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Caplan’s Stroke
Caplan’s Stroke
A Clinical Approach
Fifth Edition
Edited by
Louis R Caplan
Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA
University Printing House, Cambridge CB2 8BS, United Kingdom

Cambridge University Press is part of the University of Cambridge.

It furthers the University’s mission by disseminating knowledge in the
pursuit of education, learning and research at the highest international
levels of excellence.

www.cambridge.org
Information on this title: www.cambridge.org/9781107087293
Fifth edition © Cambridge University Press 2016
This publication is in copyright. Subject to statutory exception
and to the provisions of relevant collective licensing agreements,
no reproduction of any part may take place without the written
permission of Cambridge University Press.
First published in 1993 by Elsevier
Fourth edition: 2009 by Elsevier
Fifth edition: 2016 by Cambridge University Press
Printed in the United Kingdom by Clays, St Ives plc
A catalogue record for this publication is available from the British Library
Library of Congress Cataloguing in Publication data
Caplan, Louis R, editor. | Caplan’s stroke.
Preceded by (work):
Caplan’s stroke : a clinical approach / edited by Louis R Caplan.
Stroke
Fifth edition. | Cambridge ; New York : Cambridge University
Press, 2016. | Preceded by Caplan’s stroke / Louis R. Caplan. 4th ed.
Philadelphia : Elsevier/Saunders, c2009. | Includes bibliographial
references and index.
LCCN 2016005752 | ISBN 9781107087293 (hardback)
| MESH: Stroke – diagnosis | Stroke – therapy | Cerebrovascular
Disorders – diagnosis | Cerebrovascular Disorders – therapy
LCC RC388.5 | NLM WL 356 | DDC 616.8/1–dc23
LC record available at http://lccn.loc.gov/2016005752
ISBN 978-1-107-08729-3 Hardback
Cambridge University Press has no responsibility for the persistence or
accuracy of URLs for external or third-party internet websites referred to in
this publication, and does not guarantee that any content on such websites
is, or will remain, accurate or appropriate.
...........................................................................................................

Every effort has been made in preparing this book to provide accurate and
up-to-date information which is in accord with accepted standards and
practice at the time of publication. Although case histories are drawn from
actual cases, every effort has been made to disguise the identities of the
individuals involved. Nevertheless, the authors, editors and publishers can
make no warranties that the information contained herein is totally free
from error, not least because clinical standards are constantly changing
through research and regulation. The authors, editors and publishers
therefore disclaim all liability for direct or consequential damages resulting
from the use of material contained in this book. Readers are strongly
advised to pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
Contents
Preface vii
List of contributors viii

Part I–General principles 12 Non-atherosclerotic vasculopathies 386

Louis R Caplan and José Biller
1 Introduction and perspective 1
Louis R Caplan 13 Subarachnoid hemorrhage, aneurysms,
and vascular malformations 439
2 Pathology, anatomy, and pathophysiology Tudor Jovin and Louis R Caplan
of stroke 19
Louis R Caplan and David S Liebeskind 14 Intracerebral hemorrhage 477
Louis R Caplan and Carlos S Kase
3 Diagnosis and the clinical encounter 55
Louis R Caplan and Fernando Barinagarrementeria 15 Stroke in children and young adults 511
Gabrielle deVeber, Aneesh B Singhal,
4 Imaging and laboratory diagnosis 78 and Louis R Caplan
Louis R Caplan, Bruce Campbell, and Stephen Davis
16 Spinal cord vascular disease 534
5 Genetics of stroke 129 Louis R Caplan and Ayrton R Massaro
Stéphanie Debette and Louis R Caplan
17 Cerebral venous thrombosis 544
6 Treatment 145 Louis R Caplan and Marie-Germaine Bousser
Louis R Caplan and Jeffrey Saver

Part III–Prevention, complications,

Part II–Stroke syndromes and recovery–rehabilitation
7 Large artery occlusive disease of the anterior
circulation 217 18 Stroke prevention 567
Louis R Caplan and Lawrence Wechsler Louis R Caplan and Philip B Gorelick

8 Large vessel occlusive disease of the posterior 19 Complications in stroke patients 594
circulation 252 Louis R Caplan and Sandeep Kumar
Louis R Caplan and Jong S Kim 20 Recovery, rehabilitation, and repair 608
9 Penetrating and branch artery disease 287 Steven C Cramer and Louis R Caplan
Louis R Caplan, Geoffrey Donnan, and Marie
Dagonnier
10 Brain embolism 312
Index 627
Louis R Caplan and Pierre Amarenco
11 Hypoxic–ischemic encephalopathy, cardiac arrest, Colour plates are to be found between pp. 342 and 343.
and cardiac encephalopathy 364
Louis R Caplan and Michael DeGeorgia

v
Preface

Although this is the fifth edition of my Stroke book, in many ability to be critical about their own writing and coverage of
ways it represents a completely new endeavor. This edition is a subject. One just wants it to be finally done and sent in.
both single and multi-authored – a somewhat new concept. I Others can view the coverage freshly and critically much better
have continued to control the organization, writing style, and than the original author. So, broadening the authorship, I
patient-oriented focus of the book and each of the chapters. believe, gives this edition more credibility and depth than
The new aspect is that I have chosen respected experienced prior editions. (3) The lack of genetic information in prior
experts who have reviewed each chapter in their particular area editions. A new chapter on genetics has also been added in
of expertise. They have corrected prior mis-statements, elabo- this edition written by Dr Stéphanie Debette a clinical neurol-
rated on aspects they feel were incompletely covered, and ogist and geneticist.
updated each chapter with new information that has accrued At the same time what made this book different from
since the fourth edition was published in 2009. After receiving multi-authored texts was the simplicity, patient focus, uniform
the input of the chapter co-authors, I have re-reviewed the organization, clinical emphasis, writing style, and clarity of the
chapters, added information and references, and ensured that four prior editions. The previous books were all organized to
the finalized chapter preserves the goals, style, and main con- be read from cover to cover to teach about clinical stroke. They
tent of the book. were also organized so that information would be easily read by
Three observations stimulated this new approach. (1) Critics both novitiates and stroke specialists. I strove to maintain these
of the last edition opined that the topic of stroke has become aspects while still broadening the content by seeking the inputs
much too large for any one person to cover well. The basic of many others.
science and clinical stroke literature has expanded exponen-
tially during the last decade. There is much truth to this Louis R Caplan, MD
criticism. (2) After writing and rewriting and re-editing the Boston, MA, USA
same chapters for decades, an individual (myself) loses the

vii
 Contributors

Pierre Amarenco, MD PhD Michael DeGeorgia, MD FCCM FNCS

Professor, Department of Neurology, Bichat University Maxeen Stone and John A Flower Professor of Neurology at
Hospital, Paris, France Case Western Reserve University School of Medicine, Director,
Center for Neurocritical Care, Neurological Institute, University
Fernando Barinagarrementeria, MD Hospitals Case Medical Center, Cleveland, OH, USA
División de Ciencias de la Salud, Universidad del Valle
de México, Hospital Ángeles de Querétaro, Querétaro, Gabrielle deVeber, MD
Mexico Professor of Neurology, The Hospital for Sick Children,
Toronto, ON, Canada
José Biller, MD FACP FAAN FAHA
Department of Neurology, Loyola University Stritch School of Geoffrey Donnan, MBBS MD FRACP FRCP (Edin)
Medicine, Maywood, IL, USA Professor of Neurology, University of Melbourne, Director at
The Florey Institute of Neuroscience and Mental Health,
Marie-Germaine Bousser, MD Parkville, VIC, Australia
Professor, Department of Neurology, Lariboisière Hospital,
Paris, France Philip B Gorelick, MD MPH FACP
Professor at the Department of Translational Science and
Bruce Campbell, MBBS(Hons) BMedSc PhD FRACP Molecular Medicine, Michigan State University College of
Department of Medicine and Neurology, Royal Melbourne Human Medicine, Medical Director at Mercy Health
Hospital, University of Melbourne, Parkville, VIC, Hauenstein Neurosciences, MI, USA
Australia
Tudor Jovin, MD
Louis R Caplan, MD Associate Professor of Neurology and Neurosurgery Director,
Senior Neurologist, Beth Israel Deaconess Medical Center, UPMC Stroke Institute Director, UPMC Center for
Professor of Neurology, Harvard Medical School, Boston, Neuroendovascular Therapy, President, Society of Vascular
MA, USA and Interventional Neurology (SVIN), University of
Pittsburgh, PA, USA
Steven C Cramer, MD
Professor of Neurology, University of California Irvine, Irvine, Carlos S Kase, MD
CA, USA Department of Neurology, Boston University Medical Center,
Boston, MA, USA
Marie Dagonnier, MD
Research Fellow at the Florey Institute of Neuroscience and Jong S Kim, MD PhD
Mental Health, Melbourne, VIC, Australia Professor of Neurology at the Asan Medical Center, University
of Ulsan, Seoul, Korea
Stephen Davis, MD FRCPEd FRACP
Professor of Neurology, The Melbourne Neuroscience Sandeep Kumar, MD
Center, The Royal Melbourne Hospital, Parkville, VIC, Department of Neurology, Beth Israel Deaconess Medical
Australia Center, Boston, MA, USA
Stéphanie Debette, MD David S Liebeskind, MD
Department of Neurology, Bordeaux University Hospital, Professor of Neurology and Director, Neurovascular
Bordeaux, France Imaging Research Care, UCLA, Department of Neurology, USA

viii
 List of contributors

Ayrton R Massaro, MD Aneesh B Singhal, MD

Department of Neurology, Hospital Siro-Libanês, Sao Paulo, Department of Neurology, Massachusetts General Hospital,
Brazil Boston, MA, USA
Jeffrey Saver, MD Lawrence Wechsler, MD
Professor of Neurology, Geffen School Henry B Higman Professor and Chair, Department of Neurology,
of Medicine at UCLA, Los Angeles, University of Pittsburgh, and Vice President for Telemedicine,
CA, USA University of Pittsburgh Medical Center, Pittsburgh, PA, USA

ix
 Part I General principles
Chapter
Introduction and perspective

1 Louis R Caplan

It was then that it happened. To my shock and incredulity, to work or to assume their former effectiveness as spouses,
I could not speak. That is, I could utter nothing intelligible. parents, friends, and citizens. The economic, social, and
All that would come from my lips was the sound ab which psychological costs of stroke are enormous. In the United
I repeated again and again . . . Then as I watched it, the States, each ischemic stroke costs on average $140 000, and
telephone handpiece slid slowly from my grasp, and I, in costs related to stroke nationwide was estimated to be $62.7
turn, slid slowly from my chair and landed on the floor behind billion in 2007.5
the desk . . . At 5:15 in that January dusk I had been a person;
now at 6:45 I was a case. But I found it easy to accept my altered Important medical and historical figures
condition. I felt like a case.
Eric Hodgins1 who had strokes
The history of the world has undoubtedly been altered by
“Cheshire Puss . . . Would you tell me, please, which way I stroke. Many important leaders in science, medicine, and
ought to go from here?” politics have had their productivity cut prematurely short by
“That depends a great deal on where you want to get to,” said stroke. Marcello Malpighi, discoverer of capillaries and the
the Cat. microscopic anatomy of the lungs, kidneys, and spleen, died
“I don’t much care where –,” said Alice. of an apoplectic right hemiplegia.6 Louis Pasteur, at age 46
“Then it doesn’t matter which way you go,” said the Cat. years, had a stroke that caused a left hemiparesis, although he
“– so long as I get somewhere,” Alice added . . . continued to make important advances until additional strokes
“Oh, you’re sure to do that,” said the Cat, “if you only walk long impaired his function at age 65.6
enough.” Three important figures in twentieth century neurology –
Lewis Carroll2 Russell DeJong,7 the first editor of the journal Neurology;
Raymond Escourolle, the French neuropathologist; and
The past is always with us, never to be escaped; it alone is H. Houston Merritt, longtime Columbia professor and writer
enduring; but, amidst the changes and chances which succeed of Merritt’s Neurology –were severely disabled by multiple
one another so rapidly in this life, we are apt to live too much strokes in their later years. Two important political leaders
for the present and too much in the future. during the early twentieth century, Vladimir Lenin and
William Osler3 Woodrow Wilson, had intellectual impairment owing to
stroke while they were at the helms of their countries at
critical times in history. Lenin, at age 52 years, had the
sudden onset of dysarthria and right hemiparesis. An obser-
Numbers ver noted that “often as he spoke, the words were slurred, and
In the United States, according to 2014 statistics, 795 000 indi- he paused several times like a man who has lost the thread of
viduals have a stroke each year (610 000 are first strokes).4 In his argument.”8 Wilson, the architect of the League of
2010, one of every 19 deaths was attributed to stroke; on average Nations, had a series of small strokes that left him pseudo-
a stroke occurred every 40 seconds and someone died of stroke bulbar and with a left hemiparesis at a time when he was
about every 4 minutes. At any one time, there are approximately ardently working for world peace and cooperation. The heads
two million stroke survivors living in the United States. In of state who met at Yalta and elsewhere to divide up the
China, approximately 1.5 million people die each year because spheres of influence after the Second World War, Franklin
of stroke.5 Stroke affects three times as many women as breast D Roosevelt, Winston Churchill, and Joseph Stalin, (shown in
cancer and yet receives much less public attention. For a long Figure 1.1) all had severe cerebrovascular disease at the time.8
time, stroke has been the third leading cause of death in most Roosevelt subsequently died of a fatal stroke after years of
countries in the world, surpassed as a killer only by heart disease severe hypertension.9 History might have been different if the
and cancer. Strokes are an even more important cause of pro- brains of these leaders had not been addled by strokes. Public
longed disability. Survivors of strokes are often unable to return awareness of stroke increased dramatically when President

Caplan’s Stroke: A Clinical Approach, 5th Edition, ed. Louis R Caplan. Published by Cambridge University Press. © Cambridge
University Press, 2016.

1
 Part I: General principles

When I conjure in my own mind the personal tragedy of

stroke, I picture one of my own patients, Dr Herman Blumgart,
an extremely gifted physician, teacher, and investigator. He
was, for many years, physician-in-chief at the Beth Israel
Hospital in Boston.11 His early investigations in coronary
artery disease were landmark advances in the understanding
of vascular disease of the heart.12,13 He gave the annual intro-
ductory lecture to incoming Harvard Medical School students
about the joys and responsibilities of being a physician. I recall
his vivid, articulate lectures and bedside demonstrations. He
was, in many ways, the model physician. He was also a vocal
advocate on behalf of patients. His lecture “Caring for the
Patient,” presented in 1963 and reported in the New England
Journal of Medicine, remains a model exposition on doctoring,
Figure 1.1 A photograph taken at the Yalta conference after the Second as valid today as when it was originally delivered.14 Tragically,
World War showing (from left to right in the front row) Winston Churchill, this master of communication became in an instant, severely
Franklin D Roosevelt, and Joseph Stalin. From Toole JF. Cerebrovascular
Disorders, 4th ed. New York: Raven Press, 1990. aphasic. His Wernicke-type aphasia was so severe that he could
barely communicate verbally his basic needs and could hardly
Dwight Eisenhower developed acute dysarthria, when understand the queries and spoken and written statements of
Richard Nixon died after a large embolic cerebral hemisphere others. He could no longer read, eliminating one of his lifelong
infarction, and when Ariel Sharon the Prime Minister of joys. As a junior staff neurologist, I was one of his physicians.
Israel was left unconscious after a series of cerebrovascular The angst and frustration of his plight showed clearly on his
events. face each time I saw him. This personal disaster was palpable
and dramatic.
The personal tragedy of stroke A brief history of stroke
The mortality, morbidity, and economic toll of stroke is
impressive. Knowledge that government leaders may have In any human endeavor, the future is heavily influenced by
brains damaged and even riddled with brain infarcts and the past. As the Wonderland dialogue between Alice and the
hemorrhages is undoubtedly sobering. Yet even more impor- Cheshire Cat (quoted at the beginning of this chapter)2 tea-
tant, in my own opinion, is the effect of stroke on the indi- ches, if you want to get somewhere, you must know where you
vidual. What could be worse than the sudden inability to are going. If clinicians are to know where they are headed, they
speak, move a limb, stand, walk, see, read, or feel, or become must know where they are, and where they and their prede-
unable to understand spoken language, write, think clearly, cessors have been. History adds an important dimension to
or remember? Loss of function is often instantaneous and knowledge. The past helps focus and broaden the perspective
totally unanticipated; impairments may be transient or per- of the present and the future. Osler, and most other important
manent, slight or devastating. The first common term for medical innovators, were aware of their debt to history and of
stroke, apoplexy, literally meant in Greek “struck suddenly their inevitable entanglement with the past as well as the pre-
with violence.”10 The word stroke refers to being suddenly sent and future.3 I begin with a review of the history of stroke.
stricken. Stroke patients tell graphically about the personal Space necessitates inclusion of only a brief review of some
tragedy of their illness. Eric Hodgins, the popular author of important people and milestones to convey a sense of the
Mr. Blandings Builds His Dream House, wrote an autobio- historical context of the present state of knowledge about
graphical account of his stroke that he titled Episode, from stroke. Of course, the following view of history is eclectic and
which I quoted at the beginning of this chapter.1 He changed personal and should be recognized as such.
from a functioning human in one moment to a helpless,
dumb invalid, “a case” in the next instant. Imagine an articu- Early observers: Hippocrates to Morgagni
late author dependent for his livelihood on his use of Hippocrates (c. 400 BC) was probably the first to write about
language becoming totally unable to speak. Surely, the the medical aspects of stroke.6,10 He and his followers were
brain is wholly responsible for intelligence, capability, char- mostly interested in prognosis, predicting for the patient and
acter, wit, humor, personality, and most of the characteristics family the outcome of an illness.15–17 Hippocrates was a keen
that make us recognizable as individuals and as humans. observer and urged careful observation and recording of phe-
Losing brain function can be dehumanizing and often nomenology. Hippocrates wrote in his aphorisms on apoplexy,
makes individuals dependent on others. For these reasons, “persons are most subject to apoplexy between the ages of forty
most individuals fear stroke more than any other disease, and sixty,”16 and attacks of numbness might reflect “impend-
with the possible exception of cancer. Everyone would like to ing apoplexy.”10 He astutely noted, “when persons in good
exit this life with their capabilities and mind intact, despite health are suddenly seized with pains in the head and straight-
the inevitable aging of their bodies. away are laid down speechless and breathe with stertor, they

2
 Chapter 1: Introduction and perspective

die in seven days when fever comes on.”6,17 This description of

subarachnoid hemorrhage shows the Hippocratic emphasis on
observation and prognosis. Hippocrates also 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, and so they
named the arteries carotid, from the Greek word Karos, mean-
ing “deep sleep.”
A few hundred years after Hippocrates, Galen (131–201
AD) described the anatomy of the brain and its blood vessels
from dissections of animals. Although his early writings
emphasized observation and experimentation, much of his
later works combined mostly theorizing and speculation, in
which he attributed disease to a disequilibrium between puta-
tive body humors and secretions such as water, blood, phlegm,
bile, and so forth.15 Galen and his voluminous writings domi-
nated the 1300 years after his death. During the ensuing Dark
and Middle Ages, persons who called themselves physicians
gained their knowledge solely from studying the Galenic texts,
considered at the time to be the epitome of all medical wisdom.
Dissection, experimentation, and personal observations were
discouraged and not considered scholarly.
Andreas Vesalius (1514–1564) challenged the Galenic tra-
dition by dissecting humans and relying on his own personal
observations instead of Galen’s writings. Vesalius could not Figure 1.2 Sir Thomas Willis (1621–1675).
find the rete mirabile of blood vessels that Galen had described
(presumably in a lower animal).15 Vesalius’s dissections were
published in a volume entitled De Humani Corpis Fabrica England. Willis recognized transient ischemic attacks and the
(usually referred to as the Fabrica), which contained the phenomenology of embolism, as well as the existence of
detailed drawings his young artist and collaborator Jan occlusion of the carotid artery.20–25 Willis described clearly
Kalkar reproduced as woodcuts and copper plates.6,18 The the collateral circulation in the head and neck: “The cephalic
seventh book of the Fabrica contains 15 diagrams of the arteries, whether they be carotid or vertebrals, communicate
brain. These were the most detailed neuroanatomical studies one with the other reciprocally in various ways . . . This we have
up to that time.6 By all accounts, Vesalius had a great flair for demonstrated by injecting dark substances in only one branch
lecturing and teaching, and his works and personage stimu- and observing that the whole brain becomes colored.”22 Willis
lated much interest in anatomy and in the brain.15 was able to recruit a remarkable group of coworkers to Oxford,
During the last half of the seventeenth century, two England, including the illustrator and architect Christopher
important physicians, Johann Jakob Wepfer (1620–1695) and Wren, and the physicists Robert Hooke and Robert Boyle.24,25
Thomas Willis (1621–1675), made further anatomical and These investigators were an important stimulus for science in
clinical observations. Wepfer wrote a popular treatise on post-Elizabethan England.24
apoplexy that was originally published in 1658 and had During the eighteenth century, one of the true giants in
five subsequent editions.6,19 Wepfer performed meticulous medical history, Giovanni Battista Morgagni (1682–1771), was
examinations of the brains of patients dying of apoplexy. He able to focus attention on pathology and the cause of disease.
described the appearance of the carotid siphon and the course Up to that time, anatomy and prognostic formulas had
of the middle cerebral artery in the sylvian fissure. Obstruction prevailed. Morgagni, a distinguished professor of anatomy at
of the carotid and vertebral arteries was recognized as a the University of Padua, had a vision that the secret to under-
cause of apoplexy (the blockage preventing sufficient blood standing disease was to carefully perform necropsies on
from reaching the brain).19,20 Wepfer was the first to show humans with illnesses and then to correlate the pathological
clearly that bleeding into the brain was an important cause of findings with their symptoms during life.15 Although the
apoplexy. Thomas Willis (shown in Figure 1.2), a physician clinicopathological method is now taken for granted, this was
and neuroanatomist best known for his Cerebri Anatome, a new approach for physicians in the eighteenth century.
which contained a description of a circle of anastomotic vessels Morgagni labored his entire career to meticulously collect
at the base of the brain, was also a well-known clinician and an material for his epic work, De Sedibus et Causis Morborum
astute observer. Willis was born soon after the deaths of per Anatomen Indagatis, which was published when he was
William Shakespeare and Queen Elizabeth I when Great 79 years old.15,26 De Sedibus is a 5-volume work organized in
Britain was still basking in the artistic bloom of Elizabethan the form of 70 letters to a young man describing the cases

3
 Part I: General principles

collected. The first volume was titled Disease of the Head. brain infarcts. In the second group, patients had the sudden
Morgagni’s clinical descriptions of patients were detailed but onset of headache, vomiting, and either faintness or falling but
contained no formal physical or neurological examinations no paralysis. Undoubtedly, these patients had subarachnoid
because these were not performed during his lifetime. hemorrhages. In the third group, there was unilateral paralysis,
One of Morgagni’s descriptions illustrates the style and often with abnormal speech, but neither stupor nor headache
content of the book: was present. This group must have had small infarcts or
parenchymatous hemorrhages. Abercrombie also speculated
A certain man, who was a native of Genoa, blind of one eye, on etiological mechanisms, mentioning spasm of vessels, inter-
and liv’d by begging, being drunk, and quarreling with
ruption of the circulation, and rupture of diseased vessels
other drunken beggars, receiv’d two blows by their sticks;
causing hemorrhage.10,28
one on his hand which was slight, and another violent one
at the left temple so that blood came out of the left ear. Yet During the middle of the nineteenth century, dissemina-
soon after, the quarrel being made up, he sat down at the tion of knowledge about the pathology of stroke came with the
fire with them . . . and again fill’d himself with a great publication of four atlases, each containing plates of brain and
quantity of wine, by way of pledge of friendship being vascular lesions. Hooper’s atlas, published in 1828, clearly
renewed; and not long after, on the same night, he died.15 illustrated pontine and putaminal hemorrhages and a subdural
hematoma.29 Cruveilher (1835–1842),30 Carswell (1838),31 and
Necropsy showed a large epidural hematoma. Morgagni also Bright (1831)32 also published atlases containing lithographs of
described cases of intracerebral hemorrhage and recognized systemic and neuropathological lesions. Bright, better known
that paralysis was on the side of the body opposite to the brain for his work on nephritis, collected more than 200 neuropatho-
lesion. Morgagni’s work shifted the emphasis from anatomy logical cases and included illustrations of 25 nervous system
alone to inquiry about diseases and their pathology, causes, specimens, including cerebrovascular cases, in his volume on
and clinical manifestations during life. nervous system disorders.32
During the latter half of the nineteenth century, the most
The nineteenth and early twentieth important experimental and pathological information
centuries: Atlas makers, Virchow and Foix about vascular disease was published by Rudolf Virchow
(1821–1902) (Figure 1.3), a pathologist working in Berlin.15
During the early years of the nineteenth century, an influential
He described the phenomenology of in-situ antemortem
treatise on apoplexy was written by a prominent Irish physi-
thrombosis with subsequent embolism. In a remarkable series
cian John Cheyne (1777–1836). Cheyne’s book, which
of observations and experiments, Virchow analyzed the rela-
appeared in 1812, was titled Cases of Apoplexy and Lethargy
tionship between thrombi and infarction, locally and at a
with Observations upon the Comatose Diseases.27 In it, he
distance. Among 76 necropsies performed in 1847, Virchow
sought to separate the phenomenology of lethargy and coma
found thrombi in extremity veins in 18 patients and within the
from apoplexy. Cheyne’s description of the neurological
pulmonary arteries in 11, and reasoned that the bloodstream
abnormalities was more detailed than those of his predeces-
emanating from these veins must have been the conduit for
sors, and the “morbid appearances” of the patients’ brains were
transportation of the thrombi to distant sites such as the
emphasized after the example of Morgagni. One illustrative
patient was a woman of 32 years who was near the end of her
pregnancy. After a headache she became less responsive.
Cheyne found that “she preserved the power of voluntary
motion of the left side, but the right was completely paralytic.
She seemed perfectly conscious, attempted to speak, but could
not articulate; she signified by pointing with her left hand that
she desired to drink.”27 After describing her case history,
Cheyne discussed the available treatments (blood-letting, eme-
tics, purges, and external applications) and then described 23
other cases. The pathological findings included clear descrip-
tions of brain softenings and intracerebral and subarachnoid
hemorrhages.27 After Cheyne, developments were made con-
currently in the clinical, anatomic, and pathological aspects of
stroke.
John Abercrombie contributed a more detailed clinical
classification of apoplexy in his general text published in
1828.28 Abercrombie used the presence of headache, stupor,
paralysis, and outcome to separate apoplectics into three
clinical groups. In the first group, which he termed primary
apoplexy, the onset was sudden, unilateral paralysis; rigidity
and stupor were present, and the outcome was poor. These
patients probably had large intracerebral hemorrhages or large Figure 1.3 Rudolf Ludwig Carl Virchow (1821–1902).

4
 Chapter 1: Introduction and perspective

Figure 1.5 Sir William Osler (1849–1919).

Figure 1.4 Charles Foix (1882–1927).

descriptions of the clinical findings and prognosis of many

arteries of the lung.33,34 Virchow then used animal experi-
stroke syndromes. Sir William Osler (Figure 1.5), a famous
ments to study the fate of foreign materials placed in veins.
internist, writer, and teacher, noted in detail the neurological
He later sought and found obstruction of brain, splenic, renal,
findings in patients with bacterial endocarditis and described
and limb arteries at necropsy in patients who had cardiac valve
brain embolism in patients with rheumatic carditis. Osler first
disease and left atrial thrombi. Virchow showed systematically
described the findings in patients with hemorrhagic telangiec-
that in-situ thrombosis and embolism were the cause of infarc-
tasia (Osler, Weber, Rendu disease). The clinicopathological
tion and that the process was unrelated to inflammation, the
method culminated in descriptions by Foix and his colleagues
predominant theory at that time. Virchow described his classic
of the syndromes of infarctions in the regions of the middle
triad of vascular thrombosis: (1) Stasis of blood in a vessel;
cerebral artery,40,41 posterior cerebral artery,41,45 anterior
(2) injury to the wall of the blood vessel; and (3) an abnormality
cerebral artery,41,46 and vertebrobasilar arteries.39,41
in the balance between blood procoagulant and anticoagulant
factors. Before Virchow’s studies and reports, blood factors
and thrombosis were given little attention. Mid twentieth century and Miller Fisher
During the later part of the nineteenth and the early years After Foix, a Canadian and American neurologist, C Miller
of the twentieth centuries, the anatomical details of the arteries Fisher (Figures 1.6–1.8), did much to awaken clinical interest
supplying the brain were studied carefully. Detailed observa- in stroke. Fisher enlisted in the Canadian army during World
tions of the distribution of the arteries and veins in the cranium War II and was captured and spent years in a prisoner-of-war
were made by Düret, a French neurosurgeon, first working in camp. After the war, he was determined to make important
Charcot’s laboratory;35,36 by Stopford in Britain;37 and later by contributions to medicine. His interest in stroke was tweaked
Foix, who dissected pathological specimens at the Salpetrière by encounters with patients. One particular patient described
in France.38–41 Foix (Figure 1.4) made many key anatomical in detail his episodes of transient monocular blindness that had
and clinical observations. Also during this same period, heralded a hemisphere stroke. Fisher reviewed the literature
clinicians gathered more information on the clinical findings and found scant reference to transient episodes before stroke.
in patients with strokes that involved various brain regions. Fisher took meticulous thorough histories from patients hos-
The bulk of these data involved clinical descriptions, with little pitalized with stroke at a Veterans hospital in Canada and
interest concerning pathogenesis, laboratory confirmation, found that transient prodromal episodes were quite common.
or treatment. The general medical and neurological texts In patients with transient monocular blindness preceding
of Osler,42 Gowers,43 and Wilson44 contained detailed stroke, Fisher reasoned that the causative occlusive process

5
 Part I: General principles

Figure 1.7 Charles Miller Fisher with Louis R Caplan in 1998.

Figure 1.6 Charles Miller Fisher giving a presentation in 1978.

was likely in the internal carotid artery in the neck or head. A

patient with transient monocular blindness then died sud-
denly. After death, Fisher dissected the neck and found, as
predicted, that the internal carotid artery was occluded.47 He
then collected and reported series of patients with internal
carotid artery occlusions and described in detail the clinical
histories and neurological findings.48,49 Fisher emphasized the
frequent occurrence of warnings before stroke that he later Figure 1.8 Jay P Mohr, Charles Miller Fisher, and Robert Ackerman.
dubbed transient ischemic attacks. “Prodromal fleeting attacks
of paralysis, numbness, tingling, speechlessness, unilateral
blindness, or dizziness often preceded and warned of impend- Fisher developed the first stroke fellowship in the United States
ing strokes in patients with carotid artery disease.”9 and mentored many now senior stroke neurologists. I was
Fisher, like Foix, was both a pathologist and a clinician. fortunate to serve as his stroke fellow during 1969–1970.
During his early career in Canada, and later in Boston, he Figure 1.7 is a recent picture of Miller Fisher and I. Dr Jay P
thoroughly examined at necropsy the neck and cranial arteries Mohr, who worked with me in developing and maintaining the
and their microscopic-sized branches. He obtained specimens Harvard Stroke Registry in the early 1970s, and a leader in the
of arteries from their origins from the aorta to their major field of stroke trials, was another of Dr Fisher’s stroke fellows.
intracranial branches. During the 1950–1990 period, Fisher Dr Robert Ackerman, a pioneer in the early field of PET
made many major pathological and clinical observations scanning and stroke, and in the non-invasive evaluation of
on the pathological and clinical features of carotid artery stroke risk was a trainee and later colleague of Dr Fisher and
disease;48–52 the pathological and clinical aspects of intracer- was the organizer of the Boston Stroke Society for three dec-
ebral hemorrhage;53–56 the pathological and clinical ades. Mohr, Fisher, and Ackerman are shown in Figure 1.8.
syndromes related to lacunar brain infarction;57–59 and the Ackerman also trained stroke fellows including several future
clinical and pathological features of various posterior circula- leaders in the field: Geoffrey Donnan and Steven Davis
tion neurological signs and brain and vascular lesions.60–66 (Australia); Jean-Claude Baron (France and UK), and James
Before Fisher’s major stroke publications, Raymond Adams, Grotta and Viken Babikian (United States).
his mentor, had written a classic clinicopathological descrip- Fisher’s reports contained meticulous descriptions of the
tive report with Charles Kubik on basilar artery occlusion.67 signs and symptoms found in patients with infarcts and

6
 Chapter 1: Introduction and perspective

hemorrhages in various vascular and brain distributions. filming techniques have since made angiography safer and more
Elegant and thorough as these descriptions were, their limita- definitive.
tions included: (1) Reliance on only the fatal cases because Hounsfield of the research laboratories of Electrical
precise diagnosis was not possible during life; (2) predomi- Musical Instruments (EMI) in Britain originated the concept
nance of anecdotal cases, with few data on the incidence and of computed tomography (CT) during the mid 1960s. The
frequency of findings in large series of patients with the specific instrument was first tried at the Atkinson-Morley Hospital in
described conditions; (3) insufficient availability of technology London.6 CT scanners were first introduced to North
to allow accurate diagnosis or clarification of the pathogenesis America in 1973. Films from first-generation scanners were
or pathophysiology of the vascular lesions and their effects on quite primitive, but by the late 1970s, third-generation scan-
the brain; and (4) little information about the effectiveness of ners had made CT a useful, almost indispensable, diagnostic
various treatments. technique. By the mid 1980s, CT was readily available
throughout North America and most of Europe. CT allowed
1975 to present clear distinction between brain ischemia and hemorrhage
and allowed definition of the size and location of most
During the last quarter of the twentieth century, there was an
brain infarcts and hemorrhages. The advent of magnetic
explosive growth of interest in and knowledge about stroke.
resonance imaging (MRI) into clinical medicine in the mid
Advances in technology allowed better visualization of the
1980s was a further major advance. MRI proved superior to
anatomy and functional aspects of the brain and of vascular
CT in showing old hemosiderin-containing hemorrhages
lesions during life. Databases and registries of large numbers of
and in imaging vascular malformations, lesions abutting on
well-studied stroke patients helped identify and quantify the
bony surfaces, and posterior fossa structures. MRI also made
most common clinical and laboratory findings in patients with
it easier to visualize lesions in different planes by providing
various stroke syndromes. Epidemiological studies identified
sagittal, coronal, and horizontal sections. Improved filming
more accurately the risk factors for stroke and suggested pre-
techniques have made it possible to image the brain vascu-
vention strategies. New surgical and medical treatments were
lature through the techniques of magnetic resonance
now possible. Therapeutic trials began to evaluate systemati-
angiography72 and CT angiography.73
cally the efficacy and safety of some of these treatments.
Ultrasound was introduced into medicine in 1961 by
Physicians began to explore the use of devices that could be
Franklin and colleagues, who used Doppler shifts of
introduced through the arterial system to treat various arterial
ultrasound to study blood flow in canine blood vessels.6,74
lesions including atherosclerotic stenoses, aneurysms and vas-
B-mode ultrasound was soon used to provide images of the
cular malformations. Other devices could be used to retrieve
extracranial carotid arteries non-invasively. By the early 1980s,
thromboemboli that blocked arteries in the neck and head.
B-mode, continuous-wave (CW), and pulsed-Doppler technol-
Thrombolysis became a reality and strokes were considered a
ogy could reliably detect severe extracranial vascular occlusive
medical emergency requiring urgent attention. Stroke units
disease in the carotid and vertebral arteries in the neck.
were formed in many hospitals and greatly improved the care
Sequential ultrasound studies allowed physicians to study the
of stroke patients.
natural history of the development and progression of these
occlusive lesions and to correlate the occurrence and severity
Advances in diagnostic technology of disease with stroke risk factors, symptoms, and treatment.
The technological revolution probably began with the work of In 1982, Aaslid and colleagues introduced a high-energy bidir-
the Portuguese neurosurgeon Egas Moniz (1874–1955). Moniz ectional pulsed-Doppler system that used low frequencies
surgically exposed and temporarily ligated the internal carotid to study intracranial arteries, termed transcranial Doppler
artery in the neck and then rapidly injected by hand a 30% ultrasound (TCD).75 TCD made possible non-invasive
solution of sodium iodide, taking skull films later at regular detection of severe occlusive disease in the major intracra-
time intervals.68 He first used the technique for studying nial arteries during life, as well as sequential study of these
patients suspected of having brain tumors, but he later studied lesions.76
stroke patients. By the time of his monograph on angiography in Introduction of echocardiography and ambulatory cardiac
1931,69 Moniz had studied 180 patients; had switched to another rhythm monitoring in the 1970s and 1980s greatly improved
opaque-contrast agent, Thorotrast, because of convulsions that cardiac diagnoses and detection of cardiogenic sources of
had occurred after the injection of sodium iodide; and had embolism. By the early 1990s, clinicians could safely define
demonstrated the occurrence of occlusion of the internal carotid the nature, extent, and localization of most important brain,
artery during life.68,69 Modern angiography began with the work cardiac, and vascular lesions in stroke patients. Accurate diag-
of Seldinger in Sweden, who devised a technique by which a nosis using modern technology facilitated clinical-imaging
small catheter could be inserted into an artery over a flexible correlations in patients with non-fatal strokes, and this paved
guidewire after withdrawing the needle.70,71 Catheter angiogra- the way for monitoring the effects of various treatments. By the
phy of selected vessels in the carotid and vertebral circulations end of the twentieth century, advanced brain imaging with
was then possible without surgical incisions. Newer dyes and CT, MRI, and newer magnetic resonance (MR) modalities,

7
 Part I: General principles

including fluid-attenuated inversion recovery (FLAIR) images, of various risk factors that predispose to stroke. The present text
diffusion, perfusion, and functional MRI, and MR spectro- relies heavily on data from these studies, especially those in
scopy, were able to show clinicians the localization, severity, which I was personally involved.81,83,85
and potential reversibility of brain ischemia. Vascular lesions
could be quickly and safely defined using CT angiography, MR
angiography, and extracranial and transcranial ultrasound. Stroke units, stroke specialists, and stroke
During the first decades of the twenty-first century, nurses
high-resolution MR and CT studies of lesions imaged in
During the nineteenth and the first two-thirds of the twentieth
cross-section could better define the nature of atherosclerotic
century nearly all acute stroke patients were cared for in the
plaques and other arterial wall abnormalities. Cardiac and
general wards and rooms of hospitals. There were very few
aortic sources of stroke were studied using transesophageal
stroke specialists and no stroke nurse specialists. Some rehabi-
echocardiography. More sophisticated hematological testing
litation units, almost entirely outside of acute hospitals did
led to new insights into the role of altered coagulability in
specialize in stroke rehabilitation. During the 1960s and 1970s
causing or contributing to thromboembolism. Clinicians
Neurology departments began to be split off from Departments
were finally able to recognize and quantify quickly and accu-
of Internal Medicine within academic medical centers in the
rately the key data elements needed to logically treat patients
United States and Europe. When this occurred, hospitals with
with brain ischemia and hemorrhage.
neurology departments began to place stroke patients and other
patients with neurological diseases on neurology wards and
Data banks and stroke registries private rooms while other stroke patients continued to be trea-
During the middle years of the twentieth century, clinicians ted on medical services scattered throughout the hospitals.
had advanced knowledge of clinical phenomenology by During the 1970s and 1980s, hospitals placed very sick patients
personally studying and describing small groups of patients. requiring frequent monitoring and care into specialized inten-
In 1935, Aring and Meritt studied a group of patients coming sive care units (ICUs). Cardiac, surgical, and medical ICUs were
to necropsy at the Boston City Hospital to clarify the differ- first formed. Neurosurgeons and neurologists in large medical
ential diagnosis between brain hemorrhages and infarcts.77 centers were successful in creating Neuroscience ICUs manned
Fisher and his colleagues and students studied and described with nurses specially trained to care for very ill and acute
the clinical findings in small numbers of patients with various neurological disorders including stroke. A new neurological
cerebrovascular syndromes. During the 1970s and 1980s, the specialty – neurology intensivists began to grow.
technological advances described made it possible to define the A number of factors during the 1980s and 1990s conspired
clinical and laboratory features of non-fatal, even minor, to promote the development and proliferation of specialized
strokes and pre-stroke vascular lesions. With better knowledge stroke units. CT, MRI, ultrasound, and vascular imaging
of clinical and morphological features, clinicians naturally capabilities made it clear that strokes were complex and
sought more quantitative data. How often did intracerebral composed of very diverse etiologies and pathophysiologies.
hemorrhages or lacunar infarcts occur? How often did each of Moreover specific diagnosis could be made rather quickly
the clinical symptoms and signs occur in each subtype of and safely but required special training, expertise, and experi-
stroke? Clinicians recognized that valid, statistically meaning- ence. Funding for trials made it possible in academic medical
ful data could not be collected unless large numbers of patients centers to hire nursing coordinators. The development of
with a wide spectrum of representative cases were studied and managed care strategies in hospitals in the United States forced
analyzed. The advent of computers in medicine in the 1970s more rapid and efficient care and throughput of stroke
greatly facilitated the storage and analysis of large quantities of patients. Newer therapies, surgeries, percutaneous interven-
complex data. Collection of data on large numbers of stroke tions, and especially thrombolysis made it advantageous to
patients began with the series of Dalsgaard-Nielsen in segregate stroke patients in ICUs and specialized stroke units.
Scandinavia78 and with series of patients seen by clinicians at These specialized units were composed of nurses with
the Mayo Clinic in Rochester, Minnesota.79,80 The Harvard experience and training in stroke, internists, and stroke neu-
Cooperative Stroke Registry in the early 1970s was the first rologists. These stroke units were able to deliver: specialized
computer-based registry of prospectively studied stroke nursing care; attention to management of blood pressure, fluid
patients.81 Other stroke registries and databases were devel- volumes, and other physiological and biochemical factors;
oped around the world and provided more quantitative protocols and practices to facilitate rapid and thorough evalua-
information about clinical and laboratory phenomena and tion and treatment, monitor treatment, carry out randomized
diagnoses.82–89 Community-based studies in south Alabama90; therapeutic trials, and prevent complications; education about
Framingham, Massachusetts91; Oxfordshire in Great Britain92; stroke and its prevention to patients and their families and
the Lehigh Valley in Pennsylvania93; and various regions in caregivers.97–100 They also promoted an up-beat optimistic
North Carolina, Oregon, and New York94 generated important view of stroke recovery in contrast to the situation previously
epidemiological data. Computer-based registries and data banks present on medical wards where stroke patients were often
have undoubtedly assisted collection and analysis of a wide considered undesirable patients with hopeless outcomes.
variety of clinical, radiological, pathological, and epidemiologi- Once these units began to proliferate especially in Europe,
cal information.95,96 Especially important has been recognition it became clear that they were an important major advance.
8
 Chapter 1: Introduction and perspective

Dedicated stroke units have been convincingly shown to Sparked by clinical observations, clinicians in the mid
decrease mortality, limit stroke morbidity, and allow more twentieth century turned to drugs that affect platelet functions
patients to retain their independence and to return home after as an alternative to heparin and coumadin. Probably the first
stroke.101–103 Between the carrying out of the two large clinical observations on the potential anticoagulant functions
European thrombolytic trials (ECASS I and ECASS II),104,105 of aspirin were made by Craven who noted that dental patients
neurologists in the hospitals engaging in these trials developed bled more if they had used aspirin.6 He urged friends and
dedicated stroke units. These units attended to the general patients to take 1 or 2 aspirin tablets a day and later published
medical care of the stroke patients and prevention of complica- the effectiveness of this strategy in preventing coronary and
tions. As a result the morbidity in both the thrombolytic treat- cerebral thrombosis among 8000 men in articles during the
ment group and the placebo groups improved dramatically in mid 1950s in the Mississippi Valley Medical Journal.114,115 Case
the ECASS II trial and the good results in the placebo-treated reports from the United States and Britain on the effectiveness
group exceeded that of any prior thrombolytic trial. The milieu of aspirin in preventing attacks of transient monocular blind-
and the care in dedicated stroke units leads to better outcomes. ness brought the subject to more general attention.116,117 The
Mortality is reduced. More patients return home and less are American118 and Canadian119 aspirin trials soon followed
transferred to chronic hospitals and nursing homes. Short-term during the 1970s. These studies were the first of many trials
and long-term functional outcomes are also improved. There is of various antiplatelet agents almost invariably studied in large
no longer any doubt that stroke units work. One of the the most numbers of patients lumped together as having transient
important therapeutic advances during the last decades of the ischemic attacks or minor strokes.
twentieth century in the treatment of patients with acute stroke Subsequent trials studied the relative safety and efficacy of
was the development of stroke services, stroke nurses, stroke aspirin versus warfarin in preventing stroke recurrence in a
specialists, and stroke units. large numbers of ischemic stroke patients, the WARSS
(Warfarin–Aspirin Recurrent Stroke Study) trial,120 and in
Advances in medical and surgical therapy patients who had brain ischemia attributable to severe
intracranial arterial stenosis, the WASID (Warfarin–Asprin
and randomized trials Symptomatic Intracranial Disease) trial.121 Physicians became
During the first half of the twentieth century, researchers increasingly aware that warfarin compounds were difficult to
discovered the anticoagulant effects of warfarin and heparin use in practice. These vitamin K inhibitors worked indirectly
compounds. McLean, a medical student at Johns Hopkins, first on the coagulation system, were affected by other medications
isolated an anticoagulant compound from body tissues.6,106 and foods, and were difficult to keep in target range of optimal
Howell and Holt extended Mclean’s research and named the anticoagulation. As a result many patients were intermittently
new compound heparin.6,107 Link and colleagues found that a under anticoagulated and at risk for brain ischemia, and bleed-
natural coumarin compound found in hay was transformed ing was an important problem. Multiple frequent blood
during spoilage into a substance that led to bleeding in tests were needed to monitor anticoagulation. Because it took
cattle.6,108 Link crystallized dicumarol in 1939, and soon time for warfarin to become clinically effective, heparin was
thereafter many laboratories synthesized related warfarin- customarily used until patients were effectively anticoagulated
type compounds that could be used therapeutically.6 During with warfarin. Pharmaceutical companies placed on the mar-
the 1950s clinicians began to give these anticoagulants to ket newer anticoagulants that were direct thrombin inhibitors
patients with various clinical syndromes mostly based on the (dabigatran) and factor Xa inhibitors (apixaban, rivaroxaban,
tempo of brain ischemia – transient ischemic attacks, progres- edoxaban). These agents were all taken orally, worked quickly
sing stroke, completed stroke, etc. so that heparin was not needed initially, had fixed doses so that
One of the first randomized therapeutic trials concerned long-term blood test monitoring was not essential, and were
the effectiveness of anticoagulant therapy in patients with not as affected by other agents and foods as the vitamin
various ischemic syndromes.109 This trial, which was reported K inhibitors. Trials of these agents tested their safety and
in 1962, contained only 443 patients, 219 of whom were efficacy versus warfarin in patients with atrial fibrillation, a
anticoagulated.109 The methodology and analysis used in this known important cause of brain embolism.122–125 These newer
trial would be considered rather primitive by today’s stand- anticoagulants caused less intracranial bleeding and were at
ards. Treatment was open label, not blinded, the number of least as effective as warfarin in stroke prevention.
patients in each ischemic group was very few, and the end- Miller Fisher in his seminal reports on carotid artery dis-
points varied depending on the nature of the group; for exam- ease in the early 1950s predicted that one day in the future
ple, in patients entered in the group “thrombosis-in-evolution” surgery would be feasible on the internal carotid artery to
(128 patients) the investigators analyzed progression of infarc- prevent stroke.47,49 During the 1950s, surgeons reported their
tion and mortality. This study antedated CT scanning so that experience with surgery on the internal carotid126–128 and
estimates of progression of infarction were only clinical. other extracranial arteries.6,129–131 In order to study the
During the last decades of the twentieth century many trials effectiveness of surgery on the extracranial arteries, a host of
studied the utility of anticoagulation in a variety of causes of neurologists and adventurous surgeons led by Dr William
brain ischemia, especially prevention of stroke in patients with S Fields organized and carried out a large surgical trial during
atrial fibrillation.110–113 the 1960s.132,133 The trial was entitled the Joint Study of

9
 Part I: General principles

Figure 1.9 William S Fields (1913–2004).

Extracranial Arterial Occlusions and was supported by the

National Heart Institute. This was the first surgical versus
medical treatment trial carried out in the United States in Figure 1.10 Sir Henry J M Barnett. From Barnett HJM (ed), Cerebrovascular
Disease, Neurological Clinics Vol 1, No. 1. Philadelphia: W B Saunders, 1983.
which 6535 patients were randomly assigned to surgical versus
non-surgical treatment. Mortality in this trial was equal in the
medical and surgical groups and death was most often cardiac.
Fields (Figure 1.9) was a pioneer in the study of cerebrovascu- a trial was carried out testing the efficacy of bypass in patients
lar diseases, hosted and published many conferences in with cerebral ischemia identified by ipsilateral increased oxy-
Houston about various stroke conditions, and was the gen extraction fraction as measured by positron emission
principal investigator and organizer of pioneering stroke tomography (PET).141,142 The trial was terminated early for
trials.6,134,135 futility because of the high rate of ipsilateral ischemic strokes
During the 1960s and early 1970s Donaghy and his collea- within 30 days of creation of the surgical bypass.141,142
gues devised a microsurgical technique to anastamose small Alarmed that the number of carotid endarterectomy cases
arteries together.136,137 One of their trainees, Gazi Yasargil, was was growing out-of hand, Henry Barnett organized a trial of
mostly responsible for bringing this technique into clinical surgical versus medical treatment for patients with symptomatic
practice when he created surgical extracranial-to-intracranial carotid artery disease. This North American Symptomatic
(EC-IC) shunts to treat patients with occlusive vascular disease Carotid Endarterectomy Trial (NASCET)143,144 and the concur-
who had brain ischemia.138–140 By 1977 bypass procedures rent European Carotid Surgery Trial (ECST)145,146 showed the
usually anastamosing the superficial temporal artery to effectiveness of carotid endarterectomy in selected patients with
branches of the middle cerebral artery were being performed selected lesions performed by surgeons who had low surgical
widely in the United States and Europe. Henry Barnett mortality and morbidity results. Trials of carotid surgery in
(Figure 1.10) organized and performed a trial of these EC-IC patients who had no related symptoms soon followed in
bypass procedures, and showed that the procedure as both the United States147 and Europe.148,149 Carotid surgery
performed at the time was less successful than medical and stenting were later compared in the CREST (Carotid
treatment.141 The results of this trial, published in 1985, dras- Revascularization Endarterectomy Versus Stenting) Trial in
tically reduced the number of these procedures performed. the USA.150,151
Because neurologists and surgeons continued to posit that During the last decades of the twentieth century there
some patients with symptomatic atherosclerotic internal was an almost religious zeal for randomized clinical trials.
carotid artery occlusion and hemodynamic cerebral ischemia Some enthusiasts saw the future dominated by doctors
were at high risk for subsequent stroke when treated medically, searching computer databases of trials to choose what to do
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