Diseases of the Nervous System

Harald Sontheimer

• Publisher: Academic Press
• Year: 2015
• ISBN:
  9780128004036
• Topic: Medicine
• Subtopic: Physiology

The study of the brain continues to expand at a rapid pace providing fascinating insights into the basic mechanisms underlying nervous system illnesses. New tools, ranging from genome sequencing to non-invasive imaging, and research fueled by public and private investment in biomedical research has been transformative in our understanding of nervous system diseases and has led to an explosion of published primary research articles.

Diseases of the Nervous System summarizes the current state of basic and clinical knowledge for the most common neurological and neuropsychiatric conditions. In a systematic progression, each chapter covers either a single disease or a group of related disorders ranging from static insults to primary and secondary progressive neurodegenerative diseases, neurodevelopmental illnesses, illnesses resulting from nervous system infection and neuropsychiatric conditions. Chapters follow a common format and are stand-alone units, each covering disease history, clinical presentation, disease mechanisms and treatment protocols. Dr. Sontheimer also includes two chapters which discuss common concepts shared among the disorders and how new findings are being translated from the bench to the bedside. In a final chapter, he explains the most commonly used neuroscience jargon. The chapters address controversial issues in current day neuroscience research including translational research, drug discovery, ethical issues, and the promises of personalized medicine.

This book provides an introduction for course adoption and an introductory tutorial for students, scholars, researchers and medical professionals interested in learning the state of the art concerning our understanding and treatment of diseases of the nervous system.

• 2016 PROSE Award winner of the Best Textbook Award in Biological & Life Sciences
• Provides a focused tutorial introduction to the core diseases of the nervous system
• Includes comprehensive introductions to Stroke, Epilepsy, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, ALS, Head and Spinal Cord Trauma, Multiple Sclerosis, Brain Tumors, Depression, Schizophrenia and many other diseases of the nervous system
• Covers more than 40 diseases from the foundational science to the best treatment protocols
• Includes discussions of translational research, drug discovery, personalized medicine, ethics, and neuroscience

Part I

Static Nervous System Diseases

Outline

Chapter 1. Cerebrovascular Infarct: Stroke

Chapter 2. Central Nervous System Trauma

Chapter 3. Seizure Disorders and Epilepsy

Chapter 1

Cerebrovascular Infarct

Stroke

Harald Sontheimer

Abstract

The brain consumes an enormous amount of energy (20%) that is disproportionate to its small size (2%). It relies on the constant delivery of oxygen and glucose to produce adenosine triphosphate, the cellular energy unit required to maintain brain cells’ functioning. Even brief loss of blood flow as a result of blockage or rupture of a cerebral blood vessel, called ischemia, leads to a sudden appearance of neurological symptoms. Stroke usually affects only one side of the brain, and the perfusion field of the affected blood vessel defines the specific pattern of sensory or motor symptoms produced. In a minority of patients (10%) blood flow is disrupted because of a vessel rupture, causing a hemorrhagic stroke. The vast majority of patients have vessel blockage as a consequence of atherosclerotic plaque, narrowing cerebral blood vessels, or distant plaque, giving rise to floating fragments called emboli that can lodge in cerebral blood vessels. The most effective treatment for stroke involves the rapid opening of an occluded vessel either mechanically or using tissue plasminogen activator (tPA), a clot-busting chemical. Time is of the essence because neurons die quickly in the absence of blood flow and tPA becomes almost ineffective 3 h after a stroke. The cellular and molecular processes underlying the ischemic cascade that culminates in neuronal cell death are well understood, particularly the importance of the excitatory neurotransmitter glutamate (Glu), which is elevated to toxic concentrations after stroke. Its binding to neuronal Glu receptors triggers a process called excitotoxicity, which causes rapid necrotic and slow apoptotic neuronal death. Approximately 800,000 new stroke cases are diagnosed annually in the United States and 200,000 patients die from it. In spite of excellent poststroke physical and occupational therapy, many of the 4 million stroke survivors live with permanent disability at a huge cost to the individual, their families, and society.

Keywords

Atherosclerosis; Embolism; Energy; Excitotoxicity; Ischemia; Thrombosis; Tissue plasminogen activator

Outline

1. Case Story 3

2. History 4

3. Clinical Presentation/Diagnosis/ Epidemiology 5

4. Disease Mechanism/Cause/Basic Science 8

4.1 Causes of Vessel Occlusions: The Thrombolytic Cascade 12

4.2 The Ischemic Cascade 14

4.3 The Ischemic Penumbra 14

4.4 The NMDA Receptor and Glutamate Excitotoxicity 17

4.5 Role of Glutamate 18

4.6 NMDA Inhibitors to Treat Stroke 19

4.7 Effect of Temperature 20

5. Treatment/Standard of Care/Clinical Management 21

5.1 Treatment of Stenosis Using Intravenous tPA 21

5.2 Rehabilitation 22

5.3 Stroke Prevention 22

6. Experimental Approaches/Clinical Trials 22

6.1 Neuroprotection 23

6.2 Neuroprotection by Hypothermia 24

6.3 Improved Clot Busters 24

6.4 Mechanical Revascularization 25

6.5 Why Have So Many Promising Drugs Failed in Human Clinical Trials? 25

7. Challenges and Opportunities 26

Acknowledgments 27

References 27

General Readings Used as Source 32

Suggested Papers or Journal Club Assignments 32

1. Case Story

Although I was barely 6 years old at the time, I remember as if it were yesterday. I had anxiously waited for the day, Easter Sunday. It was an annual ritual that the entire family gathered at grandma’s house for the largest Easter egg hunt in the neighborhood. Counting well over 30 cousins, this was no small event, and there had always been intense competition for finding the most treats. But per protocol, the hunt would not get on its way until after Sunday Mass. Excited, after breakfast I ran to grandma’s house next door to meet her for the drive to church. Surprisingly, she did not answer her doorbell, and her window curtains were still drawn. This was unusual, for she was always up by the crack of dawn. Puzzled, I ran back to tell mom, who retrieved grandma’s spare key to check on her. As we entered the dark hallway, I heard strange labored breathing coming from upstairs. Mom rushed up the stairs and I followed at a close distance shouting “Grandma! Grandma!,” but we did not hear a response. The bedroom was empty, her bed untouched. Mom ran to the bathroom. There she was, stretched out on the floor, laying on her side, barely conscious. Grandma was trying to speak, but was unable to vocalize anything intelligible. Wearing only her nightgown, she was shivering. Mom ordered me to run back to the house and ask dad to call an ambulance. When I returned a short while later, mom had carried grandma to her bed. She was clearly not well. Her left face was drooping and she just gazed into space, her shallow breaths interrupted by occasional attempts to vocalize. As the paramedics arrived I was ordered out of the room. They carried grandma down the stairs, and when I caught her eyes, she seemed very afraid. Mom traveled with her to the hospital by ambulance, which sped away with blaring sirens. Hours later, as the rest of the family arrived, there was nothing festive about this Easter. Without grandma, we picked up treats without much interest and without any laughter. Mom soon returned, reporting that grandma had suffered a stroke but was in stable condition. She would have to stay in the hospital for a few days but would probably recover. Grandma did come home the following weekend, but she clearly was not herself. She could barely stand and had to use a walker to make even a few steps around the house. Her face was still drooping and her speech was unintelligible. However, she clearly understood everything I said, and while trying to answer, eventually gave up in frustration after several attempts. Throughout the following week her speech gradually returned, and by a month after her stroke, she was sitting at the dinner table eating by herself, although mostly using only her right hand. As she slowly pieced together words, we were able to have at least a rudimentary conversation. Mom had to help grandma with just about any task, from dressing to bathing. Every evening, mom and I would help her to bed, and before she retired, mom would check in on her once more for good measure. This evening, Mom did not return for a long time. I woke to sirens screaming and I feared for the worst. Mom was still not home for breakfast and called in the afternoon to report that grandma had passed away. She had suffered another stroke almost exactly a month after the first one disrupted our annual Easter gathering.

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 paralysis, 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 twentieth 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 random event.

Hippocrates explained apoplexy using his humoral theory, according to which the composition and workings of the body are based on four distinct bodily fluids (black bile, yellow bile, phlegm, and blood), which determine a person’s temperament and health. Accordingly, diseases result from an imbalance in these four humors, with apoplexy 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 evidence that a disruption of blood flow to the brain causes stroke came through a series of autopsies conducted by Jacob Wepfer in the mid-1600s.

The humoral theory of Hippocratic medicine ruled until the German physician Rudolf Virchow discredited it in his “Theories on Cellular Pathology,” published in 1858. Virchow made countless impactful contributions to medicine. With regard to stroke, he first explained that blood clots forming in the pulmonary artery cause vascular thrombosis and that fragments arising from these thrombi can enter the circulation as emboli. These emboli then 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 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 embolus, thereby causing embolization that shut off...