This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.
2000 Third Web Report
In lieu of the end of the semester, several different types of questions came to my mind. Can the body ever turn on itself? Can it turn on its own brain -- the center of all activity and behavior? In researching for a final web paper topic, I came upon several different websites for a disorder known as Multiple Sclerosis. One of the most common disorders to affect the Central Nervous System (the brain and the spinal cord), Multiple Sclerosis is a demyelinating disease, which means it destroys the fatty material that surrounds and insulates the nerves. It is believed that abnormalities within the immune system are the cause.
My objective in this paper is to firstly give a brief history of what multiple sclerosis is, its symptoms, and treatments. Secondly, I will explain different schools of thought as to what the cause of the disorder is, from past to present. There is one school of thought that dominates recent research, which is that the disorder is auto-immune. I became interested in Multiple Sclerosis because of this theory, with the idea of one system attacking another but both being in the same body. Finally, I hope to show how treatment options have been affected by the acceptance of the auto-immune theory.
Dr. Jean Martin Charcot was the first physician to describe, document and name this disorder in mid-19th century (1). He named it for the multiple lesions that he found in dissecting the CNS. Multiple Sclerosis literally means many scars. These lesions are regions of the brain where the myelin has been lost and therefore appears hardened as though scars have formed. Common amongst the elderly, in the US, 1 in 500 persons who is over the age of 50, is affected by the disorder (3). It is rarely diagnosed in young children or the elderly.
Demyelinating disorders are an important group within neurological disorders in that they are extremely disabling and occur at great frequency. Common to all these disorders is the destruction of patches of myelin sheaths, usually followed by an inflammatory response. The activation of the immune system, which means the mobilization of white blood cells and antibodies, swelling and an accumulation of fluid (2), characterize a tissue’s inflammatory response to an injury. Myelin sheaths are much like the insulation around an electric wire. They allow for electrical impulses to be conducted along the nerve fiber with speed and accuracy. Therefore, when damaged, nerves cannot sustain impulses as properly and output is slower and strained. When born, babies lack these special myelin sheaths, leading to gross, uncoordinated movements. Normal development of these supportive cells occurs during the first years of a child’s life. If this is impaired, conditions such as Tay-Sachs, Niemann-Pick or Gaucher’s syndrome can develop (3).
Historically, Multiple Sclerosis (MS) has not been as delved into as many other neurological disorders, such as Parkinsons. Formerly known as "Creeping Paralysis", Multiple Sclerosis was considered a mental condition caused by "female hysteria" (1). This led to the conclusion in 1920 that men were more susceptible to MS than women as in women it was mistakenly diagnosed. Only recently has research supported the conclusion that MS was not a psychological condition but rather a neurobiological.
Demyelination in MS can occur in any part of the CNS and therefore symptoms can vary depending on the region affected. Demyelination in the nerve paths that bring signals to the muscles causes problems with movement, while demyelination of nerve pathways that carry input to the brain causes disturbances in sensation. Major symptoms of established MS include weakness, paralysis, tingling or numbness of the limbs, loss of vision from one or both eyes, double vision, imbalance, lack of coordination, slurred speech, impaired bladder and bowel control, chronic pain, and profound fatigue (4). In 1938, Dr. V. B. Dolgopol was the first to describe a case of Optic Neuritis, caused by severe demyelination of the optic nerves (1). But despite all these disabling symptoms, many people with MS have achieved a normal life span.
The cause of multiple sclerosis is still under debate. The most widely accepted theory is that it is an auto-immune disorder in which the components of the immune system recognize normal body tissues (such as those in the central nervous system) as ‘foreign’ and tries to get rid of them. However, other modern thoughts are that this disorder is triggered by heredity and/or by the environment (3). There is a chronology of different impressions as to what causes this disorder. In the 1890s, it was believed that it was caused by the suppression of sweat and therefore treated with herbs and bedrest (1). In the 1940s, blood clots and poor circulation was theorized to be the cause and treated with drugs that would improve circulation (1).
The theory that MS is caused by an abnormality in the immune system has dominated recent research. There is a line of evidence that caused researchers to explore this line of reasoning. The first evidence was the presence of the white blood cells that react against a protein found in nerve-insulating myelin in 1965 (1). This sparked interest in the correlation between the nervous system and the immune system of the body. It is believed that MS is triggered in susceptible individuals via viral or bacterial infection that has an antigen, which mimics the MS "self antigen" on myelin. A macrophage then engulfs the pathogen. The "self-mimicking" antigen fragment derived from the pathogen is then displayed on the macrophage surface, along with a human lymphocyte antigen (HLA) molecule. If a circulating T cell recognizes the antigen-HLA complex, it will bind to it and undergo primary activation/ replication. The cloned T-cells travel around the body and attack any cells that bear the "self-mimicking" antigen. Activated T cells bind to the epithelial walls of the brain by releasing cytokines (mediator cells) such as interferon gamma and lymphotoxin. These regulate the production of complementary adhesion molecules to the cohesion molecules on the walls of the brain, causing T-cells to bind to them. Within the CNS, the cytokines released by the T-cells act on microglia, transforming them into antigen-presenting cells capable of displaying myelin fragments. These T-cells, activated to attack the myelin-mimicking antigen, bind to the myelin microglia and undergo secondary activation. After another round of proliferation, new T-cells bind to microglia and cause the release of more and more cytokines. At this time there is more and more binding of the T-lymphocytes occurring to microglia. This chaos of chemicals causes the inflammation of the blood-brain barrier, thinning it so that T-cells, B-cells and macrophages may enter. Macrophages complete the process by stripping the myelin sheath directly off the nerves. In turn, they release necrosis factor alpha, which is believed to damage oligodendracytes - the cells that produce myelin - making the damage irreparable. (2) The replication of T-cells, the secretion of more and more cytokines, and the eventual destruction caused by the macrophages is cyclic. The myelin can be come inflamed, swollen, or even detached from the nerve fibers. Eventually, it is destroyed and hardened patches of scar tissue form over the fibers (5).
Evidence for this theory is supported by the presence of T-cells in the spinal fluid of patients with MS. Some of these cells are activated, belonging to T-helper cells. In addition, when the spinal fluid was further analyzed, IgG - protein - was found in increased amounts. These underwent electrophoresis, and displayed oligoclonal banding. This evidence suggests the expansion of B-cells within the brain and further supports the auto-immune theory (6).
However, what the trigger for such an immune response is still unknown. The three main claims to fame presently are environmental factors, heredity and a virus. Each has been supported widely and many articles supported that it was a conjunction of all three factors. Environmental settings, especially in early years, show to be an important determinant in the development of the disease. MS occurs in 1 out of 2,000 persons who spend their first decade of life - development of myelin sheath occurs primarily at this time - in a temperate climate but in only 1 out of 10,000 persons born in a tropical climate. MS hardly occurs in people that live near the equator (3). Heredity also seems to have a role in the disorder. Possession of certain alleles, most notably B7 and DR2, mark increased likelihood to develop MS (6). If one family member has MS, there is a 5% chance that a sibling is affected (3). The evidence to support the theory that a viral infection causes the inflammation comes from the increase of the substance, gamma-interferon. This cytokine is usually produced by an activated T-cell when the body is fighting a virus infection. However, it was also found to cause flares in MS patients (4).
The auto-immune theory is still a theory for many reasons even though the scientific community has embraced it to be the closest to truth as to the cause of MS. Firstly, the pathogen which researchers claim triggers the T-cell response has not been identified (6). Secondly, no MS specific antigen has been identified despite a strong search (6). Thirdly, the theory is a compilation of a number of different facts learned about MS over the years, such as macrophages do attack glial cells to the presence of activated T-cells in the spinal fluid. The success of the theory stems from the scientific community’s apprehension to name the environment as the source of neurobehavioral changes. Therefore, the search for an environmental trigger falls to the wayside in search of a viral pathogen.
The acceptance of the auto-immune theory has dominoed into the type of treatments available for MS. Because cytokines are the cause of much of the damage upon the glial cells during the immune attack, researchers have sought out ways to suppress the inflammatory response. One newly FDA approved drug therapy used to treat MS is thalidomide, which has anti-inflammatory and immunosuppressant effects making it ideal for these conditions (7). Marketed in the past as a mild sedative, it was pulled off the drugstore shelves when it was proven to cause dangerous birth defects in pregnant women (7). Another drug therapy utilized to treat MS is methprednisolone, a synthetic adrenal steroid hormone, which has powerful effects on suppressing inflammation. Shortening any flare-ups of MS, the drug does not permanently retard progression of the disorder (4). Newer drugs hold greater promise of beneficial effects. Many of them are beta-interferons, which reduce the frequency of flares by about 30% by reducing the number of cytokines in the brain (4). The three forms of treatment stated above seem to be the most recent and well-prescribed by physicians who treat victims of MS. Upon searching the Internet further, it was found that there were hardly any treatments for patients with MS that were not pharmacological. One homeopathic treatment of MS dealt with strengthening the blood-brain barrier (BBB), such that no immune cells could pass through. Not approved by the FDA, it was a suggestion found on a personal home page of a man concerned with treatments for MS. He believed that the increase of flavonoids in a person’s diet would strengthen the BBB to the extent that no further breakdowns would occur (8). The nonpharmacological treatments did not seem as commonly recommended as the pharmacological. This may return to a fear of the scientific community of the unknown, of things that cannot be explained by observations and physical data.
In finishing this report, I found that I myself was falling into accepting the auto-immune theory as the cause of Multiple Sclerosis because it is so widely accepted by the scientific community. Because most of the information that I found supported this theory and only this theory, I presume that any other theories that researchers have suggested in the past have fallen to the wayside or have been forgotten. Although there are a lot of holes in the auto-immune theory, especially the lack of evidence that it is the cause, the scientific community has reasoned the chronology of infection very methodically as shown by a number of websites with the tiny facts that they do have.
In trying to incorporate this paper into something discussed in class, I found that our definition of the "I" function was very limited - focussed solely on the nervous system and our behavior. (But then again, the course is focussed on neurobiology.) However, could there be more than one "I" function? In the case of MS, there seems to be a separate "I" function for the immune system as the immune cells were incapable of recognizing the nerve cells. This suggests that they were not linked by any common identification system. Also, should there be more than one "I" function? Because the nervous system is a maze of different nerve paths, it would be hard to localize the "self". But it seems that in separating the "I" function, there are some disastrous consequences to the interplay of systems in the body.
2)The World of Multiple Sclerosis, A wonderful website, providing information on what MS is to what type of treatment options are available for victims. It is very biased towards believing that it is an auto-immune disorder and gives a slide show presentation of how the immune system attacks the nervous system.
3)Multiple Sclerosis and Related Disorders, Reputable health care professions write laymen’s guide to what MS is and how it affects the body. Outlines what the symptoms are and basic information about the disorder. One of the best sites at describing new treatments available to patients.
4)Multiple Sclerosis: The Immune System's Terrible Mistake, Written by Peter Riskind, MD, PhD., it is an article on Multiple Sclerosis. It was most useful in describing treatments of the disorder and those persons who are most at risk for contracting it.
5)Multiple Sclerosis: New leads into its cause and treatment, Published by a very reputable health research clinic, this webpage gives a great breakdown of the types of treatments available but also how each drug therapy affects the disorder and therefore the body.
6)The Demyelinating diseases, Very technical explanation of how the immune system fails to recognize the nervous system and attacks it. Explains causes of MS more than treatment options and other basic facts.
7)Thalidomide, A quick summary of what thalidomide is and how it is used to treat Multiple Sclerosis.
8)Multiple Sclerosis, The Blood Brain Barrier, and New Treatment , A personal homepage of a pastor interested in Multiple Sclerosis. He suggests a new treatment option, which is to strengthen the blood-brain barrier using natural substances like flavanoids, found in common fruits. Although not as reliable as the sites written by the Mayo Clinic or Merck, it is an interesting homeopathic suggestion.