated by intra-arterial interventional
radiology (intra-arterial thrombolysis and/or angioplasty), and (3) in whom noninvasive
testing has not shown a donor source of embolism but an arterial source is suspected.
Guidelines for the use of angiography in patients with brain ischemia have been
published (87).
CT, MRI, and MRA usually suffice to identify aneurysmally dilated, ectatic arteries
and may suggest the presence of clot within the vessels. TCD is very helpful in diagnosis
and may show reduced mean flow velocities, with relatively preserved peak flow velocities
(29). Blood flow may be to and fro within the dilated artery causing reduced antegrade
flow. The reduced antegrade flow may lead to poor opacification on MRA, falsely
suggesting occlusion of the dolichoectatic artery. CTA and standard angiography are
usually able to provide images of the dolichoectatic artery in that circumstance.
Arterial Sources of Embolism 219

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12
Ultrasound of Cervical Arteries
Michael Hennerici, Hansjoerg Baezner, and Michael Daffertshofer
Department of Neurology, University of Heidelberg, Universitätsklinikum Mannheim,
Mannheim, Germany

Ultrasound is a very important method of interrogating the neck arteries as potential donor
sources of emboli. Modern ultrasound has greatly improved evaluation of arterial disease
in the neck and head. The important advantage of ultrasound lies in the ability to image
and study the arterial wall. Other imaging techniques—dye-contrast angiography and
computed tomography and magnetic resonance angiography—provide images of the
lumen of arteries but do not give information about the arterial wall or the nature of
plaques that protrude from the arterial wall.
Rapid progress in noninvasive ultrasound techniques has resulted in a wide variety
of clinical applications, including evaluation of vascular aging as a degenerative
process, depiction of early and small vascular lesions, and demonstration of plaque devel-
opment, motion, and vulnerability. Echo-contrast agents have been used to compensate for
difficulties in visualizing late, severe, or subtotal obstructive plaques. With increasing
sophistication of ultrasound methods, it became essential to establish standards for data
acquisition and interpretation. Consensus meetings have provided detailed recommen-
dations on quantification of carotid atherosclerosis and characterization of carotid artery
plaques (1,2), as well as detection of microembolism by transcranial Doppler (3).
Although extensive research in atherosclerosis has been performed for more than a
century, the mechanisms causing atherogenesis are still poorly understood. Atherosclero-
tic arterial disease has an irregular natural course with long asymptomatic stages until
symptoms develop suddenly due to local thrombosis or distal embolism. Distinction
from normal aging has long been difficult but is now facilitated by vascular ultrasound
investigations, such as delineation of the intima – media thickness (IMT), plaque develop-
ment, and vascular remodeling. Compensatory mechanisms can also be identified in
patients with few symptoms but extensive vascular disease. These patients usually do
not need surgical or interventional treatment because of the slowly developing collateral
capacity of complex networks from large and small arteries.

INTIMA – MEDIA THICKNESS: THE INITIAL STAGE OF


ARTERIAL DISEASE

Pignoli et al. (4) using B-mode ultrasound were the first to characterize a “double line”
pattern of the normal carotid artery wall. These authors described the first echogenic
223
224 Hennerici et al.

line on the far wall as the lumen – intima interface and the second line as the media-
adventitia interface. They showed that measurements of the IMT in tissue specimens
from common carotid arteries correlated highly with the distance between these two echo-
genic lines. This first report on the measurement of IMT with B-mode ultrasound was later
validated in vitro (5) and was also shown to enable good intra- and interobserver reprodu-
cibility (6). However, Gamble et al. (7) questioned whether the double line was represen-
tative of the histologic situation. Others posited that the depiction of IMT with B-mode
ultrasound could be a border-zone reflection artifact and compared it to the double-line
pattern seen with Plexiglas, metal plates, and plastic foil (8). Notwithstanding these
debates, the vast majority of later studies validated a close correlation between the IMT
seen in histologic specimens and that measured with B-mode ultrasound.
Studies later established associations between common carotid IMT, cardiovascular
risk factors (9,10), and the prevalence of cardiovascular disease (11) using high-resolution
ultrasonography. The increasing importance of the common carotid IMT is further
reflected by its use as a surrogate end point for determining the success of interventions
that lower levels of low-density lipoprotein cholesterol. Azen et al. (12) used serial
measurements of IMT to assess the effect of supplementary vitamin E intake in reducing
progression of age-related vascular degeneration in subjects not treated with lipid-
lowering drugs. A recent report confirmed these findings and identified increased
carotid artery IMT as a risk factor for both myocardial infarction and stroke (13). In con-
trast to epidemiological and large clinical trials, other studies questioned the clinical use-
fulness of measuring carotid IMT in individual patients, because it was not specific or
sensitive enough to identify those with or without significant coronary artery disease
and is less rigorously related to atherosclerosis than to vascular degeneration. Increasing
age, male sex, and diabetes were all associated with a coronary artery disease score
significantly higher (P , 0.01) than average for any level of carotid IMT, suggesting
different associations of these traditional risk factors on atherosclerosis in the coronary
and common carotid arteries (14). Because of these controversial results, a consensus
on the value of measuring IMT has not been reached. Ultrasound imaging is able to
measure both IMT and plaque volume, nature, and development, making it possible to
analyze in large epidemiological studies the importance of each regarding stroke and
coronary artery disease (Fig. 1).

Intima – Media Thickness Sampling


The selection of precise regions for the measurement of IMT is critical, because the focal
location of reactive intimal thickening and initial plaque development in the carotid
arteries are related to geometric transitions. Because any single ultrasound examination
may fail to identify the site of maximal intimal thickening, IMT measurements over a
range of incident angles and axial locations are recommended. A variety of IMT-sampling
protocols have been proposed. Some use IMT measurements at the common carotid artery,
where the double-line pattern is easiest to visualize, whereas others choose to measure
IMT at the carotid bifurcation and within the internal carotid artery (ICA).
Site-specific measurement of IMT focuses on arterial segments showing either wall
thickening or plaques. In some studies, cut-off points of 0.75 or 1 mm are chosen to
identify subjects with an abnormal IMT. In others, the IMT was considered abnormal if
the value was one or two standard deviations above the mean for the population. In an
attempt to assess the overall extent of the atherosclerotic burden, scoring systems have
been developed for site-specific studies. These use aggregate summing of IMT
Ultrasound of Cervical Arteries 225

Figure 1 B-mode common carotid artery images showing vessel wall interface with increasing
atherosclerotic load: (A) normal arterial wall (far wall) with intima – media thickness (IMT)
,1.0 mm, (B) slightly increased IMT (1.1 mm; average from three measures), (C) slight IMT
increase (1.6 mm; average of three measures) in an asymptomatic patient with several vascular
risk factors, (D) definite atherosclerotic thickening of the intima– media complex with clear dissol-
ution of the normal IMT pattern (IMT ¼ 1.9 mm), and (E) circumscribed atherosclerotic plaque at
the carotid bifurcation.
226 Hennerici et al.

measurements from segments considered to be diseased, whereas normal-appearing


arterial walls are assigned a score of zero (15).
Other investigators calculate the mean thickness of both normal and abnormal walls
(16,17). The method of IMT sampling, that is, combined measurements at different sites
and measurements of mean or maximum wall thickness, depends on the research question
and on the relative emphasis placed on confirmed atherosclerotic lesions (18).

Assessment Over Time


A major source of error in the longitudinal assessment of IMT is the difficulty in retrieving
the same echographic view of the vessel. Although the mean IMT might be considered a
reproducible target to evaluate differences between populations exposed to diverse risk
factors, natural or therapy-induced changes in an individual may be better monitored on
predefined carotid artery sectors. External landmarks have been used to increase reprodu-
cibility (19). Another approach uses discrete Fourier transforms to minimize the vessel
contour after matching baseline ultrasonographic images with a corresponding view (20).

Morphologic Correlates of IMT


The common assumption that an increased IMT represents early atherosclerotic plaque
formation is not true. Intimal hyperplasia and fibrocellular hypertrophy are nonathero-
sclerotic reactions associated with local modifications of flow and mural tension and
likely represent adaptive or self-limiting compensatory changes continuously changing
during life. Importantly, intimal fibrocellular hypertrophy, a layered widening of both
smooth muscle cells and matrix fibers, can be extensive in a particular arterial segment
and is not necessarily of uniform width. In contrast, early atherosclerotic lesions are charac-
terized by a focal eccentric accumulation of lipid in the intima, both in the extracellular
matrix interstices and in the smooth muscle cells. These early lesions do not project into
the vessel lumen that remains anatomically intact. Intimal fibrocellular hypertrophy may
modify the arterial surface contour, and intimal hyperplasia and atherosclerosis often
coexist. IMT, as measured by B-mode ultrasound, is a heterogeneous entity, largely
independent from atherogenesis and plaque development.

PLAQUE DEVELOPMENT: THE INTERMEDIATE STAGE OF


ARTERIAL DISEASE
High-Resolution B-Mode Imaging
Owing to its noninvasive nature, real-time capabilities, and general availability, ultrasound is
the most extensively utilized imaging technique to study the morphology of carotid artery
plaques. Small atherosclerotic plaques with a luminal narrowing of ,40% are suspected
using Doppler sonography if spectral broadening is present, indicating abnormal blood-
flow components. However, as physiological flow separation and a variety of other hemody-
namic variables may confound the interpretation of spectral broadening, high-resolution,
B-mode imaging is needed to detect small atherosclerotic lesions and to assess plaque
morphology. The increased use of real-time B-mode imaging results from an advancing
transducer technology, the miniaturization of electronics through the development of
digital circuitry, advances in computer software, and improved ultrasonic focusing. This
results in continuously improving image quality and increased information content for
real-time ultrasonographic evaluation of plaque morphology.
Ultrasound of Cervical Arteries 227

Compounded Imaging
Real-time compounded imaging is a new modality that has the potential to enhance
ultrasonographic visualization and characterization of carotid artery plaques (21).
This technique acquires ultrasound beams that are steered off-axis from the orthogonal
beams used in conventional ultrasound. The number of frames and steering angles
varies depending on the transducer characteristics. Frames acquired from sufficiently
different angles contain independent random speckle patterns, which are averaged to
reduce speckle and improve tissue differentiation. In comparison with high-resolution
B-mode imaging, this new technology is able to suppress edge shadowing and
improve contrast resolution. This new technology will enhance morphologic character-
ization of plaque-surface structure and aid in assessing the location and nature of
plaque constituents.

Color Doppler Flow Imaging


Color Doppler flow imaging (CDFI) is a scanning mode that combines gray-scale imaging
with two-dimensional Doppler flow information in real time. A single representative
Doppler shift (usually the mean) at each sampling site is color encoded by hue or intensity
of color. By convention, red typically indicates motion in one direction, and blue indicates
motion in the opposite direction. High-Doppler shifts are commonly displayed by
decreased color saturation, whereas flow turbulence may also be color coded. Through
their ability to contrast the intravascular lumen, color signals on CDFI can significantly
improve evaluation of plaque surface and configuration (22 – 26). This is particularly
helpful for showing weakly echogenic plaques, often hardly distinguishable from the
intravascular lumen with B-mode scanning techniques alone (Fig. 2).

Power Doppler Imaging


Power Doppler imaging is a more recent development that displays the amplitude of
Doppler signals. Color and brightness of the signals are correlated with the number of
blood cells producing the Doppler shift. The greater sensitivity of power Doppler
imaging for the detection of blood flow when compared with that of color Doppler flow
imaging is due to several factors.
1. Noise can be assigned to a homogeneous background, thus allowing the gain to
be increased over the level of CDFI.
2. In power Doppler imaging, more of the dynamic range of the Doppler signal can
be used to increase sensitivity.
3. Power Doppler is less angle-dependent than CDFI, thus allowing better display
of curving or tortuous vessels.
4. By reliance upon Doppler amplitude, there is no aliasing, improving display of
vessel wall pathology in areas of turbulent flow.
5. Power Doppler is superior for displaying vessels with low-flow velocity.
The first report on the value of power Doppler imaging in cerebrovascular
ultrasound showed a distinct advantage for the assessment of plaque-surface
structure (Fig. 3) (27). Since then, this new technique has been further validated and
is currently the gold standard in ultrasound for characterizing carotid artery plaque
surfaces.
228 Hennerici et al.

Figure 2 Image of an atherosclerotic plaque: B-mode image (upper row; left side) that shows
heterogeneous plaque texture and an irregular plaque surface difficult to evaluate. Color mode
now displayed in grey and black (boxed area) additionally displays regular flow patterns without
significant irregularities. Doppler registration (lower row) without flow increase indicates nonvul-
nerable plaque. Note the irregular cardiac cycles.

Figure 3 Complex plaque displayed with power mode shown in the boxed region of the figure.
Power mode does not provide information about flow direction or about flow irregularities. The
high sensitivity of the mode to identify slow flow velocities facilitates otherwise impossible delinea-
tion of this highly curved and complex plaque surface and also allows detection of ulcerative niches.
Ultrasound of Cervical Arteries 229

Plaque Echogenicity
Plaques with homogeneous echogenicity consist mainly of fibrotic tissue (28,29). Ulcera-
tion is rare in homogeneous plaques, perhaps accounting for the lack of significant corre-
lation with the occurrence of focal brain ischemia. Heterogeneous plaques represent
matrix deposition, cholesterol accumulation, necrosis, calcification, and intraplaque
hemorrhage (28 – 30). High-resolution B-mode scanning can allow characterization of
echomorphologic features of carotid plaques that correlate with histopathology (31). Frag-
ments of thrombi, intraplaque hemorrhages, and accumulation of lipid materials can all
yield echolucent regions within plaques (32). Plaque calcification produces acoustic
shadowing in B-mode echotomograms. Depending on plaque location and the extent of
calcification, this artifact can be a major obstacle for adequate visualization of the
vessel and the plaque.
Initial studies of plaque echogenicity with B-mode ultrasound reported an associ-
ation between heterogeneous plaques and the occurrence of cerebrovascular events
(33 –37). Examinations of endarterectomy specimens suggested a correlation between
intraplaque hemorrhage and transient ischemic attacks and stroke (38 – 41). Later
studies did not confirm this hypothesis (42 –44). Whether differences in plaque echogeni-
city can distinguish between symptomatic and asymptomatic patients continues to be
debated. New ultrasonographic studies claim again that heterogeneous carotid plaques
are more often associated with intraplaque hemorrhage and neurologic events and con-
clude that evaluation of plaque morphology may be helpful in selecting patients for
carotid endarterectomy (45 – 47). Others argue that lipid-rich plaques are more prone to
rupture and suggest that an association between an intraplaque hemorrhage and a high-
lipid content as revealed in B-mode ultrasound may support this theory (48). Others
have found little correlation between plaque morphology and histologic specimens (49).
Recently, a definitive study on the significance of heterogeneous plaque structure found
no differences in volume of intraplaque hemorrhage, lipid core, necrotic core, or plaque
calcification in patients with highly stenotic carotid artery lesions undergoing endarterect-
omy, regardless of preoperative symptom status (50).

Interobserver and Intraobserver Agreement of


B-Mode Plaque Morphology
In the Tromsø Study in Norway, interobserver and intraobserver agreement on plaque
morphology classification was reported as high, with k-values ranging between 0.54
and 0.73 (51). However, most new studies on this subject report low interrater agreement,
indicating that unaided visual evaluation of static B-mode pictures for assessing plaque
morphology in patients with carotid stenosis is not very reliable (52). Reproducible
grading of ultrasound images is not consistently achievable among experienced observers,
and within-observer agreement may vary with time (53). In one study on subjective cat-
egorization of plaque types, the intraobserver agreement was moderate (k ¼ 0.44) and
the interobserver agreement was low (k ¼ 0.38), emphasizing that subjective B-mode
ultrasound categorization of atherosclerotic plaques cannot adequately determine the
volume of fibrosis or lipids within plaques (54). The poor interobserver and intraobserver
agreement concerning B-mode plaque morphology may explain the discrepant findings
of previous attempts to characterize carotid artery plaques in relation to clinical events.
The current subjective ultrasound characterization of carotid plaque morphology
used in clinical trials may be associated with unacceptable levels of reproducibility in
some centers.
230 Hennerici et al.

Computerized Evaluation of Plaque Echogenicity


Owing to suboptimal interobserver and intraobserver agreement in estimating visually
plaque morphology with ultrasound, various schemes for standardizing the assessment
of carotid plaques have been introduced. Linear scaling of the adventitia and blood with
gray-scale medians has been proposed for quantifying echo intensity. Using this tech-
nique, decreased echogenicity in terms of gray-scale median and percentage of echolucent
pixels has been reported for symptomatic plaques (55). Other groups have also used
computer processing to yield a measure of plaque echogenicity (56). Spectral analysis
of echo signals acquired from human carotid endarterectomy specimens has been per-
formed to improve classification of fibrous, lipid pool, and thrombus constituents (57).
By using three parameters of the calibrated power spectrum (slope, intercept, and total
power), the proportion of correctly classified tissue regions could be increased. These
studies indicate that computer-aided analysis of ultrasonic B-mode features of carotid
plaques may be valuable in multicenter clinical trials, where different operators and
equipment are used.

Plaque-Surface Structure and Ulcerations


Attempts to characterize plaque-surface structure with B-mode echotomography have
been disappointing. Relatively good differentiation among smooth, irregular, and ulcera-
tive plaque surfaces has been obtained for postmortem carotid artery specimens (29), but
in vivo accuracy when compared with findings at carotid endarterectomy is considerably
poorer (31,39,58,59). Surface defects showing a depth and a length of 2 mm with a well-
defined base in the recess are often used to identify plaque ulceration (60). Using these
criteria, B-mode imaging has failed to provide a satisfactory diagnostic yield for ulcerative
plaques with a sensitivity of only 47%. Other groups have been unable to distinguish
between the presence or the absence of intimal ulcerations with B-mode scans (61).
Diagnostic sensitivity for detecting plaque ulceration with ultrasound is affected by the
degree of carotid stenosis and increases to 77% in plaques associated with 50% stenosis
(31). Power Doppler imaging could significantly improve the yield for reliable depiction
of plaque ulcerations. Pathoanatomical comparisons with this technique, however, are
lacking.
Conventional dye-contrast angiography has likewise proven inadequate for the defi-
nition of ulcerative plaques, the sensitivity being 53% (31). Angiographic detection
of ulceration when compared with surgical specimens was poor in the North American
Symptomatic Carotid Endarterectomy Trial (NASCET) study. A sensitivity of 45.9%
and a specificity of 74.1% were found for 500 specimens, yielding a positive predictive
value of only 71.8% (62). Angiographic assessment of plaque-surface morphology
varies depending on the type of angiography and the quality of visualization of carotid
artery stenosis (63). Whether plaque surface irregularities or ulcerations are useful for
defining patients at risk for artery-to-artery embolism is debated. Advocates of a pathophy-
siological relationship maintain that ulcerations constitute a fertile ground for potential
thrombosis and consequent embolic events. A recent report contends that the presence
of an angiographically defined ulcer is associated with an increased risk of stroke in medi-
cally treated symptomatic patients (64). Some ulcers are smooth and thick and contain no
thrombus (65). Endarterectomy specimens from asymptomatic patients with carotid artery
plaques with .60% stenosis show an increased frequency of plaque hemorrhages, ulcera-
tions, and mural thrombi, as well as of numerous healed ulcerations and organized thrombi
(66). Both symptomatic and asymptomatic patients with stenotic carotid endarterectomy
Ultrasound of Cervical Arteries 231

plaques show a high frequency of complex plaque structure and complications (42,67).
There seems to be little difference in plaque constituents or plaque surface structure
between specimens from symptomatic and asymptomatic patients. These findings
confirm that a traditional description of plaque structure or identification of plaque ulcera-
tion as depicted in current clinical imaging techniques; that is, ultrasound, MRI, and angio-
graphy, is not useful for predicting which carotid plaques are most likely to become the
donor source of artery-to-artery emboli.

Characterization of Plaque Motion


Experimental work suggests that analysis of plaque motion—that is, translational plaque
movements coincident with those of arterial walls, plaque rotations, and local, plaque-
specific deformations—may provide new insights into plaque modeling and mechanisms
of plaque rupture with subsequent embolism. For example, in vitro observations on the
relative position of markers placed along plaque specimens during pressure loading
have shown that prior to plaque fissuring, the markers display asymmetrical movement.
Such plaque-surface movement may be attributable to deformations resulting from
crack propagation of multiple local internal tears in the plaque. Identification of local
variations in surface deformability could, therefore, provide information on the relative
vulnerability to plaque fissuring or rupture.
An approach for studying plaque-surface deformations has recently been reported
(68). This technique uses four-dimensional (4D) ultrasonography to acquire temporal
three-dimensional ultrasound data of carotid artery plaques. The ultrasound data are
then analyzed with motion detection algorithms to determine apparent velocity fields,
also known as optical flow, of the plaque surface. Using this method, differences in
plaque motion patterns between patients with symptomatic and asymptomatic carotid
artery disease have been characterized (68). Asymptomatic plaques typically show a
homogeneous orientation and magnitude of computed-surface velocity vectors, coincident
with arterial wall movement. Analysis of symptomatic plaques, however, has shown con-
sistent evidence for plaque deformation, irrespective of arterial wall movements, although
analysis of plaque motion in patients with carotid artery stenosis facilitates detection of
patterns that suggest an increased risk for plaque complications. Plaque vulnerability
likely depends on a number of nonlinearly active mechanisms rather than a simple
abnormality.

Possible Mechanisms of Remodeling


A very well-known phenomenon in vascular medicine is the ability of blood vessels
continually to adapt their cross-sectional size to the needs of dynamic downstream
blood supply. This dynamic process, termed “arterial remodeling,” came into the focus
of vascular research when it became clear that remodeling and not plaque size was the
primary determinant of lumen size in the presence of stable lesions. More recently,
growing evidence seems to show an association of adequate outward remodeling with
an increasing risk of plaque rupture as the underlying cause of acute coronary syndromes
and sudden cardiac death.
The term “remodeling” is used to describe various conditions as de novo
atherosclerosis, restenosis, and transplant vasculopathy. Obviously, the predominant
mechanisms involved in remodeling in each of these pathological conditions may be
quite different.
232 Hennerici et al.

Remodeling and Hemodynamic Stimuli


Under physiological conditions, vascular remodeling is a dynamic response to both flow
changes to restore normal shear stress and alterations of circumferential stretch to adjust
wall tension (69). Important factors that contribute to outward remodeling in response to
increased flow are the shear-responsive endothelial production of nitric oxide (70) and the
matrix metalloproteinases (MMPs) MMP-2 and MMP-9 (71). Nitric oxide seems to be
crucial in this process, as it has the potential to induce MMPs (72) and to inhibit proliferation
and promote apoptosis of smooth muscle cells (73). In low-flow states, mitogenic and fibro-
genic growth factors, such as platelet-derived growth factor and transforming growth factor,
are preferably produced, which probably mediates inward remodeling by increasing smooth
muscle cell proliferation and the deposition and cross-linking of collagen, whereas MMP
induction helps to reorganize vessel structure (74,75). The effect of stretch on remodeling
is less clear. Many of the earlier mentioned mediators are not only shear sensitive but also
stretch responsive, so that a significant interaction between stretch and shear signals can be
assumed (76). Most of the energy of pulsatile pressure is absorbed by elastin, whose pro-
duction is highly stretch responsive. This makes it quite probable that an alteration in
elastin production may be important in remodeling, as vessel elasticity is the chief determi-
nant of resting vessel size (77). How these molecular and cellular events are spatially coordi-
nated to result in morphological change remains unclear. Possibly certain transmembrane
proteins, such as the highly shear- and stretch-sensitive connexins that have a rapid turnover,
may play a role (78).
Theoretically, endothelial dysfunction and increasing plaque depth may prevent
remodeling in response to hemodynamic stimuli, because under such conditions effectors
of remodeling must penetrate into atherosclerotic lesions. Furthermore, in focal lesions,
the acceleration of flow both on the proximal and on the distal side of a protruding
plaque is associated with a translesional deterioration in remodeling (79). At the same
time, this leads to greater inflammatory infiltrate and less cellularity and collagen in the
upstream side (80) and increased stenosis downstream (81), indicative of persistent
shear sensitivity.

Inflammation, Scarring, and Remodeling


Several mechanisms contribute to the dynamic processes, finally leading to the atherosclero-
tic burden. First, inflammatory cells, by producing MMPs, play a major role in atherosclerotic
remodeling. Cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1)
and vascular cell adhesion molecule (VCAM), have the ability to recruit monocytes and
macrophages, which is a shear-sensitive process (82), partly explaining the predominance
of this cell type on the upstream side of focal lesions (80). Secondly, the expression of
MMPs by atherosclerotic lesions can be further promoted by an increasing infiltration of
inflammatory cells due to hyperlipidemia. The reduction of MMP expression in plaques,
mainly originating from macrophage-foam cells, is a possible mechanism of action of lipid
lowering and reduction in lipid oxidation (83,84). This may explain the apparent stimulatory
effect of hypercholesterolemia on outward remodeling response (85) that is reflected in ultra-
structural changes in the internal elastic lamina (86) very similar to those induced by high-
blood flow (87). Both processes are MMP-dependent and can therefore lead to outward
modeling.
The same local MMP activity provoked by hypercholesterolemia may explain why
some eccentric plaques appear to initiate remodeling in the vessel wall directly beneath the
plaque (88) and why medial thinning underlying a plaque is directly proportional to plaque
burden (89). Outward remodeling may be prevented by excessive collagen deposition
Ultrasound of Cervical Arteries 233

within a lesion. Under certain clinical conditions, such as after angioplasty (90) and plaque
rupture, sudden or focal fibrotic responses are induced, and scar contracture may result in
inward remodeling.

Clinical Observations Regarding the Mechanisms of


Atherosclerotic Remodeling
Although research on plaque formation has identified many factors that promote plaque
growth, much less is known about possible determinants of remodeling. Some of the vari-
ation in remodeling response depends on the vascular bed involved, so that compensatory
remodeling is often present in the carotid and coronary vessels, whereas ileofemoral
arteries are prone to inadequate outward and/or inward remodeling. In contrast, this
process is uncommon in the renal arteries (91). These regional differences possibly
reflect differences in endothelial responses to altered hemodynamics (92) or variations
in the underlying vessel composition, such as elastic versus muscular (93). Other
factors seem to influence remodeling patterns, such as systemic conditions (e.g.,
insulin-dependent versus noninsulin-dependent diabetes) (94) and the presence of such
risk factors as smoking, and make inadequate outward and inward remodeling more fre-
quent, in contrast to hypercholesterolemia (90). Despite these factors, there is often
marked variability in remodeling response along the same artery (95,96). Some lesion
specificity in remodeling response can be attributed to altered local hemodynamics,
such as in the inner curves of tortuous vessel segments, where low shear predisposes to
atheroma (97) and may similarly impair outward remodeling (98). This may be
particularly important in the carotid bifurcation, where outward remodeling is less
frequent proximal to the bifurcation (99).

Remodeling and Plaque Rupture


Plaque rupture causes unstable angina, myocardial infarction, and sudden death from cor-
onary artery disease (100). Most coronary lesions responsible for myocardial infarction
were minimally occlusive prior to rupture, as was shown by several angiographic
studies. This is consistent with the fact that many patients had no prior history of coronary
ischemia (100). Postmortem studies showed that patients who died with plaque rupture
without prior history of coronary disease had large lesions (101), suggesting that due to
considerable outward remodeling, angiography would have failed to display stenosis
despite significant histological stenosis. This is in keeping with several recent studies
showing an association between outward remodeling and plaque rupture in the coronary
circulation. Earlier findings suggest that the remodeling response correlates with mechan-
ical characteristics and the clinical presentation of the patient with the plaque. Calcified
plaques are associated with inadequate outward and/or inward remodeling in patients pre-
senting for angioplasty (96), whereas soft plaques show better compensatory enlargement
(102). Lesions responsible for unstable coronary syndromes are usually composed of
larger, softer plaques with more outward remodeling, when compared with those patients
who have stable angina and whose lesions are more fibrous and calcified (103,104,126).
The interaction of remodeling and plaque rupture can be understood through invol-
vement of MMPs and apoptosis in both processes. However, it remains uncertain whether
this interaction is causal or due to common mechanisms. In the case of a causal relation-
ship, longitudinal rates of remodeling might be able to predict acute events. In contrast, if
MMP inhibitors are used to prevent plaque rupture, this may be at the expense of increas-
ing luminal compromise and need for revascularization. If outward remodeling resulted in
234 Hennerici et al.

plaque rupture, it would be interesting to know whether subsequent fibrous healing


culminates in inward remodeling. Because inflammatory responses are important in the
association between outward remodeling and plaque rupture, anti-inflammatory and
lipid-lowering agents might be useful because of their action to decrease outward remo-
deling responses. This may be a possible explanation for a relatively small regression
in angiographic lumen stenosis, compared with the reduction in clinical events in lipid-
lowering trials (79).

Remodeling and Stroke-Specific Aspects


Although the sequence of progressive fixed stenosis and resulting ischemia is very
common in coronary and peripheral arterial disease, this does not necessarily hold true
in the cerebral circulation due to the availability of collateral circulation through the
circle of Willis. Nevertheless, carotid and vertebral artery thrombosis, with artery-to-
artery embolism to intracranial arteries, is the major cause of brain infarction. Hence,
the relationship between plaque rupture and remodeling is of great importance in the
extra- and intracranial cerebral arteries. As plaque characteristics and local remodeling
responses are extraordinarily accessible in the carotid circulation, there is great potential
to quantitate the risk of plaque rupture both systemically (106) and locally (107) and to use
statin therapy (108), anti-inflammatory drugs (60), and metalloproteinase inhibitors (109)
more selectively to prevent plaque rupture.
Remodeling in the cerebral circulation may be promoted or attenuated by several
local factors. As previously shown in bifurcations within the coronary circulation (110),
remodeling in the region of the carotid bifurcation is reduced, leading to more severe
luminal narrowing in the internal carotid artery following each increment in plaque
mass (111). In addition, the finding that blood flow in the patent carotid artery increases
as a compensatory response to contralateral occlusion is of clinical relevance as this
leads to greater local stimulation of the cascade of remodeling (79), inflammatory cell
infiltration (89), and plaque rupture.

PLAQUE DEVELOPMENT: THE FINAL STAGE

Although ultrasound technology has continued to improve, diagnosis and vessel wall charac-
terization of severe degrees of carotid artery stenoses are limited. According to NASCET
and European Carotid Surgery Trial (ECST), the distal and local degree of stenosis
can be evaluated by dye-contrast angiography, but this technique often underestimates or
overestimates the hemodynamic situation. Combined ultrasound imaging and hemodynamic
Doppler studies are more able to show the actual degree of obstructions and should prefer-
entially be used for therapeutic decisions (27) (Fig. 4). In patients with complex calcified
plaques, a very high-grade stenosis may be mistaken for a complete occlusion. To overcome
this limitation, ultrasound contrast agents have been developed to clarify arterial patency
in cases not sufficiently characterized by conventional means (112).
Such contrast agents were introduced during the early 1990s (112) and are widely
used in studies of peripheral vessels (113 –115). They consist of microbubbles filled
with air or gases that, depending on their size, are either filtered in the pulmonary capillary
territories—making them ideal to prove right-to-left shunting, for example, through a
patent foramen ovale—or survive the passage through the pulmonary capillary bed to
enhance the signal-to-noise ratio during arterial ultrasound studies. Ultrasound reflectors
(i.e., blood cells) in conventional Doppler/duplex scanning do not have ideal reflection
Ultrasound of Cervical Arteries 235

Figure 4 High-grade (.80%) carotid stenosis in cross-section (left side; A and B) and longitudi-
nal view (right side; C and D) in B-mode (upper row; A and C) and mode (lower row; B and D).
Cross-sectional B-mode display (upper left) shows an eccentric plaque with a hyperechogenic
fibrous cap and hypoechogenic core of the plaque. Longitudinal mode (lower right) shows areas
aliasing as a proxy for highly increased flow velocities.

characteristics. This is the main reason for the limited capability of conventional ultra-
sound in differentiating (carotid artery) occlusion from high-grade stenosis, because
under these circumstances, volume flow is maximally reduced, leading to a critical
decrease in ultrasound reflectors. Addition of contrast agents improves ultrasound reflec-
tions and decreases the rare of false-negative results in showing high-grade stenosis. Con-
trast agents, after intravenous injection, usually increase the Doppler signal by up to
30 dB, and, depending on the concentration of the contrast agent and on the type of admin-
istration (perfusion vs. bolus), the enhancement usually occurs 30 –60 seconds after injec-
tion, with optimal contrast lasting 3 –6 minutes (116,117). Using ultrasound contrast
agents in small groups of patients, controversial results have been reported as to the use-
fulness of these agents in the differentiation of carotid occlusion from subtotal stenosis
(118,119). A multicenter comparative study using SH U 508 A (Levovistw) evaluated
carotid artery stenosis by color and spectral Doppler sonography in patients who
showed insufficient signal intensity by means of conventional ultrasonography, and the
study showed that the contrast significantly improved diagnostic accuracy (120).
Contrast was useful in a small but important number of patients (7/71). In these
patients, grading of the severity of stenosis achieved by means of ultrasound without
and after administration of echocontrast media was consistent with the angiographic
classifications. Correlations between baseline ultrasound scans, contrast-enhanced ultra-
sound scans, and angiography showed no general improvement of ultrasound accuracy fol-
lowing contrast enhancement. Although visualization of pseudo-occlusion remained
insufficient even after contrast enhancement in three out of 71 cases, this has no
bearing on treatment, as these patients do not benefit from surgery.
236 Hennerici et al.

Originally, the underlying idea of the study to improve diagnostic accuracy was
driven by the wish not to miss potential surgical candidates. The classical concept of an
increasing stroke risk with increasing degree of stenosis (121,122) has been recently chal-
lenged. Stroke risk actually decreases considerably in patients whose severely stenosed
ICA becomes totally occluded (123,124). In angiographic studies, the lumen of the post-
stenotic ICA is often collapsed or significantly reduced over a long distance (123,124). In
the ECST, conservatively treated patients with an ICA/common carotid artery vessel
diameter ratio of 0.4 had a significantly lower 5-year stroke risk for ipsilateral stroke
(8 vs. 25%) compared with patients without poststenotic lumen narrowing (124).
Similar results occurred in subgroups in the NASCET trial (123). Finally, endarterectomy
of a very high-grade carotid artery stenosis that became symptomatic when the artery
became completely occluded is a relatively high-risk procedure, which must be performed
shortly after symptom onset. Results of such high-risk procedures are too heterogeneous to
reliably predict benefit, risk, and outcome (125,126). For these reasons, the therapeutic
relevance of contrast application to improve ultrasound quality in the evaluation of
high-grade arterial stenosis is limited to rare and very well-defined cases, where the
poststenotic lumen is not narrowed and conventional ultrasonographic measures are
insufficient to definitely differentiate high-grade stenosis from occlusion.

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PART IV: PATHOPHYSIOLOGY

13
Vascular Hemostasis and Brain Embolism

Gregory J. del Zoppo


Department of Molecular and Experimental Medicine, The Scripps Research Institute,
La Jolla, California, U.S.A.

Little is known about the characteristics of the hemostatic system responses to injury in the
central nervous system (CNS); however, hemostatic responses in the brain have been
posited to differ significantly from other vascular beds. Differences relate, at least in
part, to the uniqueness of the brain and spinal cord in terms of tissue architecture, cellular
composition, and function (1). The microvascular beds of the CNS are unique. Brain
capillaries are ternary vascular complexes consisting of an endothelial cell lining that is
separated from the astrocyte end-feet, which are also components of capillaries, by the
basal lamina or extracellular matrix (ECM). Astrocytes communicate with and support
neurons that are subserved by the microvasculature. Arterioles have a myointimal layer
that can regulate blood flow. Pericytes are located around or are embedded in the myoin-
timal layer and are near the matrix (2,3). The two permeability barriers of the microvas-
culature are represented by the interendothelial tight junctions (blood – brain barrier) and
the subtending ECM/basal lamina. Both barriers derive from the interaction of the endo-
thelial cells and astrocytes during development and require these cells for their integrity
(4 –8). The basal lamina consists of laminins, collagen type IV, fibronectin, heparan
sulfate proteoglycans, nidogen, entactin, and other glycoproteins (GPs). These cellular
and matrix relations are important for CNS vascular function, although their relation to
hemostasis is not well understood.
There is considerable functional differentiation of endothelial cells along the
microvascular axis from arterioles to venules (9,10). The continuous interaction of
the vascular endothelium with coagulation factors, components of the plasminogen acti-
vator (PA) system, platelets, and leukocytes together maintain the hemostatic system. In
cerebral gray matter, the potent procoagulant tissue factor (TF) is found around micro-
vessels .7.5 mm in diameter but not around capillaries (11). Disturbances of these
antithrombotic features of the microvasculature occur during focal cerebral ischemia
(ischemic stroke). In the CNS, alterations in hemostasis are manifest as thrombosis
or hemorrhage and produce lasting injury to the extravascular tissue that the brain
has limited capacity to repair. This chapter explores knowledge about the interaction
of cerebrovascular hemostasis with the surrounding tissue and its responses following
thromboembolism.

243
244 del Zoppo

THROMBOSIS AND THE PATHOPHYSIOLOGY OF


BRAIN ISCHEMIA

Thromboembolism from proximal arterial atherosclerotic lesions and cardiac sources are
responsible for 56 –80% of ischemic strokes (12). The impact of thrombi depends on the
size and the location of the arterial segment involved.
Thrombus formation involves the interaction of platelets with activated endo-
thelium and with fibrin generated from circulating fibrinogen via the extrinsic
pathway. Platelet adhesion requires the interactions of subendothelial matrix proteins
(e.g., collagen type IV); von Willebrand factor (vWF); the platelet GPs Ia, Ib, Ib/IIa,
and Ib/V/IX; and platelet integrins a2b1 and allbb3. Exposure of ECM collagen in
the basal lamina to flowing plasma initiates platelet adhesion via the platelet integrin
a2b1. vWF sent to the surface of activated endothelial cell from storage granules
arrests platelet transit at the site of vascular injury via interaction with the platelet
GPIb/V/IX receptor. Following adhesion, release of dense granule adenosine dipho-
sphate (ADP) from activated platelets and traces of thrombin initiate platelet aggrega-
tion. Exposure of the fibrinogen receptor, integrin allbb3 (GPIIb/IIIa), on activated
platelets generates the platelet aggregates by selective binding to fibrinogen in a flow-
dependent manner. Subsequently, platelets release a group of pro-aggregatory substances
from a granules, including b-thromboglobulin (b-TG), vWF, thrombospondin, fibrino-
gen, and PDGF, and from d granules [ADP, adenosine triphosphate (ATP), and seroto-
nin] that stimulate further aggregation of platelets. Ex vivo flow studies corroborate that
the mechanisms of platelet adhesion depend on the shear forces within the blood vessel.
Thrombin is the central effector in thrombus formation, as it links platelet activation
with fibrin formation from fibrinogen (Figs. 1 and 2). Thrombin is a serine protease that is
enzymatically cleaved from prothrombin by the prothrombinase complex (factors Va
and Xa, phospholipid, and Ca2) (13). Two different activation pathways lead to the for-
mation of this complex (Fig. 1). In the extrinsic pathway, the initiating step is the exposure
of subendothelial TF to plasma. TF is a 46 kDa membrane-bound lipoprotein that forms a
complex with factor VIIa; the TF:VIIa complex then converts factor X to factor Xa. The
intrinsic pathway is initiated by high-molecular-weight kininogen (HMWK) and prekal-
likrein, which promote factor XII activation. Factor IXa leads to the activation of factor
VIII. Factor IXa, together with platelet phospholipid, Ca2þ, and factor VIIIa (the
“tenase complex”), activates factor X to Xa. The platelet surface, which has specific recep-
tors for factors V and VIII, provides the phospholipid workbench for the activation of
coagulation. This series of serine protease activators ultimately lead to the cleavage of
prothrombin (factor II) to stoichiometrically produce thrombin and its propeptide pro-
thrombin fragment (PF) 1.2.
Thrombin cleaves soluble fibrinogen, yielding a characteristic sequence of fibrin
monomers. Factor XIIIa stabilizes the fibrin network by forming inter-fibrin linkages
and insoluble, cross-linked fibrin polymers. The activation of factor XIII is itself thrombin
dependent. In addition, thrombin promotes the generation of factors Va and VIIIa on the
platelet surface, thereby enhancing its own production in a positive feedback loop.
Moreover, thrombin is among the strongest physiological stimulators of platelet aggrega-
tion. Thrombin also interacts with specific receptors on cells in the CNS, including
PARs 1 –4. In vitro studies suggest that thrombin can augment neuron toxicity (14,15).
Hence, the perivascular distribution of protease nexin-1 (PN-1) in the CNS may limit
the toxic effects of small amounts of thrombin generated in the plasma from microvessels,
which might leak into the brain parenchyma (14 – 16).
Intact endothelial cells prevent excess thrombin production related to three mechan-
isms: TF pathway inhibitor (TFPI), thrombomodulin, and antithrombin III (AT III). TFPI
Vascular Hemostasis and Brain Embolism 245

coagulation system activation


intrinsic
extrinsic
HMWK HMWK
XI XII prekal TF
vessel
+
VII
XIIa kallikrein
TF:VIIa
XIa IX
X
VIIIa:IXa
PL Ca+2 Xa:V:II
platelet
PL Ca+2

thrombin (IIa)

fibrinogen fibrin

Figure 1 Activation of the intrinsic and extrinsic coagulation pathways. The intrinsic pathway
relies upon the presence of high molecular weight kininogen (HMWK) and the activation of
factors XI and XII. HMWK is associated with intact blood vessel wall integrity. The extrinsic
pathway is initiated when perivascular tissue factor (TF) is exposed to the circulating coagulation
factors. TF and factor VIIa interact to make the potent TF:VIIa complex. Both systems promote
the activation of factors IX, VIII, V, and X on the surface of platelets, which have specific membrane
receptors for factors V and VIII. The platelet provides a scaffold for formation of the “tenase
complex” and the “prothrombinase complex,” which require the presence of phospholipid (PL)
and Caþ2. Activation of the coagulation factors which participate in these complexes activate pro-
thrombin (II) to thrombin. Thrombin cleaves fibrinogen to fibrin and specific fragments, and also
causes feedback activation of several factors (dashed lines).

is expressed and released into the plasma by endothelial cells and circulates either bound
to lipoproteins or as a quaternary complex with factor Xa and the TF:VIIa complex.
Heparin enhances the release of TFPI. Thrombomodulin is an endothelial GP receptor
that binds thrombin with high affinity; the thrombomodulin:thrombin complex promotes
protein C activation. Together with protein S, activated protein C (APC) exerts an
anti-thrombotic effect by neutralizing factors Va and VIIIa and PA inhibitor-1 (PAI-1).
AT III and heparin cofactor II (HC II) are circulating proteins that act as anti-
thrombotic substances. HC II is a specific inhibitor of thrombin, whereas AT III also
interacts with factors IXa, Xa, XIa, and XIIa. The binding of heparin with AT III accel-
erates the inhibitory action of AT III and is partly responsible for the anti-coagulant
effects of heparin.
Growth of the platelet thrombus is limited at the site of the injured endothelium by
release of the antiaggregatory substances PGI2, adenosine, and NO from intact endothelial
cells. The presence of glycosaminoglycans on the cellular membrane also confers
antithrombotic properties to the endothelium. These are potent modulators of platelet
aggregation and thrombus growth.

CEREBROVASCULAR THROMBOSIS

Along the vascular axis, alterations in hemostasis are manifest differently. Thrombosis in
the CNS is clinically evident when large arteries or veins (.1 mm diameter) are involved
246 del Zoppo

prothrombin

thrombin

platelets PAR activation


GP Ibα, GP V binding

fibrinogen cleavage to fibrin (+ fibrinopeptides)

thrombolysis cleavage of scu-PA


cleavage of TAFI
endothelium leukocyte adhesion receptors
permeability
protein C activation
NO release
angiogenesis ( VEGF-R1, R2)
smooth muscle cells Ca2+ release, relaxation
cell homeostasis toxicity

Figure 2 The general effects of the protease thrombin on vascular hemostasis. Platelet activation
can be mediated by the interaction of thrombin with its receptors (PARs) and by binding to com-
ponents of the glycoprotein (GP) Ib-V – IX complex. Thrombin cleaves circulating fibrinogen to
fibrin and other degradation peptides (e.g., fibrinopeptides A and B). In addition, it can cleave
single-chain urokinase (scu-PA) and also the thrombin activable fibrinolysis inhibitor (TAFI). Endo-
thelial cells are also activated by thrombin. Leukocyte adhesion receptors are presented in response
to thrombin exposure. Thrombin stimulates NO release, increases angiogenesis receptor expression,
and, in conjunction with thrombomodulin, mediates protein C activation. Thrombin can stimulate
vascular smooth muscle Caþ2 release and relaxation. However, thrombin has adverse effects on a
number of cell types, including altering permeability (of endothelial cells) and direct toxic effects
(e.g., neurons). Not to be forgotten is the important upregulatory role in thrombosis played by
a-thrombin, in which it stimulates tissue factor Vlla formation. Thrombin also has many other
important effects (via the various PARs), which makes it a protein mediator of many biological
processes. Abbreviations: PAR, protease activable receptor; GP, glycoprotein; scu-PA, single
chain urokinase plasminogen activator; TAFI, thrombin activable fibrinolysis inhibitor; VEGF,
vascular endothelial growth factor.

(17). Among the artery-associated processes that alter the hemostatic balance toward
thrombus formation, atherosclerosis is the most prevalent prothrombotic condition. The
common carotid artery bifurcation and the proximal internal carotid artery (ICA) are
common predilection sites affected in 50– 80% of ischemic stroke patients, followed in
frequency by the origin of the vertebral artery, and the proximal subclavian arteries and
individual intracranial arteries. Thrombosis of the cerebral veins and dural sinuses are
less common causes of stroke. Coagulation activation contributes to cerebral venous
thrombosis, reflecting the low-shear forces associated with venous flow and possible
venular injury (e.g., inflammation or infection). Malignancy, inherited deficiencies of
endogenous anticoagulants (i.e., AT III, protein C, and protein S), acquired anti-phospho-
lipid antibody (APLA) syndrome, severe dehydration, and specific drug effects (e.g., oral
contraceptives) suggest the importance of a procoagulant etiology (18 – 20). Hereditary or
acquired disorders of hemostasis predispose to thrombosis more often in the cerebral
venous circulation than in brain-supplying arteries. These prothrombotic disorders can
Vascular Hemostasis and Brain Embolism 247

account for about 1% of ischemic strokes and are relatively more frequent in young adult
stroke patients (4 – 5%).
Thromboemboli arise from cardiac structures in 17–28% of patients with
ischemic stroke (21–25).These emboli originate from injury to the cardiac endothelial
surface or from cardiac valves injured by rheumatic fever, mechanical or xenograft valve
prostheses, areas of ventricular injury and dyskinesia (associated with myocardial infarction),
or other causes. Left atrial thrombi can be associated with atrial fibrillation in the absence of
valvular disease. Emboli migrating from the left ventricle and capable of occluding the
middle cerebral artery (MCA:O) may be quite small, even submillimeter in cross-section.
Occlusion of small arterioles (100 –500 mm in diameter) typifies certain cerebral
microangiopathies that are thought to produce an imbalance in hemostasis. The APLA
syndrome and anticardiolipin (ACL) antibodies are associated with small infarctions,
which result from small arterial occlusion (26).These are similar to lesions observed in
patients with systemic lupus erythematosis who develop neurological abnormalities
(27). The direct causes of cerebral microvascular thrombosis associated with the APLA
syndrome and ACL antibodies are not clear. However, it has been suggested that some
antibodies from these families can bind to the endothelial cell membrane and alter the
membrane’s antithrombotic properties. They may also promote systemic embolization
from central sources, including the heart.
Arterial thrombosis and downstream lodgment of thromboemboli cause brain ische-
mia. However, the evolving ischemic lesion can also provoke thrombosis within the
microvascular bed downstream from the symptomatic arterial occlusion (28). Microvascu-
lar thrombosis of limited extent may remain clinically undetectable because of the large
contribution of this bed to the cerebral vascular volume. Occlusion of the MCA, with
reperfusion, can generate downstream arteriolar obstruction that is nonembolic. Microves-
sel occlusions in the ischemic territory contain activated platelets, fibrin, and polymorpho-
nuclear (PMN) leukocytes (29 – 32). These can contribute to the “focal no-reflow
phenomenon” first described by Ames et al. (28,33). Inhibitors of the platelet – fibrin inter-
action and of the PMN leukocyte adherence to the endothelium can significantly decrease
microvessel obstruction in the ischemic bed (32). Those observations further emphasize
the importance of the interrelationship of endothelial cell activation and hemostasis in
the vascular response to ischemic injury.

HEMORRHAGIC TRANSFORMATION

In the CNS, the maintenance of normal hemostasis is essential for preventing even limited
injury to an organ with limited regenerative capacity. Both microvascular thrombosis and
hemorrhage involve local disruptions of vascular integrity. It has been assumed that
endogenous thrombolytic processes prevent or greatly limit cerebral vascular thrombosis.
However, the presence of such processes beyond the components observed in the systemic
circulation is not firmly established (34). Experiments with selective integrin allbb3
inhibitors have shown the absolute requirement for competent platelet function to limit
or prevent hemorrhage during focal brain ischemia (35,36).
Two scenarios explain the development of hemorrhage in the ischemic territory.
Hemorrhagic infarction consists of scattered or confluent petechiae, implying extravasa-
tion of blood from the microvasculature (37 – 41). Focal ischemia causes an immediate
loss of basal lamina integrity, with deterioration of laminins-1 and -5, collagen type IV,
fibronectin, and perlecan which is accompanied by the generation of pro-matrix metallopro-
teinase-2 (MMP-2), select cathepsins, and urokinase PA (u-PA). These active proteases may
248 del Zoppo

contribute to ECM degradation (42 –46). Hemorrhagic transformation is significantly


related to loss of the major microvessel matrix proteins (47). In nonhuman primates, ische-
mia-related hemorrhage is also associated with pro-MMP-9 expression in the ischemic
tissue (43). However, it is possible that the appearance of MMP-9 is a tissue response to
the hemorrhage, rather than a cause of ECM degradation (43).
Parenchymal hemorrhage consists of confluent tissue hemorrhage (or a coagulum)
originating mostly within the regions of ischemia, often producing mass effect. It is
commonly associated with cardiogenic emboli under the conditions of anticoagulation
(48 –50). These observations, experimental work, and postmortem studies imply that
parenchymal hemorrhage results from arterial rupture (51). Local arterial wall necrosis
and rupture following downstream translocation or lysis of a thromboembolism have
been proposed as the root cause (37). Both petechial and parenchymal hemorrhage can
occur in the absence of antithrombotic agents in the setting of focal ischemia, indicating
that alterations in hemostasis are not required for hemorrhagic transformation.
Nonetheless, all antithrombotic agents carry a risk of increasing the frequency of par-
enchymal hemorrhage. The risk increases from no intervention to antiplatelet agents, antic-
oagulants, and PAs monitonically. Two hypotheses are that severe hemorrhage observed
with (i) anticoagulants may reflect inhibition of fibrin-thrombus formation superimposed
on arterial rupture and (ii) PAs may reflect continuous plasmin-mediated fibrin (thrombus)
degradation in the face of arterial rupture and TF-mediated fibrin generation. The combi-
nation of excessive anticoagulation and thrombolysis may produce excessive hemorrhagic
risk in ischemic stroke (e.g., in the PROACT study) (52). The hemorrhagic risk associated
with PAs depends on patient age, hypertension, and the presence of early signs of ischemic
injury on baseline CT scan (53 –55). The incidence of hemorrhagic transformation depends
on the time from ischemic onset to exposure to PA (53). This observation and those of Ueda
et al. (56) suggest that the duration of ischemic injury and the depth of blood-flow reduction
are necessary for detectable hemorrhage to develop. This concept of the development
of hemorrhagic transformation is consistent with the causative factor being significant
alterations in vascular integrity rather than changes in hemostasis alone.

STROKE AND CONSUMPTIVE COAGULOPATHY

The content of TF in the brain, much greater in gray matter than in white matter, is the
basis for the observation that closed-head injury can produce detectable consumptive coa-
gulopathy (11). Mortality from impact injury is directly related to the degree and severity
of the coagulopathy (57). A similar hypothesis has been proposed for atherothrombotic
and embolic stroke (20). However, two sets of observations indicate that the situation
following ischemic stroke may be more interesting.
At the levels of resolution of current clinical assays, clear evidence of consumptive
coagulopathy has not been confirmed. However, experiments in human-relevant systems
demonstrate elements of consumptive coagulopathy in occluded microvessels that contain
deposits of fibrin and activated platelets (29,32,58). This indicates that the local initiation
of coagulation by the ischemic insult limits consumption to the CNS. An unanswered
question is whether the microvascular coagulation extends tissue injury during the
evolution of ischemia.
The second observation is that alterations in peripheral markers of thrombosis do
appear in the setting of ischemic stroke. Evidence for consistent measurable changes in
platelet function, thrombin activation, and fibrin breakdown products is found in the
early days following ischemic stroke (18,59 – 61).
Vascular Hemostasis and Brain Embolism 249

PLATELET ACTIVATION

Release of the platelet a-granule-specific proteins b-TG and platelet factor 4 (PF4) occurs
during the second phase of aggregation. Release of a-granule contents occurs with
manipulation of the vasculature, angiography, inflammatory disease, and widespread
atherosclerosis. In addition, elevated levels of PF4 and b-TG have been associated with
brain ischemia. For instance, plasma b-TG levels increase by the second week after
stroke and return to baseline thereafter. The underlying causes for these changes are
unknown and are partly obscured by the sensitivity of these levels to collection technique,
patient age, and vascular risk factors.

THROMBIN GENERATION

Thrombin cleaves fibrinopeptides A and B (FPA and FPB) from the NH2-terminus of the a
and b chains of fibrinogen and fibrin I, respectively, thereby converting fibrinogen to
monomeric fibrins I and II. Interaction of thrombin with circulating AT III forms the
TAT complex. Circulating detectable PF 1.2, FPA and FPB, and TAT complex levels
mark evidence of thrombin action. An increase in plasma FPA levels followed by a
gradual decline to normal levels during several weeks to months occurs after the ischemic
event. No differences in FPA levels were identified between strokes of atherothrombotic
and cardioembolic origin (18).

FIBRIN DEGRADATION

Proteolysis of soluble-fibrin monomers by plasmin provides an indication of thrombolysis.


Plasmin cleaves the fragments Bb1-42 and Bb15-42 from the NH2-terminal regions of
fibrins I and II. Degradation of fibrinogen, soluble-fibrin monomers, and cross-linked
fibrin by plasmin yields a variety of characteristic fibrin(ogen) degradation products
(FDP). The degradation products derived from fibrinogen and fibrin differ. The presence
of the D-dimer antigen specifies the presence of cross-linked fibrin in the circulation and
implies also the generation of thrombin. Fragments Bb1-42 and Bb15-42 and D-dimer are
markers for plasminogen activation and plasmin action. In addition, tissue PA (t-PA)
antigen and activity, PAI-1 antigen and activity, a2-anti-plasmin, and plasmin –
anti-plasmin complexes (PAP) can be measured directly. Normal or slightly elevated indi-
cators of plasmin activity have been noted immediately after atherothrombotic stroke and
increase substantially thereafter. A similar temporal profile of plasmin action has been
reported in TIA patients.
These hemostatic alterations do not conclusively support the generation of a sys-
temic consumptive coagulopathy with secondary fibrinolysis. This interpretation is con-
founded by the observation of activation of inflammatory cells (e.g., PMN leukocytes)
both in the brain and in the peripheral blood during focal brain ischemia. The known inter-
relationship of inflammation to ischemia and thrombosis is reflected in the evolution of
brain infarction during ischemic stroke (62).
These considerations underscore the general observation that ischemic stroke is a
vascular disorder with neurological consequences in which thrombosis plays multiple
roles.
250 del Zoppo

ENDOGENOUS PROTECTIVE MECHANISMS

The relatively low frequency of detectable cerebrovascular events during youth and their
increased frequency with age suggest that during development thrombotic causes of stroke
are unusual and that time brings alterations in the vascular and hemostatic system that pre-
dispose to ischemic stroke. Some inherited disorders affecting hemostasis, including
hyperhomocysteinemia, are certainly important causes of stroke. However, most of the
causes of focal cerebral ischemia are acquired. The observation of frequent thromboem-
boli from the ICA into the cerebral circulation by duplex and transcranial ultrasonography
in clinically asymptomatic patients suggests (i) the presence of a large reservoir rep-
resented by the brain microvasculature that can accommodate the impact of such
emboli and/or (ii) the contribution of endogenous protective mechanisms that curtail
the effects of embolism. On the basis of the limited experimental and clinical data, I con-
sider next some of the known and presumed aspects of the protective features of the cere-
brovasculature in the setting of thrombotic stroke.

CEREBROVASCULAR RESERVOIR

During normal blood flow, not all capillaries are perfused (63). Hypercapnia and anesthesia
elicit substantial increases in local blood flow that may involve the recruitment of closed
capillaries or vasodilatation of extraparenchymal arterioles (63,64). A cerebrovascular
reserve must exist that can be recruited on short notice. However, direct measurements
indicate that capillaries of the pial and cortical circulation have plasma flow, and there
is no capillary recruitment during forebrain ischemia (65,66). Observations in humans
and in nonhuman primates suggest that the low-pressure –high-flow character of portions
of the brain means that not all microvascular channels are perfused and that microvascular
obstruction is “managed” by reversal of flow through adjacent channels (67). This may
afford a type of protection. However, the presence of a nascent microvascular bed that
can be recruited in the early moments of ischemia remains uncertain.

COLLATERAL CIRCUITS

The circle of Willis, anastomoses between the anterior and the MCA territories, and con-
nections between the posterior cerebral artery and the basilar system are obvious conduits
that can reverse blood flow. Vasculopathies involving these conduits—from atherosclero-
sis, diabetes mellitus, or other injuries—can limit flow to a focal ischemic region. This
may increase stroke severity (68,69).

MICROVESSEL-ASSOCIATED PROTECTION

APL and ACL syndromes promote cerebral arterial disease (26,27,70 –72). Thrombosis
within brain arterioles has been reported with APLAs, ACLs, and the lupus anticoagulant.
Several prothrombotic mechanisms of APL antibodies have been described, including
interference with the endothelial thrombomodulin-mediated protein C activation
pathway. These are conditions that apparently overwhelm the endogenous anti-thrombotic
characteristics of the microvascular endothelium.
Vascular Hemostasis and Brain Embolism 251

ENDOGENOUS THROMBUS LYSIS

Thrombus dissolution and embolization is a continuous process. A conundrum is how


emboli from proximal ICA sources can traverse the microvascular circuit without produ-
cing evidence of ischemia, whereas other thromboemboli produce clinically evident
ischemic events. Three issues are probably relevant: (i) residual neuron injury, (ii) throm-
bus composition, and (iii) PA function. Although embolic events may be clinically
“silent,” experimental studies show evidence of irreversible injury to neurons downstream
even after short periods of arterial occlusion (73). Occlusion of microvessels, even transi-
ently, could possibly lead to permanent clinically undetectable injuries. Embolus compo-
sition is probably relevant to the dissolution during its transit. Cholesterol-containing
emboli can produce arterial occlusion and large injury volumes (74). Fibrin dissolution
is mediated by thrombus-bound plasmin, generated by t-PA at the thrombus surface.
t-PA is cosecreted with its inhibitor PAI-1 from activated endothelium (75,76). If
endogenous fibrinolysis were a major contributor to embolus transit, based on volume con-
siderations, small thrombi should be more susceptible than large. However, the evidence
for enhanced endogenous thrombus lysis in the setting of ischemia is scant (44). Within the
early hours of focal ischemia, u-PA and PAI-1 are generated in the ischemic tissue (44).
However, t-PA activity does not change. In fact, there is a transient decrease in plasma
t-PA level because of the formation of t-PA†PAI-1 complexes (44). Given the proinflam-
matory nature of early ischemic stroke, it would not be surprising if thromboembolism to
the brain would not promote thrombus lysis there but rather results in attempts locally to
limit injury extension. One problem with this notion is that in select small animal models,
extension of the regions of injury occur because of inflammation.

VASCULAR MATRIX DEGRADATION

Within capillaries and microvessels up to 100 mm diameter, the endothelium is separated


from the end-feet of astrocytes by the basal lamina, a form of the ECM. ECM also encom-
passes the cells of the neuropil, but differs in composition from the vascular ECM. Exper-
imental work has shown that during focal brain ischemia, the activities of hemostatic
proteases and those of matrix metabolism intersect (Fig. 3). Indeed, hemostasis and
matrix biology are connected. In primates, MCA:O produces an increase in u-PA and
its principal inhibitor PAI-1 (44). u-PA appears to originate from microvascular cells
and neurons (as shown by the appearance of its principal receptor) (45). PAI-1 is generated
by the vascular endothelium, where it is released into the plasma and into the tissue. In
contrast, t-PA activity does not change substantially (only decreasing transiently when
it is bound to PAI-1). It is known that plasmin (derived from plasminogen activated by
u-PA) can degrade vascular laminin, fibronectin, and collagen (77 –79). Active degra-
dation of neurovascular laminin can occur early following MCA:O, which appears to be
related in part at least to serine proteases, including u-PA (42). Importantly, these
effects appear to be local and confined to the injured tissue. One consequence could be
hemorrhagic transformation (47). However, other activities for these endogenous PAs
may exist, including cell –cell signaling (80).
Recently, it has been shown that certain MMPs, select cathepsins, and perhaps u-PA
are responsible for the degradation of components of the vascular ECM within the early
hours after MCA occlusion in the primate (46). Pro-MMP-2 is activated by membrane-
type (MT)-1 and MT-3 MMP, whereas pro-MMP-9 is activated by u-PA via plasmin.
All components are generated within the ischemic core immediately after MCA occlusion
252 del Zoppo

matrix proteases

pro-MMP-2 pro-MMP-9
plasminogen
MMP-1
MT1-MMP u-PA MMP-2
MT2-MMP t-PA MMP-3
MT3-MMP MMP-7
plasmin
plasmin protease

MMP-2 MMP-9

laminins laminins
collagen IV collagen IV collagen IV
fibronectin fibronectin fibronectin
aggrecan aggrecan
MBP
elastin elastin
vitronectin vitronectin

Figure 3 Relationships of plasminogen and select matrix metalloproteinases (MMPs). Activation


of plasminogen to plasmin can facilitate activation of pro-MMP-2 and pro-MMP-9. Active MMP-2
and MMP-9 (underlined ) can be generated through a number of possible pathways. It should be
noted that this scheme assumes that activation of the elements occurs at the cell surface. Some
cell types in vivo may not support such activation. Activation of plasminogen is mediated by
tissue plasminogen activator (t-PA) or urokinase (u-PA). During focal cerebral ischemia, u-PA is
increased, but t-PA does not change in the ischemic core. t-PA is bound to its inhibitor in the circu-
lation. The inactive precursor pro-MMP-2 is activated by cell surface– exposed membrane type
(MT)-MMPs. MT1-MMP can indirectly activate pro-MMP-2 in conjunction with plasmin. Inactive
pro-MMP-9 can be activated by specific active MMPs, plasmin, or specific serine proteases (e.g.,
chymotrypsin). Note that the matrix ligand specificity of the active matrix proteases differs.
Plasmin can degrade laminins, type IV collagen, fibronectin, and myelin basic protein. MMP-9
does not degrade laminins, whereas MMP-2 does. The cell specificity of these iterations in the
central nervous system is not resolved. Abbreviations: MBP, myelin basic protein; MMP, metallo-
proteinase; MT, membrane type.

(45). More intriguing is the appearance of protease activity that can degrade heparan
sulfate proteoglycans within the vascular and extravascular matrix (46). These hygro-
scopic GPs connect the two matrix compartments, serve as a reservoir for growth
factors, inactive MMPs, and other proteins, interact with heparins, and harbor water.
With the breakdown of the capillary permeability barrier, the transudated water accumu-
lates in the extracellular space, most probably in association with these hygroscopic
proteoglycans.

MODULATION OF THROMBIN ACTIVITY

With degradation of the two permeability barriers—the vascular matrix and the blood –
brain barrier—activated hemostatic factors pour into the intercellular space of the neuro-
pil. Among these, the impact of thrombin is so far the best characterized. Experimental
studies have suggested that high concentrations of thrombin are neurotoxic in vitro
Vascular Hemostasis and Brain Embolism 253

(81,82). PN-1, a 43 kDa protease inhibitor, is localized around brain –blood vessels and is
a tissue inhibitor of thrombin (u-PA and plasmin) (14 – 16). In the brain, PN-1 is secreted
mainly by astrocytes. PN-1 is identical to the glia-derived neurite-promoting factor or glia-
derived nexin. Its localization and specificity imply that PN-1 is a potent inhibitor that
could protect the neuropil from extravasated thrombin. Given the large local concen-
trations of thrombin likely generated during TF exposure to the plasma in the impaired
microvasculature during focal ischemia, the protective function of PN-1 may be
overwhelmed. This speculation awaits formal proof. However, thrombin can also increase
vascular permeability (e.g., pulmonary edema) (83), and its effects locally are likely to be
nefarious.

MICROVESSEL INTEGRITY, HEMOSTASIS, AND


SELECTIVE NEURON VULNERABILITY

The relationship between arterial thrombosis and neuron injury is fundamental for concep-
tualizing the brain responses to ischemia and for understanding a number of treatment
approaches. However, little is known about the impact of altered hemostasis within micro-
vessels on proximate neurons. A causal relationship of neuron injury to microvessel
obstruction has not been tested. Three considerations are relevant to the persistence of
neuron injury following transient occlusion of the arterial supply. First, the distance
from the neuron to the nearest neighboring microvessel may only be one contributor to
neuron injury. Vogt and Vogt (84) and subsequently Pulsinelli (85) advanced the
concept of selective neuronal vulnerability. Most often, neuron “vulnerability” has been
assessed days, rather than hours, after the ischemic insult. Delayed-neuron vulnerability
has been attributed to neuron subtype, differential glutamate sensitivity, ion-channel
density, altered intrinsic excitability, and other attributes (85 –87). The events contributing
to such vulnerability in the early moments after arterial occlusion are unknown.
Siesjo et al. (88) showed that transient MCA occlusion lasting 30 minutes followed
by extended reperfusion was associated with evidence of modest injury. This indicates that
short periods of significantly reduced blood flow produce sustained and localized neuron
injury. Local conditions that cause neuron injury are not yet explored. Very early follow-
ing MCA occlusion, changes in the cell – matrix interactions of the astrocytes and endo-
thelial cells are seen at the same time and only in the regions of neuron injury (89,90).
Those observations suggest that in the regions of ischemic injury, microvessel events,
and neuron injury are correlated. The roles of altered hemostasis in the relation of
altered microvascular integrity to neuron viability are now being explored.

SUMMARY

The CNS probably displays unique hemostatic characteristics when compared with other
vascular beds. Local specialization of the endothelium with functional differences along
brain’s arterial to venous axis is known to exist. Thromboembolism unleashes alterations
in the hemostatic system both locally and systemically. These events are circular. The acti-
vation of coagulation and platelets (i.e., thrombin formation) that cause the signal throm-
bus, through ischemia of the downstream bed, initiates microvascular occlusions
consisting of fibrin, activated platelets, and PMN leukocytes. Whether these local
events cause unremediable neuron injury is uncertain, although the notion is attractive.
Within the ischemic tissue (and microvasculature), u-PA, its receptor, and activated
254 del Zoppo

matrix proteases appear simultaneously with alterations in the appearance of vascular


inflammatory cell receptors, vascular matrix degradation, and neuron injury. Matrix degra-
dation and hemorrhage are linked, the latter augmented by antithrombotics. The effects of
thromboembolism in the CNS underscore the close interrelationship of thrombosis
(hemorrhage), ischemia, and inflammation.

ACKNOWLEDGMENTS

This work was supported in part by grants NS 26945 and NS 38710 of the National Insti-
tutes of Neurological Disorders and Stroke. I thank Jason Kay for his expert assistance in
preparing this chapter.

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PART V: EMBOLIC MATERIALS

14
Embolic Particles

Louis R. Caplan
Division of Cerebrovascular Disease, Harvard Medical School, and Beth Israel
Deaconess Medical Center, Boston, Massachusetts, U.S.A.

Embolism, by definition, refers to distant travel of particulate materials generated at a


distance from their ultimate destination. Potential embolic materials can be conveniently
divided into three major groups: (i) substances ordinarily residing within the body’s heart
and blood vessels, (ii) substances introduced from outside of the body, such as air,
bacteria, fungi, and foreign bodies, and (iii) substances within the body but not
normally within the vascular system, such as fat and tumor tissue. Table 1 shows this
distribution.
The nature of the embolic material is important because the effect of most prophy-
lactic treatments is specific for one substance or other. For example, heparin may effec-
tively prevent red thrombus formation and embolization but has no effect against white
thrombi, calcium particles, or bacteria. This chapter will be devoted mostly to substances
outside of the vascular system, as cardiac, aortic, and arterial sources have already been
discussed thoroughly in chapters 8, 9, and 10.

CARDIAC-ORIGIN SUBSTANCES
Red Thrombi
The most common and most well-studied material that forms in the heart and embolizes is
a red clot. Red thrombi are composed mostly of red blood cells and fibrin. They tend to
form in areas of slowed blood flow. Their formation does not require an abnormal
vessel wall or tissue thromboplastin. Figure 1 shows a typical red thrombus. Red clots
are formed by activation of circulating coagulation factors. The final step in the coagu-
lation cascade is the conversion of the soluble protein fibrinogen into insoluble polymers
called fibrin. Fibrin strands form a network of fibers that entangle the formed blood
elements (platelets, erythrocytes, and leukocytes) into a clot. Fibrin is quite adhesive
and is capable of contracting. The fibrinogen ! fibrin reaction occurs when Factor II,
prothrombin, is converted to thrombin. The amounts of circulating fibrinogen and
prothrombin are important in these reactions.
Prothrombin can be activated in two different ways. In the so-called extrinsic system
of coagulation, a tissue or endothelial injury releases thromboplastic substances, tissue
factors that, in turn, cause both platelet activation and activation of blood serine protease
259
260 Caplan

Table 1 Types of Embolic Materials

Cardiac Vascular Body Foreign

Erythrocyte-fibrin (red) thrombi Erythrocyte-fibrin (red) thrombi Air Air


Platelet-fibrin (white) thrombi Platelet-fibrin (white) thrombi Tumor tissue Foreign bodies
Bacteria, fungi (endocarditis) Cholesterol crystals Fat
Fibrin strands, bland vegetations Atheromatous debris (plaques)
Calcium (valves and MAC) Calcium
Myxoma, other cardiac tumors

Abbreviation: MAC, mitral annulus calcification.

coagulation factors, especially Factors V, VII, and X. Activation of Factor X catalyzes the
reaction of prothrombin to thrombin. Activation of platelets causes them to agglutinate, to
adhere to the injured vessel wall, and to release various intracellular substances that, in
turn, also activate the coagulation system.
The complementary intrinsic coagulation system refers to blood-coagulation factors
that circulate in inactive forms (Factors V, VIII [antihemophilic globulin], IX, X, XI, XII)
and are intrinsic to the blood. Activation of Factor XII from an inert precursor form to an
activated form triggers a series of reactions, described as the coagulation cascade in which
the various blood-clotting factors are sequentially converted to their active enzymatic
forms. Ultimately, these reactions lead to activation of Factor X, which catalyzes the
prothrombin ! thrombin reaction (1,2). Thrombin, in turn, in addition to converting
fibrinogen to fibrin, has an important influence on blood platelets, causing them to
swell, aggregate, and release substances that affect vascular tone and blood coagulability.
Also important are various natural inhibitors of coagulation: antithrombin III,
protein C, and protein S. Deficiencies in any of these serum proteins can cause increased

Figure 1 Phase microscope image of a red thrombus, composed of fibrin and erythrocytes, formed
in a thrombogenic system, in a vessel with a low flow rate (courtesy of S.H. Hanson and Ch. Kessler,
Emory University, Division of Hematology). Source: From Ref. 120.
Embolic Particles 261

coagulability. Genetically transmitted disorders, such as the presence of the Leiden factor
that causes functional resistance to the anticoagulant effects of activated protein C (3,4)
and mutations in the prothrombin gene (5), can also lead to hypercoagulability. There
are also naturally occurring factors that act to lyse clots once they are formed. Tissue
plasminogen activator and other substances activate plasminogen to form plasmin,
a potent fibrinolytic enzyme. Plasminogen is also activated by various coagulation
factors, such as Factor XII, so that the process of coagulation itself activates the thrombo-
lytic system. Various plasmin inhibitors (antiplasmins) are also present (6).
Red thrombi are most apt to develop when flow is reduced. Dilated cardiac atria—
especially those with inefficient contractility, as found with atrial fibrillation, regions of
hypokinesia of the cardiac ventricles, and frank ventricular aneurysms—commonly
harbor red clots. Red thrombi are also often formed in heart chambers when ejection frac-
tions are low, that is, 25% or lower. Red thrombi tend to form on the surface of myocardial
infarcts. Thrombi formed in the leg and pelvic veins that pass through defects in the
cardiac atrial and ventricular septa or pass through arteriovenous fistulae in the lungs
are nearly always red thrombi. Both red and white thrombi often form along damaged
heart valves, especially those made of prosthetic materials.

White Thrombi
These so-called white clots are composed of platelets and fibrin and do not contain red
blood cells (Fig. 2). White clots form almost exclusively in areas in which the endothelial
surface is abnormal, characteristically in fast-moving bloodstreams. Irregular valvular and
endothelial surfaces predispose to platelet-fibrin thrombi forming in areas of irregularities.
In many cases, the thrombus begins as a white platelet fibrin clot, and then a red thrombus
is laid down as a cap over the initial platelet mass (7,8).

Figure 2 Phase microscope image of a white fibrin-platelet thrombus formed in a high-flow


system (courtesy of S.H. Hanson and Ch. Kessler, Emory University, Division of Hematology).
Source: From Ref. 120.
262 Caplan

Platelets and platelet masses have been found on the surface of heart valves in a
number of conditions that are inflammatory but not infective. The initial report of
fibrous endocarditis by Libman and Sacks (9) contained descriptions of heart valve and
endocardial abnormalities that consisted of fibrous valve thickening, often with grossly
visible vegetations that contained mixtures of blood platelets and fibrin. The pathologist
Libman found deposits of agglutinated blood platelets over large flat areas, beneath
which the endocardial tissues were infiltrated with polymorphonuclear leukocytes and
round cells. The blood platelet masses showed regions of fibroblastic invasion, resulting
in vegetation formation and thickening of the atrial and ventricular surfaces of the
valves (9). Later, Klemperer and Baehr, students of Libman described similar pathological
findings and recognized that the disorder was a part of the syndrome of systemic lupus
erythematosis (10,11). Similar vegetations occur in some patients with the antiphospholi-
pid antibody syndrome (12,13) and in nonbacterial thrombotic endocarditis (13 – 16)
(also called marantic endocarditis because of its association with cancer and debilitating
illnesses). The cardiac valve and endothelial lesions in these three conditions—systemic
lupus erythematosis, antiphospholipid antibody syndrome, and nonbacterial thrombotic
endocarditis—are very similar and probably indistinguishable grossly and micro-
scopically. Platelet deposition, incorporation of fibrin, and the formation of platelet
thrombi on valve and endocardial surfaces are common to all three conditions.

Calcified Particles
Calcific emboli have been noted within the brain on computed tomography (CT) scans in
patients who have calcific aortic valves (17 – 21). In each patient the calcific embolus was
identified on noncontrast CT as a dense intravascular density. Bicuspid aortic valves are
often the seat of the calcification, and, occasionally, calcium is present in other valves,
especially those affected by rheumatic fever.
Another potential source of calcific material is mitral annulus calcification (MAC).
Calcification of the mitral annulus has a predilection for the posterior portion of the mitral
annulus ring, but calcific masses may extend as far as 3.5 cm into the adjacent myocardium
and, often, project superiorly toward the atrium and centrally into the cavity of the left
ventricle (22). Calcified material may ulcerate and extrude through overlying cusps into
the ventricular cavity in some patients (23). Thrombi may be attached to the ulcerated
regions (23 – 27). The embolic material can be either calcium (as has also been shown
in calcific aortic stenosis) or thrombus. Cranial CT scans in patients with MAC and
brain embolism can show calcific flecks within intracranial branch arteries (26).

Infectious Material: Bacteria and Fungi


Because of poor vascularization of cardiac valves, when bacteria or fungi colonize upon
valves they may form relatively large vegetations. Valvular vegetations in patients with
infective endocarditis are composed of platelets, fibrin, erythrocytes, and inflammatory
cells attached to the damaged endothelium of native and prosthetic valves. Organisms
are enmeshed within the fibrinous material often deep within the vegetations, explaining
why antibiotics have difficulty sterilizing them. Vegetations range in size from several
millimeters to several centimeters, and their potential for embolization relates to their
size and friability (13).
Embolization of infected material can cause meningitis and arterial aneurysms.
These so-called mycotic aneurysms are caused by embolization of infected material
into the wall and adventitia of brain arteries. The aneurysms usually occur distally
Embolic Particles 263

along arteries and tend to be multiple. Multiple brain abscesses can also develop in
patients with staphylococcal endocarditis. Cessation of embolization is associated with
sterilization of bacterial endocarditis.

Fibrin Strands
Strands are mobile, thin, threadlike filaments attached to cardiac valves. They were first
described during investigation of hearts at necropsy and are now often found during echo-
cardiographic studies during life. The cause and significance of valvular strands remains
uncertain even now. In 1856 Lambl first described filamentous outgrowths from the ven-
tricular surfaces of aortic valves that he occasionally discovered at necropsy (28). Since
his description, these fibrous strandlike lesions have often been referred to as Lambl
excrescences. Magarey, nearly a century later, found similar filiform strands attached to
the atrial surface of mitral valves examined at necropsy (29). The mitral valve strands,
composed of a cellular connective tissue core covered by endothelium, were usually
quite thin and long, measuring ,1 mm thick and ranging in length from 1 to 10 mm
(29). Magarey noted that hearts with strands often had thickened mitral valves and
posited that strands were derived from fibrinous deposits on the valve surfaces (29).
Transesophageal echocardiography (TEE) has recently begun to show thin filamen-
tous structures similar to those described by Lambl and Magarey at necropsy (30,31).
Nighoghossian et al. (32) reported three patients who had brain ischemic events and
mitral valve strands who had cardiac surgery. The valve lesions were described as a float-
ing mass 6 mm thick on the ventricular surface of the mitral valve, a 6 mm lesion on the
anterior mitral valve leaflet, and a sessile 5 mm lesion on the anterior mitral valve leaflet.
Extensive evaluation, including angiography, showed no cause for stroke other than the
abnormal strands attached to cardiac valves (32). Histopathological examinations
showed that the cardiac lesions were composed of an acellular fibrous core with surround-
ing rings of granular material and endothelial cells. Thrombi were attached to the strands
in two of the patients (32). Mitral valve strands are significantly more common in patients
with brain infarcts than in controls and in patients with mitral valve thickening, defined as
mitral valves .3 mm in thickness on two-dimensional (2D) TEEs (33,34). The TEE data
and pathological studies suggest that strands are probably derived from fibrinous deposits
on abnormal valve surfaces. The strands could potentially act as embolic particles, and
emboli can arise from thrombi formed on the surfaces of the valves or formed on the
strands. Many nonrheumatic, noninfective conditions cause the deposition of fibrous
tissue, fibrin, and platelets within cardiac valves and on their surfaces.

Myxomatous and Other Tumor Tissue


Myxomas are the most common heart tumors. The cells of origin are endocardial and arise
from multipotential mesenchymal cells that persist as embryonal remnants during septa-
tion of the heart (35). Most myxomas originate from the interatrial septum at the edge
of the fossa ovalis, but some originate from the posterior or anterior atrial walls or the auri-
cular appendage, and they occasionally arise from the region of the heart valves (34,35).
They are more common in the left atrium. Embolism is estimated to occur in 30– 50% of
patients with cardiac myxomas (34 –40). Most emboli arise from the left atrium and go to
the brain, eye, and systemic organs.
Papillary fibroelastomas are another type of cardiac tumor that can give rise to brain
embolism (41,42). The lesions consist of multiple papillary fronds that radiate from an
264 Caplan

avascular fibrocollagenous core attached by a short pedicle to the endothelium and most
often arising from the aortic valves (44).

ARTERIAL ORIGIN SOURCES

Plaques within the aorta and systemic arteries contain a mixture of lipid, smooth muscle,
fibrous and collagen tissues, and inflammatory cells (13,44 –46). Both white platelet –
fibrin and red erythrocyte –fibrin thrombi form on the surfaces of irregular and ulcerated
arterial endothelia. Atherosclerotic plaques also often calcify. Some substances that
embolize from aortic and arterial lesions—white and red thrombi and calcific plaque—
are similar to those that originate from the heart.
The major substance unique to arterial versus cardiac lesions is cholesterol.
Atheromatous emboli have been found in the brain at necropsy often in or near arterial
border zones (47 –49). Cholesterol crystals and plaque debris containing cholesterol and
other lipids can be released from plaques, especially after manipulation surgically or by
angiography. They are especially commonly liberated during cardiac surgery when the
aorta is clamped and manipulated (50 – 53).

SUBSTANCES THAT ORIGINATE FROM OUTSIDE THE


CARDIOVASCULAR SYSTEMS

Some embolic materials that enter the systemic and brain circulations do not originate in
the heart, aorta, or cervico-cranial arteries and are not composed of blood elements or
thrombi. The types of particles are diverse as are the clinical syndromes and circumstances
of brain embolization. These emboli types are all very uncommon when compared to
emboli that arise from the heart, aorta, and great vessels discussed so far. Fat and gas
bubbles cause microembolism to many small brain arteries, causing an encephalopathy-
type syndrome, whereas tumor and foreign body emboli usually block single discrete
arteries, causing strokes.

FAT EMBOLISM

Fat embolism occurs most often after serious physical trauma that causes bone fractures.
The first known report is usually credited to Zenker who, in 1861, in a monograph about
lung anatomy and physiology included a description of fat droplets in the lungs of a
railway worker who had sustained a severe crush injury (54). Since then, the frequency,
clinical and laboratory features, and circumstances of the fat-embolism syndrome have
been extensively described (55). The syndrome consists of a triad of respiratory distress,
decreased alertness, and a petechial rash developing 24 to 48 hours after an injury. Table 2
lists the major features in patients with the fat-embolism syndrome. Fat embolism is most
often found after blunt physical trauma with fractured bones but can occur after cardiac
surgery and in patients who have bone infarctions.
In patients with injuries, the long bones and pelvis are most often involved,
especially the femurs. The fat-embolism syndrome is unusual in children and in patients
with fractures limited to the upper extremities (55). Often, there are multiple fractures
resulting from vehicular accidents (55 –61). Investigators retrospectively reviewed
10 years experience of the fat-embolism syndrome found at one trauma center and
found 27 instances (0.9%) of long bone fractures among 3026 patients (56).
Embolic Particles 265

Table 2 Fat Embolism

Major clinical features


Dyspnea and respiratory distress
Decreased alertness and cognitive function
Petechiae
Other findings
Fever
Tachycardia
Retinal infarcts
Jaundice
Laboratory and imaging
Anemia
Thrombocytopenia
Hypoxia
Abnormal chest X-ray
Fat globules and lipid in the urine
Microembolism during transcranial Doppler monitoring
Fat emboli visible during transesophageal echocardiography
MRI showing multiple infarcts and small hemorrhages

Abbreviation: MRI, magnetic resonance imaging.

Occasionally, the fat-embolism syndrome develops after cardiac surgery, when the
atria or ventricles are entered (62,63). The exact mechanism of fat embolism after open
heart surgery is unclear, but fat from the sternotomy or epicardial fat may directly enter
the systemic circulation (63). Cardiotomy suction tubes draining the pericardium during
cardiopulmonary bypass contain variable quantities of fat globules (64).
Fat embolism has also been reported in patients with sickle-cell anemia (homozy-
gous S– S and those who have S –C disease) (65 – 68). In sickle-cell disease patients,
the fat originates from bone and bone marrow infarcts. Bone and joint pain and crisis
may precede fat embolism in some patients.
Fat embolism has also been described after therapeutic procedures that use lipid
substances to form stable drugs for injection. Lipiodol has been used to mix with antican-
cer drugs that are fat soluble to form stable covalent conjugates. This mixture is then
injected into an artery feeding a tumor, for example, in the liver. Fat embolism has
been described after such therapeutic procedures (68). The clinical findings included
dyspnea and decreased alertness. Hypoxemia preceded or accompanied stupor. Magnetic
resonance imaging (MRI) showed multiple focal abnormalities, mostly in border-zone
regions. The neurological signs were severe but transient and cleared completely within
weeks. None of the three reported patients had cardiac shunts demonstratable by echocardio-
graphy (68).
Two main hypotheses of the pathogenesis of the fat-embolism syndrome are usually
proffered. These are referred to as the mechanical and biochemical theories. According to
the mechanical theory, the source of fat is the bone marrow and other loci where fat is
stored (55,56,69,70). Bone or deposits of adipose tissue are injured, and fat globules
enter damaged blood capillaries and veins at the site of injury. Increase in local tissue
pressure related to the trauma promotes fat entry into the intravascular compartment.
According to the biochemical theory, intravascular fat is derived from lipid mobilized
from fat deposits in the body. Catecholamine release, loss of chylomicra emulsion stab-
ility, biochemical perturbations that result from trauma, and a variety of acute illnesses
266 Caplan

promote the formation and mobilization of fat globules. Fat that embolizes to the lungs is
converted metabolically to free fatty acids by pulmonary lipases. Free fatty acids are toxic
to the lungs and damage capillaries and small arterioles and veins, causing lung edema,
hemorrhage, and atelectasis (55,61). Thromboplastin is also released after local tissue
injury and induces platelet aggregation on injured surfaces and on fat globules enhancing
thromboembolism. Fat within the lungs enters pulmonary veins and passes through the left
side of the heart into the systemic circulation. In some cases, fat traverses a patent foramen
ovale (PFO) to enter the systemic circulation (71 – 75). The two mechanisms, mechanical
and biochemical, may coexist and interact. Fat first mechanically enters into the vascular
system in relation to local traumatic injury. The primary injury and embolization of fat and
marrow into the lungs can set in motion biochemical changes that enhance fat-globule for-
mation, mobilization, and embolization.
The fat-embolism syndrome usually develops after a delay of a few hours up to a few
days after trauma. In one series of 14 patients, all of whom had traumatic injuries with
long-bone fractures, the latency of onset of signs of fat embolism after trauma ranged
from 12 to 72 hours (mean, 41 hours) (60). At times the clinical manifestations of fat
embolism can be delayed for as long as five days (61). Most patients have symptom
onset between 24 and 72 hours after injury.
The major clinical manifestations of the fat embolism syndrome are dyspnea,
tachypnea, fever, tachycardia, petechiae, and neurological dysfunction. Jaundice can
also occur. Neurological symptoms and signs may precede or follow respiratory distress
and are characterized as confusion with delirium, often followed by a decrease in the
level of consciousness. Neurological symptoms and signs are present in .80% of patients.
Most often, patients develop an encephalopathy characterized by restlessness, agitation,
confusion, poor memory, and decreased alertness. This state often passes into stupor or
coma. Seizures are common at onset or early during the course of illness. Seizures can
be focal or generalized. Focal neurological signs are also common and include hemipar-
esis, conjugate eye deviation, aphasia, and visual-field abnormalities. Motor abnormal-
ities, including increased tone in the lower extremities, Babinski signs, and decerebrate
rigidity, are often found. Focal neurological signs were noted in 33% of patients in one
series (61). Some patients have scotomas and other visual abnormalities related to
retinal dysfunction caused by fat embolism.
Pulmonary symptoms develop shortly after or concurrent with the neurological
symptoms. Dyspnea and tachypnea are prominent, and patients may become cyanotic.
Tachycardia, high fever, and circulatory collapse also occur; hypotension is often
related to blood loss, hypoxemia, and hypovolemia. Renal failure can develop.
An important clue to the presence of fat microemboli is the presence on physical
examination of petechiae. Petechiae are found in 50– 75% of patients with the fat embo-
lism syndrome. They are most often found in the lower palpebral conjunctivae and the skin
of the neck, shoulder, and the axillary folds (55,58,59). Another important clinical clue is
the appearance of fat emboli within the arteries of the eye. Microinfarcts are sometimes
visible in the optic fundus, especially in the perimacular regions. Small hemorrhages,
sometimes with white, pale centers, are also found. Fat globules can sometimes be seen
within retinal arteries (58). Papilledema is occasionally found. In one series, 11 of 24
(46%) patients with fat embolism showed abnormalities during the ocular funduscopic
examination (58).
Laboratory tests are often helpful in diagnosis. Many patients develop abnormal
chest X-rays. Fine stippling and fluffy lung infiltrates are common and are seen diffusely
through the lung fields. Most patients have a drop in hemoglobin and hematocrit due to
traumatic loss of blood and hemolysis. Thrombocytopenia, prolonged prothrombin time,
Embolic Particles 267

and activated partial thromboplastin times are common and are attributed to a consumptive
coagulopathy. Frank disseminated intravascular coagulation may also occur.
Transcranial Doppler (TCD) monitoring of patients with long bone fractures can
document fat emboli (76 –78). Forteza et al. (78) performed TCD monitoring of five
patients with long-bone fractures and detected fat emboli in all of them. The microembolic
signals disappeared by day 4. TEE during orthopedic procedures also can show fat
embolism, occasionally in extensive amounts (79,80). In one patient, closure of a PFO
dramatically decreased the quantity of fat emboli detected by TCD (76).
Brain imaging may show small hemorrhages, brain edema, and focal infarcts,
usually manifested by regions of gyral enhancement on CT or MRI scans. CT scans are
most often normal but may show areas of hypodensity and small hemorrhages. MRI is
much more sensitive and often shows abnormalities within the white matter and in border-
zone regions (80). Fluid attenuating inversion recovery (FLAIR) and contrast-enhanced
images are particularly helpful in showing microinfarcts (80). Figure 3 shows FLAIR
MRI images in a patient who suddenly became unconscious 18 hours after a fracture of
his right femur. Innumerable small embolic infarcts are seen throughout the cerebral hemi-
spheres bilaterally. Magnetic resonance spectroscopy (MRS) can also be used to identify
the presence of