DISEASES OF THE NERVOUS SYSTEM H S arald ontHeimer University of Alabama Birmingham, AL, USA AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2015 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. 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ISBN: 978-0-12-800244-5 British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress For information on all Academic Press publications visit our website at http://store.elsevier.com/ Acquisition Editor: Melanie Tucker Editorial Project Manager: Kristi Anderson Production Project Managers: Karen East and Kirsty Halterman Designer: Matthew Limbert Typeset by TNQ Books and Journals www.tnq.co.in Printed and bound in the United States of America Dedication To the most important people in my life: My wife Marion and my daughters Melanie and Sylvie. Their encouragement is my motivation; their love and their smiles are the greatest reward. Acknowledgments English is a second language for me. To make Christopher B. Ransom, MD, PhD, University of up for my shortcomings, I am indebted to my Washington Assistant, Anne Wailes, who tirelessly edited Erik Roberson, MD, PhD, University of Alabama and polished every sentence in this book. She Birmingham also tracked down the copyrights for hundreds James H. Meador-Woodruff, MD, University of of figures that were reproduced in this book. Alabama Birmingham Anne did all this while attending to the many Jeffrey Rothstein, MD, PhD, Johns Hopkins daily tasks of administrating a large research University center and looking after my trainees in my Leon Dure, MD, University of Alabama absence. This was a monumental undertaking Birmingham and words cannot describe how fortunate I feel Louis Burton Nabors, MD, University of Alabama to have had her support throughout this journey. Birmingham Each chapter went through two stages of Richard Sheldon, MD, University of Alabama scientific review. The first stage of review was Birmingham conducted by a tremendously gifted young sci- Stephen Waxman, MD, PhD, Yale University entist, Dr Alisha Epps, who, for an entire year, Steven Finkbeiner, MD, PhD, The Gladstone spent almost every weekend reading and cor- Institute for Neurological Disease recting book chapters as I completed them. Ali- Thomas Novack, PhD, University of Alabama sha had a talent to simplify and clarify many Birmingham difficult concepts, and, if needed, she found William Britt, MD, University of Alabama suitable figures or even drew them from scratch. Birmingham Her contributions to this book were tremendous To be able to spend a year writing a book is a and I am indebted to her generous support. luxury and privilege that, even in academia, only The second stage of review involved experts a few people enjoy. I am grateful for the support in the respective disease. I am privileged to have of my employer, the University of Alabama at a number of friends who are clinicians or clinician– Birmingham, for allowing me to devote much scientists and who were willing to selflessly of my professional time to writing this book. spend countless hours correcting the mistakes I I thank the Dean, President, and my Chairman had made. While I am acknowledging each per- David Sweatt for enthusiastically supporting son with the very chapter they reviewed, I like this endeavor. to acknowledge all of them in this introduction During the spring semester of 2014, by name. I became a visiting Professor, embedded among Alan Percy, MD, PhD, University of Alabama the wonderful faculty of Rhodes college in Birmingham Memphis TN, a picturesque small liberal Amie Brown McLain, MD, University of arts college. I am thankful for the hospital- Alabama Birmingham ity and support of all the Rhodes administra- Anthony Nicholas, MD, PhD, University of tors and faculty, many of whom I engaged Alabama Birmingham in inspirational discussion during lunch or xi xii ACKNOWLEDGMENTS coffee breaks. I am particularly grateful to the Jessica Baker, Morgan Cantor, Shelley Choudhury, Neuroscience program, Doctors Kim Gerecke, Jason Crutcher, Sarah Evans, Nancy Gallus, David Kabelik, Rebecca Klatzkin, and Robert Kyle Jenkins, Megan LaBarreare, Mallory Mor- Strandburg, for letting me participate in ris, Swati Pandita, Hayden Schill, Nathan Sharf- their curriculum and take residence in Clough man, and Sara Anne Springfellow. Hall. Many students provided invaluable feedback I trust that all of them are either in Graduate toward this book, some formal, using a pre- or Medical school by now, and I wish them well. scribed feedback form, other informal during My final acknowledgment goes to my pub- office hours. I am thankful to all the students lisher, Elsevier Academic Press for their tremen- who attended the Rhodes Spring 2014 NEU365 dous work editing, publishing, and marketing course, as I have received feedback from all of this book. Particularly to the editorial project you. The following students took a particular manager Kristi Anderson, the senior acquisi- interest and regularly provided recommenda- tions editor Melanie Tucker and the production tion for improvements: team. Introduction The study of nervous tissue and its role in tumors and intractable epilepsy, surgeons such learning and behavior, which we often call neu- as Harvey Cushing and Wilder Penfield would roscience, is a very young discipline. Johannes have had no justification to open the human skull Purkinje first described nerve cells in the early of awake persons to establish functional maps 1800s, and by 1900, the pathologist Ramón y of the cortex. Absent unexpected consequences Cajal generated beautifully detailed histologi- of surgery, such as the bilateral removal of the cal drawings illustrating all major cell types hippocampi in H.M. that left him unable to form in the brain and spinal cord and their interac- new memories, or unfortunate accidents exem- tions. Cajal also described many neuron specific plified by the railroad worker, Phineas Gage, structures including synaptic contacts between who destroyed his frontal lobe in a blast acci- nerve cells, yet how these structures informed dent, we would not have had the opportunity the brain to function like a biological com- to learn about the role of these brain structures puter remained obscure until recently. Although in forming new memories or executive function, Luigi Galvani’s pioneering experiments in the respectively. Such fascination with nervous sys- late-1700s had already introduced the world to tem disease and injury continues to date, and concept of biological electricity, ion channels it is probably fair to say that neuroscience is as and synaptic neurotransmitter receptors were much a study of health as that of disease. only recognized as “molecular batteries” in the For the past 15 years, I have been teaching a late-1970s and early 1980s. The first structural graduate course entitled “Diseases of the Ner- image of an ion channel was generated even vous System” and more recently I added an more recently in 1998, and for many ion chan- undergraduate course on the same topic as well. nels and transmitter receptors such information Every year, almost without fail, students would still eludes us. ask me whether I could recommend a book that Surprisingly, however, long before neurosci- they could use to accompany the course. I would ence became a freestanding life science disci- usually point them to my bookshelf, filled with pline, doctors and scientists had been fascinated countless neuroscience and neurology textbooks with diseases of the nervous system. Absent any ranging from Principles in Neuroscience to Mer- understanding of cellular mechanisms of sig- ritt’s Neurology. I concluded that there was naling, many neurological disorders were quite no such book and there really should be one. accurately described and diagnosed in the early For the next year I kept my eyes peeled for this to mid-1800s, including Epilepsy, Parkinson textbook to appear. Surely, sooner or later some disease, Schizophrenia, Multiple Sclerosis, and brave neuroscientist would venture to write a Duchenne’s muscular dystrophy. During this book about neurological illnesses. Surprisingly, period and still today, the discovery process has as of this writing, this has not happened so two been largely driven by a curiosity about dis- years ago I decided to fill this void. My initial ease processes. What happens when things go inclination was to produce a multiauthor edited wrong? Indeed, much of the early mapping of book. By calling on many friends and colleagues brain function was only possible because things to each write a chapter on their favorite disease went very wrong. Had it not been for brain this should be a quick affair. However from own xiii xiv INTRODUCTION experience I know that book chapters are always a broader coverage of small and less well- the lowest priority on my “to do” list, and I really known conditions. I found it useful to group was eager to pester my colleagues monthly to the diseases into five broad categories that deliver their goods. Ultimately they would provided some logical flow and progression. surely ask a senior postdoc to take the lead and Specifically, I begin with static illnesses, where in the end, the chapters would be heterogeneous an acute onset causes immediate disability and not necessarily at a level appropriate for a that typically does not worsen over time. This college audience. For my target audience this group is best exemplified by stroke and CNS book needed to be a monograph. While I did trauma but also includes genetic or acquired not know at the time what I was getting into, epilepsy (Chapters 1–3). I next covered the roughly 18 months later, having read over 2500 classical primary progressive neurodegenera- scientific papers and reviews and after writing tive diseases including Alzheimer, Parkinson, for about 7–10 h daily, I feel exhausted but also Huntington, and ALS (Chapters 4–7). For each quite a bit more educated than before. of these chapters I added some important The target audience for this book is any stu- related disorders. For example, the chapter on dent interested in neurological and neuropsy- Alzheimer includes frontal temporal demen- chiatric illnesses. This includes undergraduates, tia; for Parkinson I included essential tremors early graduate students, and medical students and dystonia, and for Huntington I touch on taking a medical neuroscience course. I also related “repeat disorders” such as spinocer- expect the material to be of benefit to many ebellar ataxia. The chapter that covers ALS health professionals who are not experts in the includes a variety of disease along the motor field. The book may even appeal to science writ- pathway essentially moving from diseases ers or simply a science minded layperson, pos- affecting the motor neurons themselves (ALS), sibly including persons affected by one of the their axons (Guillain–Barre Syndrome), to the illnesses. Purposefully, the book lacks a basic presynaptic (Lambert Eaton Myotonia), and introduction to neuroscience and I would expect postsynaptic (myasthenia gravis) neuromus- the reader to have a basic understanding of neu- cular junction. robiology. Many excellent textbooks have been Next, I progressed to neurodegenerative dis- written, each of which would prepare one well eases that are secondary to an insult yet still to comprehend this text. I feel that I could not cause progressive neuronal death. I call these have done justice to this rapidly expanding field secondary progressive neurodegenerative dis- had I attempted to write a short introduction. eases and the examples I am covering include However, to at least partially make up for this, Multiple sclerosis, Brain tumors, and infections I include an extensive final chapter that is called (Chapters 8–10). It may be unconventional to “Neuroscience Jargon.” I consider this more call these secondary neurodegenerative dis- than just a dictionary. It has a succinct summary eases yet in multiple sclerosis the loss of myelin of approximately 500 of the most important causes progressive axonal degeneration, brain terms and is written as nontechnically as possible. tumors cause neurological symptoms by gradu- I hope that this will assist the reader to get his/ ally killing neurons, and infection causes pro- her bearings as needed. gressive illnesses again by progressively killing The book makes every effort to cover all neurons. Nervous system infection could have the major neurological illnesses that affect the quickly become an unmanageable topic since far central nervous system though it is far from too many pathogens exist that could affect the complete. My intention was to go fairly deep nervous system. I therefore elected to discuss into disease mechanisms and this precluded important examples for each class of pathogen INTRODUCTION xv (prion proteins, bacteria, fungi, viruses, single- I took a sabbatical leave. This strategy assured and multicellular parasites). While none of these that I would stay motivated and on task. pathogens are brain specific, I chose examples in Rhodes College in Memphis TN, a small and which the nervous system is primarily affected highly selective Liberal Arts college, became including meningitis, botulism, tetanus, polio- my temporary academic home. Rhodes has myelitis, neurosyphilis, brain-eating ameba, been offering a neuroscience major for the past neurosistercosis, neuroaids, and prion diseases. 5 years, and it has grown to be among the more I also used this chapter as an opportunity to popular majors at the college. I was elated to highlight the tropism displayed by some viruses learn that 25 brave Rhodes students elected to for the nervous system and how this can be har- take my NEUR365, Diseases of the Nervous sys- nessed to deliver genes to the nervous system tem class, in spite of not knowing a shred about for therapeutic purposes. their professor who, being a medical school edu- For the section on neurodevelopmental disor- cator, was not listed on the “rate my college pro- ders I similarly chose four important examples fessor” Web site. including Down syndrome, Fragile X, Autism, With 5 chapters completed prior to my arrival, and Rett syndrome. These disorders have so 14 of the 16 chapters came together while teach- many commonalities that it made sense to cover ing the class. Each week, I handed out a new them in a single chapter (Chapter 11). disease chapter, and after giving a 75-minute No contemporary book of nervous system lecture, small groups of students had to prepare disease would be complete without coverage of independent lectures that they delivered to the neuropsychiatric illnesses and I elected to devote class based on recent influential clinical and one chapter each to depression (Chapter 12) basic science papers that I assigned (and list in and Schizophrenia (Chapter 13). this book with each chapter). Each week, using Taken together, I believe the material covers a questionnaire, the students provided detailed the “big” brain disorders that any neuroscien- feedback on how accessible, interesting, and tist or medical student should know. However, complete my chapters were, and how well the anyone looking for more detailed information book prepared them for the assigned papers that on rare disorders or disorders primarily affect- they had to present in class. I took their com- ing the peripheral nervous system or sensory ments very seriously, frequently spending days organs is referred to some of the excellent neu- incorporating their suggestions. I am thankful rology textbooks that I cite as my major sources to all of them and acknowledge a number of throughout the book. exceptionally helpful students in the acknowl- To assure that the material is presented in an edgment section by name. accessible, yet comprehensive format, the book A challenge that became immediately evi- was developed in a uniquely student-centered dent was the sheer magnitude of the available way, using my target audience as a focus group. literature. Moreover, writing about a disease To do so, I wrote the book as accompanying that is outside ones’ personal research specialty text to an undergraduate course, writing each leaves one without a compass to decide which chapter as I was teaching it to a class of neuro- facts are important and which are not. Narrow- science majors. Rather than embarking on this ing literature searches to just “diseases” and project on my home turf, I elected to enter a “review articles” did not help much and only self-imposed exile, free from the distraction of marginally reduced the number of hits from the family and friends, which would allow for sub- tens of thousands into the thousands. While it mersive reading, writing, and teaching for lit- was gratifying to see the enormous amount of erally every awake hour of every day. In short, information that has been published, it was xvi INTRODUCTION daunting to filter and condense this material of these conditions were modern at all. Historic into a manageable number of sources. In the accounts similarly suggest that environmental end, I developed a strategy to first identify the exposures are unlikely contributors to stroke or “opinion leaders” in each field, and then, using epilepsy. Yet, by contrast, the earliest accounts of their high impact reviews, widen my search to Parkinson disease align perfectly with the early include reviews that appeared to cover the most industrial revolution of the mid-1800 making salient points on which the entire field appears industrial pollutants potential disease contribu- to largely agree upon, while staying largely out tors. Even more extreme, no historic account of more tentative emerging and controversial for autism exists prior to the 1930s. Clearly, for topics. This was important since the objective of some of those diseases, human influences must this textbook was to introduce current accepted be considered as contributory factors. concepts rather than speculations. The historic adventures also allowed me to Another challenge I faced was to keep the examine diseases in the context of society at a material interesting. As teacher of medical neu- given time in history, clearly important lessons roscience I have long recognized the value of when teaching neuroscience at a Liberal Arts clinical cases. I decided to start each disease college. Our classes included how patients with chapter with case story, which is either an actual epilepsy were labeled witches and burned in case or one close to cases that I have actually medieval Europe; how the heritability of dis- witnessed in some form or other. The students eases such as Huntington corrupted even doc- liked this format, particularly since many of tors to subscribe to the reprehensible teachings the cases I describe involve young people. To of the eugenics movement; or how the infamous offer perspective on each disease, I also elected Tuskegee syphilis studies served as the founda- to provide a brief historic review for each dis- tion for the protection of human subjects partici- ease. How long has society been dealing with pating in human clinical trials, measures that we stroke, epilepsy, Huntington, or autism? What take for granted today. Another lesson learned were early interpretations on the disease cause, from the ancient accounts of Down syndrome is how was disease treated, and what were the that child birth late in a mother’s life occurred most informative milestones. This was possibly throughout history, but more importantly that the hardest section for me to write, since good those children were cared for in many societies sources were difficult to find. Yet it was also with the same love and compassion we have for the most fascinating. The students initially had them today. little appreciation for these sections and really The majority of pages in this book are devoted did not see much value in them. However, this to the biology of each disease. It is remarkable changed after we discussed the value of what I how much we know and how far we have come call “science forensics” and the historic insight in just the past few decades, from the historic that could be gleaned. We discussed how the disease pathology focused approach to contem- history of disease, when viewed in the context porary considerations of genes and environmen- of the history of mankind, allows us to dismiss tal interactions causing disease in susceptible or consider human endeavors and exposure to individuals. It is fascinating to note how cum- man-made chemicals as disease causes. After bersome the initial positional cloning efforts we discussed how Mexican vases made over were that identified the first candidate genes for 600 years ago already depicted children with disease compared to today’s large genome-wide Down syndrome, or how Polio crippled chil- association studies that identify large networks dren were portrayed on Egyptian stilts that were of gene and their interactions. Clearly, we expe- over 2000 years old, it became clear that neither rience a transformational opportunity to study INTRODUCTION xvii and understand disease through the study of place a source citation behind every statement rare genetic forms of familial diseases that can I make. In the context of this book, however, inform us about general disease mechanisms and I could only cite a few articles restricting myself allow us to reproduce disease in genetic animal to ones that I felt were particularly pertinent to models. At the same time, it is sobering to see a given statement. A list of general sources that how often findings in the laboratory fail to sub- most informed me in my reading is included at sequently translate into better clinical practice. the end of each chapter. I am concerned, how- I devote a considerable amount of discussion ever, that I may have gotten a few facts wrong, to such challenges and end each chapter with a and that some of my colleagues will contact me, personal assessment of challenges and oppor- offended that I ignored one of their findings that tunities. After completing the disease chapters, they consider ground breaking; or if I mentioned it was clear that there were many cross-cutting them, that I failed to explicitly credit them for shared mechanisms and features of neurological their contribution. It was a danger that I had to disease that I elected to devote an entire chap- accept, albeit with trepidation and I hope that ter solely to shared mechanisms of neurological any such scientists will accept my preemptive illnesses (Chapter 14). apologies. To mitigate against factual errors, Not surprisingly, almost all the class discus- I reached out to many colleagues around the coun- sions sooner or later gravitated toward ways try, clinical scientists whom I consider experts in to translate research findings from the bench the respected disease, and asked them to review to the bedside. Yet few of the students had any each chapter. I am indebted to these colleagues, idea what this really entails or the challenges whom I credit with each chapter, who selfishly that clinical trials face. Having been fortunate devoted many hours to make this a better book. enough to develop an experimental treatment for Their effort has put me at greater ease and hope- brain tumors in my laboratory that I was able to fully will assure the reader that this book repre- advance from the bench into the clinic through a sents the current state of knowledge. venture capital supported biotech start-up, I felt Given that the book was developed as an well equipped to discuss many of the challenges accompaniment to a college course, I expect that in proper perspective. So I devoted an entire it may encourage colleagues to offer a similar chapter (Chapter 15) to this important, albeit not course at their institution. I certainly hope that neuroscience specific, topic. The class included this is the case. To facilitate this, I am happy important discussions on the placebo effect and to share PowerPoint slides of any drawings or frank conversations as to why many scientific figures contained in this book, as well as any findings cannot be reproduced, and why most of the 1000 + slides that I made to accompany clinical trials ultimately fail. this course. I can be contacted by email at I also added several provocative topics to [email protected]. Also, for each chapter I class discussions such as the questionable uses am listing a selection of influential clinical and of neuroscience in marketing and advertising basic science articles that I used in class. These and the controversial use of neuroscience in the are just my personal recommendations and courtroom. Since neither relates to specific neu- not endorsements of particular themes or top- rological diseases, I elected to leave this out of ics. These papers have generated valuable dis- the book but encourage neuroscience teachers to cussion and augmented the learning provided bring such topics into the classroom as well. through the book. One thing that troubled me throughout my Finally, as I finish editing the book, I keep writing was the way in which sources are cred- finding more and more articles reporting excit- ited in textbooks. As a scientist, I reflexively ing new scientific discoveries that I would have