PLS VIM 003113
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 1/269
`
`

`
`People with epilepsy today want to be partners in their own health care. This
`book provides the kind of information that will help them achieve that goal.
`Dr. Bazil takes the time to explain complex ideas in ways that are understand(cid:173)
`able, and his book is a welcome addition to the growing library of health care
`resources on epilepsy:'
`-Eric R. Hargis, president and CEO, Epilepsy Foundation
`
`How and why seizures occur
`
`How to get the right diagnosis
`
`Alternative methods: do they
`work?
`
`Pros and cons of surgery
`
`Treatments on the horizon
`
`Support and strategies for
`living better day by day
`
`PLS VIM 003116
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 2/269
`
`

`
`PLS VIM 003117
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 3/269
`
`

`
`LIVING WELL WITH
`
`An Expert Explains
`
`What You Really
`
`Need to Know
`
`CARL W. BAZIL, M.D., Ph.D.
`
`'l
`
`• -Harper Resource
`
`An Imprint of HarperCollinsPublishers
`
`PLS VIM 003118
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 4/269
`
`

`
`LIVING WELL WITH EPILEPSY AND OTHER SEIZURE DISORDERS. Copyright
`© 2004 by Carl W. Bazil. All rights reserved. Printed in the Unitea States
`of America. No part of this book may be used or reproduced in any manner
`whatsoever without written permission except in the case of brief quotations
`embodied in critical articles and reviews. For information. address Harper(cid:173)
`Collins Publishers Inc., 10 East 53rd Street, New York, NY 10022.
`
`\_
`
`HarperCollins books may be purchased for educational, business, or sales
`promotional use. For information please write: Special Markets Department,
`HarperCollins Publishers Inc., 10 East 53rd Street, New York, NY 10022.
`
`FIRST EDITION
`
`Designed by Joy O'Meara
`
`Library of Congress Cataloging-in-Publication Data ·
`
`Bazil, Carl W .
`. Living well with epilepsy and other seizure disorders: an expert
`explains what you really need to know I Carl W. Bazil.-1st ed.
`p. em.
`Includes index.
`ISBN 0-06-053848-1
`1. Epilepsy-Popular works.
`
`I. Title.
`
`RC372.B39 2004
`616.8 153-dc22
`
`2004047493
`
`04 05 06 07 08
`
`10 9 8 7 6 5 4 3 2 1
`
`PLS VIM 003119
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 5/269
`
`

`
`MEDICAL DISCLAIMER
`
`This book contains advice and information relating to health care.
`It is not intended to replace medical advice and should be used to
`supplement rather than replace regular care by your doctor. It is
`recommended that you seek your physician's advice before embarking
`on any medical program or treatment. All efforts have been made to
`assure the ac<;pracy of the information contained in this book as of
`the date of publication. The publisher and the auth~r disclaim liability
`for any medical outcomes that may occur as a result of applying the
`methods suggested in this book.
`
`PRIVACY DISCLAIMER
`
`The names of the individuals discussed in this book have been
`changed to protect their privacy.
`
`PLS VIM 003120
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 6/269
`
`

`
`To all those living with epilepsy, particularly those whom
`I have had the pleasure to treat and who hf!-ve taught me the most
`important thing in disease as in life: if's all about living well.
`
`PLS VIM 003121
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 7/269
`
`

`
`CONTENTS
`
`Acknowledgments
`Introduction
`
`PART ONE: About Epilepsy
`1 From Normal Thoughts to Seizures:
`The Workings of the Brain
`2 Tickling the Brain in Many Ways:
`The Many Types of Sei2.ures
`3 How Does It Happen? Causes of Epilepsy
`4 Children Are Different
`5 Seizures in Older Adults
`6 When Seizures Are Not Epilepsy: Other Conditions
`That Look Like Epilepsy
`7 Making the Diagnosis: The Process and
`the Tests Involved
`
`PART TWO: Treating Epilepsy
`8 The Mainstay of Treatment: Many Medicines
`for Epilepsy
`9 A Chance to Cure: Is Surgery a Possibility for Me?
`10 Seizures Are Random-or Are They?
`Day-to-Day Things That Might Affect Seizures
`·.11 Thinking Outside the Box:
`Alternative and Herbal Treatments for Epilepsy
`
`XI
`1
`
`5
`
`15
`34
`49
`59
`
`65
`
`76
`
`95
`126
`
`148
`
`158
`
`ix
`
`PLS VIM 003122
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 8/269
`
`

`
`X Contents
`
`12 What Happens Next: Future Directions in Epilepsy
`and Its Treatment
`
`173
`
`PART THREE: Living Well with Epilepsy
`181
`13 Staying Safe
`14 Other Medical Problems Common in Epilepsy Patients:
`193
`Depression, Migraine, and Sleep Disorders
`15 Pregnancy, Childbirth, and 1'ssues
`Particularly Related to Women with Epilepsy
`16 Preventing Prejudice: Education Is the Key
`'
`17 Finding What Works fo~ You
`Appendix: Sources of Further Information
`Index
`
`201
`212
`221
`227
`245
`
`PLS VIM 003123
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 9/269
`
`

`
`ACKNOWLEDGMENTS
`
`My sincerest t~anks to all who have helped me in this long ~ndeavor.
`First, my many teachers in medicine, pharmacology, neurology, and
`epilepsy; and particularly my main mentors in epilepsy: Martha
`Morrell, M.D., and Tin:lothy Pedley, M.D., gave me the foundation
`on which to build an understanding of health in general and
`epilepsy in particular. The entire staff of the Columbia Compre(cid:173)
`hensive Epilepsy Center-physicians, nurses, nurse practitioners,
`research associates, administrators, and administrative assistants(cid:173)
`constantly show me the true meaning of care. Thanks also to all at
`HarperCollins, particularly Cathy Hemming, Megan Newman, Nick
`Darrell, and Toni Sciarra, and to the staff at Witherspoon Associates,
`especially David Forrer and Kim Witherspoon, for their unending
`patience and guidance in this, my first nonacademic book. Others
`who helped with reading, advice, or moral support are; Alison
`Pack, M.D., Linda Leary, M.D., Kelly Parden, David Ebershoff,
`Jerry Meyer, and my parents and family. The inspiration, motivation,
`and persistence needed to complete this book came from Eric Price.
`Finally, the relevance and perspective for everything in this book
`came from the many people with epilepsy I have met and hopefully
`helped, particularly those who took the extra time with me to discuss
`or read this work, and those whose stories appear within its pages.
`
`PLS VIM 003124
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 10/269
`
`

`
`""·
`
`Diagnosis with any medical condition can be worrisome, particu(cid:173)
`
`larly if you are not well informed about it. Often the uncertainty
`and misunderstanding can be worse than the disease itself. This is
`perhaps true of epilepsy more than any other condition. Epilepsy in(cid:173)
`volves the brain, a complicated and poorly understood part of the
`body that nonetheless is the seat of not only our experiences and our
`thoughts, but also our sense of self. A condition that affects the
`brain can therefore be more troubling, perhaps, than one that af(cid:173)
`fects other parts of the body. Most people do not have a good un(cid:173)
`derstanding of how the brain works, and therefore of the ways
`epilepsy could (and more important, co~ld not) affect daily life. In
`addition, epilepsy has been the subject of prejudice and misunder(cid:173)
`standing since the beginning of time. While today people with this
`sometimes confusing condition are no longer thought to be pos(cid:173)
`sessed by demons, and many legal safeguards protect all people in
`the workplace, the general public is still widely confused about
`many aspects of this condition. If you have epilepsy, you may find
`yourself having to educate family, friends, and colleagues while cop-
`. ing with it yourself.
`
`1
`
`PLS VIM 003125
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 11/269
`
`

`
`2
`
`Introduction
`
`With any medical condition, information is often the most im(cid:173)
`portant aspect of care. Armed with a full understanding, people
`know what to expect, what to look out for-and what not to fear.
`This book is meant to offer comprehensive information about all as(cid:173)
`pects of epilepsy. It serves as a guide for those with the condition,
`and for their family members and friends who would like a more
`complete understanding of the condition. It is also a guide for pro(cid:173)
`fessionals or others wanting to know more about this common,
`sometillfeS gebilitating condition that raises many questions about
`the human brain: about the source of our thoughts and our fears,
`and about the meaning of creativity and insight.
`Part 1 starts with a description of the normal brain, and how
`epilepsy can occur. Chapters discuss the different types of seizures
`and causes of epilepsy, and how epilepsy occurs in specific age
`groups. Part 2 covers treatment of epilepsy, from traditional to al(cid:173)
`ternative methods. Part 3 delves into the practical aspects of living
`with epilepsy, including safety, lifestyle, other conditions and their
`relationship with epilepsy, and childbirth.
`I hope that this book contains all of the information needed to
`fully understand epilepsy and, more important, to live a fulfilling
`and complete life after diagnosis.
`
`PLS VIM 003126
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 12/269
`
`

`
`PLS VIM 003127
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 13/269
`
`

`
`The brain is an incredibly complex organ that controls not only
`
`what people think and do, but who they are. Ancient philoso(cid:173)
`phers believed that the heart was the seat of the soul, but we now
`know that it is actually the brain that is the organ of feelings and
`thoughts, the source of reactions to the world and our interpreta(cid:173)
`tions of it. The brain makes us move and speak, see and hear, feel
`and understand. The brain is also the source of epilepsy, which is
`probably why epilepsy is such a con1plicated disease, with manifes(cid:173)
`tations as diverse as the brains from which it arises. Understanding
`epilepsy, then, begins with an understanding of the workings of the
`brain.
`The brain is an organ of communication, whose job is to process
`all of the information important to its owner. All of the complicated
`things that our brain helps us do~translate the spiky shapes of let(cid:173)
`ters and lines on a page into words and thoughts; steer around a
`pedestrian who suddenly steps into the street; recognize the face of
`a child and feel overwhelming love for her-consist of electrical and
`chemical signals that pulse between neurons, which are specialized
`· brain cells. It's sometimes helpful to think of the brain as a living
`
`5
`
`PLS VIM 003128
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 14/269
`
`

`
`6 About Epilepsy
`
`computer. Both brains and computers are made up of individual cir(cid:173)
`cuits, both run (more or less) on electricity, and both are capable of
`retaining and processing information. Both can also malfunction: as
`a computer screen can briefly freeze, so can a human brain pause
`during a seizure. But there are differences as well. The human brain
`can regenerate and heal itself. This is fortunate, because although
`we can upgrade and buy new computers, we have only one brain
`throughout life. We sometimes feel that computers do things much
`more efficiently and easily than our own brains. But no computer
`can match the creativity and depth of experience that a single hu(cid:173)
`man brain has.
`This chapter is a brief guided tour through the brain, from the
`relatively simple individual neuron that is either "on" or "off" to
`the complex networks of thought and feeling that make us human.
`
`The Brain Cell: The Smal-lest Unit of Thought
`
`The brain is made up of billions of nerve cells called neurons. Akin
`to the wires and circuits of the brain, neurons are held together by
`structural cells, called glia, that protect and insulate the circuits of
`the brain. Glia are like the insulation on a wire and the backing on
`which the circuits are mounted. Fundamentally, a neuron (or more
`accurately a group of neurons) in your brain interprets incoming in(cid:173)
`formation, mulls it over, then sends 9ff a signal that results in ac(cid:173)
`tions. It is also a neuron (or a group of neurons) that, probably
`beginning in much the same way, causes all kinds of seizures.
`Structurally, a neuron has a cell body that holds most of its
`workings: the genetic material that determined how it was formed,
`enzymes that make proteins and transmitter substances, and other
`machinery for producing energy to run the cell (Figure 1-1 ). The cell
`also has "dendrites "-arms of the cell that branch out to the sur(cid:173)
`rounding- area, listening to other neurons in the area and taking in-
`
`PLS VIM 003129
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 15/269
`
`

`
`From Normal Thoughts to Seizures: The Workings of the Brain 7
`
`Dendrites
`
`~ Axon j
`
`Cell body
`
`FIGURE 1-1: The Neuron
`
`formation back to the cell body. Some neurons have relatively sim(cid:173)
`ple "dendritic trees" that connect with only one or two other neu(cid:173)
`rons; others have extensive branches connecting with dozens or
`more. Neurons also have.an ''axon": the output arm. of the cell. The
`axon carries each individual neuron's message to other cells. A neu(cid:173)
`ron, then, looks a little like a scorpion: arms out in all directions, a
`body that runs the show and decides when to respond, and a stinger
`that carries a single message to the outside.
`The neuron is constantly processing ~nformation from other neu(cid:173)
`rons, deciding \\fhether it should "fire" (send a message itself) or stay
`quiet. When a neuron fires, it releases one or more chemicals called
`neurotransmitters-serotonin, norepinephrine, epinephrine, and glu(cid:173)
`tamate are examples. Each of these chemicals can either excite-so
`that the receiving cell gets a buzz and thinks about firing itself-or
`inhibit-quieting, encouraging the receiving neuron to stay still.
`When a neuron fires, only other neurons with an appetite for its par(cid:173)
`ticular transmitter will be aroused at what are called receptor sites,
`
`PLS VIM 003130
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 16/269
`
`

`
`8 About Epilepsy
`
`the place where the neurotransmitter attaches. One neuron may re(cid:173)
`spond to glutamate but not to serotonin. No receptor, and the trans(cid:173)
`mitter bounces off and tries to find another neuron that's listening.
`So neurons are selective in which other neurons they listen to.
`Is a single neuron firing a thought, or can it be a tiny seizure? So
`far as we understand these, it can be neither. Neuronal firing can
`only be thought of as a spark. If it falls on ready tinder, a flame can
`result, but if it falls on water or dust, it fizzles and remains unnoticed.
`
`Neural Networks: From a Spark to a Thought
`
`It may be difficult to imagine how the simple "on-off" system of a
`neuron can translate into the complex thoughts and reactions of the
`·human brain. The system begins to get more complex when the con(cid:173)
`cept of neural networks comes in. Every brain contains billions of
`neurons, each of which can talk to one or many other neurons, and
`each of which listens to other (or the same) neurons. These create
`hundreds of thousands of neural pathways in a brain, where neu(cid:173)
`rons are connected to other neurons, and there are an infinite num- ,
`her of possible messages. Moreover, neurons can learn. As neurons
`talk and listen to each other, fire and quiet, they can develop rela(cid:173)
`tionships among themselves. Some pathways between neurons be(cid:173)
`come grooved with frequent contact, and like a well-worn path
`through the woods a memory is formed. Other paths become over(cid:173)
`grown and hard to find if only used once or twice. The first time any
`child tries to coordinate the many muscles required to maintain bal(cid:173)
`ance while operating a bicycle, it's tough. She must pedal evenly to
`move forward, shift weight through a turn, and feel the strain in her
`legs to know when to shift gears. The brain coordinates this process,
`and as she rides again and again, the same systems are used and re(cid:173)
`fined. They become stronger and easier to access and use each time.
`Once she masters the skill, -the neuromuscular pathways are well
`
`PLS VIM 003131
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 17/269
`
`

`
`From Normal Thoughts to Seizures: The Workings of the Brain 9
`
`paved and clear: get on a bicycle even after many years, and those
`procedural pathways will waken and guide with an eerie accuracy.
`The same holds true for other things. Go back to an old neighbor(cid:173)
`hood, one you haven't seen since the age of three or four, and you
`may find that you mysteriously know the woods' back paths and
`where the wild tulips grow. The knowledge is engraved in the neural
`networks, the brain's interstates and country roads. On the other
`hand, try speaking French after a twenty-year interval. Those road(cid:173)
`ways have been repaved with the sticky tar of English, hardened
`now to crust. it will take a lot of work to clear the clogged channels.
`Thus the simple neuron, firing and quiet, evolves into our living
`thoughts, skills, and memories over years of use.
`
`Anatomy of the Brain
`
`Understanding of how the brain works must go beyond the neuron
`to the way the brain grows and develops. The most primitive struc(cid:173)
`tures of the brain-concerned with breathing, eating, sexual activ(cid:173)
`ity, and emotion-are located at the base of the brain in an area
`called the brainstem. This part is present in some form in all ani(cid:173)
`mals. The newer part of the brain, or "neocortex" (new brain), sur(cid:173)
`rounds the brainstem and is most highly developed in humans. This
`area is responsible for most of the remainder of brain functions,
`from complex reasoning to sensation and movement. The neocortex
`is divided into regions separated mainly by folds in the surface of
`the brain. Neurons are located mainly in this surface. As humans
`developed, they needed more and more neurons. To fit all these cells
`in, rather than growing in size, the brain increased area through
`many folds in the surface known as sulci. There is a large division
`between the left and right side of the brain. There is also a large sul(cid:173)
`cus, called the central sulcus, which runs more or less from ear to
`ear. These large. folds in the brain determine the major regions, or
`
`PLS VIM 003132
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 18/269
`
`

`
`10 About Epilepsy
`
`Frontal lobe
`
`Parietal lobe
`
`Temporal lobe
`
`Occipital lobe
`
`FIGURE 1-2: Lobes of the Brain
`
`"lobes," of the brain (Figure 1-2). The frontal lobes are located in
`front of the central.sulcus, and the parietal lobes behind. Roughly
`perpendicular to the central sulcus is the Sylvian fissure, which runs
`backward from the ear and divides the parietal lobe (above it) from
`the temporal lobes below. The occipital lobes are at the back of the
`head and are not precisely defined by sulci.
`Some structures seem to be in place before a thought ever occur~.
`For reasons that are not understood, but are probably at least partly
`genetic, the brain develops particular skills in the same regions in
`nearly every normal person. The major site for movement is always
`located just in front of the central sulcus (in. the frontal lobe), and
`each side of the brain controls the opposite side of the body (Figure
`1-3). The distribution of control is also nearly identical from person
`to person: e.g., leg control is deep inside the fissure that separates
`the hemispheres, hand control is on the side, tongue control is lower
`down. The finer the control needed, the more brain is involved, so
`
`PLS VIM 003133
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 19/269
`
`

`
`From Normal Thoughts to Seizures: The Workings of the Brain 11
`
`Sensation
`
`Movement
`
`Vision
`
`Speech
`
`FIGURE 1-3: Functional Areas of the Brain
`
`the hand and the lips use up much more cortical space in-the brain
`than do the back and the neck. The sense of touch is directly behind
`the motor areas, in the parietal lobes~ Vision is located in the back
`of the head, in the occipital lobes.
`Language, a complex human skill, requires several areas. One is
`located in the frontal lobe, close to the motor areas that control the
`lips and tongue. This region, known as Broca's area, is primarily
`concerned with the production of speech rather than its interpreta(cid:173)
`tion. Another area, called Wernicke's, is in the temporal lobe and is
`necessary for understanding speech. A person with a stroke (or a
`seizure} restricted to Wernicke's area may speak apparently nor(cid:173)
`mally, but be completely unable to interpret things that are said to
`him. If Broca's area is affected, he may understand all that is said,
`but be incapable of speaking back (except for "automatic" speech
`such as yes~ no, or sometimes profanities; these do not seem to re(cid:173)
`quire the complex control that Broca's area provides). In nearly all
`right-handed people, both Wernicke's and Broca's areas are located
`
`PLS VIM 003134
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 20/269
`
`

`
`12 About Epilepsy
`
`in the left brain. With left-handed people, language can be on the
`right, the left, or "mixed," where both sides are used.
`
`The Abnormal Thought: A Seizure
`
`How, then, do these same pathways give rise to a seizure? For one of
`countless reasons, a group of neurons, or a neuronal pathway, be(cid:173)
`comes hyperactive. Perhaps those cells were starved of oxygen for a
`time at birth. Maybe they were bruised during a motorcycle acci(cid:173)
`dent, or maybe they were genetically misprogrammed and grew up
`in the wrong place or with overactive receptors. In many people
`with epilepsy, the brain looks completely normal. Maybe in these
`people, the constant reorganization of neurons just randomly made
`a bad connection, and reinforcement of that abnormal path caused
`it to grow in strength. In any case, epileptic neurons (or more likely
`pathways) tend to spurt a lot more transmitter, and far more fre(cid:173)
`quently than they should. As a result, millions of other, normal neu(cid:173)
`rons, caught up in the commotion, begin to fire. If nothing stops it
`(there are, remember, inhibitory pathways), soon large parts of the
`brain are triggered and aroused: a single spark, then a flame, and fi(cid:173)
`nally a forest fire. In a tonic-clonic (grand mal) seizure, every single
`neuron is firing simultaneously, a massive lightning storm thunder(cid:173)
`ing through the head, so the person cannot think or feel, and all of
`his muscles are commanded to violently contract, out of control.
`Because of the complexity of the brain, epilepsy, to an extent like
`no other disease, is about individuals: each seizure experience is
`unique, and each person is touched by it in very different ways. Not
`only do the different areas of the brain have very different func(cid:173)
`tions, but everyone's brain is wired in a unique manner. A seizure
`will result in the perception or the response associated with the part
`of the brain involved. Seizures that begin in the visual areas of the
`brain begin with the perception of colors and shapes. These can be
`
`PLS VIM 003135
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 21/269
`
`

`
`From Normal Thoughts to Seizures: The Workings of the Brain 13
`
`amorphous and vague: swirls of colors, or a floating, moving object
`like a huge butterfly. Or they can be incredibly distinct: the face of a
`deceased relative, or (as in one of my patients) Tweetybird. Other
`seizures may be accompanied by intense inexplicable feelings of
`dread; in these cases, the excitation involves the brain's amygdala, a
`fascinating structure that is involved with emotion, including f~ar.
`Sometimes a seizure ripples through the auditory (hearing) regions,
`and then the person hears clashes, clangs, or lovely strains of music.
`If the language area is affected, the person may hear, but voices sud(cid:173)
`denly sound strange and meaningless, "like Charlie Brown's
`teacher" as several of my patients have explained it. If the gustatory
`(taste) center is involved, then metal, vinegar, or chocolate can be
`tasted. ·
`While these examples are fascinating, the majority of people do
`not experience anything so specific. They may lose consciousness
`before remembering ap.ything or may only have a vague sense that
`'
`something is different: a seizure starting'in one of the brain's many
`areas without a function we can easily recognize.
`Most seizures start spontaneously, seemingly out of nowhere, but
`in. a few cases they can be brought on by highly specific external
`cues. In these cases, the normal response to sound, light, or move(cid:173)
`ment must hit an irritated area, and the connection is such that a
`seizure begins. I once had a patient who loved Billy Joel's music,
`then began to have seizures every time she heard "Piano Man." In ~
`well-publicized case, a woman had seizures specifically triggered by
`newscaster Mary Hart's voice; in another, hundreds of Japanese
`children had seizures from watching a single episode of Pokemon.
`Although unusual, this sort of reaction should not be surprising; af(cid:173)
`ter all, the irritated brain involved in seizures remains intimately
`connected to the normal surrounding areas. So just as a seizure can
`produce sensations that seem real, so can a real sensation occasion(cid:173)
`ally trigger a seizure.
`Depending upon the individual and the meaning she attaches to
`
`PLS VIM 003136
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 22/269
`
`

`
`14 About Epilepsy
`
`these strange states, seizures can have very different impacts on the
`person who experiences them. They can be seen as a gift, a curse, a
`bother, a bore. But all impact the person;s life in ways that can be
`confusing, terrifying, or even dangerous, particularly in the absence
`of adequate knowledge of what is happening. Seizures begin
`through the same machinery that produces our thoughts and feel(cid:173)
`ings; some of the small ones may even be difficult to distinguish
`from normal feelings. Most seizures, however, are at least ptoblem(cid:173)
`atic and frequently disruptive. The next chapter describes specific
`seizure types in more detail.
`
`PLS VIM 003137
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 23/269
`
`

`
`0 ne of the most common misperceptions about epilepsy is that it
`
`is a single disease. In fact, epilepsy actually includes a wide vari(cid:173)
`ety of conditions that have one thing in common: the brain mal(cid:173)
`functions spontaneously, then returns to normal. Usually this means
`entirely normal: I have patients who are doctors, nurses, actors,
`artists, and writers, all successful in their fields. This process of nor(cid:173)
`mal functioning most of the time, but interrupted by seizures,
`sounds rather simple but is in fact complicated. Epilepsy comes
`about for a variety of reasons, from conditions that change the
`structure of the brain (like a stroke) to genetic conditions that alter
`the way the brain reacts. The latter are mostly "generalized epilep(cid:173)
`sies" and will be described in detail in the second part of this chap(cid:173)
`ter. Generalized seizures are one of the two broad divisions in
`seizure type. They are called generalized because they seem to begin
`in all areas of the brain at once. The other seizure type, and the most
`common, is "partial seizures": seizures that begin in a discrete area
`of the brain and can then spread to involve other areas or the entire
`brain. Because each part of the brain has distinct functions, partial
`seizures are incredibly variable in different people.
`
`15
`PLS VIM 003138
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 24/269
`
`

`
`16 About Epilepsy
`
`Many people think that partial seizures are somehow less severe
`or serious than generalized seizures. This is not necessarily true; the
`terms have only to do with how the seizure starts, and not with
`severity. Arguably the most "mild" seizures are "absence seizures,"
`· consisting only of a brief staring; however, this is a generalized(cid:173)
`seizure type. It is also confusing that a grand mal (generalized tonic(cid:173)
`clonic) seizure can be either partial or generalized; it depends only
`on whether it starts small and spreads (partial, and knuyvn as a sec(cid:173)
`ondarily generalized tonic-clonic seizure) or whether it seems to
`start all over the brain (called a primary generalized tonic-clonic
`seizure). It may in fact be impossible for even a well-trained neurol(cid:173)
`ogist to distinguish a primary from a secondarily generalized seizure
`as she watches them.
`
`The Many Types of Partial Seizures
`
`As mentioned above, although one seizure type is called partial, that
`does not mean that they any less severe, debilitating, or dramatic
`than generalized seizures. The term refers only to the discrete onset
`of each seizure: partial seizures begin in one part of the brain.
`A commonly used scale ranks the severity of partial seizures: they
`may be simple, complex, or secondarily generalized.
`A "simple partial" seizure means that the seizure is small enough
`that the person does not experience any confusion or loss of aware(cid:173)
`ness. For instance, a patient can have a seizure that begins with a
`thumb jerking back and forth. She is fully aware that the thumb is
`misbehaving and remains aware as the other fingers or the arm join
`in. This is a simple partial motor seizure. Some simple partial
`seizures that do not involve movement are called auras. Most people
`(including many physiCians) think of an aura as a warning rather
`than an actual seizure, but in reality it is a small seizure. Common
`auras are a feeling of dread or doom, a feeling of deja vu, or a sud-
`
`PLS VIM 003139
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 25/269
`
`

`
`,..
`
`Tickling the Brain in Many Ways: The Many Types of Seizures 17
`
`den foul smell. An aura can be distinguished from other simple par(cid:173)
`tial seizures because it is totally subjective: the person experiencing
`it is the only one who can feel or see that it is happening.
`A "complex partial" seizure includes some degree of confusion.
`A simple partial seizure can become complex by spreading to in(cid:173)
`volve more of the brain. Probably, there has to be some involvement
`of both sides of the brain before awareness is- altered. During a com(cid:173)
`plex partial seizure, a person can appear fairly normal: he may con(cid:173)
`tinue to stand; walk, or even talk, but he is partly or completely
`unaware of what is happening around him. Afterward, he may have
`no memory of what transpired during the seizure.
`A "secondarily generalized" seizure starts in one area of the
`brain, but slowly or quickly spreads to involve the entire brain. It
`may appear identical to a "primary generalized" seizure, described
`above. Or the jerking thumb can become a jerking hand, arm, arm
`and leg, then start on the other side (originally described in the nine(cid:173)
`teenth century by a well-known neurologist named Hughlings Jack(cid:173)
`son, this "traveling" seizure is called a Jacksonian march). The end
`result of both primary and secondarily generalized seizures is that
`the person becomes stiff in all extremities, ("tonic~') followed by
`rhythmic ("clonic") jerking movements of the entire body. With a
`secondarily generalized seizure, the person may not remember the
`first part, when the seizure is small. In some cases, the "aura" will
`give enough warning that the person can get to a place of safety be-.
`fore losing consciousness (but typically loss of consciousness occurs
`within no more than about thirty seconds).
`
`Seizures Vary by Their Region of Onset
`In many cases, it is possible to tell where in the brain a seizure
`starts simply by what it looks or feels like. Although the exact func(cid:173)
`tion of vast areas of the brain is unknown, many areas are also
`. known to govern specific functions in all people with normal brains.
`Much of this information was determined early in the twentieth
`
`PLS VIM 003140
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2079 - 26/269
`
`

`
`18 Abou