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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.
II
Neurodegenerative Diseases
4. Aging, Dementia, and Alzheimer Disease
Nervous System Diseases
1. Cerebrovascular Infarct: Stroke
5.
Parkinson Disease
2. Central Nervous System Trauma
6.
Diseases of Motor Neurons and Neuromuscular Junctions
7. Huntington Disease
HARALD
1
Neurological Conditions
11. Neurodevelopmental Disorders
8. Multiple Sclerosis
HARALD
1
5
V
Neuropsychiatric Illnesses
12. Mood Disorders and Depression
HARALD
9. Brain Tumors
HARALD
1
5
13. Schizophrenia
10. Infectious Diseases of the Nervous System
HARALD
14.
HARALD
15. Drug Addiction
HARALD
1
VI
Common Concepts in Neurological and Neuropsychiatric Illnesses
17. Drug Discovery and Personalized Medicine
VIII Neuroscience Jargon
18. “Neuro”-Dictionary
HARALD
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 comparative 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 cellular & molecular neuroscience from the University of Heidelberg, studying biophysical changes that accompany the development of oligodendrocytes, the principal 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 major 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 clinical development of his discoveries, Dr. Sontheimer started a biotechnologies company, Transmolecular Inc., which conducted both phase I and phase II clinical trials with the anticancer agent, chlorotoxin. Morphotec Pharmaceuticals, which will be conducting the phase III clinical trials, recently acquired this technology. As educator, Dr. Sontheimer has been active in teaching medical neuroscience, graduate cellular and molecular neuroscience, and, for the past 10 years, he has offered both graduate and undergraduate courses on diseases of the nervous system. In 2005, Dr. Sontheimer became director of the Civitan International Research Center, a philanthropically
supported center in Birmingham AL devoted to the study and treatment of children with developmental disabilities, ranging from Down’s syndrome to autism. In this capacity, Dr. Sontheimer was frequently tasked with explaining 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 undergraduates 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 neuroscience education to an increasing number of undergraduates. 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, systems, 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 ranging from undergraduates to postdoctoral scientists. Dr. Sontheimer has trained over 50 PhD and MD/PhD students and postdoctoral fellows, many of whom have independent 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 undertaking 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 weekend 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 figures 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 examines cultural and societal difference in the application of Neuroscience to Medicine. Co-teaching this course entitled “Global Perspectives in Neuroscience” I realized that my chapters must take a more global look at disease epidemiology and consider discrepancies in disease presentations 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 correcting 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
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 visiting 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 grateful to their Neuroscience program for letting me participate 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
my classes at Rhodes, UAB, and Virginia Tech and who took a particular interest and regularly provided recommendation 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, publishing, and marketing this book. Particularly to the editorial 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 pathologist Ramón y Cajal generated beautifully detailed histological 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 biological computer remained obscure until recently. Although Luigi Galvani’s pioneering experiments in the late-1700s had already introduced the world to biological electricity, ion channels and synaptic neurotransmitter receptors 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 receptors, such information still eludes us.
Surprisingly, however, long before neuroscience became a freestanding life science discipline, doctors and scientists had been fascinated with diseases of the nervous system. Absent any understanding of cellular mechanisms 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 muscular dystrophy. During this period and still today, the discovery process has been largely driven by a curiosity 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 human skull of awake persons to establish functional maps of the cortex. Absent unexpected consequences of surgery, such as the bilateral removal of the hippocampi in HM that left him unable to form new memories, or unfortunate 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 continues to date, and it is probably fair to say that neuroscience is as much a study of health as that of disease.
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, students 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 countless 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 neuroscientist 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 always 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 audience, 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 repeated 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 interested 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 expect the reader to have a basic understanding of neurobiology. Many excellent textbooks have been written, each of which would prepare one well to comprehend
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 nontechnically 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 system though it is far from complete. My intention was to go fairly deep into disease mechanisms and this precluded 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 illnesses, where an acute onset causes immediate disability 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 neurodegenerative 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 disease along the motor pathway essentially moving from diseases affecting the motor neurons themselves (ALS), their axons (Guillain-Barre syndrome), to the presynaptic (Lambert Eaton myotonia), and postsynaptic (myasthenia 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 neurodegenerative 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 degeneration, brain tumors cause neurological symptoms by gradually killing neurons, and infection causes progressive 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 pathogen (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, botulism, 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 neuropsychiatric 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 student should know. However, anyone looking for more detailed information on rare disorders or disorders primarily affecting the peripheral nervous system or sensory 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 accessible, yet comprehensive format, the book was developed 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 sabbatical 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 chapters 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 immediately evident was the sheer magnitude of the available literature. Moreover, writing about a disease that is outside ones’ personal research specialty leaves one without a compass to decide which facts are important
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 identify 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 objective 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 disease, 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 appreciation 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 historic 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 human 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 industrial revolution of the mid-1800, making industrial pollutants potential disease contributors. Even more extreme, no historic account for autism exists prior to the 1930s. Clearly, for some of those diseases, human influences 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 history,
clearly important lessons when teaching neuroscience at a Liberal Arts college. Our classes included how patients with epilepsy were labeled witches and burned in medieval 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 foundation 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 susceptible 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 experience a transformational opportunity to study and understand disease through the study of rare genetic forms of familial diseases that can inform us about general disease 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 subsequently translate into better clinical practice. I devote a considerable amount of discussion to such challenges and end each chapter with a personal assessment of challenges 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 research 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 fortunate enough to develop an experimental treatment for brain tumors in my laboratory that I was able to advance 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 important, albeit not neuroscience-specific, topic. The class included important discussions on the placebo effect and frank conversations as to why many scientific findings cannot be reproduced, and why most clinical trials ultimately fail.
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