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DISEASES OF
THE NERVOUS SYSTEM
Harald Sontheimer
DISEASES OF THE NERVOUS SYSTEM
 ELSEVIER science &
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Diseases of the Nervous System, Second Edition

Harald Sontheimer
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DISEASES OF THE
NERVOUS SYSTEM
SECOND EDITION

Harald Sontheimer
Harrison Distinguished Professor and Chair, Department of Neuroscience,
University of Virginia, School of Medicine, Charlottesville, VA, United States
Academic Press is an imprint of Elsevier
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 Dedication

To my daughters Melanie and Sylvie, and to all the students

who I taught over the past decades.
You have served as a constant inspiration and ­motivated me to make
Neuroscience more accessible to a broad readership.
 Contents

About the Author xi II

Acknowledgments xiii
Introduction xv Progressive Neurodegenerative Diseases

4. Aging, Dementia, and Alzheimer Disease

I HARALD SONTHEIMER

Static Nervous System Diseases 1 Case Story 81

2 History 82
1. Cerebrovascular Infarct: Stroke 3 Clinical Presentation/Diagnosis/Epidemiology 83
HARALD SONTHEIMER 4 Disease Mechanism/Cause/Basic Science 87
5 Treatment/Standard of Care/Clinical
1 Case Story 3 Management 97
2 History 4 6 Experimental Approaches/Clinical Trials 102
3 Clinical Presentation/Diagnosis/Epidemiology 5 7 Challenges and Opportunities 104
4 Disease Mechanism/Cause/Basic Science 8 Acknowledgments 105
5 Treatment/Standard of Care/Clinical Management 17 References 106
6 Experimental Approaches/Clinical Trials 20
7 Challenges and Opportunities 22
5. Parkinson Disease
Acknowledgment 23
HARALD SONTHEIMER
References 23
1 Case Story 109
2. Central Nervous System Trauma 2 History 110
HARALD SONTHEIMER 3 Clinical Presentation, Diagnosis, and Epidemiology 111
4 Disease Mechanism/Cause/Basic Science 115
1 Case Story 25
5 Treatment/Standard of Care/Clinical
2 History 26
Management 126
3 Clinical Presentation/Diagnosis/Epidemiology 28
6 Experimental Approaches/Clinical Trials 129
4 Disease Mechanism/Cause/Basic Science 34
7 Challenges and Opportunities 131
5 Treatment/Standard of Care/Clinical Management 44
Acknowledgment 131
6 Experimental Approaches/Clinical Trials 45
References 131
7 Challenges and Opportunities 47
Acknowledgments 48
References 48 6. Diseases of Motor Neurons and Neuromuscular
Junctions
3. Seizure Disorders and Epilepsy HARALD SONTHEIMER
HARALD SONTHEIMER
1 Case Story 135
1 Case Story 51 2 History 136
2 History 52 3 Clinical Presentation/Diagnosis/Epidemiology 137
3 Clinical Presentation/Diagnosis/Epidemiology 53 4 Disease Mechanism/Cause/Basic Science 143
4 Disease Mechanism/Cause/Basic Science 57 5 Treatment/Standard of Care/Clinical
5 Treatment/Standard of Care/Clinical Management 69 Management 154
6 Experimental Approaches/Clinical Trials 74 6 Experimental Approaches/Clinical Trials 155
7 Challenges and Opportunities 75 7 Challenges and Opportunities 158
Acknowledgments 75 Acknowledgments 158
References 75 References 158

vii
viii Contents

7. Huntington Disease 6 Challenges and Opportunities 254

HARALD SONTHEIMER
Acknowledgments 254
References 254
1 Case Story 161
2 History 162
3 Clinical Presentation/Diagnosis/Epidemiology 163 IV
4 Disease Mechanism/Cause/Basic Science 166
Developmental Neurological Conditions
5 Treatment/Standard of Care/Clinical Management 175
6 Experimental Approaches/Clinical Trials 176
7 Challenges and Opportunities 178 11. Neurodevelopmental Disorders
Acknowledgments 178 HARALD SONTHEIMER
References 179
1 Case Study 259
2 History 260
III 3 Development of Synapses in the Human
Cortex and Diseases Thereof 261
Secondary Progressive Neurodegenerative 4 Down Syndrome 263
Diseases 5 Fragile X Syndrome 267
6 Rett Syndrome 270
7 Autism Spectrum Disorder (ASD) 272
8. Multiple Sclerosis
8 Common Disease Mechanism 277
HARALD SONTHEIMER
9 Challenges and Opportunities 278
1 Case Story 183 Acknowledgment 278
2 History 184 References 278
3 Clinical Presentation/Diagnosis/Epidemiology 186
4 Disease Mechanism/Cause/Basic Science 189
5 Treatment/Standard of Care/Clinical Management 198 V
6 Experimental Approaches/Clinical Trials 201 Neuropsychiatric Illnesses
7 Challenges and Opportunities 204
Acknowledgments 204
References 204 12. Mood Disorders and Depression
HARALD SONTHEIMER
9. Brain Tumors
1 Case Story 283
HARALD SONTHEIMER
2 History 284
1 Case Story 207 3 Clinical Presentation/Diagnosis/Epidemiology 285
2 History 208 4 Disease Mechanism/Cause/Basic Science 287
3 Clinical Presentation/Diagnosis/Epidemiology 210 5 Treatment/Standard of Care/Clinical
4 Disease Mechanism/Cause/Basic Science 213 Management 295
5 Treatment/Standard of Care/Clinical Management 225 6 Experimental Approaches/Clinical Trials 298
6 Experimental Approaches/Clinical Trials 227 7 Challenges and Opportunities 300
7 Challenges and Opportunities 231 Acknowledgment 300
Acknowledgments 232 References 300
References 232
13. Schizophrenia
10. Infectious Diseases of the Nervous System HARALD SONTHEIMER
HARALD SONTHEIMER
1 Case Story 303
1 Case Story 235 2 History 304
2 History 236 3 Clinical Presentation/Diagnosis/Epidemiology 305
3 Clinical Presentation/Diagnosis/Epidemiology/Disease 4 Disease Mechanism/Cause/Basic Science 306
Mechanism 237 5 Treatment/Standard of Care/Clinical
4 Beyond the Infection: Bona Fide Brain Disorders Involving Management 318
Pathogens 251 6 Experimental Approaches/Clinical Trials 319
5 Experimental Approaches/Clinical Trials 252 7 Challenges and Opportunities 323
 Contents ix
Acknowledgments 323 3 Glutamate Toxicity 386
References 323 4 Protein Aggregates and Prion-Like Spread of Disease 391
5 Mitochondrial Dysfunction 393
14. Pain 6 Heritability of Disease With Elusive Genetic Causes 395
HARALD SONTHEIMER 7 Epigenetics 398
8 Noncell Autonomous Mechanisms 401
1 Case Study 326 9 Inflammation 402
2 History 326 10 Vascular Abnormalities 407
3 Clinical Presentation/Diagnosis/Epidemiology 327 11 Brain-Derived Neurotrophic Factor 408
4 Disease Mechanism/Cause/Basic Science 329 12 Challenges and Opportunities 412
5 Common Forms of Pain and Currently Approved References 412
Treatments 339
6 Experimental Approaches/Clinical Trials 351
7 Challenges and Opportunities 354 VII
Acknowledgments 354
References 354 Bench-To-Bedside Translation

15. Drug Addiction 17. Drug Discovery and Personalized Medicine

HARALD SONTHEIMER HARALD SONTHEIMER

1 Case Story 357 1 Introduction 417

2 History of Drug Use and Addiction 358 2 How Did We Get to This Point? A Brief History 417
3 Biology of Substance Use and Addiction 361 3 Drug Discovery: How Are Candidate Drugs Identified? 418
4 Common Substance Use Disorders, Underlying Biology, 4 What Are Clinical Trials and Why Do Them? 420
Epidemiology, and Treatment 368 5 The Placebo Effect 424
5 Challenges and Opportunities 379 6 Why Do Clinical Trials Fail? 425
Acknowledgments 379 7 Personalized Medicine 427
References 379 8 Challenges and Opportunities 427
References 428

VI
Common Concepts in Neurological and VIII
Neuropsychiatric Illnesses Neuroscience Jargon

16. Shared Mechanisms of Disease 18. “Neuro”-Dictionary

HARALD SONTHEIMER HARALD SONTHEIMER

1 Introduction 386
2 Neuronal Death 386 Index 469
 About the Author
Dr. Sontheimer is a researcher and educator with a
lifelong interest in neuroscience. A native of Germany,
he obtained a Master’s degree in evolutionary compar-
ative neuroscience from the University of Ulm in which
he worked on the development of occulomotor reflexes.
In 1989, he obtained a doctorate in biophysics and cel-
lular & molecular neuroscience from the University of
Heidelberg, studying biophysical changes that accom-
pany the development of oligodendrocytes, the princi-
pal myelinating cells of the nervous system. He moved
to the United States, where he later became a citizen, for
postdoctoral studies at Yale University. His independent
research career began at Yale in 1991 and continued at the
University of Alabama Birmingham during 1994–2015,
and, more recently, at Virginia Tech and the University of
Virginia. His research focuses on the role of glial support
cells in health and disease. His laboratory has made ma-
jor discoveries that led to two clinical trials using novel
compounds to treat malignant gliomas. His research
led to over 190 peer-­reviewed publications. For the clin-
ical development of his discoveries, Dr. Sontheimer
started a biotechnologies company, Transmolecular Inc.,
which conducted both phase I and phase II clinical tri-
als with the anticancer agent, chlorotoxin. Morphotec
Pharmaceuticals, which will be conducting the phase III
clinical trials, recently acquired this technology. As edu-
cator, Dr. Sontheimer has been active in teaching medical
neuroscience, graduate cellular and molecular neurosci-
ence, and, for the past 10 years, he has offered both gradu-
ate and undergraduate courses on diseases of the nervous
system. In 2005, Dr. Sontheimer became director of the
Civitan International Research Center, a philanthropically
xi
supported center in Birmingham AL devoted to the study
and treatment of children with developmental disabil-
ities, ranging from Down’s ­syndrome to autism. In this
capacity, Dr. Sontheimer was frequently tasked with ex-
plaining complex scientific processes to a lay audience.
Recognizing the need to further educate the public about
neurological disorders using language that is accessible to
an educated public motivated Dr. Sontheimer to write a
textbook on diseases of the nervous system. To ensure that
the material is comprehensive yet readily understandable,
he wrote large parts of this text while on sabbatical leave
at Rhodes College in Memphis, where he taught under-
graduates while testing his book on this group of talented
third- and fourth-year neuroscience students. In 2015, Dr.
Sontheimer was tapped to found a school of neuroscience
at Virginia Tech with the goal to offer a unique neurosci-
ence education to an increasing number of undergrad-
uates. As the first of its kind, this enterprise devoted an
entire school to a variety of neuroscience experiences that
include majors in clinical, experimental, cognitive, sys-
tems, computational, and social neuroscience. In 2020,
Dr. Sontheimer was recruited to the University of Virginia
School of Medicine as the Chair of Neuroscience with the
mission to build this department into a leading research
enterprise devoted to discovery and translation science in
neuroimmunology and neurodegenerative diseases. Dr.
Sontheimer continues to manage a very active research
laboratory where he involves a spectrum of trainees rang-
ing from undergraduates to postdoctoral scientists. Dr.
Sontheimer has trained over 50 PhD and MD/PhD stu-
dents and postdoctoral fellows, many of whom have in-
dependent faculty positions today.
 Acknowledgments
English is a second language for me. To make up for
my shortcomings, I am indebted to several colleagues
who have meticulously reviewed every word I wrote.
Foremost, my long-term Assistant, Anne Wailes, who
tirelessly edited and polished every sentence in the first
edition of this book. She also tracked down the copyrights
for hundreds of figures that were reproduced in this book.
Anne did all this while attending to the many daily tasks
of administrating a large research center and looking after
my trainees in my absence. This was a monumental un-
dertaking and words cannot describe how fortunate I feel
to have had her support throughout this journey.
In addition, each chapter went through two stages of
scientific review. The first stage of review was conducted
by two colleagues to whom I am tremendously indebted.
The first edition was reviewed for scientific content and
accuracy by a tremendously talented postdoc, Dr. Alisha
Epps, who, for an entire year, spent almost every week-
end reading and correcting book chapters as I completed
them. Alisha had a talent to simplify and clarify many
difficult concepts, and, if needed, she found suitable fig-
ures or even drew them from scratch. The second edition
was reviewed by my colleague and friend Dr. Kristin
Phillips. As collegiate Professor in Neuroscience, she is
an equally enthusiastic reader of Neuroscience literature
and had developed a study abroad course that exam-
ines cultural and societal difference in the application of
Neuroscience to Medicine. Co-teaching this course en-
titled “Global Perspectives in Neuroscience” I realized
that my chapters must take a more global look at disease
epidemiology and consider discrepancies in disease pre-
sentations and outcomes. Her contributions to this book
were tremendous and I am indebted to her generous
support.
The second stage of review involved experts in the
respective disease. I am privileged to have a number of
friends who are clinicians or clinician–scientists and who
were willing to selflessly spend countless hours correct-
ing the mistakes I had made. While I am acknowledging
each person with the very chapter they reviewed, I like
to acknowledge all of them in this introduction by name.
Alan Percy, MD, PhD, University of Alabama
Birmingham
Amie Brown McLain, MD, University of Alabama
Birmingham
Anthony Nicholas, MD, PhD, University of Alabama
Birmingham
xiii
Christopher B. Ransom, MD, PhD, University of
Washington
Erik Roberson, MD, PhD, University of Alabama
Birmingham
James H. Meador-Woodruff, MD, University of Alabama
Birmingham
Jeffrey Rothstein, MD, PhD, Johns Hopkins
University
Leon Dure, MD, University of Alabama Birmingham
Louis Burton Nabors, MD, University of Alabama
Birmingham
Richard Sheldon, MD, University of Alabama
Birmingham
Stephen Waxman, MD, PhD, Yale University
Steven Finkbeiner, MD, PhD, The Gladstone Institute for
Neurological Disease
Thomas Novack, PhD, University of Alabama
Birmingham
William Britt, MD, University of Alabama
Birmingham
Warren Bickel, PhD, Virginia Tech
To be able to spend a year and a half writing a book
is a luxury and privilege that, even in academia, only a
few people enjoy. The first edition was developed while
I was still at the University of Alabama at Birmingham. I
like to thank the Dean, President, and my Chairman for
enthusiastically supporting this endeavor.
During the spring semester of 2014, I became a visit-
ing Professor, embedded among the wonderful faculty
of Rhodes College in Memphis TN, a picturesque small
liberal arts college. I am thankful for the hospitality and
support of all the Rhodes administrators and faculty,
many of whom I engaged in inspirational discussion
during lunch or coffee breaks. I am particularly grate-
ful to their Neuroscience program for letting me partic-
ipate in their curriculum and take residence in Clough
Hall. The writing of the second edition accompanied my
building the School of Neuroscience at Virginia Tech,
which, over the course of 5 years grew to be one of the
largest undergraduate programs in the country. Here
I took on several undergraduate courses ranging from
Neuroscience of the Mind, Brain and Pain, to my flagship
course for which this book was written: Disease of the
Nervous System. Throughout, many students provided
invaluable feedback on this book, some formal, using a
prescribed feedback form, other informal during office
hours. I am thankful to the many students who attended
xiv Acknowledgments

my classes at Rhodes, UAB, and Virginia Tech and who
took a particular interest and regularly provided recom-
mendation for improvements. I trust that many of them
are either in Graduate or in Medical school by now, and
I wish them well.
My final acknowledgment goes to my publisher, Elsevier
Academic Press, for their tremendous work editing, pub-
lishing, and marketing this book. Particularly to the edito-
rial project manager Kristi Anderson, the senior acquisitions
editor Melanie Tucker, and their production team.
 Introduction
The study of nervous tissue and its role in learning
and behavior, which we often call neuroscience, is a
very young discipline. Johannes Purkinje first described
nerve cells in the early 1800s, and by 1900, the patholo-
gist Ramón y Cajal generated beautifully detailed histo-
logical drawings illustrating all major cell types in the
brain and spinal cord and their interactions. Cajal also
described many neuron-specific structures including
synaptic contacts between nerve cells; yet how these
structures informed the brain to function like a biologi-
cal computer remained obscure until recently. Although
Luigi Galvani’s pioneering experiments in the late-1700s
had already introduced the world to biological electric-
ity, ion channels and synaptic neurotransmitter recep-
tors were only recognized as “molecular batteries” in
the late-1970s and early 1980s. The first structural image
of an ion channel was generated even more recently in
1998, and for many ion channels and transmitter recep-
tors, such information still eludes us.
Surprisingly, however, long before neuroscience be-
came a freestanding life science discipline, doctors and
scientists had been fascinated with diseases of the ner-
vous system. Absent any understanding of cellular mech-
anisms of signaling, many neurological disorders were
quite accurately described and diagnosed in the early
to mid-1800s, including epilepsy, Parkinson Disease,
schizophrenia, multiple sclerosis, and Duchenne mus-
cular dystrophy. During this period and still today, the
discovery process has been largely driven by a curios-
ity about disease processes. What happens when things
go wrong? Indeed, much of the early mapping of brain
function was only possible because things went very
wrong. Had it not been for brain tumors and intractable
epilepsy, surgeons such as Harvey Cushing and Wilder
Penfield would have had no justification to open the hu-
man skull of awake persons to establish functional maps
of the cortex. Absent unexpected consequences of sur-
gery, such as the bilateral removal of the hippocampi in
HM that left him unable to form new memories, or un-
fortunate accidents exemplified by the railroad worker,
Phineas Gage, who destroyed his frontal lobe in a blast
accident, we would not have had the opportunity to
learn about the role of these brain structures in forming
new memories or executive function, respectively. Such
fascination with nervous system disease and injury con-
tinues to date, and it is probably fair to say that neurosci-
ence is as much a study of health as that of disease.
xv
For the past 20 years, I have been teaching a graduate
course entitled “Diseases of the Nervous System” and
more recently, I added an undergraduate course on the
same topic as well. Every year, almost without fail, stu-
dents would ask me whether I could recommend a book
that they could use to accompany the course. I would
usually point them to my bookshelf, filled with count-
less neuroscience and neurology textbooks ranging from
Principles in Neuroscience to Merritt’s Neurology. When I
started this book project, there was indeed no such book,
yet I hoped that sooner or later some brave neuroscien-
tist would venture to write a book about neurological
illnesses. Surprisingly, this did not happen, so in 2014,
I decided to fill this void. My initial inclination was to
produce a multiauthor edited book. By calling on many
friends and colleagues to each write a chapter on their
favorite disease, this should be a quick affair. However,
from own experience, I knew that book chapters are al-
ways the lowest priority on my “to do” list, and I really
was eager to pester my colleagues monthly to deliver
their goods. Ultimately, they would surely ask a senior
postdoc to take the lead and in the end, the chapters
would be heterogeneous and not necessarily at a level
appropriate for a college audience. For my target audi-
ence, this book needed to be a monograph. While I did
not know at the time what I was getting into, I spent the
majority of 2014 and 2015 reading over 2500 scientific
papers and review articles while also writing for about
7–10 h daily. I felt exhausted yet also became quite a bit
more educated in the process. Given the rapid progress
in research and discovery, 5 years later, in 2019–20, I re-
peated this exercise and wrote this second edition, which
includes major updates and new additional chapters on
Pain and Addiction.
The target audience for this book is any student in-
terested in neurological and neuropsychiatric illnesses.
This includes undergraduates, early graduate students,
and medical students taking a medical neuroscience
course. I also expect the material to be of benefit to many
health professionals who are not experts in the field.
The book may even appeal to science writers or simply
a science-minded layperson, possibly including persons
affected by one of the illnesses. Purposefully, the book
lacks a basic introduction to neuroscience as I would ex-
pect the reader to have a basic understanding of neu-
robiology. Many excellent textbooks have been written,
each of which would prepare one well to comprehend
xvi Introduction
this text. I feel that I could not have done justice to this
rapidly expanding field had I attempted to write a short
introduction. However, to at least partially make up for
this, I include an extensive final chapter that is called
“Neuroscience Jargon.” I consider this more than just a
dictionary. It has a succinct summary of approximately
500 of the most important terms and is written as non-
technically as possible. I hope that this will assist the
reader to get his/her bearings as needed.
The book makes every effort to cover all the major
neurological illnesses that affect the central nervous sys-
tem though it is far from complete. My intention was
to go fairly deep into disease mechanisms and this pre-
cluded a broader coverage of small and less well-known
conditions. I found it useful to group the diseases into
five broad categories that provided some logical flow
and progression. Specifically, I begin with static ill-
nesses, where an acute onset causes immediate disabil-
ity that typically does not worsen over time. This group
is best exemplified by stroke and CNS trauma but also
includes genetic or acquired epilepsy (Chapters 1–3). I
next covered the classical primary progressive neuro-
degenerative diseases including Alzheimer, Parkinson,
Huntington, and ALS (Chapters 4–7). For each of these
chapters, I added some important related disorders.
For example, the chapter on Alzheimer includes frontal
temporal dementia; for Parkinson, I included essential
tremors and dystonia, and for Huntington, I touch on
related “repeat disorders” such as spinocerebellar ataxia.
The chapter that covers ALS includes a variety of dis-
ease along the motor pathway essentially moving from
diseases affecting the motor neurons themselves (ALS),
their axons (Guillain-Barre syndrome), to the presynap-
tic (Lambert Eaton myotonia), and postsynaptic (myas-
thenia gravis) neuromuscular junction.
Next, I progressed to neurodegenerative diseases that
are secondary to an insult yet still cause progressive
neuronal death. I call these secondary progressive neu-
rodegenerative diseases and the examples I am covering
include multiple sclerosis, brain tumors, and infections
(Chapters 8–10). It may be unconventional to call these
secondary neurodegenerative diseases yet in multiple
sclerosis, the loss of myelin causes progressive axonal de-
generation, brain tumors cause neurological symptoms
by gradually killing neurons, and infection causes pro-
gressive illnesses again by progressively killing neurons.
Nervous system infection could have quickly become an
unmanageable topic since far too many pathogens exist
that could affect the nervous system. I therefore elected
to discuss important examples for each class of patho-
gen (prion proteins, bacteria, fungi, viruses, single- and
multicellular parasites). While none of these pathogens
are brain-specific, I chose examples in which the nervous
system is primarily affected including meningitis, botu-
lism, tetanus, poliomyelitis, neurosyphilis, brain-eating
amoeba, neurosistercosis, neuroaids, and prion diseases.
I also used this chapter as an opportunity to highlight
the tropism displayed by some viruses for the nervous
system and how this can be harnessed to deliver genes to
the nervous system for therapeutic purposes.
For the section on neurodevelopmental disorders, I
similarly chose four important examples including Down
syndrome, Fragile X, autism, and Rett syndrome. These
disorders have so many commonalities that it made
sense to cover them in a single chapter (Chapter 11).
No contemporary book of nervous system disease
would be complete without coverage of neuropsychiat-
ric illnesses and I elected to devote one chapter each to
depression (Chapter 12) and schizophrenia (Chapter 13).
Finally, for the second edition, I also included pain
(Chapter 14) and addiction (Chapter 15), two topics that
intersect on the pervasive issue of addiction to opioid
pain killers.
Taken together, I believe the material covers the “big”
brain disorders that any neuroscientist or medical stu-
dent should know. However, anyone looking for more
detailed information on rare disorders or disorders pri-
marily affecting the peripheral nervous system or sen-
sory organs is referred to some of the excellent neurology
textbooks that I cite as my major sources throughout the
book.
To ensure that the material is presented in an acces-
sible, yet comprehensive format, the book was devel-
oped in a uniquely student-centered way, using my
target audience as a focus group. To do so, I wrote the
book as accompanying text to an undergraduate course,
writing each chapter as I was teaching to neuroscience
majors. The first edition was written while on sabbati-
cal leave at Rhodes College in Memphis TN, a small and
highly selective Liberal Arts college. The second edition
I wrote at Virginia Tech, where I moved in 2015 to build
the School of Neuroscience, an entire School devoted to
Neuroscience. Each week, I handed out a new disease
chapter, and after giving a 75-min lecture, small groups
of students had to prepare independent lectures that
they delivered to the class based on recent influential
clinical and basic science papers that I assigned (and
list in this book with each chapter). Each week, using a
questionnaire, the students provided detailed feedback
on how accessible, interesting, and complete my chap-
ters were, and how well the book prepared them for the
assigned papers that they had to present in class. I took
their comments very seriously, frequently spending days
incorporating their suggestions. I am thankful to all of
them, as it made the book a better read.
As I began my research, a challenge that became im-
mediately evident was the sheer magnitude of the avail-
able literature. Moreover, writing about a disease that
is outside ones’ personal research specialty leaves one
without a compass to decide which facts are ­important
 Introduction
and which are not. Narrowing literature searches to
just “diseases” and “review articles” did not help much
and only marginally reduced the number of hits from
the tens of thousands into the thousands. While it was
gratifying to see the enormous amount of information
that has been published, it was daunting to filter and
condense this material into a manageable number of
sources. In the end, I developed a strategy to first iden-
tify the “opinion leaders” in each field, and then, using
their high-impact reviews, widen my search to include
reviews that appeared to cover the most salient points
on which the entire field appears to largely agree upon,
while staying largely out of more tentative emerging and
controversial topics. This was important since the objec-
tive of this textbook was to introduce current accepted
concepts rather than speculations.
Another challenge I faced was to keep the material
interesting. As teacher of medical neuroscience, I have
long recognized the value of clinical cases. I decided to
start each disease chapter with case story, which is either
an actual case or one close to cases that I have actually
witnessed in some form or other. The students liked this
format, particularly since many of the cases I describe
involve young people. To offer perspective on each dis-
ease, I also elected to provide a brief historic review for
each disease. How long has society been dealing with
stroke, epilepsy, Huntington, or autism? What were early
interpretations on the disease cause, how was disease
treated, and what were the most informative milestones?
This was possibly the hardest section for me to write,
since good sources were difficult to find. Yet it was also
the most fascinating. The students initially had little ap-
preciation for these sections and really did not see much
value in them. However, this changed after we discussed
the value of what I call “science forensics” and the his-
toric insight that could be gleaned. We discussed how
the history of disease, when viewed in the context of the
history of mankind, allows us to dismiss or consider hu-
man endeavors and exposure to man-made chemicals as
disease causes. After we discussed how Mexican vases
made over 600 years ago already depicted children with
Down syndrome, or how Polio crippled children were
portrayed on Egyptian stilts that were over 2000 years
old, it became clear that neither of these conditions was
modern at all. Historic accounts similarly suggest that
environmental exposures are unlikely contributors to
stroke or epilepsy. Yet, by contrast, the earliest accounts
of Parkinson Disease align perfectly with the early in-
dustrial revolution of the mid-1800, making industrial
pollutants potential disease contributors. Even more ex-
treme, no historic account for autism exists prior to the
1930s. Clearly, for some of those diseases, human influ-
ences must be considered as contributory factors.
The historic adventures also allowed me to examine
diseases in the context of society at a given time in h
­ istory,
xvii
clearly important lessons when teaching neuroscience at
a Liberal Arts college. Our classes included how patients
with epilepsy were labeled witches and burned in me-
dieval Europe; how the heritability of diseases such as
Huntington corrupted even doctors to subscribe to the
reprehensible teachings of the eugenics movement; or how
the infamous Tuskegee syphilis studies served as the foun-
dation for the protection of human subjects participating
in human clinical trials, measures that we take for granted
today. Another lesson learned from the ancient accounts
of Down syndrome is that childbirth late in a mother’s life
occurred throughout history, but more importantly that
those children were cared for in many societies with the
same love and compassion we have for them today.
The majority of pages in this book are devoted to the
biology of each disease. It is remarkable how much we
know and how far we have come in just the past few
decades, from the historic disease pathology-focused
approach to contemporary considerations of genes and
environmental interactions causing disease in suscepti-
ble individuals. It is fascinating to note how cumbersome
the initial positional cloning efforts were that identified
the first candidate genes for disease compared to today’s
large genome-wide association studies that identify large
networks of gene and their interactions. Clearly, we expe-
rience a transformational opportunity to study and un-
derstand disease through the study of rare genetic forms
of familial diseases that can inform us about general dis-
ease mechanisms and allow us to reproduce disease in
genetic animal models. At the same time, it is sobering
to see how often findings in the laboratory fail to sub-
sequently translate into better clinical practice. I devote
a considerable amount of discussion to such challenges
and end each chapter with a personal assessment of chal-
lenges and opportunities. After completing the disease
chapters, it was clear that there were many cross-cutting
shared mechanisms and features of neurological disease
that I elected to devote an entire chapter solely to shared
mechanisms of neurological illnesses (Chapter 16).
Not surprisingly, almost all the class discussions
sooner or later gravitated toward ways to translate re-
search findings from the bench to the bedside. Yet few
of the students had any idea what this really entails or
the challenges that clinical trials face. Having been for-
tunate enough to develop an experimental treatment
for brain tumors in my laboratory that I was able to ad-
vance from the bench into the clinic through a venture
capital-supported biotech startup, I felt well equipped to
discuss many of the challenges in proper perspective. So
I devoted an entire chapter (Chapter 17) to this import-
ant, albeit not neuroscience-specific, topic. The class in-
cluded important discussions on the placebo effect and
frank conversations as to why many scientific findings
cannot be reproduced, and why most clinical trials ulti-
mately fail.
xviii Introduction
I also added several provocative topics to class dis-
cussions such as the questionable uses of neuroscience
in marketing and advertising and the controversial use
of neuroscience in the courtroom. Since neither relates to
specific neurological diseases, I elected to leave this out
of the book but encourage neuroscience teachers to bring
such topics into the classroom as well.
One thing that troubled me throughout my writing
was the way in which sources are credited in textbooks.
As a scientist, I reflexively place a source citation behind
every statement I make. In the context of this book, how-
ever, I could only cite a few articles restricting myself
to ones that I felt were particularly pertinent to a given
statement. A list of general sources that most informed
me in my reading is included at the end of each chapter.
I am concerned, however, that I may have gotten a few
facts wrong, and that some of my colleagues will contact
me, offended that I ignored one of their findings that they
consider ground breaking; or if I mentioned them, that I
failed to explicitly credit them for their contribution. It
was a danger that I had to accept, albeit with trepidation
and I hope that any such scientists will accept my pre-
emptive apologies. To mitigate against factual errors, I
reached out to many colleagues around the country, clin-
ical scientists whom I consider experts in the respected
disease, and asked them to review each chapter. I am
indebted to these colleagues, whom I credit with each
chapter, who selflessly devoted many hours to make this
a better book. Their effort has put me at greater ease and
hopefully will assure the reader that this book represents
the current state of knowledge.
Given that the book was developed as an accom-
paniment to a college course, I expect that it may en-
courage colleagues to offer a similar course at their
institution. I certainly hope that this is the case. To
facilitate this, I am happy to share PowerPoint slides
of any drawings or figures contained in this book, as
well as any of the 1000 + slides that I made to accom-
pany this course. I can be contacted by email at hson-
theimer@gmail.com. Also, for each chapter I am listing
a selection of influential clinical and basic science ar-
ticles that I used in class. These are just my personal
recommendations and not endorsements of particular
themes or topics. These papers have generated valu-
able discussion and augmented the learning provided
through the book.
Finally, as I finish editing the second edition of
this book, in which I incorporated many scientific ad-
vances and clinical trials occurred since the first pub-
lication in 2015, I still keep finding more and more
articles reporting exciting new scientific discoveries
that I would have liked to include. However, if I did,
this book would never reach the press. It is refreshing
to see that neuroscience has become one of the hottest
subjects in colleges and graduate schools and even the
popular press. Neuroscience research is moving at a
lightning pace. It is therefore unavoidable that the cov-
ered material will only be current for a brief moment
in time, and, as you read this book, that time will have
already passed.
Harald Sontheimer
 S E C T I O N I

STATIC NERVOUS SYSTEM

DISEASES
 C H A P T E R

1
Cerebrovascular Infarct: Stroke
Harald Sontheimer
O U T L I N E

1 Case Story 3 5.3 Anticlotting Factors to Prevent Recurrence 19

5.4 Treatment of Hemorrhagic Stroke 19
2 History 4
5.5 Rehabilitation 19
3 Clinical Presentation/Diagnosis/Epidemiology 5 5.6 Stroke Prevention 19
4 Disease Mechanism/Cause/Basic Science 8 6 Experimental Approaches/Clinical Trials 20
4.1 Causes of Vessel Occlusions: The Thrombolytic 6.1 Neuroprotection 20
Cascade 10 6.2 Hypothermia 21
4.2 The Ischemic Cascade 11 6.3 Improved Clot Busters 21
4.3 The Ischemic Penumbra 13 6.4 Brain Rewiring After Stroke 21
4.4 The NMDA Receptor and Glutamate 6.5 Why Have So Many Promising Drugs Failed in
Excitotoxicity 15 Human Clinical Trials? 22
4.5 Role of Glutamate 15
7 Challenges and Opportunities 22
4.6 NMDA Inhibitors to Treat Stroke 15
4.7 Effect of Temperature 16 Acknowledgment 23
4.8 Stroke Genetics 17
References 23
5 Treatment/Standard of Care/Clinical
General Readings Used as Source 24
Management 17
5.1 Chemical Thrombolysis Using Intravenous tPA 17 Suggested Papers or Journal Club Assignments 24
5.2 Mechanical Thrombolysis by Endovascular Clinical Papers 24
Therapy for Ischemic Stroke 18 Basic Papers 24

1 CASE STORY
Natalie was excited to start her senior year at Virginia
Tech. She saved some of the most interesting art his-
tory and creative writing classes for her last year. She
was equally excited to participate one last season in
Cheerleading for the Hokies football team. She still gets
a rush by the pregame pageantry and a stadium trem-
bling as the players enter the stadium to the roaring
sounds of “Enter Sandman.” This Saturday morning,
she woke unusually early and was not feeling well at all.
Her head hurt and although she had been partying the
night before, this did not feel like a hangover headache.
After rolling in pain for a few minutes, she decided to
get up and take some ibuprofen. However, getting out
of bed turned into a struggle. She did not sense her right
hand and could not move her right leg. As she rolled to-
ward the edge of the bed, her vision blurred. Her eyes
felt like they were pushing out of her head. “Where is
the phone?” She used her left hand to scan her night
stand one handspan at a time. Once her hand made con-
tact with her cell phone, she struggled to recognize the
screen. She was panicking. Who to call? Amy, her best
friend should be up by now. After 20 rings, Amy finally
answered. “Why up so early? I am sleeping.” “Amy, I
can’t move, I am trapped in my bed with a brutal head-
ache and I can’t see well.” It didn’t take Amy long 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
2 years and had ran several codes quite similar to this
one. But never in a person Natalie’s age! She rushed to
Natalie’s apartment while calling VT rescue on her way.
They arrived just a minute apart and the team pried
open the door with force only to find Natalie next to her
bed crying unconsolably. At this point, she was barely
responding to the rescue team. Her right face was droop-
ing, and her arm was limb. Realizing that this may be a
stroke, the team called ahead to Louis Gale Hospital to
have the emergency room ready. Everything was a blur.
Natalie was lifted on the gurney and quickly carried to
the ambulance where Amy jumped in next to her, hold-
ing her friends hand all the way.
The 6-min drive seemed like ages, and by the time
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,
Natalie had near complete loss of blood flow in her left
brain, particularly the central part. Ischemic stroke is
most likely caused by an embolus or thrombus in the
middle cerebral artery. This occludes blood flow to the
most important parts of the brain controlling sensation
and movement of the right body as well as speech and
language. “Who has last seen her responsive?” asked the
emergency room physician. Thankfully Amy was there
to describe the events this morning. “How long ago did
she call you?” “About 50 minutes ago,” Amy answered.
As imaging has ruled out a hemorrhage, and Natalie’s
blood pressure was 123/78, the emergency team de-
cided to deliver a bolus injection of tPA, a clot-busting
chemical, and hooked her up to a continuous infusion
to deliver more of the drug. The next hour, however,
did not yield any improvement and a subsequent CT
scan showed little change. “Get her to Roanoke for sur-
gical thrombectomy,” ordered the attending neurolo-
gist, “and use the helicopter to get there fast.” Less than
30 min later, Natalie arrived on the helipad of Roanoke
Memorial Hospital and was greeted by a medical team
that would take her to the angio suite where the radiol-
ogist threaded a catheter up her femoral vein toward
the head and into the MCA. Once he navigated to the
blocked artery, he actuated a small mesh that encap-
sulated the thrombus and slowly began to pull back.
Within no time, blood flow returned, and Natalie started
talking. Almost miraculously, she was able to move her
right arm and her speech, while still slurred, was intelli-
gible. Two hours later, Natalie was talking to Amy in the
recovery room, and she was seriously considering going
to the football game that evening. While that obviously
did not happen, Natalie was back home 2 days later on
a prescription of warfarin, a blood thinning medication.
Had it not been for Amy quickly recognizing her friend’s
condition and the proximity to a level one trauma cen-
ter with a skilled interventional radiologist, Natalie may
I. STATIC NERVOUS SYSTEM DISEASES
have ­permanently lost movement of her right body or
worse, may have died. She was among the 1 out of every
20 patients who were able to benefit from recent medical
advances in stroke management using a combination of
chemical and mechanical clot busters. During her med-
ical follow-up, it was determined that she suffered from
a congenital heart condition, a patent foramen ovale, in
which the left and right atria of the heart are connected
by a hole. This probably allowed a thrombus from her
lower legs to find its way into the cerebral circulation
rather than being filtered out by passing through the
lungs. On the recommendation of her cardiologist,
Natalie had heart surgery to close the foramen ovale
3 months after her stroke. This should lower her risk for
stroke recurrence to that of the general population.
2 HISTORY
Without recognizing its underlying cause, Hippocrates
(460 BC), the “father of medicine,” provided the first
clinical report of a person being struck by sudden paral-
ysis, a condition he called apoplexy. This Greek word,
meaning “striking away,” refers to a sudden loss of
the ability to feel and move parts of the body and was
widely adopted as a medical term until it was replaced
by cerebrovascular disease at the beginning of the 20th
century. Most patients and the general public prefer the
term stroke, which first appeared in the English language
in 1599. It conveys the sudden onset of a seemingly ran-
dom event.
Hippocrates explained apoplexy using his humoral
theory, according to which the composition and work-
ings of the body are based on four distinct bodily fluids
(black bile, yellow bile, phlegm, and blood), which de-
termine a person’s temperament and health. Diseases
result from an imbalance in these four humors, with ap-
oplexy specifically affecting the flow of humors to the
brain. Humors were rebalanced through purging and
bloodletting, which became the treatment of choice for
stroke throughout the middle ages. The first scientific ev-
idence that a disruption of blood flow to the brain causes
stroke came through a series of autopsies conducted by
Jakob Wepfer in the mid-1600s, yet the humoral theory
of Hippocratic medicine ruled until the German physi-
cian Rudolf Virchow discredited it in his “Theories on
Cellular Pathology,” published in 1858. Virchow, who
made countless impactful contributions to medicine,
was the first to explain that blood clots forming in the
pulmonary artery can cause vascular thrombosis, and
fragments arising from these thrombi can enter the cir-
culation as emboli. These emboli are carried along with
blood into remote blood vessels, where they can occlude
blood flow or rupture vessels. His theory was initially
based only on patient autopsies. However, together with
 3 Clinical presentation/diagnosis/epidemiology
his student, Julius Cohnheim, Virchow went on to test
this idea by injecting small wax particles into the arteries
of a frog’s tongue to show that the wax acted as an em-
bolus that shut off blood flow to the parts of the tongue
supplied by this vessel. In subsequent studies, Cohnheim
showed that an embolus can cause either blockade (isch-
emic stroke) or rupture (hemorrhagic stroke), contradict-
ing competing views at the time that suggested that only
blood vessel malformations or aneurisms could hemor-
rhage. It is worth noting that in the early 20th century, the
recognition that emboli cause the selective abolition of
blood flow in cortical blood vessels gave neurologists the
first insight into functional neuroanatomy, showing se-
lective and predictive deficits in sensory and motor func-
tion depending on where an embolus occluded a vessel.
Throughout history and well into the 19th century, it
was common to view stroke as a divine intervention, a
summons to duty. Stroke was regarded as God’s pun-
ishment for unacceptable behavior. Shockingly, in spite
of Virchow’s discoveries on thromboembolism, even
major medical textbooks continued to blame the patient
for the disease. For example, Osler’s medical textbook
(1892) suggested that “the excited action of the heart in
emotion may cause a rupture.” Others even suggested
that a patient’s physical attributes, namely, a short,
thick neck, and a large head, were predisposing factors.1
Interestingly, a diet “high in seasoned meat, poignant
sauces and plenty of rich wine” was already accurately
predicted by Robinson as a stroke risk factor in 1732.1, 2
We have obviously come a long way in the past 100 years.
The routine medical use of X-rays, introduced in 1895,
ultimately led to the development of the now widely
available computed tomography (CT), with which it is
possible to quickly and accurately localize blood clots
or bleeds to guide further intervention. Surgical, me-
chanical, or chemical recanalization are now standard
procedures, and various forms of image-guided stenting
procedures, adopted from cardiac surgery, are now able
to open cerebral vessels. The discovery of tissue plas-
minogen activator (tPA), approved as a chemical “clot
buster” in 1996, was a major advance in the clinical man-
agement of acute stroke. Together with widely adopted
rehabilitation, the outlook for many stroke patients has
improved considerably.
3 CLINICAL PRESENTATION/
DIAGNOSIS/EPIDEMIOLOGY
Cerebrovascular infarct is defined by the sudden onset
of neurological symptoms as a result of inadequate blood
flow. This is commonly called a stroke because the disease
comes on as quickly as a “stroke of lightning” and without
warning; we use the terms stroke and cerebrovascular infarct
interchangeably throughout. We typically distinguish
I. STATIC NERVOUS SYSTEM DISEASES
5
three major stroke types that differ by their underlying
cause and presentation. Focal ischemic strokes make up
the vast majority of cases (γ  80%) and result from vessel
occlusion by atherosclerosis or blockage by an embolus or
thrombus that causes a focal neurological deficit. Global
ischemic strokes, often called hypoxic-ischemic injury,
are more rare (10%) and result from a global reduction in
blood flow, for example, through cardiac insufficiency. The
neurological deficit affects the entire brain and is typically
associated with a loss of consciousness. Finally, hemor-
rhagic strokes result from rupture of fragile blood vessels
or aneurysm. These account for 10% of all strokes and can
present with focal deficits if a small vessel is affected or
global deficits if massive intracranial bleeding occurs. For
the majority of patients who suffer an ischemic stroke,
maximal disability occurs immediately after the blockage
forms, without further worsening unless secondary intra-
cranial bleeding occurs. Once the obstruction clears, the
patient’s symptoms improve. However, a stroke patient
has a greatly increased likelihood of recurrence: 20–30%
of patients experience a second stroke within a year af-
ter the first insult. Hemorrhagic stroke is a severe medical
emergency, with mortality approaching 40%. Symptoms
are often progressive as bleeding continues, and a loss of
consciousness is common.
Neurological symptoms of stroke vary depending on
the brain region affected; most strokes are focal and af-
fect only one side of the body with muscle weakness and
sensory loss. Telltale signs (Table 1) include a drooping
face, change in vision, inability to speak, weakness and
sensory loss (preferentially on one side of the body), and
severe sudden-onset headaches. Many of these symptoms
clear once blood flow to the affected brain region is re-
stored. Therefore, rapid diagnosis and immediate medical
intervention are of the essence, and anyone suspected of
suffering a stroke should immediately call for emergency
medical services. The popular catchphrase: “Time lost is
TABLE 1 Common symptoms of a focal stroke.
Alteration in consciousness; stupor or coma, confusion or agitation/
memory loss seizures, delirium
Headache, intense or unusually severe often associated with
decreased level of consciousness/neurological deficit, unusual/severe
neck or facial pain
Aphasia (incoherent speech or difficulty understanding speech)
Facial weakness or asymmetry, paralysis of facial muscles (e.g., when
patients speak or smile)
Incoordination, weakness, paralysis, or sensory loss of one or more limbs
(usually one half of the body and in particular the hand)
Ataxia (poor balance, clumsiness, or difficulty walking)
Visual loss, vertigo, double vision, unilateral hearing loss, nausea,
vomiting, photophobia, or phonophobia
6 1. Cerebrovascular Infarct: Stroke
TABLE 2 Act FAST emergency response issued by the National
Stroke Association.
Use the FAST test to remember warning signs of stroke
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?
S = SPEECH Ask the person to repeat a simple sentence. Does the
speech sound slurred or strange?
T = TIME If you observe any of these signs (independently or
together), call 9-1-1 immediately.
brain lost,” highlights the sense of urgency. In the case
of hemorrhaging stroke, symptoms may worsen rapidly
because intracranial bleeding affects vital brain functions,
and patients may lose consciousness. To encourage rapid
admission of potential stroke victims to a hospital, the
National Stroke Association devised the Face Arm and
Speech Test (FAST), which aids the public in quickly iden-
tifying the major warning signs of the disease (Table 2).
Once the patient is receiving medical care, a diagnos-
tic decision tree is typically followed to guide treatment,
as illustrated in Figure 1.
Immediately upon admission to a hospital, the dis-
tinction between ischemic (occluding) stroke and hem-
orrhagic stroke must be established because treatment
for the two differs completely. CT, essentially a three-­
dimensional X-ray, is the preferred test. It is quick, rel-
atively inexpensive, and widely available, even in small
hospitals or community clinics. Moreover, it is very
sensitive for detecting intracranial bleeding because
iron in the blood’s hemoglobin readily absorbs X-rays.
Examples of CT scans from two patients, one with an
ischemic stroke and one with a hemorrhagic stroke, are
illustrated in Figure 2.
FIGURE 1 Stroke diagnosis. Upon admission to a hospital, a phy-
sician uses this decision tree to establish the most likely diagnosis and
aid in subsequent treatment. First, a focal neurological deficit must be
established. If it resolves spontaneously, it suggests a transient isch-
emic attack (TIA). If the deficit persists for more than 24 h, a stroke is
suspected. The imaging results determine whether the infarct is hem-
orrhagic, with evidence of blood that results in high-density areas on
the computed tomographic (CT) scan. If this is not the case, an isch-
emic infarct is the most likely diagnosis.
I. STATIC NERVOUS SYSTEM DISEASES
FIGURE 2 Representative examples of computed tomography
(CT) scans from two patients. The left image illustrates a hemorrhagic
stroke in the basal ganglia; the increased signal (hyperdensity, arrow)
signifies bleeding. The right is a characteristic ischemic stroke with
reduced density in the infarct region (hypodensity, arrows) suggestive
of stroke-associated edema. Images were kindly provided by Dr. Surjith
Vattoth, Radiology, University of Alabama Birmingham.
The ischemic lesion contains more water because of
edema and therefore presents with reduced density on
CT, whereas the absorption of X-rays by blood creates a
hyperdense image on CT in a hemorrhagic stroke.3
If bleeding is detected, any attempt to stop blood en-
tering the brain (including surgical, if possible) must
be considered. In the absence of bleeding, restoring
blood flow to the affected brain region as quickly and
effectively as possible is imperative. Major advances to
restore blood flow using chemical or mechanical recanal-
ization of occluded blood vessels have been made and
are extensively discussed in Section 5.
If the symptoms resolve spontaneously and quickly,
within less than 24 h, we typically consider the insult a
transient ischemic attack (TIA) as opposed to a stroke.
However, the distinction between TIA and stroke is less
important regarding treatment decisions because we do
not have the luxury to wait 24 h before providing treat-
ment. If, as is often the case, symptoms resolve within
minutes to an hour, the diagnosis of TIA is an important
risk factor for the patient, who has an elevated risk of
developing a stroke in the future (5% within 1 year).
It is possible to misdiagnose a stroke in an emergency
room setting, where time is of the essence and diagnoses
must be made quickly. A number of conditions can mimic
stroke symptoms, including migraine headaches, hypo-
glycemia (particularly in diabetic patients), seizures, and
toxic-metabolic disturbances caused by drug use. Some
of these can be ruled out by simple laboratory tests; hy-
poglycemia is a good example. Others can be excluded
through a detailed patient history and, in particular, the
ability of the physician to establish a definitive history of
focal neurological symptoms, ideally corroborated by an
eye witness.
Rapid diagnosis is facilitated by the use of a simple, 15-
item stroke assessment scale established by the National
 3 Clinical presentation/diagnosis/epidemiology
Institutes of Health. This assessment, called the National
Institutes of Health Stroke Scale, assesses level of con-
sciousness, ocular motility, facial and limb strength, sen-
sory function, coordination, speech, and attention.4
The pathophysiology of stroke is well understood,
and the treatments available to date are effective for
many patients. Unfortunately, the underlying disease
causes, including atherosclerosis and hypertension, can
rarely be completely removed, although a combination
of lifestyle changes and chronic medical management of
risk factors can reduce the likelihood of recurrence.
Numerous risk factors have been identified, many
of which are modifiable through changes in lifestyle or
medication. By far the largest risk factor is a person’s
age, which increases incidence almost exponentially,
doubling with every 5 years of life. Put in perspective,
only 1:10,000 persons are at risk of suffering a stroke at
age 45; that number climbs to 1 in 100 by age 75. The
second-leading risk factor is hypertension, which in-
­ countries including the United States and Europe have
creases stroke risk about 5-fold, followed by heart dis-
ease (3-fold), diabetes (2- to 3-fold), smoking (1.5- to
2-fold), and drug use (1- to 4-fold). Note that these risk
factors are additive, and thus a 75-year-old diabetic
smoker who drinks and has heart disease has a greatly
compounded risk. African Americans are twice as likely
to suffer a stroke as Caucasians. Men are slightly more
likely than women to suffer a stroke and die from it.
7
Epidemiological data established what is often called
the “stroke belt,” namely, a geographic region within the
United States where annual stroke deaths are highest
(Figure 3). This is readily explained by the confluence of
risk factors of race, diabetes, and obesity among the pop-
ulation in the southern and southeastern United States.
Stroke is the most common neurological disorder in
the United States affecting close to 800,000 people each
year. It is the fifth-leading cause of death, with ~  150,000
stroke-related deaths annually. Many patients survive
but remain permanently disabled, making stroke the
leading cause of permanent disability in the United
States with ~  6.4 million stroke survivors. Globally,
stroke is the second-leading cause of death with an es-
timated 13.7 million new stroke cases causing 5.5 mil-
lion deaths. It is also a leading cause of disability with
80 million stroke survivors worldwide (GDB stroke
collaborators, Lancet Neurology 2019). High-income
seen declining rates of incidence and mortality, most
likely as a result of improved awareness and manage-
ment of risk factors such as hypertension and hyper-
cholesterolemia. However, the global burden of stroke
continues to increase. Significant differences in stroke
disease burden exist between countries. For example,
incidence is four times higher in China than in Latin
America, yet this d ­ ifference is entirely attributable

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.

I. STATIC NERVOUS SYSTEM DISEASES

8 1. Cerebrovascular Infarct: Stroke
to the average age of the population as age-adjusted
stroke incidence is identical around the globe.
4 DISEASE MECHANISM/CAUSE/BASIC
SCIENCE
Stroke is conceptually a simple disease wherein the
brain’s “plumbing” is defective. We have a fairly good
understanding of causes and remedies. In its most ele-
mentary form, a stroke is the direct result of inadequate
blood flow to a region of the brain, with ensuing death
of neurons as a consequence of energy loss. To fully ap-
preciate the vulnerability of the brain to transient or per-
manent loss of blood flow, it is important to discuss the
unique energy requirements of the brain and the cerebral
vasculature that delivers this energy.
The brain is the organ that uses the largest amount of
energy in our body. At only 2% of body mass, an adult
brain uses 20% of total energy, whereas a child’s brain
uses as much as 40%. The cellular energy unit is adenos-
ine triphosphate (ATP), the majority of which is produced
by the oxidative metabolism of glucose to carbon diox-
ide (CO2) and water. To supply sufficient ATP, an adult
brain requires 150 g glucose and 72 L of oxygen per day.
While the developing brain still uses a significant amount
of energy for the biosynthesis of cellular constituents, par-
ticularly myelin, the adult brain has very little synthetic ac-
tivity because few cells and membranes are ever replaced.
Thus, the vast majority of energy is used to shuttle ions
across the cell membrane to establish and maintain ionic
gradients necessary for electrical signaling (Figure 4).
FIGURE 4 Cellular energy use of neurons in the brain. Adenosine
triphosphate (ATP) produced in the mitochondria directly fuels ATP-
driven pumps such as the Na+  K+ ATPase and the Ca2  +-ATPases and
indirectly provides the energy for Na+-coupled transporters.
I. STATIC NERVOUS SYSTEM DISEASES
Of greatest importance is the extrusion of Na+ and the
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
maintains a negative resting membrane potential that
neurons assume between action potentials. Moreover, the
electrochemical gradient for Na+ is harnessed to transport
glucose and amino acids across the membrane and to reg-
ulate intracellular pH. Therefore, these transport systems
are indirectly coupled to the ATP used by the Na+/K+
ATPase. Additional important consumers of cellular ATP
are Ca2  +-ATPases that transport Ca2  + against a steep con-
centration gradient either out of the cell or into organelles.
Intracellular Ca2  + is maintained around 100 nM, which is
10,000-fold lower than the 1 mM concentration of Ca2  + in
the extracellular space. Ca2  + functions as a second mes-
senger in only a very narrow concentration range of 100–
1000 nM and therefore must be carefully regulated by the
Ca2  +-ATPases. Any increase above this range activates
enzymes and signaling cascades that are largely destruc-
tive (discussed in more detail later in this chapter). Finally,
ATP serves as an important source for high-energy phos-
phates that can attach to proteins and enzymes through
phosphatases that act as on/off switches to regulate the
activity of these proteins and enzymes.
ATP stores in neurons are exhausted after only 120 s.
Therefore, neurons must continuously produce ATP from
glucose via oxidative metabolism of glucose in the mi-
tochondria. Glucose is the most readily available energy
source throughout the body, and most cells can store some
readily available glucose in the form of glycogen gran-
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-
strates. For example, hypoglycemia may occur in a dia-
betic patient who receives an excess amount of i­nsulin,
and anoxia can occur in a patient in a near-drowning
 4 Disease mechanism/cause/basic science
situation who stops breathing. In general, however, cere-
brovascular infarction is the result of reduced blood flow
that limits both glucose and oxygen delivery; this condi-
tion is called ischemia.
It is important to note that while energy consumption
throughout the body varies with activity, most notably
in skeletal muscles and the heart, the brain’s metabolic
activity is fairly constant and not measurably affected by
changes in mental state. Therefore, the overall regulation
of blood flow to the brain simply ensures a constant flow
of oxygenated blood to the brain. However, regional dif-
ferences in energy consumption occur and give rise to
the blood oxygen concentrations measured by functional
magnetic resonance imaging. For every region with en-
hanced regional blood flow, there is another that has re-
duced blood flow, effectively canceling each other for a
constant metabolic activity.
The cerebral vasculature receives its main supply of
oxygenated blood via the two common carotid arteries
on each side of the neck, which branch into the internal
carotid artery (ICA) and external carotid artery (ECA),
respectively (Figure 5).
The ICA is the predominant supply line, carrying
γ  75% of the total blood volume to the brain, whereas
the ECA primarily feeds the neck and face. Two vertebral
arteries at the back of the neck provide an additional mi-
FIGURE 5 The cerebral vasculature in a schematic view. The main
supply of oxygenated blood to the brain is through the two common
carotid arteries on each side of the neck, which branch into the internal
(ICA) and external carotid arteries (ECA), respectively. The ICA is the pre-
dominant supply line, carrying ~  75% of the total blood volume to the
brain, while the ECA primarily feeds the neck and face. The ICA ends by
dividing into the middle (MCA) and anterior cerebral (ACA) arteries. Two
vertebral arteries at the back of the neck provide an additional minor sup-
ply pathway for the brain; this pathway becomes important in situations
where the carotids are narrowed or blocked. Image by Ian Kimbrough, PhD.
I. STATIC NERVOUS SYSTEM DISEASES
9
FIGURE 6 Perfusion fields of the major cerebral arteries. ACA,
anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior
cerebral artery.
nor supply pathway for the brain; this pathway becomes
important in situations where the carotids are narrowed
or blocked. The ICA ends by dividing into the mid-
dle cerebral artery (MCA) and anterior cerebral artery
(ACA). The MCA is the largest branch and divides into
12 smaller branches; together, these 12 branches supply
almost the entire cortical surface, including the frontal,
parietal, temporal, and occipital lobes (Figure 6).
At its stem, the MCA gives rise to additional vessels
that supply the midbrain, including the globus pallidus
and caudate nucleus. The ACA supplies primarily the
frontal lobes. The vertebral arteries supply the cerebel-
lum and medulla. The basilar artery branches off the ver-
tebral artery and supplies the pons and lower portions
of the midbrain, hypothalamus, and thalamus. The pos-
terior cerebral artery branches off the basilar artery and
feeds the occipital lobe.
Many of the major vascular branches are intercon-
nected and form a network that allows blood to circum-
vent obstructions if present. One particular structure
that deserves mentioning is the circle of Willis. This ring-
like connection of the cerebral vasculature is established
by the anterior commissure connecting the left and right
branches of the ACAs and the posterior commissures
connecting the posterior cerebral arteries. By contrast,
smaller arteries less than 100 ∼m in diameter are end ar-
teries that are not interconnected, and any blockage re-
sults in loss of perfusion to the innervated brain region.
Note that from an evolutionary point of view, the
brain’s vasculature is a catastrophe waiting to happen.
With the massive expansion of the cortex in humans, the
MCA has to supply a much larger part of the brain than
originally intended. Importantly, almost all of the brain
supplied by the MCA is considered our “eloquent brain,”
areas responsible for motor and sensory function, lan-
guage, and cognition. Hence, a reduction in blood flow
through the MCA causes a disproportionate functional
loss of eloquent brain function in humans.
10 1. Cerebrovascular Infarct: Stroke
FIGURE 7 Vascular cast of a human brain shows the extensive
branching of vessels into finer and finer structures. The cast was pre-
pared by injection of a plastic emulsion into the brain vessels, and,
upon hardening, the brain parenchymal tissue was enzymatically dis-
solved. Reproduced with permission from Ref. 5.
Each heartbeat delivers about 70 mL of oxygenated
blood to the aorta, 10–15 mL of which are allocated to
the brain. Every minute about 500 mL of blood circulate
through the brain. To ensure constant perfusion, pres-
sure and blood flow are highly regulated. The first line
of regulation is via the arterial walls of the major arteries,
which constrict in response to increases in blood pressure.
Arterioles are exquisitely sensitive to changes in the partial
pressure of CO2 such that when the CO2 content increases,
indicating high metabolic activity, arterioles dilate. This
dilation causes increased blood flow and enhances deliv-
ery of oxygenated blood. When CO2 decreases, vessels
constrict to reduce blood flow. As noted earlier, functional
activity within subregions of the brain adjusts regional
blood flow without affecting the overall delivery of blood
to the brain, which remains about 500 mL/min.
The brain is very sensitive to even a modest decrease
in blood flow. A drop from a normal value of 20–30 to
16–18 mL/100 g tissue causes infarction within 1 h, and
any further reduction kills brain tissue in just minutes.
As illustrated in a vascular cast of a human brain
(Figure 7), arterioles branch extensively, giving rise to
capillaries so small that erythrocytes have to bend to
fit through their lumen. This site is where the major
exchange of glucose and blood gases with brain tissue
occurs. Since diffusion of gas in tissue is very limited,
capillaries reach within about 50 ∼m of any neuron
throughout the brain.
4.1 Causes of Vessel Occlusions: the
Thrombolytic Cascade
The loss of blood flow in stroke patients is the result
of insufficient arterial flow due to vessel narrowing, com-
plete blockage, or rupture. The underlying causes are
directly related to biochemical events involved in the for-
mation of blood clots. The ability of blood to coagulate
and stop bleeding from wounds (hemostasis) is essential
I. STATIC NERVOUS SYSTEM DISEASES
for survival. Coagulation involves two steps: the initial
formation of a cellular plug by circulating platelets and
a secondary reinforcement of this plug by an aggregate
of fibrin fiber strands. The end product is a blood clot or
thrombus that seals the vessel wall. The clotting process is
well understood and involves numerous clotting factors.
Clotting proceeds along two pathways: the intrinsic (con-
tact activation) pathway and the extrinsic (tissue factor)
pathway. The latter is the pathway we are most concerned
within the context of stroke. Here, following damage to the
vessel wall, the serine protease thrombin causes the pro-
duction of fibrin from fibrinogen. Fibrin fibers then form
the hemostatic plug. Normally, as a wound heals, blood
clots are dissolved through a process called fibrinolysis.
The main protein mediating the dissolution of the plug is
plasmin. Plasmin is derived from a precursor molecule,
plasminogen (PLG), which is a component of blood serum
produced in the liver. The cleavage of the precursor PLG
to the active plasmin is catalyzed by tPA, a serine protease
produced by endothelial cells in blood vessels (Figure 8).
Plasmin in turn helps degrade the clot. Therefore, tPA is an
important regulator of clotting, and recombinant tPA is an
effective thrombolytic agent, often called a “clot-buster.”
We discuss its clinical use later in this chapter.
In many stroke patients, the obstruction of blood flow
is the result of atherosclerosis, a chronic vascular disease
that causes a thickening of the arterial wall with plaque
deposits that narrow the vessel lumen (Figure 9). Plaques
contain Ca2  + and fatty acids, including triglycerides and
cholesterol, as well as macrophages and white blood
cells. Atherosclerotic plaque formation is promoted
by low-density lipoproteins, often called “bad choles-
terol,” which enters into the vessel wall and causes an
immune response. This in turn sends macrophages and
T-lymphocytes to the affected vessel, causing them to ag-
gregate locally. In addition to a narrowing of the arterial
lumen, this causes a hardening of the vessel wall and in-
flammation of the surrounding smooth muscle.
FIGURE 8 Breakdown of thrombotic deposits or blood clots by
tissue plasminogen activator (tPA). Schematically shown is the lumen
of an arterial blood vessel formed by capillary endothelial cells. tPA
activates the conversion of plasminogen (PLG) to plasmin, which cat-
alyzes the breakdown of fibrin clots into fibrin degradation products.
Plasmin can be inhibited by antiplasmin (AP).
 4 Disease mechanism/cause/basic science
FIGURE 9 Examples of atherosclerosis critically narrowing
vessel lumen and thereby significantly reducing blood flow. From
Wiki-Commons.
Atherosclerosis can affect essentially all arterial vessels
in the body and is considered a chronic condition that
typically proceeds asymptomatically for many years or
decades. Even a small narrowing of the vessel lumen has
a profound effect on blood flow and hence energy deliv-
ery to the brain. The weakened vessel wall becomes prone
to rupture and may cause a hemorrhagic stroke, particu-
larly in patients with chronic hypertension.. Plaques are
covered by a fibrous cap of collagen, which is highly clot
promoting. This cap is typically weak and prone to rup-
ture. If it enters the bloodstream, it forms a thrombus that
attracts additional platelets and white blood cells. It even-
tually attaches at a vessel branch point, where it occludes
blood flow. A small particle breaking off from a thrombus
or the plaque is called an embolus. It floats along with the
blood into smaller and smaller penetrating arteries where
it eventually becomes lodged. This process is illustrated in
Figure 10. We refer to ischemic strokes caused by thrombi
or emboli as thromboembolic strokes.
Historically, we assumed that atherosclerosis is
mostly influenced by diet, with fatty and highly pro-
cessed foods being often considered the major culprits.
Hence, modern humans would be predisposed to
stroke as a consequence of their diet. However, recent
I. STATIC NERVOUS SYSTEM DISEASES
11
FIGURE 10 Schematic view of thromboembolic ischemia showing
a reduction of blood flow by the buildup of thrombolytic plaque ma-
terial on the inside of the vessel wall. This thrombus can break off and
fragment; so-called emboli travel with the blood and can plug finer
vessels. Occlusions therefore often have been called thromboembolic
because no distinction is made between stationary buildup and float-
ing debris. Drawing by Emily Thompson, PhD.
use of MRI to examine blood vessels in mummified
bodies of four different ancient human populations
showed the presence of atherosclerotic plaque com-
parable to that of modern humans even at a relatively
young age.6 Plaques were also present in mummies
suspected to have consumed a meat-free diet. These
findings challenge the commonly held notion that ath-
erosclerosis can be readily explained by dietary choice.
They do not, however, question the obvious link be-
tween atherosclerosis and stroke.
4.2 The Ischemic Cascade
The loss of blood flow resulting from either leak-
age or blockage of a blood vessel starts what is known
as the ischemic cascade. From decades of experimen-
tation in animals and humans, we have an excellent
understanding of the cellular and molecular changes
that occur in the affected brain. The time course and
the major cellular changes are illustrated graphically
in Figures 11 and 12.
Following the fairly rapid exhaustion of ATP, the
neuronal membrane slowly depolarizes as the Na+/K+
ATPase fails to maintain the resting membrane potential.
After just a few minutes, most affected neurons reach the
activation threshold for Na+ channel-mediated action
potentials, causing a transient period of hyperexcitabil-
ity that further depolarizes the membrane. The depolar-
ization opens voltage-gated Ca2  + channels and causes
the removal of the Mg2  + block that normally safeguards
the N-methyl-d-aspartate (NMDA) receptor. This in turn
causes further uncontrolled influx of Ca2  +. Note that
while NMDA receptors typically cause a brief excitatory
postsynaptic current that is largely due to Na+ influx, the
channel per se has fivefold higher permeability to Ca2  +
than Na+. At this stage, all pathways for Ca2  + entry are
FIGURE 11 Time course of ischemia; cellular and molecular events that contribute to injury are indicated. Different pathways lead to either
apoptotic or necrotic cell death.

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
open and the Ca2  +-ATPase that normally sequesters Ca2  +
into organelles is inactivated by the loss of ATP. To aggra-
vate matters further, surrounding astrocytes also exhaust
their small glycogen stores and their failure to produce
ATP results in astrocytic depolarization. This dissipates
the transmembrane gradient for Na+ that is required for
uptake of glutamate (Glu) into astrocytes. The depolar-
ized neurons release more Glu, which is no longer cleared
by astrocytes. This causes a catastrophic scenario whereby
sustained activation of neuronal Glu receptors causes Ca2  +
influx, which feeds forward on further vesicle fusion and
Glu release. Ultimately, within 5–10 min, irreversible neu-
ronal death begins in the core of the ischemic lesion. Early
neuronal and glial cell death occurs primarily through a
necrotic pathway, where the influx of ions, including Na+
and Cl′, causes cytotoxic edema or cell swelling as water
follows these ions into the cells. This in turn ruptures cell
membranes, causing spillage of cytoplasm and creating a
toxic extracellular space. Later, the Ca2  + increase activates
a secondary programmed cell death cascade, which is ex-
plained further in the following.
4.3 The Ischemic Penumbra
The ischemic lesion is surrounded by brain tissue that
still receives some blood flow via collaterals; however,
this blood flow is not of sufficient quantity to maintain
normal brain function. This hypoperfused brain tissue,
schematically illustrated in Figure 13, is called the isch-
emic penumbra and is the focus of all intervention strat-
egies. Here, neurons and glial cells are in a latent state,
paralyzed from participating in proper neuronal func-
tion but clinging to life. If perfusion occurs within a rea-
sonable amount of time (6–24 h), the ischemic penumbra
can recover completely. If not, tissue in the penumbra
gradually dies and becomes part of the expanding isch-
emic core. The viability of the ischemic penumbra has
been extensively studied in rodents and monkeys, and
our best estimates suggest that neurons in the penumbra
remain viable for at least 3–6 h, although some studies
suggest that this time period may be as long as 24–48 h.
However, based on consensus data from many studies,
4.5 h has been adopted as the critical time period during
which reperfusion provides maximal benefit, and this is
often called the “window of opportunity.” In agreement
with this suggestion, chemical recanalization using tPA,
discussed in the following paragraph, provides maximal
benefit to patients who are only less than 4.5 h removed
from the insult, with declining benefits between 4.5 and
6 h and essentially none thereafter. Realizing this win-
dow of opportunity, clinicians are urging patients to seek
rapid attention because “time lost is brain lost.”
Our understanding of the ischemic penumbra is not
quite as clear as that of the ischemic core. It seems, how-
ever, that neuronal death in the penumbra p ­ rimarily
I. STATIC NERVOUS SYSTEM DISEASES
13
FIGURE 13 The ischemic penumbra is the area surrounding a
stroke lesion where blood flow is still reversible and where tissue can
potentially be rescued if blood flow is restored in a timely manner. It
can be divided into two regions: one in which diffusion is abnormal,
suggesting structural damage, and one in which diffusion is normal
but perfusion of tissue with blood is abnormal. This area in particu-
lar can be rescued through rapid restoration of blood flow. Drawing by
Emily Thompson, PhD.
occurs via programmed cell death, called apoptosis.
Increases in Ca2  + to supraphysiological, but not cat-
astrophic, levels activate several of the apoptosis-­
promoting pathways. Activation of these pathways then
culminates in the release and activation of caspases, a
family of cysteine proteases that cleave cellular proteins,
resulting in slow cellular disassembly. This goes hand
in hand with changes to the mitochondrial membrane,
which releases proapoptotic molecules such as cyto-
chrome C. The opening of a large ion channel, called the
mitochondrial transition pore, breaks down the voltage
gradient across the mitochondrial membrane required
for the production of ATP. This in turn further compro-
mises the production of energy by brain tissue, further
contributing to a vicious cycle of neuronal cell death.
The ischemic penumbra is also a site of extensive in-
flammation. Both astrocytes and microglial cells are ac-
tivated during a stroke, and blood-borne immune cells,
including leukocytes, T-lymphocytes, and natural killer
cells, infiltrate the region as well. These inflammatory
cells release cytokines, which in turn exacerbate the neu-
ral injury by stimulating nitric oxide production and en-
hancing NMDA-mediated excitotoxicity.
In both the ischemic core and the penumbra, the in-
tegrity of the blood-brain barrier is compromised. This
is partly due to the activation of matrix metalloprotein-
ases and the retraction of astrocytic endfeet. The break-
down of the blood-brain barrier enhances penetration
of blood-borne toxins and immune cells, each of which
contributes to the further decline of tissue health.
14 1. Cerebrovascular Infarct: Stroke

It is commonly assumed that the ischemic core cannot

be rescued, whereas the penumbra can, hence the objec-
tive of treatment is to maximize survival of cells in the
ischemic penumbra by limiting excitotoxic or inflamma-
tory injury and to restore normal blood flow. Therefore,
noninvasively defining whether a penumbra exists for
a given patient and determining the size of this area is
of great importance. A combination of imaging tech-
niques now allows us to gain this insight. Specifically,
magnetic resonance imaging studies can readily distin-
guish between perfusion and diffusion within tissue.
Diffusion-weighted images show structural, and hence
permanent, destruction, thereby identifying the ischemic
core. Perfusion images, on the other hand, show changes
in relative perfusion or blood flow and presumably the
brain region with abnormally low, but not absent, blood
flow. By overlaying these two images, one can identify
an area in which there is a mismatch between diffusion
and ­perfusion and this area represents the penumbra.
Example images in Figure 14 illustrate this approach. FIGURE 14 Mismatch of perfusion and diffusion using magnetic
While a potentially powerful predictor of vulnera- resonance imaging can identify the presence and size of the penumbra.
ble brain tissue and proven to be of clinical value, this Red demarcates the infarct zone, with irreversible injury, blue demar-
cates the zone with reduced blood flow containing at-risk tissue, and
approach requires imaging capacity only available at the green mismatch zone shows the area in which at-risk tissue can be
­specialized hospitals, and sufficient time to acquire im- saved. Reproduced with permission from Ref. 7.
ages without compromising rapid treatment.
Decades of research using animal models of stroke following, none of the treatments that were success-
have provided a fairly detailed understanding of the ful in animal models of stroke translated into effective
cellular and molecular changes that cause necrotic treatments in humans. The molecule that received the
or apoptotic cells death, and example is illustrated in most attention is the NMDA receptor, believed to be the
Figure 12. Many of the identified molecules and path- pivotal pathway for the entry of toxic Ca2  + in ischemia
ways predicted cures, yet, as further discussed in the (Figure 15).

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.

I. STATIC NERVOUS SYSTEM DISEASES

 4 Disease mechanism/cause/basic science
4.4 The NMDA Receptor and Glutamate
Excitotoxicity
The NMDA receptor (NMDA-R) is a Glu-gated cation
channel that is a member of the ionotropic Glu receptor
family. Like the other family members, it is a heteromeric
channel composed of four subunits, namely, two GluN1
and two GluN2 subunits. The GluN2 subunit comes in
four isoforms named GluRN2A–D. The channel is gated
by the binding of Glu, but it requires a modulatory site
to be occupied by glycine. The channel distinguishes it-
self from all other Glu receptors by its multiple modula-
tory sites. In addition to the glycine site, which can bind
d-­serine instead of glycine, there are sites for modula-
tion via nitric oxide, H+, and phencyclidine. The chan-
nel is the target of several anesthetic drugs, including
ketamine and phencyclidine (“Angel Dust”), which are
often used as recreational hallucinogenic drugs. Other
common agonists of differing potency include ethanol,
memantine, dextrorphan, and methadone.
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-
tic transmission occurs via the β-amino-3-hydroxy-
5-methyl-4-­ isoxazolepropionic acid (AMPA) and
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-
sponse to Glu. NMDA-Rs, in contrast to AMPA-Rs, are
normally not available for activation by Glu because, at
the resting potential of the postsynaptic membrane, a
Mg2  + ion is lodged in the pore of the channel, preventing
it from allowing ions to permeate. This Mg2  + binding is
dependent on voltage, and with depolarization of the
membrane, Mg2  + is released from the pore. Under nor-
mal physiological conditions, Mg2  + keeps the NMDA-R
closed at all times. Should the postsynaptic terminal be
depolarized, however, the Mg2  + ion pops out, causing
cations to flux through NMDA-Rs. While the vast ma-
jority of the current is carried by Na+, which is the most
abundant extracellular cation, the NMDA pore is five-
fold more permeable to Ca2  + than to Na+. As a conse-
quence, a considerable amount of Ca2  + fluxes through
the NMDA-R. This Ca2  + influx plays an important role
during learning and memory, allowing the NMDA-R to
function as a coincidence detector. As more extensively
discussed in Box 1, Chapter 4, only if multiple signals
arrive on the same terminal within 50 ms of each other
is the Mg2  + removed. Removal of the Mg2  + ion causes
Ca2  + influx, thereby signaling the cell of the coincident
occurrence of two events. This is believed to be an essen-
tial component of learning and memory. In the situation
of a stroke, the coincident activation is bypassed by the
chronic, long-lasting depolarization of the postsynap-
tic membrane due to energy failure. This energy failure
permanently removes the Mg2  + block, opening the flood
I. STATIC NERVOUS SYSTEM DISEASES
15
gates for Ca2  + to enter unimpeded through this recep-
tor. Hence, the very protein that is so critical in allowing
for human learning can also make us vulnerable to cell
death by excitotoxicity following a stroke.
The concept of Glu excitotoxicity was originally intro-
duced by Olney in the 1960s and has been extensively
studied since. Excitotoxicity appears to be the final com-
mon death pathway in numerous disorders, including
many neurodegenerative diseases. The precipitating
cause of the chronic depolarization of the neuronal
membrane may differ in each case, yet the principal
involvement of the NMDA-R as an influx pathway for
Ca2  + is shared.
While NMDA-R plays the most important role in isch-
emic neuronal death, other family members participate or
can substitute. The depolarization that occurs as a result of
activation of AMPA or kainate-type Glu receptor depolar-
izes the postsynaptic cell, thereby allowing Ca2  + to enter
via voltage-gated Ca2  + channels. Furthermore, at least one
variety of the AMPA receptor is also permeable to Ca2  +.
4.5 Role of Glutamate
While Olney suspected Glu as a major toxin in disease,
suffering a stroke was necessary. Early studies measured
Glu directly by microdialysis, a technique through which
the extracellular milieu in the brain can be sampled con-
tinuously and with high accuracy. They demonstrated
that occlusion of the middle cerebral artery (MCA) causes
a 60- to 100-fold increase in Glu within a relatively short
time. The increase extends to the ischemic penumbra and
even affects the composition of the cerebrospinal fluid
(CSF) bathing the brain. CSF can be examined by lumbar
puncture in patients in whom microdialysis would rarely
be feasible unless the patient underwent surgery. Glu in
the CSF rises eightfold in stroke patients and has been
suggested to have predictive value for disease severity.9 It
is important to note that persistent increases in Glu, such
as that measured after a stroke, require the neuroprotec-
tive uptake of Glu by astrocytes to fail, suggesting that
astrocyte impairments in the penumbra contribute to the
progression of disease.
4.6 NMDA Inhibitors to Treat Stroke
Having identified the role of the NMDA-R in stroke,
examining the many modulatory sites of this receptor
and how they may be exploited therapeutically is worth-
while. In principle, blocking NMDA-R ameliorates
neuronal death. However, it also impairs most higher
cognitive function. This is exemplified by ketamine,
used as a powerful anesthetic, or by phencyclidine, a
potent, mind-altering substance, both of which have
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Title: A brief and remarkable narrative of the life and extreme

sufferings of Barnabas Downs, Jun
Who was among the number of those who escaped
death on board the privateer brig Arnold, James
Magee, commander, which was cast away near
Plymouth-Harbour, in a most terrible snow-storm,
December 26, 1778, when more than sixty persons
were frozen to death. Containing also a particular
account of said shipwreck

Author: Barnabas Downs

Release date: September 29, 2023 [eBook #71758]

Language: English

Original publication: Boston: E. Russell, 1786

Credits: Steve Mattern, David Wilson and the Online Distributed

Proofreading Team at https://www.pgdp.net

*** START OF THE PROJECT GUTENBERG EBOOK A BRIEF AND

REMARKABLE NARRATIVE OF THE LIFE AND EXTREME
SUFFERINGS OF BARNABAS DOWNS, JUN ***
 A brief and remarkable
N A R R AT I V E
o f t h e
L I F E
And extreme Sufferings of
B A R N A B A S D O W NS,
Jun.
Who was among the Number of thoſe who eſcaped Death
on board the Privateer Brig Arnold, James Magee,
Commander, which was caſt away near Plymouth-
Harbour, in a moſt terrible Snow-Storm,
December 26, 1778, when more than Sixty Perſons
were frozen to Death.——Containing alſo
A particular Account of ſaid Shipwreck.
Printed by E. Russell, for the Author, 1786
Printing-Office Liberty-square, Sept. 22, 1786.
In the Preſs, and in a few Days will be publiſhed and
ready for Sale, by E. Russell, at his Office, near Liberty
Pole, by the Thouſand, Hundred, Groce or leſſer Quantity,
at the moſt reaſonable Rate:—Alſo may be had of
Mr. Benjamin Guild, at the Boſton Book-Store, near the
State-Houſe in Cornhill; Col. Ebenezer Battelle,
Bookſeller, at the London Book-Store, in Marlboro’-Street;
Mr. William Green, Bookſeller, at Shakeſpear’s-Head, in
Newbury-Street; Capt. William Green, at his Grocery
and Weſt-India Store near the Bridge, in Boſton;
Mr. Lemuel Cox, and Mr. Trumbull, Innholder, near the
Bridge, and Mr. Edward Hayes, in Charleſton;
Mr. Edward Killins, at his Store, near the Market, in
Salem; Mr. Bulkly Emerson, at the Poſt-Office, in
Newbury-Port; Mr. Alford Butler, Bookſeller, in
Portſmouth, New-Hampſhire, and by many other Printers,
Bookſellers, Shopkeepers and Travelling-Traders in Town
and Country.

B I C K E R S T A F F’s
genuine and
correct
B O S T O N A L M A N A C K,
For the Year of our
Redemption, 1787.
Which will contain a great Variety of uſeful and
entertaining Matter, in Prose and Verse.
This Work will be likewiſe ornamented with a large
Number of engraved Plates, ſome of which repreſent the
twelve Signs of the Zodiack in Miniature, and the ſeveral
Employments and Diverſions of the Gentlemen Farmers,
throughout the different Seaſons of the Year:—Alſo a
curious Repreſentation of a County Convention,
debating on State-Affairs; at the Head of the Table is a
Figure of H O N E S T U S, that renowned Champion and
bold Atteſtor of the Liberty of the Subject, and ſworn
Enemy to Lawyers, who is converſing with one of the
Order; over his Head is a Label with theſe Words “No
Courts, no L A W Y E R S:” Another Plate repreſents a
very curious and droll Scene of a large Group of the
Black Order, or the Sons of Littleton and Coke,
mounted on Jack-Aſſes, Peacocks, &c. returning from a
rich Feaſt at Concord Court, &c.
 P R E FA CE.
To the R E A D E R, into whoſe
Hands this N a r r a t i v e
may fall; eſpecially my
Seafaring B r e t h ­r e n.

F R I E N D S,

HEN any remarkable

circum­ſtances take place
in a man’s life, he feels
commonly a diſpoſition to
communicate them to the world: If
they have been deliverances from
great and ſignal dangers, he will
make this communication from a
principle of gratitude to the Being
who hath protected and preſerved
him: He will wiſh to engage others
to be thankful on his behalf; and a
knowledge of the kindneſs of
Heaven to him may lead others to
truſt in GOD, when they are
brought into like diſtreſs and
danger. By theſe motives the
Subject of the following pages
hopes he is influenced in
publiſhing them to the world; which
is all the apology that may be
expected from the P u b l i c k’s
diſtreſſed Friend,
B A R N. D O W N E S, Jun.

Barnstable,
Septem­ber 10,
1786.

☞ The Author gratefully

acknowledges himſelf indebted
to a Reverend
G e n t l e m a n in Boſton for
his kindneſs in correcting the
following ſheets.
 A

N A R R A T I V E, &c.
W A S born in Barnſtable, in New-
England, October 2, 1757, of
credible Parents, whom I ſerved as
an obedient Son, I hope, until the
commencement of the late war called me
from my home, and led me to exchange the
occupation of a Huſbandman, to which I was
bred for the more dangerous employment of
a Soldier. In this capacity I served my
Country 3 campaigns, and know not that my
behaviour was censured by my officers.

After having returned for a time to the

Farming-Buſineſs, I concluded to try my
fortune at ſea: I entered accordingly on board
the ſchooner Bunker-Hill, Captain Iſaac Cobb,
Commander, on a privateering voyage: But
we had not been out more than 6 days
before we were taken by the brig Hope, one
Brown, Commander, and carried into Halifax.
We were committed to jail and kept very
ſhort: Then I was taken with the ſmall-pox,
thro’ which GOD ſafely carried me when
deſtitute of the neceſſaries of life, and under
great preſſure of mind. But after my being
recovered ſo far as to be returned to the jail
from the hoſpital, in conſequence of my
having nothing but a ſmall allowance of ſalt
proviſions, which were next to poiſon for a
ſick perſon, I was taken with a violent fever,
which returned me again to the hoſpital, and
brought me to the gates of the grave. No
perſon who hath not experienced it can
imagine how gloomy and diſtreſſing it is to be
under ſuch circumſtances: To be far diſtant
from our deareſt Friends; to be among
perſons who are not only without any
concern for us, or intereſt in our fate, but who
are our profeſſed enemies, and not governed
even by the common principles of humanity,
is a caſe truly melancholy. In this ſituation I
was attacked with a bleeding of the noſe, (to
which I had before been ſubject) which
brought me to the very borders of eternity!

After this I was, by the ſmiles of heaven

recovered and reſtored, by a cartel, with 400
of my Countrymen to our own homes. How
welcome they were to us, and how pleaſant it
was to me to ſee the faces of my Friends
again, any one may imagine more eaſily than
I can deſcribe!
But tho’ I had been ſo unſucceſſful in my
firſt attempt at ſea, I could not reſiſt the
inclination I had to try once more what
Providence would do for me: I left my native
place, went to Boſton, and entered on board
the brig Arnold, James Magee, Commander.
I well remember I felt an unusual dejection
when I entered on this undertaking; and tho’
I pretend not to ſay that this foreboded the
miſfortunes I was to meet with in this fatal
veſſel, yet I have often reflected upon it ſince
with a degree of admiration.
While the brig lay in the harbour, I
attempted with ſome other hands to go on
board another veſſel in a ſmall boat, but the
wind ſuddenly riſing we were in danger of
being drowned; the boat run on Governor’s-
Iſland, and we were obliged to ſtay there
24 hours before we could get off. Providence
preſerved my life in this danger, in order that
I might live thro’ greater, and teſtify to his
loving kindneſs and mercy.
 On December 24, 1778, Capt. Magee
ſailed from Boſton: We had been at ſea but a
few hours, when a moſt terrible gale of wind
aroſe, ſo that the water was almoſt knee deep
on the leeward ſide of the quarter-deck. We
continued in the Bay that day and the night
following, but on the next day we got into
Plymouth. The wind was abated, but the cold
was ſevere and intenſe beyond deſcription.
We came to anchor a little below Beach-
Point, in the Harbour of Plymouth.

On Saturday, December 26, about

6 o’clock in the morning, from the violent
motion of the ſea, the brig ſtruck the bottom
as tho’ it would drive her keel in. As there
was not depth of water enough to work the
veſſel in the place where we lay, and we ſaw
a heavy ſtorm coming on, our Commander
thought it beſt to cut our cables and let her
drive, which was immediately done. The
ſtorm increaſed very faſt, ſo that we were
obliged to cut away the main-maſt, and we
drifted upon an hard flat a little to the
weſtward of Beach-Point.
This was early on Saturday morning, and
we now laboured hard in throwing over our
wood and getting our guns off the decks into
the hold, but the veſſel began to leak very
faſt, and with every motion of the ſea ſhe
ſtruck the bottom as tho’ ſhe would ſplit in
pieces. We kept 2 pumps going, but could
not gain upon the water. The ſtorm now
increaſed to a moſt prodigious degree: It
ſnowed ſo thick that we could ſee but a very
little way from the brig, and the cold was
extreme; we continued hard at work all day
without eating or drinking any thing ſcarcely,
having but little appetite with the proſpect of
death continually before our eyes.
Until now we had hopes of eſcape, but
juſt before night we looked into the hold and
ſaw the caſks floating about; this drove us to
deſpair, and we forſook the pumps without a
ray of hope but from the immediate
interpoſition of divine Providence. Many of
the people now began to pray, and I went
into the cabbin and ſat upon one of the gun-
carriages. I had not been there long before I
ſaw cheſts floating about, and perceived that
the tide was flowing on us very faſt; by
direction of the Capt. all left the cabbin and
came upon the quarter-deck.
It is not poſſible to deſcribe my ſenſations
at this period; death appeared inevitable,
and we waited every moment for its
approach! Even now, when I recollect my
feelings it is difficult to ſteady my pen! And
indeed I had ground enough for my
apprehenſions, for we had not been long
upon the quarter-deck before the water upon
the main-deck was even with it. Our fore-
maſt was ſtill ſtanding, which cauſed the veſſel
to roll very much, but when we had cut that
away ſhe lay ſtiller. The brig now lay ſunk; the
tide was flowing faſt and the ſea broke very
heavily over us. We were all upon the
quarter-deck, and the water came in upon us
ancle deep.
There was a ſail in the netting upon the
windward-quarter, which we contrived to laſh
over us, but there were ſo many under it that
we ſhould have been ſtifled for want of
breath, if we had not cut places to let in the
air. The tide was then about at its height but
the ſtorm did not abate. There was nothing to
be heard around but ſcreeches, groans and
deep lamentations for themſelves and their
families, and earneſt cries to G O D for
mercy and relief!
There was ſuch a croud upon the quarter
deck we could not ſtand up without treading
upon one another. Being in a ſtruggle I was
thrown down and trampled upon as if the
breath would be crouded out of my body:
However I ſoon recovered my feet and
trampled upon others in my turn; for the
immediate regard which every man had to
his own life prevented him from attending to
the diſtreſſes of his neighbours!
Struggling in this manner and trying to
clear ourſelves from thoſe who fell down had
pulled off moſt of our ſhoes, and the wet and
cold ſoon froze our feet. Nature could ſuſtain
it no longer and the people began to die all
around me. Capt. John Ruſſell of Barnſtable
was the firſt of thoſe with whom I was
acquainted that died, but many others ſoon
followed him. Fatigue and diſtreſs, added to
the extreme cold and deſpair of relief, put a
period to the lives of great numbers. Thoſe
who were able to ſtand were obliged to
huddle up cloſe together, and breathe in
each other’s faces to preſerve them from
freezing to death, while their comrades were
dying around them all night. In the morning a
moſt awful ſight preſented itſelf to us; 60 of
our Comrades lay dead acroſs each other,
and but 2 of my Townſmen were among the
living!
On Lord’s-Day, Dec. 27, the ſtorm abated
and the ſun appeared clear, but the ſevere
cold ſtill continued. We ſaw Plymouth and a
number of people coming along the ſhore for
our relief: We could diſcern them puſh off two
boats and make an hard trial to come to us,
but the harbour was ſo full of ice they could
not reach us: We ſaw them return and it gave
us an inexpreſſible ſhock. The elevation
which their appearance gave us tended to
ſink us the lower. Our ſituation was very
gloomy; we had little to ſupport nature except
rum; no ſhoes on our feet, and very much
frozen; the Heavens was our only covering!
I retained my ſenſes until about 2 o’clock
on Lord’s-Day, but was then deprived of
them and lay on the quarter-deck until the
next day, when a boat got to us in order to
carry the living aſhore, which amounted only
to 32. When they were looking around to
collect the ſurvivors, they at firſt ſuppoſed me
to be dead, but ſeeing one of my eye-lids
move they took me up and laying me in the
boat carried me aſhore.
 I was carried to Mr. Bartlet’s tavern,
whoſe kindneſs to me I would thus publickly
acknowledge, and hope I ſhall always
remember with gratitude. My cloaths were
firſt cut from off me and I was put into cold
water in order to take out the froſt: I was then
placed in bed and having my teeth forced
open had ſome cordials poured down my
throat, but I have no remembrance of any of
theſe tranſactions, for I lay perfectly ſenſeleſs
until 2 o’clock on Monday, when my ſenſes
came to me at once. My eyes were not open,
but I heard the voices of perſons talking
around me, and the firſt idea which ſtruck me
was, that I was ſtill on board the brig, but that
a boat come to our relief. I ſoon however
opened my eyes and was informed of what
had happened and where I then was.
I recovered gradually, but was obliged
to paſs thro’ the painful operation of having
ſome of my limbs ſeperated from my body:
But after all theſe diſtreſſes I am ſtill among
the living to praiſe G O D! Let my ſpared life
be devoted to his ſervice, and may I ever be
mindful of his benefits!