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DISEASES OF
THE NERVOUS SYSTEM
Harald Sontheimer
DISEASES OF THE NERVOUS SYSTEM
ELSEVIER science &
technology books
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Harald Sontheimer
Harrison Distinguished Professor and Chair, Department of Neuroscience,
University of Virginia, School of Medicine, Charlottesville, VA, United States
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ISBN 978-0-12-821228-8
vii
viii Contents
VI
Common Concepts in Neurological and VIII
Neuropsychiatric Illnesses Neuroscience Jargon
1 Introduction 386
2 Neuronal Death 386 Index 469
About the Author
Dr. Sontheimer is a researcher and educator with a supported center in Birmingham AL devoted to the study
lifelong interest in neuroscience. A native of Germany, and treatment of children with developmental disabil-
he obtained a Master’s degree in evolutionary compar- ities, ranging from Down’s syndrome to autism. In this
ative neuroscience from the University of Ulm in which capacity, Dr. Sontheimer was frequently tasked with ex-
he worked on the development of occulomotor reflexes. plaining complex scientific processes to a lay audience.
In 1989, he obtained a doctorate in biophysics and cel- Recognizing the need to further educate the public about
lular & molecular neuroscience from the University of neurological disorders using language that is accessible to
Heidelberg, studying biophysical changes that accom- an educated public motivated Dr. Sontheimer to write a
pany the development of oligodendrocytes, the princi- textbook on diseases of the nervous system. To ensure that
pal myelinating cells of the nervous system. He moved the material is comprehensive yet readily understandable,
to the United States, where he later became a citizen, for he wrote large parts of this text while on sabbatical leave
postdoctoral studies at Yale University. His independent at Rhodes College in Memphis, where he taught under-
research career began at Yale in 1991 and continued at the graduates while testing his book on this group of talented
University of Alabama Birmingham during 1994–2015, third- and fourth-year neuroscience students. In 2015, Dr.
and, more recently, at Virginia Tech and the University of Sontheimer was tapped to found a school of neuroscience
Virginia. His research focuses on the role of glial support at Virginia Tech with the goal to offer a unique neurosci-
cells in health and disease. His laboratory has made ma- ence education to an increasing number of undergrad-
jor discoveries that led to two clinical trials using novel uates. As the first of its kind, this enterprise devoted an
compounds to treat malignant gliomas. His research entire school to a variety of neuroscience experiences that
led to over 190 peer-reviewed publications. For the clin- include majors in clinical, experimental, cognitive, sys-
ical development of his discoveries, Dr. Sontheimer tems, computational, and social neuroscience. In 2020,
started a biotechnologies company, Transmolecular Inc., Dr. Sontheimer was recruited to the University of Virginia
which conducted both phase I and phase II clinical tri- School of Medicine as the Chair of Neuroscience with the
als with the anticancer agent, chlorotoxin. Morphotec mission to build this department into a leading research
Pharmaceuticals, which will be conducting the phase III enterprise devoted to discovery and translation science in
clinical trials, recently acquired this technology. As edu- neuroimmunology and neurodegenerative diseases. Dr.
cator, Dr. Sontheimer has been active in teaching medical Sontheimer continues to manage a very active research
neuroscience, graduate cellular and molecular neurosci- laboratory where he involves a spectrum of trainees rang-
ence, and, for the past 10 years, he has offered both gradu- ing from undergraduates to postdoctoral scientists. Dr.
ate and undergraduate courses on diseases of the nervous Sontheimer has trained over 50 PhD and MD/PhD stu-
system. In 2005, Dr. Sontheimer became director of the dents and postdoctoral fellows, many of whom have in-
Civitan International Research Center, a philanthropically dependent faculty positions today.
xi
Acknowledgments
English is a second language for me. To make up for Christopher B. Ransom, MD, PhD, University of
my shortcomings, I am indebted to several colleagues Washington
who have meticulously reviewed every word I wrote. Erik Roberson, MD, PhD, University of Alabama
Foremost, my long-term Assistant, Anne Wailes, who Birmingham
tirelessly edited and polished every sentence in the first James H. Meador-Woodruff, MD, University of Alabama
edition of this book. She also tracked down the copyrights Birmingham
for hundreds of figures that were reproduced in this book. Jeffrey Rothstein, MD, PhD, Johns Hopkins
Anne did all this while attending to the many daily tasks University
of administrating a large research center and looking after Leon Dure, MD, University of Alabama Birmingham
my trainees in my absence. This was a monumental un- Louis Burton Nabors, MD, University of Alabama
dertaking and words cannot describe how fortunate I feel Birmingham
to have had her support throughout this journey. Richard Sheldon, MD, University of Alabama
In addition, each chapter went through two stages of Birmingham
scientific review. The first stage of review was conducted Stephen Waxman, MD, PhD, Yale University
by two colleagues to whom I am tremendously indebted. Steven Finkbeiner, MD, PhD, The Gladstone Institute for
The first edition was reviewed for scientific content and Neurological Disease
accuracy by a tremendously talented postdoc, Dr. Alisha Thomas Novack, PhD, University of Alabama
Epps, who, for an entire year, spent almost every week- Birmingham
end reading and correcting book chapters as I completed William Britt, MD, University of Alabama
them. Alisha had a talent to simplify and clarify many Birmingham
difficult concepts, and, if needed, she found suitable fig- Warren Bickel, PhD, Virginia Tech
ures or even drew them from scratch. The second edition To be able to spend a year and a half writing a book
was reviewed by my colleague and friend Dr. Kristin is a luxury and privilege that, even in academia, only a
Phillips. As collegiate Professor in Neuroscience, she is few people enjoy. The first edition was developed while
an equally enthusiastic reader of Neuroscience literature I was still at the University of Alabama at Birmingham. I
and had developed a study abroad course that exam- like to thank the Dean, President, and my Chairman for
ines cultural and societal difference in the application of enthusiastically supporting this endeavor.
Neuroscience to Medicine. Co-teaching this course en- During the spring semester of 2014, I became a visit-
titled “Global Perspectives in Neuroscience” I realized ing Professor, embedded among the wonderful faculty
that my chapters must take a more global look at disease of Rhodes College in Memphis TN, a picturesque small
epidemiology and consider discrepancies in disease pre- liberal arts college. I am thankful for the hospitality and
sentations and outcomes. Her contributions to this book support of all the Rhodes administrators and faculty,
were tremendous and I am indebted to her generous many of whom I engaged in inspirational discussion
support. during lunch or coffee breaks. I am particularly grate-
The second stage of review involved experts in the ful to their Neuroscience program for letting me partic-
respective disease. I am privileged to have a number of ipate in their curriculum and take residence in Clough
friends who are clinicians or clinician–scientists and who Hall. The writing of the second edition accompanied my
were willing to selflessly spend countless hours correct- building the School of Neuroscience at Virginia Tech,
ing the mistakes I had made. While I am acknowledging which, over the course of 5 years grew to be one of the
each person with the very chapter they reviewed, I like largest undergraduate programs in the country. Here
to acknowledge all of them in this introduction by name. I took on several undergraduate courses ranging from
Alan Percy, MD, PhD, University of Alabama Neuroscience of the Mind, Brain and Pain, to my flagship
Birmingham course for which this book was written: Disease of the
Amie Brown McLain, MD, University of Alabama Nervous System. Throughout, many students provided
Birmingham invaluable feedback on this book, some formal, using a
Anthony Nicholas, MD, PhD, University of Alabama prescribed feedback form, other informal during office
Birmingham hours. I am thankful to the many students who attended
xiii
xiv Acknowledgments
my classes at Rhodes, UAB, and Virginia Tech and who My final acknowledgment goes to my publisher, Elsevier
took a particular interest and regularly provided recom- Academic Press, for their tremendous work editing, pub-
mendation for improvements. I trust that many of them lishing, and marketing this book. Particularly to the edito-
are either in Graduate or in Medical school by now, and rial project manager Kristi Anderson, the senior acquisitions
I wish them well. editor Melanie Tucker, and their production team.
Introduction
The study of nervous tissue and its role in learning For the past 20 years, I have been teaching a graduate
and behavior, which we often call neuroscience, is a course entitled “Diseases of the Nervous System” and
very young discipline. Johannes Purkinje first described more recently, I added an undergraduate course on the
nerve cells in the early 1800s, and by 1900, the patholo- same topic as well. Every year, almost without fail, stu-
gist Ramón y Cajal generated beautifully detailed histo- dents would ask me whether I could recommend a book
logical drawings illustrating all major cell types in the that they could use to accompany the course. I would
brain and spinal cord and their interactions. Cajal also usually point them to my bookshelf, filled with count-
described many neuron-specific structures including less neuroscience and neurology textbooks ranging from
synaptic contacts between nerve cells; yet how these Principles in Neuroscience to Merritt’s Neurology. When I
structures informed the brain to function like a biologi- started this book project, there was indeed no such book,
cal computer remained obscure until recently. Although yet I hoped that sooner or later some brave neuroscien-
Luigi Galvani’s pioneering experiments in the late-1700s tist would venture to write a book about neurological
had already introduced the world to biological electric- illnesses. Surprisingly, this did not happen, so in 2014,
ity, ion channels and synaptic neurotransmitter recep- I decided to fill this void. My initial inclination was to
tors were only recognized as “molecular batteries” in produce a multiauthor edited book. By calling on many
the late-1970s and early 1980s. The first structural image friends and colleagues to each write a chapter on their
of an ion channel was generated even more recently in favorite disease, this should be a quick affair. However,
1998, and for many ion channels and transmitter recep- from own experience, I knew that book chapters are al-
tors, such information still eludes us. ways the lowest priority on my “to do” list, and I really
Surprisingly, however, long before neuroscience be- was eager to pester my colleagues monthly to deliver
came a freestanding life science discipline, doctors and their goods. Ultimately, they would surely ask a senior
scientists had been fascinated with diseases of the ner- postdoc to take the lead and in the end, the chapters
vous system. Absent any understanding of cellular mech- would be heterogeneous and not necessarily at a level
anisms of signaling, many neurological disorders were appropriate for a college audience. For my target audi-
quite accurately described and diagnosed in the early ence, this book needed to be a monograph. While I did
to mid-1800s, including epilepsy, Parkinson Disease, not know at the time what I was getting into, I spent the
schizophrenia, multiple sclerosis, and Duchenne mus- majority of 2014 and 2015 reading over 2500 scientific
cular dystrophy. During this period and still today, the papers and review articles while also writing for about
discovery process has been largely driven by a curios- 7–10 h daily. I felt exhausted yet also became quite a bit
ity about disease processes. What happens when things more educated in the process. Given the rapid progress
go wrong? Indeed, much of the early mapping of brain in research and discovery, 5 years later, in 2019–20, I re-
function was only possible because things went very peated this exercise and wrote this second edition, which
wrong. Had it not been for brain tumors and intractable includes major updates and new additional chapters on
epilepsy, surgeons such as Harvey Cushing and Wilder Pain and Addiction.
Penfield would have had no justification to open the hu- The target audience for this book is any student in-
man skull of awake persons to establish functional maps terested in neurological and neuropsychiatric illnesses.
of the cortex. Absent unexpected consequences of sur- This includes undergraduates, early graduate students,
gery, such as the bilateral removal of the hippocampi in and medical students taking a medical neuroscience
HM that left him unable to form new memories, or un- course. I also expect the material to be of benefit to many
fortunate accidents exemplified by the railroad worker, health professionals who are not experts in the field.
Phineas Gage, who destroyed his frontal lobe in a blast The book may even appeal to science writers or simply
accident, we would not have had the opportunity to a science-minded layperson, possibly including persons
learn about the role of these brain structures in forming affected by one of the illnesses. Purposefully, the book
new memories or executive function, respectively. Such lacks a basic introduction to neuroscience as I would ex-
fascination with nervous system disease and injury con- pect the reader to have a basic understanding of neu-
tinues to date, and it is probably fair to say that neurosci- robiology. Many excellent textbooks have been written,
ence is as much a study of health as that of disease. each of which would prepare one well to comprehend
xv
xvi Introduction
this text. I feel that I could not have done justice to this amoeba, neurosistercosis, neuroaids, and prion diseases.
rapidly expanding field had I attempted to write a short I also used this chapter as an opportunity to highlight
introduction. However, to at least partially make up for the tropism displayed by some viruses for the nervous
this, I include an extensive final chapter that is called system and how this can be harnessed to deliver genes to
“Neuroscience Jargon.” I consider this more than just a the nervous system for therapeutic purposes.
dictionary. It has a succinct summary of approximately For the section on neurodevelopmental disorders, I
500 of the most important terms and is written as non- similarly chose four important examples including Down
technically as possible. I hope that this will assist the syndrome, Fragile X, autism, and Rett syndrome. These
reader to get his/her bearings as needed. disorders have so many commonalities that it made
The book makes every effort to cover all the major sense to cover them in a single chapter (Chapter 11).
neurological illnesses that affect the central nervous sys- No contemporary book of nervous system disease
tem though it is far from complete. My intention was would be complete without coverage of neuropsychiat-
to go fairly deep into disease mechanisms and this pre- ric illnesses and I elected to devote one chapter each to
cluded a broader coverage of small and less well-known depression (Chapter 12) and schizophrenia (Chapter 13).
conditions. I found it useful to group the diseases into Finally, for the second edition, I also included pain
five broad categories that provided some logical flow (Chapter 14) and addiction (Chapter 15), two topics that
and progression. Specifically, I begin with static ill- intersect on the pervasive issue of addiction to opioid
nesses, where an acute onset causes immediate disabil- pain killers.
ity that typically does not worsen over time. This group Taken together, I believe the material covers the “big”
is best exemplified by stroke and CNS trauma but also brain disorders that any neuroscientist or medical stu-
includes genetic or acquired epilepsy (Chapters 1–3). I dent should know. However, anyone looking for more
next covered the classical primary progressive neuro- detailed information on rare disorders or disorders pri-
degenerative diseases including Alzheimer, Parkinson, marily affecting the peripheral nervous system or sen-
Huntington, and ALS (Chapters 4–7). For each of these sory organs is referred to some of the excellent neurology
chapters, I added some important related disorders. textbooks that I cite as my major sources throughout the
For example, the chapter on Alzheimer includes frontal book.
temporal dementia; for Parkinson, I included essential To ensure that the material is presented in an acces-
tremors and dystonia, and for Huntington, I touch on sible, yet comprehensive format, the book was devel-
related “repeat disorders” such as spinocerebellar ataxia. oped in a uniquely student-centered way, using my
The chapter that covers ALS includes a variety of dis- target audience as a focus group. To do so, I wrote the
ease along the motor pathway essentially moving from book as accompanying text to an undergraduate course,
diseases affecting the motor neurons themselves (ALS), writing each chapter as I was teaching to neuroscience
their axons (Guillain-Barre syndrome), to the presynap- majors. The first edition was written while on sabbati-
tic (Lambert Eaton myotonia), and postsynaptic (myas- cal leave at Rhodes College in Memphis TN, a small and
thenia gravis) neuromuscular junction. highly selective Liberal Arts college. The second edition
Next, I progressed to neurodegenerative diseases that I wrote at Virginia Tech, where I moved in 2015 to build
are secondary to an insult yet still cause progressive the School of Neuroscience, an entire School devoted to
neuronal death. I call these secondary progressive neu- Neuroscience. Each week, I handed out a new disease
rodegenerative diseases and the examples I am covering chapter, and after giving a 75-min lecture, small groups
include multiple sclerosis, brain tumors, and infections of students had to prepare independent lectures that
(Chapters 8–10). It may be unconventional to call these they delivered to the class based on recent influential
secondary neurodegenerative diseases yet in multiple clinical and basic science papers that I assigned (and
sclerosis, the loss of myelin causes progressive axonal de- list in this book with each chapter). Each week, using a
generation, brain tumors cause neurological symptoms questionnaire, the students provided detailed feedback
by gradually killing neurons, and infection causes pro- on how accessible, interesting, and complete my chap-
gressive illnesses again by progressively killing neurons. ters were, and how well the book prepared them for the
Nervous system infection could have quickly become an assigned papers that they had to present in class. I took
unmanageable topic since far too many pathogens exist their comments very seriously, frequently spending days
that could affect the nervous system. I therefore elected incorporating their suggestions. I am thankful to all of
to discuss important examples for each class of patho- them, as it made the book a better read.
gen (prion proteins, bacteria, fungi, viruses, single- and As I began my research, a challenge that became im-
multicellular parasites). While none of these pathogens mediately evident was the sheer magnitude of the avail-
are brain-specific, I chose examples in which the nervous able literature. Moreover, writing about a disease that
system is primarily affected including meningitis, botu- is outside ones’ personal research specialty leaves one
lism, tetanus, poliomyelitis, neurosyphilis, brain-eating without a compass to decide which facts are important
Introduction xvii
and which are not. Narrowing literature searches to clearly important lessons when teaching neuroscience at
just “diseases” and “review articles” did not help much a Liberal Arts college. Our classes included how patients
and only marginally reduced the number of hits from with epilepsy were labeled witches and burned in me-
the tens of thousands into the thousands. While it was dieval Europe; how the heritability of diseases such as
gratifying to see the enormous amount of information Huntington corrupted even doctors to subscribe to the
that has been published, it was daunting to filter and reprehensible teachings of the eugenics movement; or how
condense this material into a manageable number of the infamous Tuskegee syphilis studies served as the foun-
sources. In the end, I developed a strategy to first iden- dation for the protection of human subjects participating
tify the “opinion leaders” in each field, and then, using in human clinical trials, measures that we take for granted
their high-impact reviews, widen my search to include today. Another lesson learned from the ancient accounts
reviews that appeared to cover the most salient points of Down syndrome is that childbirth late in a mother’s life
on which the entire field appears to largely agree upon, occurred throughout history, but more importantly that
while staying largely out of more tentative emerging and those children were cared for in many societies with the
controversial topics. This was important since the objec- same love and compassion we have for them today.
tive of this textbook was to introduce current accepted The majority of pages in this book are devoted to the
concepts rather than speculations. biology of each disease. It is remarkable how much we
Another challenge I faced was to keep the material know and how far we have come in just the past few
interesting. As teacher of medical neuroscience, I have decades, from the historic disease pathology-focused
long recognized the value of clinical cases. I decided to approach to contemporary considerations of genes and
start each disease chapter with case story, which is either environmental interactions causing disease in suscepti-
an actual case or one close to cases that I have actually ble individuals. It is fascinating to note how cumbersome
witnessed in some form or other. The students liked this the initial positional cloning efforts were that identified
format, particularly since many of the cases I describe the first candidate genes for disease compared to today’s
involve young people. To offer perspective on each dis- large genome-wide association studies that identify large
ease, I also elected to provide a brief historic review for networks of gene and their interactions. Clearly, we expe-
each disease. How long has society been dealing with rience a transformational opportunity to study and un-
stroke, epilepsy, Huntington, or autism? What were early derstand disease through the study of rare genetic forms
interpretations on the disease cause, how was disease of familial diseases that can inform us about general dis-
treated, and what were the most informative milestones? ease mechanisms and allow us to reproduce disease in
This was possibly the hardest section for me to write, genetic animal models. At the same time, it is sobering
since good sources were difficult to find. Yet it was also to see how often findings in the laboratory fail to sub-
the most fascinating. The students initially had little ap- sequently translate into better clinical practice. I devote
preciation for these sections and really did not see much a considerable amount of discussion to such challenges
value in them. However, this changed after we discussed and end each chapter with a personal assessment of chal-
the value of what I call “science forensics” and the his- lenges and opportunities. After completing the disease
toric insight that could be gleaned. We discussed how chapters, it was clear that there were many cross-cutting
the history of disease, when viewed in the context of the shared mechanisms and features of neurological disease
history of mankind, allows us to dismiss or consider hu- that I elected to devote an entire chapter solely to shared
man endeavors and exposure to man-made chemicals as mechanisms of neurological illnesses (Chapter 16).
disease causes. After we discussed how Mexican vases Not surprisingly, almost all the class discussions
made over 600 years ago already depicted children with sooner or later gravitated toward ways to translate re-
Down syndrome, or how Polio crippled children were search findings from the bench to the bedside. Yet few
portrayed on Egyptian stilts that were over 2000 years of the students had any idea what this really entails or
old, it became clear that neither of these conditions was the challenges that clinical trials face. Having been for-
modern at all. Historic accounts similarly suggest that tunate enough to develop an experimental treatment
environmental exposures are unlikely contributors to for brain tumors in my laboratory that I was able to ad-
stroke or epilepsy. Yet, by contrast, the earliest accounts vance from the bench into the clinic through a venture
of Parkinson Disease align perfectly with the early in- capital-supported biotech startup, I felt well equipped to
dustrial revolution of the mid-1800, making industrial discuss many of the challenges in proper perspective. So
pollutants potential disease contributors. Even more ex- I devoted an entire chapter (Chapter 17) to this import-
treme, no historic account for autism exists prior to the ant, albeit not neuroscience-specific, topic. The class in-
1930s. Clearly, for some of those diseases, human influ- cluded important discussions on the placebo effect and
ences must be considered as contributory factors. frank conversations as to why many scientific findings
The historic adventures also allowed me to examine cannot be reproduced, and why most clinical trials ulti-
diseases in the context of society at a given time in h
istory, mately fail.
xviii Introduction
I also added several provocative topics to class dis- Given that the book was developed as an accom-
cussions such as the questionable uses of neuroscience paniment to a college course, I expect that it may en-
in marketing and advertising and the controversial use courage colleagues to offer a similar course at their
of neuroscience in the courtroom. Since neither relates to institution. I certainly hope that this is the case. To
specific neurological diseases, I elected to leave this out facilitate this, I am happy to share PowerPoint slides
of the book but encourage neuroscience teachers to bring of any drawings or figures contained in this book, as
such topics into the classroom as well. well as any of the 1000 + slides that I made to accom-
One thing that troubled me throughout my writing pany this course. I can be contacted by email at hson-
was the way in which sources are credited in textbooks. theimer@gmail.com. Also, for each chapter I am listing
As a scientist, I reflexively place a source citation behind a selection of influential clinical and basic science ar-
every statement I make. In the context of this book, how- ticles that I used in class. These are just my personal
ever, I could only cite a few articles restricting myself recommendations and not endorsements of particular
to ones that I felt were particularly pertinent to a given themes or topics. These papers have generated valu-
statement. A list of general sources that most informed able discussion and augmented the learning provided
me in my reading is included at the end of each chapter. through the book.
I am concerned, however, that I may have gotten a few Finally, as I finish editing the second edition of
facts wrong, and that some of my colleagues will contact this book, in which I incorporated many scientific ad-
me, offended that I ignored one of their findings that they vances and clinical trials occurred since the first pub-
consider ground breaking; or if I mentioned them, that I lication in 2015, I still keep finding more and more
failed to explicitly credit them for their contribution. It articles reporting exciting new scientific discoveries
was a danger that I had to accept, albeit with trepidation that I would have liked to include. However, if I did,
and I hope that any such scientists will accept my pre- this book would never reach the press. It is refreshing
emptive apologies. To mitigate against factual errors, I to see that neuroscience has become one of the hottest
reached out to many colleagues around the country, clin- subjects in colleges and graduate schools and even the
ical scientists whom I consider experts in the respected popular press. Neuroscience research is moving at a
disease, and asked them to review each chapter. I am lightning pace. It is therefore unavoidable that the cov-
indebted to these colleagues, whom I credit with each ered material will only be current for a brief moment
chapter, who selflessly devoted many hours to make this in time, and, as you read this book, that time will have
a better book. Their effort has put me at greater ease and already passed.
hopefully will assure the reader that this book represents
Harald Sontheimer
the current state of knowledge.
S E C T I O N I
1
Cerebrovascular Infarct: Stroke
Harald Sontheimer
O U T L I N E
1 CASE STORY get up and take some ibuprofen. However, getting out
of bed turned into a struggle. She did not sense her right
Natalie was excited to start her senior year at Virginia hand and could not move her right leg. As she rolled to-
Tech. She saved some of the most interesting art his- ward the edge of the bed, her vision blurred. Her eyes
tory and creative writing classes for her last year. She felt like they were pushing out of her head. “Where is
was equally excited to participate one last season in the phone?” She used her left hand to scan her night
Cheerleading for the Hokies football team. She still gets stand one handspan at a time. Once her hand made con-
a rush by the pregame pageantry and a stadium trem- tact with her cell phone, she struggled to recognize the
bling as the players enter the stadium to the roaring screen. She was panicking. Who to call? Amy, her best
sounds of “Enter Sandman.” This Saturday morning, friend should be up by now. After 20 rings, Amy finally
she woke unusually early and was not feeling well at all. answered. “Why up so early? I am sleeping.” “Amy, I
Her head hurt and although she had been partying the can’t move, I am trapped in my bed with a brutal head-
night before, this did not feel like a hangover headache. ache and I can’t see well.” It didn’t take Amy long to
After rolling in pain for a few minutes, she decided to realize that her friend was in serious trouble. Amy had
Diseases of the Nervous System. https://doi.org/10.1016/B978-0-12-821228-8.00001-9 3 Copyright © 2021 Elsevier Inc. All rights reserved.
4 1. Cerebrovascular Infarct: Stroke
been volunteering for the VT Rescue Squad for the past have permanently lost movement of her right body or
2 years and had ran several codes quite similar to this worse, may have died. She was among the 1 out of every
one. But never in a person Natalie’s age! She rushed to 20 patients who were able to benefit from recent medical
Natalie’s apartment while calling VT rescue on her way. advances in stroke management using a combination of
They arrived just a minute apart and the team pried chemical and mechanical clot busters. During her med-
open the door with force only to find Natalie next to her ical follow-up, it was determined that she suffered from
bed crying unconsolably. At this point, she was barely a congenital heart condition, a patent foramen ovale, in
responding to the rescue team. Her right face was droop- which the left and right atria of the heart are connected
ing, and her arm was limb. Realizing that this may be a by a hole. This probably allowed a thrombus from her
stroke, the team called ahead to Louis Gale Hospital to lower legs to find its way into the cerebral circulation
have the emergency room ready. Everything was a blur. rather than being filtered out by passing through the
Natalie was lifted on the gurney and quickly carried to lungs. On the recommendation of her cardiologist,
the ambulance where Amy jumped in next to her, hold- Natalie had heart surgery to close the foramen ovale
ing her friends hand all the way. 3 months after her stroke. This should lower her risk for
The 6-min drive seemed like ages, and by the time stroke recurrence to that of the general population.
they arrived, Natalie was no longer responding to Amy
calling her name. Without delay, Natalie was moved
to the imaging center for a CT scan. Low and behold, 2 HISTORY
Natalie had near complete loss of blood flow in her left
brain, particularly the central part. Ischemic stroke is Without recognizing its underlying cause, Hippocrates
most likely caused by an embolus or thrombus in the (460 BC), the “father of medicine,” provided the first
middle cerebral artery. This occludes blood flow to the clinical report of a person being struck by sudden paral-
most important parts of the brain controlling sensation ysis, a condition he called apoplexy. This Greek word,
and movement of the right body as well as speech and meaning “striking away,” refers to a sudden loss of
language. “Who has last seen her responsive?” asked the the ability to feel and move parts of the body and was
emergency room physician. Thankfully Amy was there widely adopted as a medical term until it was replaced
to describe the events this morning. “How long ago did by cerebrovascular disease at the beginning of the 20th
she call you?” “About 50 minutes ago,” Amy answered. century. Most patients and the general public prefer the
As imaging has ruled out a hemorrhage, and Natalie’s term stroke, which first appeared in the English language
blood pressure was 123/78, the emergency team de- in 1599. It conveys the sudden onset of a seemingly ran-
cided to deliver a bolus injection of tPA, a clot-busting dom event.
chemical, and hooked her up to a continuous infusion Hippocrates explained apoplexy using his humoral
to deliver more of the drug. The next hour, however, theory, according to which the composition and work-
did not yield any improvement and a subsequent CT ings of the body are based on four distinct bodily fluids
scan showed little change. “Get her to Roanoke for sur- (black bile, yellow bile, phlegm, and blood), which de-
gical thrombectomy,” ordered the attending neurolo- termine a person’s temperament and health. Diseases
gist, “and use the helicopter to get there fast.” Less than result from an imbalance in these four humors, with ap-
30 min later, Natalie arrived on the helipad of Roanoke oplexy specifically affecting the flow of humors to the
Memorial Hospital and was greeted by a medical team brain. Humors were rebalanced through purging and
that would take her to the angio suite where the radiol- bloodletting, which became the treatment of choice for
ogist threaded a catheter up her femoral vein toward stroke throughout the middle ages. The first scientific ev-
the head and into the MCA. Once he navigated to the idence that a disruption of blood flow to the brain causes
blocked artery, he actuated a small mesh that encap- stroke came through a series of autopsies conducted by
sulated the thrombus and slowly began to pull back. Jakob Wepfer in the mid-1600s, yet the humoral theory
Within no time, blood flow returned, and Natalie started of Hippocratic medicine ruled until the German physi-
talking. Almost miraculously, she was able to move her cian Rudolf Virchow discredited it in his “Theories on
right arm and her speech, while still slurred, was intelli- Cellular Pathology,” published in 1858. Virchow, who
gible. Two hours later, Natalie was talking to Amy in the made countless impactful contributions to medicine,
recovery room, and she was seriously considering going was the first to explain that blood clots forming in the
to the football game that evening. While that obviously pulmonary artery can cause vascular thrombosis, and
did not happen, Natalie was back home 2 days later on fragments arising from these thrombi can enter the cir-
a prescription of warfarin, a blood thinning medication. culation as emboli. These emboli are carried along with
Had it not been for Amy quickly recognizing her friend’s blood into remote blood vessels, where they can occlude
condition and the proximity to a level one trauma cen- blood flow or rupture vessels. His theory was initially
ter with a skilled interventional radiologist, Natalie may based only on patient autopsies. However, together with
F = FACE Ask the person to smile. Does one side of the face
droop?
A = ARMS Ask the person to raise both arms. Does one arm
drift downward?
FIGURE 3 Color-coded annual stroke deaths by region show an elevated incidence in the Southern United States, a region often dubbed the
“stroke belt.” Stroke death rate for adults over 35 and including all races and all genders for the time period 2008–2010. Produced with data from
Centers for Disease Control and Prevention, Atlanta, GA, USA.
to the average age of the population as age-adjusted Of greatest importance is the extrusion of Na+ and the
stroke incidence is identical around the globe. import of K+ through Na+/K+ ATPase. This pump not
only establishes the inward gradient for Na+ needed to
generate an electrical impulse or action potential but also
4 DISEASE MECHANISM/CAUSE/BASIC maintains a negative resting membrane potential that
SCIENCE neurons assume between action potentials. Moreover, the
electrochemical gradient for Na+ is harnessed to transport
Stroke is conceptually a simple disease wherein the glucose and amino acids across the membrane and to reg-
brain’s “plumbing” is defective. We have a fairly good ulate intracellular pH. Therefore, these transport systems
understanding of causes and remedies. In its most ele- are indirectly coupled to the ATP used by the Na+/K+
mentary form, a stroke is the direct result of inadequate ATPase. Additional important consumers of cellular ATP
blood flow to a region of the brain, with ensuing death are Ca2 +-ATPases that transport Ca2 + against a steep con-
of neurons as a consequence of energy loss. To fully ap- centration gradient either out of the cell or into organelles.
preciate the vulnerability of the brain to transient or per- Intracellular Ca2 + is maintained around 100 nM, which is
manent loss of blood flow, it is important to discuss the 10,000-fold lower than the 1 mM concentration of Ca2 + in
unique energy requirements of the brain and the cerebral the extracellular space. Ca2 + functions as a second mes-
vasculature that delivers this energy. senger in only a very narrow concentration range of 100–
The brain is the organ that uses the largest amount of 1000 nM and therefore must be carefully regulated by the
energy in our body. At only 2% of body mass, an adult Ca2 +-ATPases. Any increase above this range activates
brain uses 20% of total energy, whereas a child’s brain enzymes and signaling cascades that are largely destruc-
uses as much as 40%. The cellular energy unit is adenos- tive (discussed in more detail later in this chapter). Finally,
ine triphosphate (ATP), the majority of which is produced ATP serves as an important source for high-energy phos-
by the oxidative metabolism of glucose to carbon diox- phates that can attach to proteins and enzymes through
ide (CO2) and water. To supply sufficient ATP, an adult phosphatases that act as on/off switches to regulate the
brain requires 150 g glucose and 72 L of oxygen per day. activity of these proteins and enzymes.
While the developing brain still uses a significant amount ATP stores in neurons are exhausted after only 120 s.
of energy for the biosynthesis of cellular constituents, par- Therefore, neurons must continuously produce ATP from
ticularly myelin, the adult brain has very little synthetic ac- glucose via oxidative metabolism of glucose in the mi-
tivity because few cells and membranes are ever replaced. tochondria. Glucose is the most readily available energy
Thus, the vast majority of energy is used to shuttle ions source throughout the body, and most cells can store some
across the cell membrane to establish and maintain ionic readily available glucose in the form of glycogen gran-
gradients necessary for electrical signaling (Figure 4). ules. These glycogen granules are a polysaccharide of glu-
cose that can be quickly converted back to glucose when
needed for energy. Unfortunately, neurons do not contain
glycogen stores and therefore rely on a constant, uninter-
rupted supply of glucose from the blood. From an evolu-
tionary point of view, the cellular space saved by giving up
energy stores allows the important benefit of an increased
number of nerve cells packed into a finite cranial space.
To meet its high-energy demands, it is also essential
that the brain metabolizes all glucose in the most ef-
fective way possible, by oxidative metabolism, which
yields 36 mol ATP/mol glucose. This far exceeds the an-
aerobic glycolytic production of ATP, which only yields
2 mol ATP/mol glucose. Unlike most other cells in the
body, neurons are not able to switch to glycolysis in the
absence of oxygen, necessitating a constant delivery of
sufficient oxygen. The convergence of high-energy de-
mand, the absence of glycogen stores, and exclusively
aerobic metabolism makes the brain uniquely vulnerable
to injury in situations where glucose or oxygen supply is
disrupted. Rare conditions limit only one of these sub-
FIGURE 4 Cellular energy use of neurons in the brain. Adenosine
triphosphate (ATP) produced in the mitochondria directly fuels ATP- strates. For example, hypoglycemia may occur in a dia-
driven pumps such as the Na+ K+ ATPase and the Ca2 +-ATPases and betic patient who receives an excess amount of insulin,
indirectly provides the energy for Na+-coupled transporters. and anoxia can occur in a patient in a near-drowning
FIGURE 12 The ischemic cascade and pathways activated as a result. Initiated by energy failure, (1) presynaptic release of glutamate aber-
rantly activates N-methyl-d-aspartate receptors (NMDA-Rs). (2) The uncontrolled influx of Ca2 + and Na+ as a result of NMDA-R activation causes
(3) cell swelling, (4) activation of destructive enzymes, (5) mitochondrial damage, and the generation of reactive oxygen species (ROS). These
processes culminate in (6) DNA damage and (7) membrane damage during apoptosis. This may cause (8) microglial activation and (9) leukocyte
recruitment from the peripheral blood. Drawing by Emily Thompson, PhD.
4 Disease mechanism/cause/basic science 13
FIGURE 15 N-Methyl-d-aspartate receptor (NMDA-R) as mediator of excitotoxicity and target for therapeutic drugs. Permeation of Ca2 + via
NMDA-Rs (left) causes activation of the mitogen-activated protein kinase (MAPK) cascade as well as release of cytochrome c from the mitochon-
dria, each culminating in apoptotic cell death. The NMDA-R harbors many regulatory sites that can be exploited for therapy (right), including sites
for the drugs memantine and MK-801 as well as the coagonist sites for Zn2 + and glycine (Gly). Reproduced with permission from Ref. 8.
4.4 The NMDA Receptor and Glutamate gates for Ca2 + to enter unimpeded through this recep-
Excitotoxicity tor. Hence, the very protein that is so critical in allowing
for human learning can also make us vulnerable to cell
The NMDA receptor (NMDA-R) is a Glu-gated cation death by excitotoxicity following a stroke.
channel that is a member of the ionotropic Glu receptor The concept of Glu excitotoxicity was originally intro-
family. Like the other family members, it is a heteromeric duced by Olney in the 1960s and has been extensively
channel composed of four subunits, namely, two GluN1 studied since. Excitotoxicity appears to be the final com-
and two GluN2 subunits. The GluN2 subunit comes in mon death pathway in numerous disorders, including
four isoforms named GluRN2A–D. The channel is gated many neurodegenerative diseases. The precipitating
by the binding of Glu, but it requires a modulatory site cause of the chronic depolarization of the neuronal
to be occupied by glycine. The channel distinguishes it- membrane may differ in each case, yet the principal
self from all other Glu receptors by its multiple modula- involvement of the NMDA-R as an influx pathway for
tory sites. In addition to the glycine site, which can bind Ca2 + is shared.
d-serine instead of glycine, there are sites for modula- While NMDA-R plays the most important role in isch-
tion via nitric oxide, H+, and phencyclidine. The chan- emic neuronal death, other family members participate or
nel is the target of several anesthetic drugs, including can substitute. The depolarization that occurs as a result of
ketamine and phencyclidine (“Angel Dust”), which are activation of AMPA or kainate-type Glu receptor depolar-
often used as recreational hallucinogenic drugs. Other izes the postsynaptic cell, thereby allowing Ca2 + to enter
common agonists of differing potency include ethanol, via voltage-gated Ca2 + channels. Furthermore, at least one
memantine, dextrorphan, and methadone. variety of the AMPA receptor is also permeable to Ca2 +.
The feature that is of greatest relevance for stroke
is the unique gating of the channel by voltage and
intracellular Mg2 +. Normal, fast, excitatory synap- 4.5 Role of Glutamate
tic transmission occurs via the β-amino-3-hydroxy-
5-methyl-4- isoxazolepropionic acid (AMPA) and While Olney suspected Glu as a major toxin in disease,
kainate-type Glu receptors. These too are cation-
showing its contribution to stroke in animals and humans
permeable, ionotropic Glu receptors that open in re- suffering a stroke was necessary. Early studies measured
sponse to Glu. NMDA-Rs, in contrast to AMPA-Rs, are Glu directly by microdialysis, a technique through which
normally not available for activation by Glu because, at the extracellular milieu in the brain can be sampled con-
the resting potential of the postsynaptic membrane, a tinuously and with high accuracy. They demonstrated
Mg2 + ion is lodged in the pore of the channel, preventing that occlusion of the middle cerebral artery (MCA) causes
it from allowing ions to permeate. This Mg2 + binding is a 60- to 100-fold increase in Glu within a relatively short
dependent on voltage, and with depolarization of the time. The increase extends to the ischemic penumbra and
membrane, Mg2 + is released from the pore. Under nor- even affects the composition of the cerebrospinal fluid
mal physiological conditions, Mg2 + keeps the NMDA-R (CSF) bathing the brain. CSF can be examined by lumbar
closed at all times. Should the postsynaptic terminal be puncture in patients in whom microdialysis would rarely
depolarized, however, the Mg2 + ion pops out, causing be feasible unless the patient underwent surgery. Glu in
cations to flux through NMDA-Rs. While the vast ma- the CSF rises eightfold in stroke patients and has been
jority of the current is carried by Na+, which is the most suggested to have predictive value for disease severity.9 It
abundant extracellular cation, the NMDA pore is five- is important to note that persistent increases in Glu, such
fold more permeable to Ca2 + than to Na+. As a conse- as that measured after a stroke, require the neuroprotec-
quence, a considerable amount of Ca2 + fluxes through tive uptake of Glu by astrocytes to fail, suggesting that
the NMDA-R. This Ca2 + influx plays an important role astrocyte impairments in the penumbra contribute to the
during learning and memory, allowing the NMDA-R to progression of disease.
function as a coincidence detector. As more extensively
discussed in Box 1, Chapter 4, only if multiple signals 4.6 NMDA Inhibitors to Treat Stroke
arrive on the same terminal within 50 ms of each other
is the Mg2 + removed. Removal of the Mg2 + ion causes Having identified the role of the NMDA-R in stroke,
Ca2 + influx, thereby signaling the cell of the coincident examining the many modulatory sites of this receptor
occurrence of two events. This is believed to be an essen- and how they may be exploited therapeutically is worth-
tial component of learning and memory. In the situation while. In principle, blocking NMDA-R ameliorates
of a stroke, the coincident activation is bypassed by the neuronal death. However, it also impairs most higher
chronic, long-lasting depolarization of the postsynap- cognitive function. This is exemplified by ketamine,
tic membrane due to energy failure. This energy failure used as a powerful anesthetic, or by phencyclidine, a
permanently removes the Mg2 + block, opening the flood potent, mind-altering substance, both of which have
been associated with cognitive impairment. The ideal This is indeed observed in rats after MCA occlusion,
drug would therefore block only those NMDA-Rs that where the development of an infarct can be significantly
experience a pathophysiological depolarization by cata- reduced by hypothermia10 (Figure 16). Interestingly,
strophic increases in Glu, while sparing those receptors some of the early neuroprotective trials using rats and the
exposed to physiological concentrations. Such drugs ac- NMDA antagonist MK-801 that led to the development
tually exist and are, generally speaking, poor NMDA an- of many other NMDA antagonists for use in stroke are
tagonists. One of these, memantine, is an open-channel now being reinterpreted after it was found that MK-801
blocker that inhibits NMDA channels poorly under lowers the brain temperature by about 2 degrees. Hence,
physiological conditions but becomes more effective as the neuroprotective effect seen with MK-801 may have
Glu concentrations increase. Memantine has been used been partially attributable to the hypothermia rather
in experimental clinical trials for amyotrophic lateral than just the blockage of NMDA-Rs. A correlation with
sclerosis and dementia. It is very effective in animal fever and poor stroke outcome was reported as early as
models of stroke, where it almost completely protects the 18th century,10 and clinical studies now conclusively
the brain after MCA occlusion; it is currently being eval- show that even slightly elevated temperature after an
uated in a placebo-controlled Phase 1 trial (www.clini- acute stroke leads to a much worse outcome and is as-
caltrials.gov, identifier NCT02144584). There is hope that sociated with significantly higher risk of death.12 From
other open-channel NMDA blockers may be developed a mechanistic point of view, it is interesting that clinical
for future use in the clinical treatment of stroke. studies have also shown a twofold increase in Glu in the
CSF of ischemic stroke patients who had elevated body
temperature. Moreover, clinical studies of stroke patients
4.7 Effect of Temperature showed that a stroke per se can cause a local increase in
Most biological processes are dependent on tempera- brain temperature, suggesting active brain inflamma-
ture. In the brain, ion transport via the various ATPases tion in the ischemic penumbra. These findings provide
changes two- to threefold with every 10 °C change in ample reasons to consider lowering brain temperature
temperature. Because the ischemic cascade is driven by in patients with a stroke to improve outcome as further
a loss of function of these ATPases, one would expect discussed. At a minimum, one must control fever when
that increases in temperature would accelerate damage, present in stroke patients using drugs such as acetamin-
whereas lowering temperature would slow the injury. ophen or ibuprofen.
FIGURE 16 Effect of hypothermia on stroke volume after middle cerebral arterial occlusion in a rat. Reduction in temperature to 32 °C
greatly reduces the size of the ischemic lesion with no further benefit when reduced to 27 °C. Tissue damage is indicated by more intense colors.
Normothermic (37 °C) animals show a large consistent cortical and subcortical infarct at multiple coronal levels. Both intraischemic and postisch-
emic hypothermia to 32 °C are associated with marked reductions in the frequency of cortical infarction. intra, intraischemic; post, postischemic.
Reproduced with permission from Ref. 11.
4.8 Stroke Genetics inclusion criteria are met.14 Most important of these is
the time that has elapsed since the stroke. Typically,
Stroke is not a genetic disease in the strictest sense. treatment with tPA must begin within 4.5 h from the be-
We do not yet have evidence for single or multiple genes ginning of stroke symptoms. If the time of the event can-
that, when inherited, are sufficient to cause stroke, as is not be conclusively determined, tPA treatment cannot be
the case in Alzheimer or Parkinson Disease. However, given. Unfortunately, this is often the case particularly if
a number of individual stroke risk factors are heritable, the stroke occurred at night and the victim is not found
including hypercholesterolemia, atherosclerosis, diabe- until the next morning. If no one witnessed the attack,
tes, heart disease, and therefore can “run in families.” It the last time the patient was seen in a normal condition
is therefore reasonable to expect that conglomerations of will be used as a substitute.
genes can be identified that together increase the risk of Once in the hospital, a number of additional tests
stroke. A genome-wide search of human stroke patients must be completed for a patient to be eligible all within
suggests that up to 38% of stroke cases show some herita- this 4.5-h time window. These include a noncontrast CT
bility.13 However, this information does not yet allow us to scan of the head to rule out hemorrhage and a blood glu-
determine a risk factor based on genetic analysis for any cose test through finger-stick to rule out hypoglycemia.
individual. Note that the field of complex genetics is still Other factors, such as recent surgery, a history of head
in its infancy as only recently large patient datasets be- trauma or stroke, or high blood pressure (> 185 mmHg
came available along with the computing power to study systolic), would rule out tPA use as well. As a result of
genome-wide trait associations in such large patient co- these stringent criteria, fewer than 5% of stroke patients
horts. Hence, there is hope that ultimately a genetic test are eligible to receive tPA. Following the outcome of two
may be developed that will compute a relative stroke risk large phase III clinical studies conducted by the National
and may even identify the stroke subtype of greatest risk. Institute of Neurological Disorders and Stroke,15 tPA is
administered at 0.9 mg/kg, with 10% injected as a sin-
gle bolus and the remaining dose administered through
5 TREATMENT/STANDARD OF CARE/ continuous infusion over the next 60 min. During this
CLINICAL MANAGEMENT infusion period, the patient is monitored for any signs
of intracerebral hemorrhage, determined by neurologi-
From the previous discussion on mechanisms under- cal signs such as headache, nausea, or vomiting. These
lying stroke injury, it is clear that the greatest therapeutic signs would be cause for immediate termination of tPA
benefit can be achieved by rapid reperfusion of the in- infusion. The largest risk associated with tPA is intracra-
farcted brain, particularly to rescue the ischemic penum- nial hemorrhage, which occurs in 6–7% of cases and car-
bra that is at high risk of tissue destruction. In principle, ries a very high mortality of 45%.15 Data reported in the
there are two approaches to removing the obstructive original clinical study suggest that patients treated with
embolus or thrombus: (1) chemical dissolution using tPA, tPA within 3 h were at least 30% more likely to have mini-
or (2) mechanical retrieval using endovascular thrombec- mal or no disability 3 months after treatment. Additional
tomy with a wire-guided retrieval device. In either case, studies have since explored the use of tPA for up to 4.5 h
time is of the essence, and immediate admission to the after the incident and report smaller but still significant
hospital is required to achieve a maximum therapeutic improvements of outcome with an acceptable increase in
benefit. Once admitted to the emergency room, the clinical risk. Based on these findings tPA is now approved for up
team must work expeditiously to determine the course of to 4.5h after an infarct.16
action deemed most beneficial. During the initial evalua- A fascinating vignette from the original tPA study is
tion, the decision tree in Figure 1 is followed to categorize the “Lazarus effect” (named after the miraculous res-
the underlying event as either ischemic or hemorrhagic as urrection of Lazarus 4 days after his death). Of patients
the latter excludes both mechanical and chemical recanal- treated with tPA, 20% showed a dramatic, indeed almost
ization. This is best accomplished in a specialized Stroke miraculous, improvement 24 h after treatment. Such a
Center that has optimized the work flow. Not surprisingly, phenomenon has been previously reported following
stroke centers often achieve better clinical outcomes. cardiac arrest, where spontaneous, unexplained reperfu-
sion of the heart occurred in some patients after resusci-
5.1 Chemical Thrombolysis Using tation efforts were suspended.
A newer thrombolytic agent with similar mechanism
Intravenous tPA
of action, Tenecteplase, was recently introduced as alter-
The only US Food and Drug Administration-approved native to Alteplase. It has the advantage of being admin-
drug for chemically opening vessels is the recombinant istered as a single injected dose. In clinical studies, it was
human plasminogen activator (alteplase/activase). Its found to be equally effective and showed a similar safety
use is now considered standard of care provided certain profile and hence may be a more convenient alternative.
5.2 Mechanical Thrombolysis by Endovascular functionally independent 90 days after treatment com-
Therapy for Ischemic Stroke pared to 35% that received only tPA. Not surprisingly,
the greatest benefits were achieved in patients in which
Microcatheters have long been used to place stents brain images suggested the presence of a salvageable
into cardiac blood vessels. These devices are small penumbra. Indeed, in patients in which the clinical defi-
enough to be inserted into cerebral arteries as well and cit was larger than would be expected based on imag-
have been refined into sophisticated clot dissolution ing data, mechanical thrombectomy administered up to
and retrieval devices. In their simplest form, repeated 24 h after the stroke, still achieved functional indepen-
passage of a wire through a thrombus helps to disinte- dence in 49% of patients compared to 13% receiving
grate it mechanically. In a more advanced form, these standard of care.19 Taken together, these clinical studies
devices contain a soft silicon balloon that can be ex-
panded to open a collapsed artery or a wire mesh to
retrieve an embolus and restore blood flow. This ap-
proach is particularly promising for opening larger ar-
teries such as the MCA or ICA. Successful opening of an
artery and placement of a stent is shown in Figure 17,
with Figure 18 illustrating balloon angioplasty and
stent placement.
In 2015, five large, multicenter clinical studies con-
ducted in different parts of the world independently
explored whether the combined use of mechanical and
chemical thrombectomy may be superior to tPA treat-
ment alone. All used a wire-guided retrieval device
called a stent retriever. It is threaded through an artery
in the groin up to the blockage where the stent opens
and retrieves the clot. The five studies differed slightly
regarding the relative timing of tPA versus mechanical
retrieval. All five studies reported that combined chem-
ical and mechanical thrombectomy is far superior than FIGURE 18 Schematic depiction of mechanical recanalization us-
tPA alone.18 Up to 100% brain reperfusion was achieved ing balloon angioplasty with placement of a stent. Illustration by Emily
24 h after combined treatment, and 60% of patients were Thompson, PhD.
FIGURE 17 Successful recanalization of the anterior cerebral artery (ACA) and middle carotid artery (MCA) by balloon angioplasty: (left)
before and (right) after angioplasty and placement of a stent. (A) Left internal carotid artery cerebral angiography demonstrates severe stenoses
of the ACA and MCA, which are confluent at the carotid terminus. (B) After angioplasty alone of the ACA and stent-assisted angioplasty of the
MCA, there is normal caliber of the previously stenosed ACA and MCA. Arrows denote the proximal and distal ends of the stent. Reproduced with
permission from Ref. 17.
c alculated in disability adjusted life years (DALYs). Poor invested billions of dollars into translating these find-
diet and sedentary lifestyle habits are also the major con- ings into clinically useful neuroprotective drugs, and
tributors to hypertension. Globally, the second-leading some representative drugs that were tested clinically are
preventable risk factor is exposure to smoke, in the form of listed in Table 3. In total, 114 neuroprotective drugs were
air pollution, smoke from cigarettes, or household fuels. tested in humans and failed. In the following, we review
These account for 33% of productivity loss. Another some of these trials and provide a critical discussion of
significant global risk factor is consumption of alcohol. why they might have failed. In addition, we look at alter-
While tobacco use contributes equally to stroke burden native strategies that are showing clinical promise.
in low- and high-income countries, alcohol consump-
tion contributes twice as much to stroke burden in high-
income countries compared to low-income countries. 6.1 Neuroprotection
Given the prominent role of NMDA-R-mediated Ca2 +
entry, numerous modulators of the NMDA-R have been
6 EXPERIMENTAL APPROACHES/ studied in humans. For example, dextrorphan is a non-
CLINICAL TRIALS competitive NMDA antagonist that unfortunately causes
unacceptable side effects, including hallucinations and se-
Following a period of intense study of neuronal rious hypotension, which limited its use. The competitive
cell death throughout the 1960–1990s which identi- NMDA-R antagonist, Selfotel, increased rather than de-
fied several core pathways involved in ischemic injury, creased mortality, and consequently trials were halted.
tremendous enthusiasm ensued with not only hope
To limit the hallucinogenic side effects experienced
but also conviction that effective neuroprotective drugs with NMDA antagonists, a new drug called GV150526
were just around the corner. Indeed, during the period was designed. It acts on the modulatory glycine site on
of 1960–1980, basic researchers published 1026 different the NMDA-R. This drug was safe and well tolerated in
experimental treatments for stroke.25 Drug companies 1367 patients but failed to show clinical improvements.
TABLE 3 Experimental neuroprotective strategies that are the subject of clinical trials.
Proposed neuroprotection Drug Mechanism of action Results
Potassium channel activator Maxipost (BMS-204352) Activates KCNQ “M-channels” Complete/no benefit
Free radical scavengers Recombinant neutrophil lr Blocks interaction between Complete/no benefit
neutrophils (white blood cells)
and fibrinogen
Intracellular Mg2 + blocks Ca2 + influx via NMDA-R an ambulance, and even in the emergency room, are not
and in theory would be a great modulator. This provided trivial. For this reason, researchers have been exploring
the rationale for a large multicenter study examining other strategies. Some drugs, for example, the Parkinson’s
intravenous Mg2 + given as magnesium sulfate to 2589 drug Talipexole, cause a reduction of body temperature as
patients 12 h after an acute stroke. Unfortunately, those a side effect. These presumably act on dopamine receptors
receiving treatment did not show improvement over the that are involved in temperature regulation in the hypo-
placebo group. A follow-up trial evaluated prehospital thalamus. Researchers are now exploring ways to harness
administration of Mg2 + given within less than 2 h in this side effect to therapeutically reduce body and brain
1500 patients. While it was safe, it also did not improve temperature in an effort to confer similar neuroprotection
disability outcome at 90 days. to that observed by physically cooling the body or blood
Targeting the AMPA receptor may be beneficial by flow through the carotid arteries.27
limiting the depolarization of the postsynaptic mem-
brane following a stroke. The AMPA receptor antagonist
YM-872 was safe in patients, but no benefits were de-
6.3 Improved clot busters
tected in a placebo-controlled phase II study. Recombinant tPA remains the only approved chemical
Given the role of Ca2 + channels in synaptic Glu re- agent to recanalize vessels, and having second-generation
lease as well as postsynaptic entry of Ca2 + during the drugs with enhanced ability to do so is desirable. Not
ischemic cascade, Ca2 + channel blockers have been eval- surprisingly, there are a number of candidates at vari-
uated in numerous clinical studies, but, disappointingly, ous stages of clinical testing. Some have an improved
none of these have shown efficacy. half-life; others promise to offer faster and more com-
Yet another attractive strategy that emerged from our un- plete clot-busting activity.
derstanding of the ischemic cascade was reducing oxidative An interesting experimental approach aimed at im-
damage. The free radical trapping reagent NXY-059 was proving outcome is the combination of tPA with tran-
studied in a phase III study that enrolled 1722 patients with scranial ultrasound. The ultrasound mechanically
acute stroke. While it initially provided promising results, assists in the disintegration of the clot, which is chemi-
a follow-up clinical trial failed to reproduce these findings. cally weakened by tPA. This approach, called “clotbust,”
showed dramatic results, with 49% of patients achieving
complete recanalization.28 A further refinement of this
6.2 Hypothermia approach involves nanobubbles that are infused into the
We have already discussed the effect of temperature on bloodstream. These bubbles adhere to the clot surface
tissue damage after stroke, particularly the importance of and are activated to burst through ultrasound energy.
avoiding elevated temperature, and clinical studies clearly Because they burst like small microexplosions, they help
establish that increased body and/or brain temperatures to mechanically degrade the clot.
cause significantly worse outcome.10, 12 Together with
promising studies in animal models (Figure 16), a strong
6.4 Brain Rewiring after Stroke
rationale to explore the therapeutic benefit of hypother-
mia in stroke exists. The key idea behind hypothermia The effectiveness of physical therapy after stroke to
treatment is to slow the rate of tissue decline and extend regain function is undisputed. Indeed, it is among the
the therapeutic time window for treatment. Ideally, a pa- best therapies we currently have. Unfortunately, follow-
tient suffering from a stroke would be cooled very quickly ing a stroke, a significant number of neurons are com-
until they reach a hospital. To do so, the whole body can pletely lost. For example, the hemiparesis that is typical
be cooled using cold blankets, ice packs, and the like. after an MCA occlusion is due to the loss of neurons in
However, a number of more sophisticated cooling de- the motor cortex. These upper motor neurons send ax-
vices have been developed, including catheters inserted ons through the corticospinal tract to innervate the lower
into the inferior vena cava to cool the blood in circula- motor neurons in the spinal cord that control movement
tion. Prior feasibility studies have been conducted only in of our limbs. These pathways wire during development
patients beyond the time limit to receive tPA treatment; in an activity-dependent manner. Yet once they are es-
these studies showed that hypothermia was a safe proce- tablished, and their axons are myelinated, their ability to
dure with only minimal side effects.26 A follow-up phase sprout and form new connections is lost.
II study (COOLIST: NTR2616) enrolled 22 patients who In Chapter 2, we extensively discuss environmental
were within 4.5 h after an ischemic stroke to be surface factors that the axons encounter, including a nonper-
cooled to 34 °C, 34.5 °C, and 35 °C for 24 h. Results were missive extracellular matrix laid down by reactive as-
disappointing and failed to show evidence for neurologi- trocytes and Nogo-A, a protein present on the surface
cal improvement, and 8 patients suffered pneumonia. The of myelin in the CNS that paralyzes the growing tips
logistical challenges of widely administering cooling in of axons. Following decades of research on the role of
Nogo-A in preventing adult plasticity in the central ume, not by neurological or cognitive status, with little
nervous system, the discoverer of this molecule, Martin long-term follow-up. By comparison, patients enrolled
Schwab and his colleagues, questioned whether its re- in stroke studies tend to be old and have a host of health
moval may allow the brain to sprout new connections conditions ranging from heart disease to atherosclerosis.
after a stroke.29 They used a rat model of MCA occlusion, The arterial obstructions vary greatly in size and region,
which led to the loss of corticospinal axons and resulted and the delay until treatment ranges from a few hours to
in forelimb paralysis in the rats. Following vessel block- many days after the insult. A patient’s response to treat-
ade, they infused antibodies to Nogo-A into the affected ment is not measured by infarct size but by behavioral
motor cortex. Two weeks later, they began a forced outcomes that are assessed 3–6 months later. Clearly, the
exercise regimen to move the paralyzed limb. Within preclinical studies of rodents do not adequately model
weeks, the animals regained almost complete control of the human condition.
the previously paralyzed limb on the contralateral side Second, most clinical studies conducted to date were
of the body. Histological analysis showed that the ani- statistically underpowered to detect the effect size they
mals had sprouted axons from the corticospinal tract of attempted to measure. In other words, they never en-
the uninjured side of the spinal cord to the injured side. rolled a sufficient number of patients to show a signif-
As a result, the remaining functional motor cortex was icant improvement.31 As an example, showing a 5%
now controlling both sides of the body rather than just reduction in patient deaths or disability 6 months after
the contralateral one. This remarkable finding suggests a stroke with typical 80% power requires enrollment of
that there is tremendous adult plasticity and a potential 3148 patients. Only 2% of all clinical trials conducted
to enhance therapy in stroke patients by combining it were appropriately powered to show this 5% clinical
with Nogo-A antibodies. Of note, clinical use of such benefit.
antibodies has been shown to be safe in a recent clini- Third, a review of the 1026 drugs that showed ther-
cal study in spinal cord injury (www.clinicaltrials.gov, apeutic benefit in preclinical studies25 concluded that
identifier NCT00406016), hence clinical evaluation in the 114 drugs that were selected for use in patients were
stroke patients is likely to begin soon. not any more effective than the 912 drugs that were not
used. The rationale for selecting the drugs that were ad-
vanced to the clinic is therefore unclear.
6.5 Why Have so Many Promising Drugs Failed Based on this sober assessment, several changes are
in Human Clinical Trials? required. Foremost, making studies using animal mod-
Between 1955 and 2000, 178 stroke trials enrolled a els more relevant to human disease and measuring simi-
total of 73,949 patients. Of these, 88 trials pursued neu- lar behavioral outcomes at different times after the insult
roprotective strategies, 59 pursued antithrombotic ap- are imperative. Also, consideration should be given
proaches, and 26 used a combination of the two. These to conducting trials using rodents that are not in good
trials were based on solid preclinical evidence typically health but mimic the fragility of the human stroke popu-
obtained using established and validated rodent models lation. We must ensure that clinical trials have the statis-
of stroke. A partial list of the drugs and their presumed tical power to be able to detect the subtle improvements
targets is listed in Table 3. Not one of the 88 neuroprotec- they set out to find. If we do trials, we must do them
tive trials had a positive outcome, and only two drugs right! Moreover, the notion that a single reagent is suffi-
emerged from the revascularization trials, namely, tPA cient to treat a complex disorder must be abandoned and
and aspirin. replaced with polytherapy that combines drugs with
How can this be explained? Is there any reason to pur- different mechanisms of action, possibly administered at
sue this any further? A careful analysis of both clinical different stages of disease. The combination of early tPA
trials conducted during the past 40 years30 and the pre- with mechanical thrombectomy, followed by an NMDA
clinical data on which they were based31 provides some inhibitor such as dextrorphan, with a caspase inhibitor
important lessons. such as ZVAD-fmk to limit neuronal cell death may be
First, the vast majority of preclinical studies are done an example.
on healthy, young adult mice or rats, which do not suf-
fer from diabetes, heart disease, or hypertension. They
neither smoke nor drink and have little genetic predis- 7 CHALLENGES AND OPPORTUNITIES
position to disease. Each receives an identical vascular
insult to induce a stroke, most commonly ligation of the During human evolution, some vulnerabilities were
MCA. Treatment is administered quickly, within 30 min accepted to meet the demand of packaging an increas-
to a few hours at most, and each subject is treated at the ing number of neurons into the cranial space. Wasteful
same time after the insult. The effectiveness of treatment glycolytic generation of ATP and energy storage in the
is then measured by the relative decrease in infarct vol- form of glycogen were abandoned, making neurons re-
21. Wolf SL, et al. The EXCITE stroke trial: comparing early 2. Nogueira RG, et al. Thrombectomy 6 to 24 hours after stroke with a
and delayed constraint-induced movement therapy. Stroke. mismatch between deficit and infarct. N Engl J Med. 2018;378:11–21.
2010;41:2309–2315. 3. Wolf SL, et al. The EXCITE stroke trial: comparing early
22. Raber I, et al. The rise and fall of aspirin in the primary prevention and delayed constraint-induced movement therapy. Stroke.
of cardiovascular disease. Lancet. 2019;393:2155–2167. 2010;41(10):2309–2315.
23. Pandian JD, et al. Prevention of stroke: a global perspective. Lancet. 4. Lee HK, et al. Natural allelic variation of the IL-21 receptor mod-
2018;392:1269–1278. ulates ischemic stroke infarct volume. J Clin Invest. 2016;126:2827–
24. Feigin VL, et al. Update on the global burden of ischemic 2838. https://doi.org/10.1172/jci84491.
and hemorrhagic stroke in 1990-2013: the GBD 2013 study. 5. Campbell BC, et al. Endovascular therapy for ischemic stroke with
Neuroepidemiology. 2015;45:161–176. perfusion-imaging selection. N Engl J Med. 2015;372:1009–1018.
25. O'Collins VE, et al. 1,026 Experimental treatments in acute stroke. https://doi.org/10.1056/NEJMoa1414792.
Ann Neurol. 2006;59:467–477. 6. Pandian JD, et al. Prevention of stroke: a global perspective. Lancet.
26. Horn CM, et al. Endovascular reperfusion and cooling in cerebral 2018;392:1269–1278.
acute ischemia (ReCCLAIM I). J Neurointerv Surg. 2014;6:91–95. 7. Allman C, et al. Ipsilesional anodal tDCS enhances the functional
27. Johansen FF, et al. Drug-induced hypothermia as beneficial benefits of rehabilitation in patients after stroke. Sci Transl Med.
treatment before and after cerebral ischemia. Pathobiology. 2016;8:330re331.
2014;81:42–52.
28. Alexandrov AV, et al. Ultrasound-enhanced systemic thromboly- Basic Papers
sis for acute ischemic stroke. N Engl J Med. 2004;351:2170–2178. 1. Johansen FF, et al. Drug-induced hypothermia as beneficial
29. Wahl AS, et al. Neuronal repair. Asynchronous therapy restores treatment before and after cerebral ischemia. Pathobiology.
motor control by rewiring of the rat corticospinal tract after stroke. 2014;81(1):42–52.
Science. 2014;344:1250–1255. 2. Campos F, et al. Influence of temperature on ischemic brain: basic
30. Kidwell CS, Liebeskind DS, Starkman S, Saver JL. Trends in and clinical principles. Neurochem Int. 2012;60(5):495–505.
acute ischemic stroke trials through the 20th century. Stroke. 3. Huttner HB, Bergmann O, Salehpour M, et al. The age and ge-
2001;32:1349–1359. nomic integrity of neurons after cortical stroke in humans. Nat
31. Gladstone DJ, Black SE, Hakim AM. Toward wisdom from failure: Neurosci. 2014;17(6):801–803.
lessons from neuroprotective stroke trials and new therapeutic di- 4. Shih AY, Blinder P, Tsai PS, et al. The smallest stroke: occlusion of
rections. Stroke. 2002;33:2123–2136. one penetrating vessel leads to infarction and a cognitive deficit.
Nat Neurosci. 2013;16(1):55–63.
5. Wu F, Catano M, Echeverry R, et al. Urokinase-type plasmino-
General Readings Used as Source gen activator promotes dendritic spine recovery and improves
1. Sacco RL. Pathogenesis, classification, and epidemiology of cere- neurological outcome following ischemic stroke. J Neurosci.
brovascular disease [chapter 35]. In: Lewis P, Rowland, eds. 2014;34(43):14219–14232.
Merritt’s Textbook of Neurology. 10th ed. Baltimore, MD: Lippincott 6. Wahl AS, et al. Neuronal repair. Asynchronous therapy restores
Williams & Wilkins; 2000. motor control by rewiring of the rat corticospinal tract after stroke.
2. Smith WS, English JD, Johnston S. Cerebrovascular diseases [chap- Science. 2014;344(6189):1250–1255.
ter 370]. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson 7. Llovera G, et al. Results of a preclinical randomized controlled
J, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. multicenter trial (pRCT): anti-CD49d treatment for acute brain
New York, NY: McGraw-Hill; 2012. ischemia. Sci Transl Med. 2015;7(299):299ra121.
3. Bhardwai A, Alkayed NJ, Kirsch Richard JR, Traystman J, eds. Acute 8. Thompson RC, et al. Atherosclerosis across 4000 years of human
Stroke: Bench to Bedside. CRC Press; 2013. history: the Horus study of four ancient populations. Lancet.
4. Hankey GJ. Stroke. Lancet. 2017;389:641–654. 2013;381(9873):1211–1222.
9. Lee HK, et al. Natural allelic variation of the IL-21 recep-
tor modulates ischemic stroke infarct volume. J Clin Invest.
2016;126:2827–2838.
Suggested Papers or Journal Club Assignments 10. Rust R, et al. Nogo-A targeted therapy promotes vascular repair
and functional recovery following stroke. Proc Natl Acad Sci U S A.
2019;116:14270–14279.
Clinical Papers
1. Saver JL, et al. Stent-retriever thrombectomy after intravenous t-PA
vs. t-PA alone in stroke. N Engl J Med. 2015;372:2285–2295.
2
Central Nervous System Trauma
Harald Sontheimer
O U T L I N E
1 CASE STORY in Innsbruck, near the Austrian Alps, she fondly remem-
bers being on the slopes on every possible occasion. When
How much Jamie had missed the snow. Although the opportunity presented to join the management of her
Tennessee receives a few inches of snow on occasion, investment firm for a retreat in Snowbird, Utah, there
nothing compares to the dry, powdery coat that covers was no hesitation. Waking up to blue skies, she took the
the high mountains in winter. Since moving to the south- day’s first gondola to Hidden Peak, quietly moving high
ern United States some 20 years earlier, she had not been above the hills covered in virgin powder. From the top of
on skis once. On occasion, when asked to join friends on the mountain she started out on Cirque Travers, a gentle
skiing trips to the Appalachians, she dismissed the low glide toward the valley. Shaking off her initial hesitation
hills of Virginia as inadequate for her skills. Growing up and rustiness, she quickly got into a smooth, rhythmic
Diseases of the Nervous System. https://doi.org/10.1016/B978-0-12-821228-8.00002-0 25 Copyright © 2021 Elsevier Inc. All rights reserved.
26 2. Central Nervous System Trauma
motion as the skis carved into the snow below. It seemed that skiing would most likely be in her past. Her collision
like she had never stopped her passion and felt right at had fractured her spinal column and injured her spinal
home in the powder. Her colleagues would soon lose cord between the fourth and fifth cervical spine. Had the
touch with her as, clearly, no one came close to her skiing lesion been any higher, she could have died on the spot,
skills. Even after all those years, she still knew how to go unable to breathe on her own. Lucky enough to survive,
hard and fast. Not knowing the mountain, she turned she was left quadriplegic, unable to use either her arms
toward Wilbere Bowl, a double-diamond slope winding or legs and with little hope for even a modest recovery.
through the trees. She still had her jumps down and was
going faster and faster, soon hitting the moguls hidden
under a foot of fresh powder. As the hill got steeper, her 2 HISTORY
concentration started to fade and as her legs tired the ski-
ing became labored. She lost her footing jumping over As long as man has roamed the earth, injuries to the
the next mogul, accelerated out of control, and panicked head or spinal cord have been a common and often
before she could react, with a tree coming toward her deadly occurrence. As hunters, humans faced many inju-
fast. She doesn’t remember what happened next. ries that were inflicted chasing wild animals or resulted
“Can you move your finger? Can you wiggle your from brawls with unwelcome neighbors. The transition
toe? Stay right where you are, don’t move.” She was to walking upright on two legs made Homo erectus able
feeling anxious and her head hurt. She panicked, since to travel long distances and quickly expand throughout
she clearly could not move her feet or hands. She didn’t the globe, but it also came with an increased incidence
even feel them. Where were her colleagues? Would they of falls, which, when they occurred, were more volatile.
be searching for her? Who called the ski patrol? “I am Judging from archaeological evidence, head injuries
Jim, and this is Josh. You wiped out good. Just stay still were common in ancient times, and typically the injured
and don’t try to move. We will take you down the moun- individuals did not survive. An old Egyptian medical pa-
tain.” Jim and Josh carefully lifted her into a toboggan, pyrus from 1700 BC, purchased by Edwin Smith in 1862,
while she faded in and out of consciousness. Jamie barely revealed after its translation surgical procedures and rec-
remembers the ride to the valley, where an ambulance ommended treatment utilized in 48 cases of traumatic
was already waiting for her transfer to Intermountain injury (Figure 1). Of these, six involved the spinal cord.
Medical Center in Murray. When she awoke, she was These are believed to be the earliest known medical docu-
disoriented, in a hospital emergency room, hooked up ments describing head and spinal cord trauma, along with
to all sorts of monitors and wearing a neck brace. Her proposed treatments. Sadly, for those suffering from spi-
whole body was motionless, trapped in a plastic mold, nal cord injury (SCI), the author recommended that these
with straps over her torso and legs. That day she learned should not be treated at all: “an ailment not to be treated.”
FIGURE 1 The Edwin Smith Medical Papyrus (c. 1700 BC) is the oldest known document describing trauma surgery (public domain).
and restore function. I would argue that the tragic ac- of all deaths worldwide and eclipse the total number of
cident of “Superman,” Christopher Reeve, on May 30, deaths due to malaria, tuberculosis, and HIV combined.
1995, was a sad but much-needed catalyst for change. We will discuss TBI and SCI together, because both pres-
An expert equestrian, Christopher, participated in the ent with common underlying pathology and neurophys-
Commonwealth Dressage finals in Culpeper, Virginia. iological challenges. Both are part of the CNS and are
As he approached the third of 18 jumps, a 3½-foot-high enclosed by the same meningeal coverings that separate
triple bar, his horse stopped abruptly, unable to find the the CNS from the rest of the body (Box 1). They share
right footing for the jump. Christopher rolled along the the same vascular supply and are equally protected by
horse’s neck and fell head first to the ground. Although the blood–brain barrier (Box 1). Finally, many of the sen-
he was wearing a helmet and protective vest, he fell un- sory or motor pathways affected in each form of injury
conscious immediately. Emergency personnel initiated have axonal cell processes in both structures. However,
mouth-to-mouth resuscitation and Christopher first sur- since TBI and SCI are clinically well-delineated health
vived the medical transport to Culpeper Medical Center conditions, we will discuss epidemiology and treatment
and then the transfer to the University of Virginia Medical approaches separately and later converge on common
Center. Here, he was diagnosed with a life-threatening themes under disease mechanisms.
complex fracture to the first and second vertebrae, leav-
ing him with no movement and without the ability to
breathe on his own. The location of Christopher’s frac- 3.1 Traumatic Brain Injury
ture was essentially incompatible with life and, in hind- TBI constitutes a major health problem, with an esti-
sight, it is astonishing that he ever made it to the hospital mated 27 million people worldwide experiencing a new
alive. Against all odds, Christopher was able to gradu- TBI each year and 55 million persons living with disabil-
ally acquire the ability to breathe on his own for periods ities resulting from TBI. This number has increased by
of time, allowing him to get off his respirator to speak. about 8% worldwide since 1990, most likely due to in-
And speak he did. He became the most powerful voice creased use of motor vehicles in the developing world as
for research on SCI. He would not accept “no” as an an- incidence and prevalence in the United States, and similar
swer, and his main crusade was against complacency. high-income countries have declined by almost 10% over
His public efforts have been transformative and have in- the same time span. In the United States, approximately
jected much-needed energy, enthusiasm, and hope into 1 million new cases are reported with 2.3 Mio living with
the medical and scientific community. TBI. The actual numbers of TBI cases may indeed be
Sadly, traumatic brain injury (TBI) has never had a com- much larger, as many mild injuries go unreported and
parable spokesperson and still carries a significant stigma. often do not receive medical attention. Of the approxi-
However, coincident with Reeve’s tragic SCI, reports of mately 500,000 patients reporting to the emergency room,
athletes suffering from the consequences of sports-related 275,000 are admitted to the hospital, and 52,000 die each
concussions injected palpable interest in understanding year in the United States. While head trauma can occur in
how repeated, seemingly small injuries may aggregate to any individual at any time, it is much more common in
produce severe physiological changes that impair cogni- males than in females (3:1) and is most prevalent in very
tive function. The public interest is fueled by recent prom- young children (< 4 years), followed by adolescents and
inent cases, including Aaron Hernandez, a tight end for older adults (> 65 years). The increased TBI prevalence
the New England Patriots, Pro Football Hall of Famers in adolescents is largely due to increased risk-taking be-
Tony Dorsett and Joe DeLamielleure and the former NFL havior, motor vehicle accidents, and sports-related inju-
All-Pro Leonard Marshall, who suffer from chronic trau- ries. In the young and elderly, the increased incidence is
matic brain inflammation as a result of repeated sports due to falls and age-related instability. Overall, falls are
injuries. Examination of autopsies of these and other for- responsible for the majority of head injuries (35%), fol-
mer professional athletes shows concerning pathological lowed by motor vehicle accidents (17.3%), being hit by
changes similar to those observed in Alzheimer Disease an object (16.5%), and assaults (10%). However, of the
but at a much younger age. For the first time, we recog- moderate to severe TBIs, motor vehicle accidents remain
nize injury prevention as a major health challenge. the largest cause. The total cost to society is immense
and not fully quantifiable. Acute healthcare costs alone
for an individual with a mild form of TBI are estimated
3 CLINICAL PRESENTATION/ at $80,000–100,000, that of a patient with severe TBI at
DIAGNOSIS/EPIDEMIOLOGY ∼$3 million. Even mild forms of TBI cause significant dis-
ability and loss of mental capacity, leaving many patients
Worldwide nearly 6 million people die each year from who are in otherwise good health unable to reach their
neurotrauma, physical injury to the head or spinal cord. full economic potential. Those with severe TBI may never
These injuries are largely preventable, yet account for 10% participate in work and require life-long care.
BOX 1
BOX 1-FIGURE 1 Comparison of peripheral and central blood vessels. Peripheral vessels lack tight junctions that seal the endothe-
lial cells, thereby preventing leakage of molecules across the vessel wall. Central vessels contain pericytes and astrocytes that induce and
maintain tight junctions and formation of the blood–brain barrier. Redrawn with permission from a cartoon by Dr. Thomas Caseci, Virginia
Maryland Regional College of Veterinary Medicine, and Dr. Samir El-Shafey, of the Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
Continued
BOX 1 (cont’d)
it is floating in fluid, the brain’s effective mass is reduced can generate pressure within the brain, causing headaches
30-fold, thereby reducing the impact experienced by ac- and possibly hydrocephalus. Tapping CSF through the lum-
celerations and decelerations. CSF plays an important role bar spinal cord has become invaluable to assess the CNS for
in clearing debris after injury and removing cellular waste evidence of infection or disease. For example, the presence
products, and has been compared to the lymphatic system of leukocytes would indicate breakdown of the BBB as a re-
found elsewhere in the body.4 Any obstruction to its flow sult of inflammation.
BOX 1-FIGURE 2 (A) Flow of CSF from the choroid plexus where it is produced, through the ventricles and into the subarachnoid
space, where CSF is absorbed into the venous system, thereby clearing waste products from the brain. The CSF essentially surrounds the
entire brain, and through the buoyancy effect reduces the brain’s effective weight and provides a cushion effect. (B) Meningeal covers
of the brain include the pia mater that is directly in contact with the brain surface, the dura mater on the skull side, and the arachnoid
mater in between. It contains the arachnoid trabecula, a space that is filled with CSF. This fluid-filled space serves as a cushion for the
brain as the head moves. Reproduced with permission from Ref. 3.
Injuries are often classified as either closed or open GCS. Consciousness is only lost for a very short period
head injuries based on whether the integrity of the skull (< 30 min), if at all, and memory loss is typically mild
was or was not compromised. Open head injuries natu- and transient, lasting for less than 24 h. Patients often
rally have an increased potential to present with bleed- have headaches, are confused, and may have difficulty
ing and may be associated with extensive inflammation, sleeping. Dizziness, vertigo, irritability, impulsiveness,
as pathogens can readily enter the brain through an open and difficulty concentrating are other common symp-
wound. toms, which typically resolve within a few hours or
TBI can be divided into three grades of severity, which days. Concussions are particularly common among
reflect the relative impairment of a patient irrespective of athletes, with football, soccer, hockey, and boxing
the underlying cause. These impairments can be quickly among the leading sports causing concussions. We now
assessed by the Glasgow Coma Scale (GCS, Table 1), recognize that even if there are no visible changes on
which measures the level of consciousness on a 15-point brain scans, the injuries can have profound effects on
scale. Values in three categories are added, yielding a fi- brain function as many p atients with an mTBI show
nal score range of 3 for a comatose individual to a 15 for persistent headaches, memory, and cognitive problems.
a normal functioning person. Moderate TBI has a GCS of 9–12 and is typically associ-
Mild TBI (mTBI) is often used synonymously with ated with prolonged loss of consciousness and neurological
concussion and represents a score range of 13–15 on the deficits that do not readily disappear on their own. Minor
Mrs. Sladen had not only given Mrs. Brande a piece of news; she
had introduced her to a grand idea—an idea that took root and grew
and flourished in that lady’s somewhat empty mind, as she sat alone
in her drawing-room over a pleasant wood-fire, which she shared
impartially with a sleek, self-conscious fox-terrier.
All the world admitted that once upon a time “old Mother Brande”
must have been a beautiful woman. Even now her fair skin, blue
eyes, and chiselled features entitled her to rank as a highly
respectable wreck. Who would have thought that refined, fastidious,
cynical Pelham Brande would have married the niece of a lodging-
house keeper? Perhaps if he had anticipated the career which lay
before him—how unexpectedly and supremely successful he was to
be, how the fierce light inseparable from high places was to beat
upon his fair-haired Sarabella—he might have hesitated ere he took
such a rash and romantic step. Little did he suppose that his fair-
haired Sally, who had waited so capably on him, would one day
herself be served by gorgeous scarlet-clad Government chupprassis;
or that she was bound to walk out of a room before the wives of
generals and judges, and that she would have a “position” to
maintain! But who is as wise at two and twenty as he is at fifty-two?
At two and twenty Pelham Brande had just passed for the India Civil
Service, and was lodging in London; and whilst preparing for the Bar
he got typhoid fever, and very nearly died. He was carefully tended
by Mrs. Batt, his landlady, and her lovely niece Sarabella, who was
as fair as a June rose, and as innocent as a March lamb.
The best medical authorities assure us, that nothing is so
conducive to convalescence as a skilful and pretty nurse, and under
the influence of Sara’s ministrations Mr. Brande made rapid progress
towards recovery, but fell a victim to another malady—which proved
incurable. He did not ask his relations for permission or advice, but
married his bride one morning at St. Clement Danes, took a week’s
trip to Dover, and two first-class passages to Bombay.
As a rule, junior civilians are despatched without ruth to lonely
jungle districts, where they never see another white face for weeks,
and their only associates are their native subordinates, their staffs of
domestics, and the simple dwellers in the neighbouring villages. Now
and then they may chance on an opium official, or a forest officer,
and exchange cheroots, and newspapers; but these meetings are
rare. After a busy university career, after an immense strain on the
mental faculties, necessary to passing a severe examination, the
dead sameness of that life, the silence and loneliness of the jungle
(aggravated by the artless prattle of the office baboo), is enough to
unhinge the strongest mind. Miles and miles from the haunts of his
countrymen, from books and telegrams, and the stir and excitement
of accustomed associations, the plunge from the roar of the London
streets, and life at high pressure, to the life in a solitary up-country
district, is indeed a desperate one; especially if the new-comer’s
eyes and ears are not open to the great book of Nature—if he sees
no beauty in stately peepul-trees, tracts of waving grain, venerable
temples, and splendid sunsets; if he does not care to beat for pig, or
shoot the thirsty snipe, but merely sits in his tent door in the cool of
the evening, his labours o’er, and languishes for polo, cards, and
theatres. Then he may well curse his lot; he is undeniably in a bad
way.
Pelham Brande had nothing to fear from loneliness or ennui. Sara
made him an excellent helpmate. She picked up the language and
customs with surprising facility; she proved a capital housekeeper,
and as shamelessly hard at a bargain as any old native hag. But she
never took to books, or to the letter “h.” For years the Brandes lived
in out-of-the-way districts, and insignificant stations, until by slow
degrees his services and abilities conducted him to the front. As
advancing time promoted him, his wife declined in looks, and
increased in bulk, and her tastes and eccentricities became fixed.
Pelham was not actually ashamed of his partner, but he was alive to
the fact, that, with a cultivated gentlewoman at the head of his
establishment, he would have occupied a vastly more agreeable
social position. But he never admitted—what his friends loudly
affirmed—that, as he sat opposite to Sara day after day, he was also
sitting face to face with the one great mistake of his life!
Twice he had taken her to Australia for six months, but never (nor
did she desire it) to her native land. Once, years ago, he ran home
himself, and was received by his relations, as relations generally
welcome a wealthy, childless, and successful man. They even
brought themselves to ask, somewhat timidly, for Sara; and she, on
her part, sent them generous consignments of curry powder, red
pepper, and her own special and far-famed brand of chutney. The
good lady had not many resources beyond housekeeping. She read
the daily paper, and now and then a society novel, if it was plentifully
peopled with lords and ladies; she could write an ordinary note,
invitation, or refusal, and a letter (with a dictionary beside her). She
was fond of her cows, and poultry, and adored her dog Ben; gave
excellent, but desperately dull dinners; dressed sumptuously in
gorgeous colours; enjoyed a gossip; loved a game of whist—and
hated Mrs. Langrishe. She lived a monotonous and harmless life,
vibrating between the hills and plains each season, with clockwork
regularity.
As Mrs. Brande sat before her fire, and watched the crackling
pinewood, she was not happy. Officially she was the chief lady of the
place, the “Burra mem sahib;” but clever Mrs. Langrishe was the real
leader of society, and bore away all the honours—the kernel, so to
speak, of distinction, leaving her but the miserable shell. With a
young and pretty girl as her companion, she would be more
insufferable and more sought after than ever. As it was, she, Sara
Brande, could make but little stand against her; and once her enemy
was allied to a charming and popular niece, she might figuratively lay
down her arms and die. She was a friendless, desolate old woman. If
her little Annie had lived, it would have been different; and she had
no belongings, no nieces. No! but—happy thought!—Pelham had no
less than three, who were poor and, by all accounts, pretty. He had
helped their mother, his sister, to educate them; he sent them money
now and then. Why should she not adopt one of these girls, and
have a niece also? Yes, she would write herself; she would speak to
Pelham that very evening after dinner (it was his favourite dinner).
The more she became accustomed to the idea, as she turned it over
in her mind, the more she was filled with delight, resolve, and
anticipation. The girl’s route, steamer, room, dresses, were already
chosen, and she was in the act of selecting her future husband,
when Mr. Brande entered, brisk and hungry.
After dinner, when Mr. Brande was smoking a cigarette, his artful
wife opened the subject next to her heart, and remarked, as she
handed him a cup of fragrant coffee—
“Pelham, you are often away on tour, are you not? and I feel
uncommon lonely, I can tell you. I am not as active or as cheerful as
I used to be. I’m too old for dancing, and tennis, and riding. Not that I
ever was much hand at them.”
“Well, do you want to come on tour? or shall I buy you a pony, or
hire you a companion?” inquired Mr. Brande facetiously—a clean-
shaven, grey-haired man, with thin mobile lips, keen eyes, and, at a
little distance, a singularly boyish appearance. “What would you like
to do?”
“I should like to ride and dance by proxy,” was the unexpected
answer. “Let us ask out one of those Gordon girls, your nieces. I’d be
very good to her; and you know, Pel, I’m a lonely creature, and if our
own little Annie had lived, I would not be wanting to borrow another
woman’s daughter to keep me company.”
Mr. Brande was surveying his wife with a severely judicial
expression; it relaxed as she spoke of their only child, buried far
away, under a tamarind tree, on the borders of Nepaul.
Yes, their little Annie would have been five and twenty had she
lived, and doubtless as lovely as Sally Batt, who had turned his
head, mitigated his success, and whom he rarely repented of having
married.
“Your sister has three girls,” she continued, “and she is badly off.
What is the pension of a colonel’s widow? Why, less than some folks
give their cooks.”
“It is not considerable, certainly, and Carrie finds it hard enough to
make both ends meet; she never was much of a manager. But, Sally,
a girl is a great responsibility, and you are not accustomed to young
people.”
“No; but I can learn to study them, for I’m fond of them. Say ‘Yes,’
Pel, and I’ll write. We will pay her passage, of course, and I’ll meet
her myself at Allahabad.”
Mr. Brande tossed the end of his cigarette into the fire, fixed his
eye-glass firmly in his eye, and contemplated his wife in silence. At
last he said—
“May I ask what has put this idea into your head all of a sudden?”
“It’s not—exactly—sudden,” she stammered; “I’ve often a sort of
lonely feel. But I must truthfully say that I never thought of your niece
till to-day, when I heard that Mrs. Langrishe is getting up one of hers
from Calcutta.”
Mr. Brande jerked the glass hastily on to his waistcoat, and gave a
peculiarly long whistle.
“I see! And you are not going to be beaten by Mrs. Langrishe—you
mean to run an opposition girl, and try which will have the best
dresses, the most partners, and be married first? No, no, Sally! I
utterly refuse to lend myself to such a scheme, or to allow one of
Carrie’s daughters to enter for that sort of competition.” And he
crossed his legs, and took another cigarette.
“But listen to me, Pel,” rising as she spoke; “I declare to you that I
won’t do what you say, and, any way, your niece will be in quite a
different position to the Langrishe’s girl. I’ll be as good to her as if
she was my own—I will indeed!” and her voice trembled with
eagerness. “I’m easy to get on with—look how long I keep my
servants,” she pleaded. “These Gordons are your nearest kin; you
ought to do something for them. I suppose they will come in for all
your money. Your sister is delicate, and if anything happened to her
you’d have to take, not one girl, but the whole three. How would you
like that? Now, if one of them was nicely married, she would make a
home for her sisters.”
“You are becoming quite an orator, and there is something in what
you say. Well, I’ll think it over, and let you know to-morrow, Sally. As
to leaving them my money, I’m only fifty-two, and I hope to live to
spend a good slice of it myself.” And then Mr. Brande took up a
literary paper and affected to be absorbed in its contents. But
although he had the paper before him, he was not reading; he was
holding counsel with himself.
He had not seen Carrie’s girls since they counted their ages in
double figures; they were his nearest of kin, were very poor, and led
dull lives in an out-of-the-way part of the world. Yes, he ought to do
something, and it would please the old lady to give her a companion,
and a pretty, fresh young face about the house would not be
disagreeable to himself. But what would a refined and well-educated
English girl think of her aunt, with her gaudy dresses, bad grammar,
mania for precedence, and brusque, unconventional ways? Well,
one thing was certain, she would soon discover that she had a
generous hand and a kind heart.
The next morning Mr. Brande, having duly slept on the project,
gave his consent and a cheque, and Mrs. Brande was so dazzled
with her scheme, and so dazed with all she had to think of, that she
added up her bazaar account wrong, and gave the cook a glass of
vinegar in mistake for sherry—which same had a fatal effect on an
otherwise excellent pudding.
In order to compose her letter comfortably, and without distraction,
Mrs. Brande shut herself up in her own room, with writing materials
and dictionary, and told the bearer to admit no one, not even Mrs.
Sladen. After two rough copies and two hours’ hard labour, the
important epistle was finished and addressed, and as Mrs. Brande
stamped it with a firm hand, she said to herself aloud—
“I do trust Ben won’t be jealous. I hope he will like her!”
Being mail day, Mrs. Brande took it to the post herself, and as she
turned from dropping it into the box, she met her great rival coming
up the steps, escorted by two men. Mrs. Langrishe was always
charming to her enemy, because it was bad style to quarrel, and she
knew that her pretty phrases and pleasing smiles infuriated the other
lady to the last degree; and she said, as she cordially offered a
neatly gloved hand—
“How do you do? I have not seen you for ages! I know it’s my
business to call, as I came up last; but, really I have so many
engagements, and such tribes of visitors——”
“Oh, pray don’t apologize!” cried Mrs. Brande, reddening; “I’d quite
forgotten—I really thought you had called!” (May Sara Brande be
forgiven for this terrible falsehood.)
It was now Mrs. Langrishe’s turn to administer a little nip.
“Of course you are going to dine at the Maitland-Perrys’ next
week?” (well knowing that she had not been invited). “Every one who
is anybody is to be there. There are not many up yet, it is so early;
but it will be uncommonly smart—as far as it goes—and given for the
baronet!”
“No, I am not going, I have not been asked,” rejoined Mrs. Brande
with a gulp. She generally spoke the truth, however much against
the grain.
“Not asked! how very odd. Well,” with a soothing smile, “I dare say
they will have you at their next. I hear that we are to expect quite a
gay season.”
“And I was told that there will be no men.”
“Really! That won’t affect you much, as you don’t ride, or dance, or
go to picnics; but it is sad news for poor me, for I am expecting a
niece up from Calcutta, and I hope the place will be lively.”
“But I do mind, Mrs. Langrishe, just as much as you do,” retorted
the other, with a triumphant toss of her head. “Perhaps you may not
be aware that I am expecting a niece, too?” (How could Mrs.
Langrishe possibly divine what the good lady herself had only known
within the last few hours?) “Yours is from Calcutta, but mine is all the
way from England!” And her glance inferred that the direct Europe
importation was a very superior class of consignment. Then she
added, “Other people has nieces too, you see!” And with a
magnificent bow, she flounced down the steps, bundled into her
rickshaw, and was whirled away.
Mrs. Langrishe stood watching the four blue and yellow jampannis,
swiftly vanishing in a cloud of dust, with a smile of malicious
amusement.
“Other people has nieces too, you see!” turning to her companions
with admirable mimicry. “She is not to be outdone. What fun it is!
Cannot you fancy what she will be like—Mrs. Brande’s niece, all the
way from England? If not, I can inform you. She will have hair the
colour of barley-sugar, clothes the colours of the rainbow, and not an
‘h’!”
CHAPTER IV.
THE THREE YOUNG MAIDS OF HOYLE.
It was true that Mrs. Gordon and her daughters resided in a dull,
out-of-the-way part of the world; but they could not help themselves.
They lived at Hoyle, in the first instance, because it was cheap; and,
in the second place, because living at Hoyle had now become
second nature to Mrs. Gordon, and nothing short of a fire or an
earthquake could remove her.
Hoyle is in the south of England, within a stone’s throw of a shingly
beach, and commands a full view of the white shores of France. It is
an old-fashioned hamlet, at least fifty years behind the age, where
the curfew is still sounded, the sight of a telegraph envelope is only
interpreted as a messenger of death, and is cut off from the bustling
outer world by the great expanse of Romney Marsh. In deference to
this fin de siècle age, a single line of rail crawls across the seaside
desert, and once or twice a day a sleepy train stops just one mile
short of the village. The village of Hoyle was once a chartered town,
and was built many centuries before trains were invented. It was
even out of the track of the lively stage-coaches, and owed its wealth
and rise—and fall—entirely to its convenient proximity to the sea, its
seclusion, its charming view of the opposite coast. Yes, its solid
prosperity—low be it spoken—was due to smuggling. The High
Street is lined by picturesque red-brick houses, which are occupied
by the descendants of—shall we say sailors?—a well-to-do primitive,
most respectable community, though from yonder upper window the
present tenant’s grandfather shot a preventive officer stone dead;
and in the chimney of the next cottage (a most innocent-looking
abode) three men who were in trouble lay concealed for a whole
week. The capacious cellars of the Cause is Altered inn, were, within
living memory, no strangers to bales of silk and casks of brandy.
Between the village and the inn there stands a solid old red house,
with a small enclosed garden in front, and a paved footpath leading
to its mean little green hall-door. The windows are narrow, the rooms
irregular, and the ceilings absurdly low—but so is the rent. It suits its
tenants admirably; it is warm, roomy, and cheap; it boasts of a fine
walled garden at the rear, of acres of cellarage, and is known by the
name of Merry Meetings. This jovial designation is not of modern
date, but points back to the grand old days when it was the
residence of the chief man in Hoyle; when it was club, bank,
receiving-house, and fortress. Many were the carousals that took
place in Mrs. Gordon’s decent panelled parlour. To what grim tales
and strange oaths have its walls given ear! There have been merry
meetings, of a much tamer description in the present time, when the
maidens of the neighbourhood have gathered round the table, and
chatted and laughed over cups of honest tea, brewed in Mrs.
Gordon’s thin old silver teapot. Pretty girls have discussed dress,
tennis, and weddings, where formerly weather-beaten, bearded men
assembled to celebrate the safe arrival of a newly-run cargo, and to
appraise filmy laces, foreign silks, and cigars, and to quaff prime
cognac and strange but potent waters.
The widow and her daughters have occupied Merry Meetings for
fifteen years, ever since the death of Colonel Gordon. He had retired
from the service and settled down near a garrison town, intending to
turn his sword into a ploughshare; but in an evil moment he ventured
his all in a tempting speculation, hoping thereby to double his
income; but instead of which, alas! water came into the Wheal
Rebecca, and swept away every penny. Seeing nothing between him
and the poor-house but a small pension, Colonel Gordon was not
brave enough to face the situation, and died of a broken heart—
though it was called a rapid decline—leaving his widow and three
little girls to struggle with the future as best they could.
Colonel Gordon’s connections were so furious with him for losing
his money, that they sternly refused to assist his widow; therefore
she meekly collected the remains of the domestic wreck, and retired
to Hoyle with her children and an old servant, who had strongly
recommended her native place, where her “mistress could live in
peace and quiet until she had time to turn herself round and make
plans.” Mrs. Gordon took Merry Meeting, which was partly furnished,
for three months, and had remained there for fifteen years. Her plans
were still undeveloped; she constantly talked of moving, but never
got beyond that point. Occasionally she would say, “Well, girls, I
really will give notice this term. We must move; we must decide
something. I will write to a house agent. And, Honor, you need not
mind getting the garden seeds, or having the kitchen whitewashed.”
But when to-morrow came these plans had melted into air, and the
garden-seeds were set, and the kitchen renovated, as usual.
Mrs. Gordon was something of an invalid, and became more
lethargic year by year, and a prey to an incurable habit of
procrastination. She resigned her keys, purse, and authority into the
hands of her eldest daughter, and contented herself with taking a
placid interest in the garden, the weather, the daily paper, and
sampling various new patent medicines. She still retained the
remains of remarkable personal beauty and a fascination of manner
that charmed all who came in contact with her, from the butcher’s
boy to the lord of the soil. People said that it was shamefully unfair to
her girls, the way in which Mrs. Gordon buried herself—and them—
alive. She never made the smallest effort to better their lot, but
contented herself with sitting all day in a comfortable easy-chair,
making gracious remarks and looking handsome, stately, and
languid.
Life was monotonous at Merry Meetings. Two or three tennis-
parties in summer, two or three carpet-dances in winter, now and
then a day’s shopping in Hastings, were events which were varied by
long gray stretches of uneventful calm. The daily paper was a most
welcome arrival; and the Miss Gordons entertained as eager an
expectation of letters, of stirring news, of “something coming by the
post,” of “something happening,” as if they lived in the midst of a
large and busy community.
And what of the three Miss Gordons?
Jessie, the eldest, is twenty-six, and quite surprisingly plain. She
has pale eyes and a dark complexion, instead of dark eyes and a
pale complexion, also a nose that would scarcely be out of place in a
burlesque. She is clever, strong-willed, and practical, and manages
the whole family with admirable tact, including Susan, the domestic
treasure.
Jessie Gordon’s name is well known as the author of pretty stories
in girls’ and children’s magazines. She earns upwards of a hundred
a year by her pen (which she generally adds to the common purse),
and is regarded by her neighbours with a certain amount of pride,
slightly tempered with uneasiness. Supposing she were to put some
of her friends into a book! However, they criticize her work sharply to
her face, make a great virtue of purchasing the magazines in which
her tales appear, and magnify her merits, fame, and earnings to all
outsiders.
Fairy, whose real name is Flora, comes next to Jessie in age; she
is about two and twenty, and has a perfectly beautiful face—a face to
inspire poets and painters, faultless in outline, and illumined by a pair
of pathetic blue eyes. A most delicate complexion—of which every
care, reasonable or unreasonable, is taken—and quantities of fine
sunny brown hair, combine to complete a vision of loveliness. Yes,
Fairy Gordon is almost startlingly fair to see; and seen seated at a
garden-party or in a ball-room, all the strange men present instantly
clamour for an introduction; and when it has been effected, and the
marvellously pretty girl rises to dance, behold she is a dwarf—a poor
little creature, with a shrill, harsh voice, and only four feet four inches
in height! Her figure is deceptive—the body very long in proportion to
the limbs.
Many and many a shock has Fairy administered to a would-be
partner. Did she ever read their consternation in their faces?
Apparently never; for no matter who remained at home, Fairy could
not endure to miss an entertainment, even a school feast or a
children’s party. It was an unwritten family law that Fairy must always
come first, must always be shielded, petted, indulged, amused, and
no one subscribed to this rule more readily than the second Miss
Gordon herself. She was keenly alive to her own beauty, and talked
frankly to her intimates of her charms; but she never once referred to
her short stature, and her sisters but rarely alluded to the fact
between themselves, and then with bated breath. Even six inches
would have made all the difference in the world; but four feet four
was—well, remarkable. Of course the neighbours were accustomed
to Fairy—a too suggestive name. They remembered her quite a little
thing, a lovely spoilt child, a child who had never grown up. She was
still a little thing, and yet she was a woman—a woman with a sharp
tongue and a despotic temper. Fairy had true fairy-like fingers. She
embroidered exquisitely, and made considerable sums doing church
needlework, which sums were exclusively devoted to the decoration
of her own little person. She was also a capital milliner and amateur
dressmaker; but she had no taste for music, literature,
housekeeping, or for any of the “daily rounds, the common tasks.”
She left all those sort of things to her sisters.
Honor, the youngest Miss Gordon, is twenty years of age, slight,
graceful, and tall—perhaps too tall. She might have spared some
inches to her small relative, for she measures fairly five feet eight
inches. She has an oval face, dark grey eyes, dark hair, and a
radiant smile. In a family less distinguished by beauty she would
have been noteworthy. As it is, some people maintain that in spite of
Fairy’s marvellous colouring and faultless features, they see more to
admire in her younger sister—for she has the beauty of expression.
Honor is the useful member of the family. Jessie could not arrange
flowers, cut out a dress, or make a cake, to save her life. Honor can
do all these. She has a sort of quick, magic touch. Everything she
undertakes looks neat and dainty, from a hat to an apple-pie. Her
inexhaustible spirits correspond with her gay, dancing eyes, and she
is the life and prop of the whole establishment. She plays the violin in
quite a remarkable manner. Not that she has great execution, or can
master difficult pieces, but to her audience she and her violin seem
one, and there is a charm about her playing that listeners can neither
explain nor resist.
The youngest Miss Gordon has her faults. Chief of these, is an
undesirable bluntness and impudent recklessness of speech—a
deplorable fashion of introducing the truth, the whole truth, and
nothing but the truth, no matter how unwelcome or how naked—and
a queer, half-absent, and wholly disconcerting way of thinking aloud.
Her friends (who are many) declare that she is young, and will
grow out of these peculiarities, and at any rate she is by far the most
popular of the three sisters!
One gusty March morning, the sea displayed towering grey waves,
with cream-coloured crests, the rain beat noisily against the window
in which Jessie Gordon stood waiting for the kettle to boil, and
watching for the postman. Here he came at last, striding up the
paved path in his shining oilskins, and with a thundering bang, bang!
he is gone.
“The paper, a coal bill, and an Indian letter,” said Jessie to Fairy,
who, wrapped in a shawl, was cowering over the fire. “I’ll take them
upstairs whilst you watch the kettle.”
Mrs. Gordon always breakfasted in bed, to “save trouble,” she
declared, but to whom she omitted to mention. She turned the letters
over languidly, and exclaimed—
“One from India from Sara Brande. Wonders will never cease!
What can she want? Well, let me have my tea at once, and when I
have read her epistle, I will send it down to you. And, here—you can
take the paper to Fairy.”
Jessie returned to her tea-making—she and Honor took the
housekeeping week about. In the middle of breakfast, Susan stalked
into the room—an unusual occurrence—and said—
“Miss Jessie, the mistress is after pulling down the bell-rope. I
thought the house was on fire. You are to go upstairs to her this
minute.”
Jessie was absent about a quarter of an hour, and when she
appeared, beaming, and with a letter in her hand, she had such an
air of suppressed exultation, that it was evident to her sisters, even
before she opened her lips, that the long-expected “something” had
happened at last.
CHAPTER V.
AN INDIAN LETTER.
“Great, great news, girls!” cried Jessie, waving the letter over her
head. “Mrs. Brande—I mean Aunt Sally—has written to ask one of
us to go out and live with her, and she seems quite certain that her
offer will be accepted, for she encloses a cheque for outfit and
passage-money. It is a short invitation, too; whoever elects to see
India must start within the next fortnight.”
Honor and Fairy gazed at one another incredulously, and Fairy’s
delicate complexion changed rapidly from pink to crimson, from
crimson to white.
“I’ll read it to you,” continued Jessie, sitting down as she spoke.
“The writing is peculiar, and some of the words are only underlined
four times. Ahem!
“‘Rookwood, Shirani.
“‘Dear Sister-in-law,
“‘It is not often that I take up my pen, but I have something
most important to say to you. I am not as young as I was, and
I feel the want of some sort of company. Pelham is away a
good deal, and I am left alone with Ben; he is the best-
hearted creature in the world, and knows every word I say,
but he can’t talk, nor help in the housekeeping, nor go to balls
and church, being only a dog. What would you think of letting
me have one of your girls? You have three, and might spare
one. Indeed, three unmarried daughters must be a really
terrible anxiety to any mother. We expect to be home in about
a year, so if the worst comes to the worst, you will have her
back again in twelve months’ time. Whoever you send, you
may be sure I will be a mother to her, and so will Pelham. She
shall have the best of everything in the way of society and
clothes, and I guarantee that she only knows the nicest
beaux, and that she will be very happy. The hot weather is
coming on, and travelling after April is dangerous, both by
land and sea, so I would like you to send her as soon as
possible. She ought to start not later than a fortnight after you
receive this, otherwise, it will be no use her coming at all. She
could not set out again till October, and it would not be worth
her while to come to us for six months. Pel encloses a cheque
for her passage, and thirty-five pounds extra for boxes,
gloves, petticoats, etc. I prefer to devise her dresses myself,
and will turn her out smart. No doubt you are not in the way of
seeing the new fashions, and we are uncommonly dressy out
here. If she could be in Bombay by the middle of April, I could
meet her at Allahabad and bring her up, for I don’t approve of
girls travelling alone. Pel is anxious, too, and hopes you won’t
refuse us. You know he has a good deal in his power; your
girls are his next-of-kin, and a nod is as good as a wink to a
blind horse—of course, not meaning that you are a blind
horse. This place is gay in the season, and has plenty of
tamashas; as for snakes, there is no such thing; and with
regard to climate, you can make yourself quite easy.
“‘The climatological conditions of these hill-districts are a
most important element in their physical geography, and will
therefore require to be treated at considerable length. An
extensive discussion of the meteorology cannot be attempted,
but sufficient data have already been collected to serve as a
basis for general description of the climate. In this respect the
Himalayas, on account of their less distance from the equator,
present many points of advantage as compared with the Alps
and other European mountains.’” (The above, with the
exception of the italics, had been boldly copied from a
gazetteer found in Mr. Brande’s writing-room.)
“‘There is generally a fair sprinkling of young men, and of
course we entertain a great deal. She shall have a nice quiet
pony, and a new rickshaw, so we shall expect her without fail.
Love to your daughters, and especially to our one.