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About Multiple Sclerosis


What is MS?-An Overview

Causes of Multiple Sclerosis

The Role of the Immune System

Making the Diagnosis

Beyond the diagnosis

What is MS?-An Overview

Multiple sclerosis (MS) is a chronic, often disabling disease of the central nervous system (CNS). Converging lines of evidence suggest that the disease is caused by a disturbance in immune function. This disturbance permits cells of the immune system to attack myelin, the insulating sheath that surrounds the nerve fibers (axons) located in the CNS (i.e., the brain and spinal cord). When myelin is damaged, electrical impulses cannot travel quickly along nerve fiber pathways in the brain and spinal cord. Disruption of electrical conductivity results in fatigue and disturbances of vision, strength, coordination, balance, sensations, and bladder and bowel function.

Why was this disease called multiple sclerosis? Physicians during the 19th century noticed that the brains and spinal cords of patients with MS contained many areas where the nervous tissue was hard to the touch and appeared scarred. The Latin word for scar is sclerosis. Thus, the term multiple sclerosis was chosen to describe the appearance of the brain in patients who died with this illness. Pathologists call these scars plaques. When observed microscopically, plaques consist of inflammatory cells, astroglial cells, increased water (edema), and destroyed myelin fragments. Larger plaques may be seen on magnetic resonance imaging (MRI) scans of the brain and spinal cord.

The loss of normal myelin is called demyelination. Demyelination produces a situation analogous to that resulting from cracks or tears in the insulator surrounding an electrical lamp cord. When the insulating surface is disrupted, the lamp will short-circuit and the light bulb will flicker or no longer illuminate. Similarly, loss of myelin surrounding nerve fibers results in short-circuits in nerves traversing the brain and spinal cord that result in symptoms of MS.

In contrast to a single wire pathway in a lamp cord, there are thousands of nerve pathways in the brain and spinal cord, the two components of the CNS. The symptoms of multiple sclerosis depend largely on which particular nerve fiber pathway is involved in the CNS. Tingling, numbness, sensations of tightness, or weakness may result when loss of myelin occurs in the spinal cord. If the nerve fibers to the bladder are affected, urinary incontinence may follow. If the cerebellum of the brain is affected, imbalance or incoordination may result. Since the plaques of MS can arise in any location of the CNS, it is easy to understand why no two MS patients have exactly the same symptoms.
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Causes of Multiple Sclerosis

Although the cause of multiple sclerosis is unknown, evidence suggests that the disease may result from an environmental agent that triggers the illness in a genetically susceptible individual. These lines of evidence have given rise to both environmental and genetic explanations for MS.

The environmental theory: The environmental theory proposes that an environmental factor triggers the symptoms of MS. Support for this theory includes the observation that multiple sclerosis is diagnosed more frequently in temperate than tropical or subtropical climates. A map of the United States shows that the prevalence of MS increases with northern latitude. For example, the prevalence of MS in North Dakota is approximately twice that observed in Florida. The prevalence of MS in northern California is 150 cases per 100,000 individuals.

The relationship between latitude and prevalence of MS is also evident in other countries throughout Europe, New Zealand, and Australia. Investigators have explored the possibility that exposure to viral or bacterial infections, environmental toxins, duration of sunlight, changes in temperature and humidity, or diet might in some way produce or aggrivate MS. To date, no specific environmental factor has been proven to cause MS.

Studies of population migration support the notion that an environmental factor may contribute to the risk to develop MS. Specifically, susceptibility to develop MS appears to be influenced by age of residence within certain geographical areas. Individuals who are born in high-risk areas appear to acquire a lower risk if they relocate and establish residence in low-risk areas before age 15 years. In contrast, individuals born in low-risk areas may acquire a higher risk if they move and establish residence in a high-risk area before age 15 years.

Might the environmental factor be a viral infection? Certain viruses may cause demyelination in the brain and spinal cord of humans and animals. In addition, MS attacks are more likely when individuals experience non-specific viral syndromes than they are at other times. However, the clinical pattern of disease following such infections is not identical to MS. Also, viral proteins have not been reliably isolated from MS brains. In the absence of reliable isolation of infectious material from the brains of patients with MS, the relationship between MS and infectious agents (e.g., human herpes virus-6, chlamydia, etc.) remains uncertain.

Nonetheless, it remains possible that viral infections may trigger attacks of MS even if they do not actually cause the disease. For example, as mentioned above, MS exacerbations are more frequent following upper respiratory infections and flu-like illnesses. Reassuringly, immunization for influenza does not appear to exacerbate MS symptoms.

The genetic theory: The genetic theory proposes that susceptibility to develop MS is influenced by genetic factors. Several lines of evidence support this theory. MS is common in Caucasians but occurs rarely in Native Americans, Blacks native to Africa, and Asians living in high-risk areas in the United States. This suggests that if an environmental factor contributes to MS, only those who are genetically susceptible actually develop the illness.

Indeed, certain genes occur more frequently in persons with MS than those without MS. Studies of families in which more than one member has MS indicate unaffected family members are at increased risk to develop MS when compared to unaffected individuals in the general population. The risk of developing MS in the general population is approximately 0.15%. However, the risk to members of families who have a father, mother, sister, or brother with MS is between 1.0 and 4.0%.

Twin studies provide an opportunity to compare genetically identical siblings (identical twins) with twins who do not share identical genes (fraternal twins). If a disease is under genetic control, identical twins should both have MS more frequently than fraternal twins. The risk for developing MS in an unaffected fraternal twin is 2%, and the risk in an identical twin is 25-30%. These data strongly support the hypothesis that genetic factors play a significant role in disease susceptibility. However, they also point to a strong environmental influence because only a minority of genetically identical twins are both affected with MS.
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The Role of the Immune System

Whatever the cause of MS, there is considerable evidence that demyelination is accompanied by or results from a disturbance of immune function. This diagram illustrates a complex model, as yet unproven, of how an environmental factor might trigger and sustain an immune mediated attack on myelin.

In this model, the process begins with an infection by a virus or other external antigen (a substance, foreign to the body, that excites an immune response). Once this antigen gets into the blood stream, it is "eaten" by a macrophage, which digests the proteins of the virus or antigen to form smaller particles called peptides. Some of these peptides are then brought to the macrophage cell surface, where they are displayed inside a hand-like structure called an MHC (major histocompatability complex) molecule. In the cartoon, the peptide appears as a small oval ball held in the MHC. This MHC-peptide display can be recognized by special receptors on the surface of a particular white blood cell called the T cell. Only the TH1 subset of T cells that have receptors with a perfect fit for the MHC-peptide complex will recognize this display. Once recognition occurs, the TH1 cell undergoes activation of its cellular functions. This activation results in a proliferation of the number of TH1 cells that are capable of recognizing the MHC-peptide complex and the expression of additional T cell surface receptors that are capable of sticking to the so-called endothelial cells which line the blood vessel wall. Once attached, the TH1 cell secretes chemicals called proteases that facilitate migration through the endothelial cells and into the CNS. Once the TH1 cell arrives in the CNS, it may encounter a glial cell. Like the macrophage in the blood stream, the glial cell is also capable of presenting a MHC-peptide complex to T-cells. In MS, there is reason to believe that the peptide presented by the glial cell is a breakdown product of myelin, which is indistinguishable from the original viral peptide recognized by the TH1 cell. This "mistaken identity restimulates the TH1 cell to proliferate and undergo further activation of cellular function. This activation leads to the production of chemicals called cytokines, which are small proteins that have effects on other cells. Some of these cytokines produced by TH1 cells, such as interleukin-2 (IL-2), interferon-gamma (IFN-g), tumor necrosis factor-alpha (TNF-a), and interleukin-1 (IL-1), promote inflammation. Another subset of T-cells called TH2 cells secrete different cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and tumor growth factor-beta (TGF-b), which counteract or regulate pro-inflammatory cytokines. The balance between pro-inflammatory and immuno-modulating cytokines is probably important in regulating disease activity. An imbalance favoring pro-inflammatory cytokines may result in demyelination.
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Making the Diagnosis

The diagnosis of MS is based upon a clinical evaluation including documentation of "symptoms" and "signs" of the disease. Symptoms are the experiences of the patient. Examples of symptoms include double vision, tingly sensations, or difficulty controlling the bladder. Signs are abnormalities found on neurological examination and must be evident to the neurologist. Examples of signs include weakness of specific muscles, hyperactive reflexes, incoordination (ataxia), and abnormal eye movements. The diagnosis of clinically definite MS requires documentation of two distinct episodes of symptoms and two or more signs evident on the neurological examination. Episodes of symptoms must last at least 24 hours and be separated by one or more months. Signs must be due to involvement of 2 or more separate parts of the brain and spinal cord. Electrophysiological tests called evoked potentials can be helpful in documenting involvement in more than one location in the CNS.

The diagnosis of MS can be difficult to establish, especially when the initial symptoms are unaccompanied by signs, abnormalities on MRI or electrophysiological tests, or analyses of spinal fluid. Even when the initial symptoms is accompanied by abnormalities on the neurological examination, it is still possible that the correct diagnosis is something other than MS. For this reason, MS is said to be a "diagnosis of exclusion". This means that other medical conditions must be considered and excluded before the diagnosis of MS can be made confidently. Medical conditions that can mimic MS include metabolic or vitamin deficiencies, unusual infections, inflammation of the blood vessels of the brain (arteritis), degenerative disorders of the nervous system, or cancers that have spread to the brain. This is why blood tests, X-rays, brain and spine MRI's, and spinal taps to analyze cerebrospinal fluid may be required before a diagnosis of MS can be made with certainty. In some cases, even after extensive testing, a confident diagnosis cannot be made and future developments must be awaited.

Diagnostic tests can facilitate the diagnosis of MS, particularly when there are fewer than two abnormal signs on the neurological examination. In this instance, an abnormal test can be used to document a second sign.

Magnetic resonance imaging (MRI): An MRI of the brain is the most sensitive test for detecting structural abnormalities due to MS-related disease activity. MRI scans show focal brain abnormalities in more than 90% of patients with clinically definite MS. The MRI scan can also distinguish between new or old lesions, and thus provides a measure of disease activity. The MRI is also useful for excluding other neurological conditions that might be confused with MS. Because the imaging abnormalities seen in MS patients can also be seen in other medical conditions, a diagnosis of definite MS cannot be based solely upon the MRI.

Evoked Potentials : Evoked potentials reflect changes in the electrical activity that occurs within the CNS due to sensory input (a stimulus). The electrical response to the stimulus is measured by electrodes applied to the scalp. Visual evoked potentials are obtained by stimulating the eye with a checkerboard pattern of light and dark squares that are alternated on a television monitor. Brain stem auditory evoked potentials are produced by click sounds applied through earphones. Somatosensory evoked potentials are produced by electrically stimulating nerves in the hands or feet. The time between application of the stimulus and occurrence of the evoked potential provides a measure of the nerve's ability to conduct electrical impulses from one point to another. If the response time is slowed, this suggests that the nerve pathway is not functioning properly as a result of demyelination. These tests are abnormal in 70-90% of patients with clinically definite MS and often detect abnormalities that are not apparent on neurological examination. Because these tests measure function within the brain or spinal cord, they complement the information about brain structure provided by the MRI.

Lumbar Puncture (Spinal Tap): Cerebrospinal fluid abnormalities are detected in 80-90% of patients with clinically definite MS. These abnormalities include an increase in the number of cells and immunoglobulin proteins suggesting an inflammation or a heightened immune response. This test may be used to establish a diagnosis in patients who have experienced a slowly progressive decline in function without exacerbations (i.e., patients with so-called primary progressive MS) and who have no abnormalities seen on the brain MRI scan. In such instances, a diagnosis of definite MS cannot be made without an abnormality in the spinal fluid. The spinal fluid analysis may also be useful in excluding an infection that may be difficult to distinguish from MS.
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Beyond the diagnosis

The natural history of MS
What is going to happen to me? Can you tell me if I will be disabled? Is there anything I can do to improve my prognosis? These are some of the most common questions asked by recently diagnosed MS patients. Studies of the natural history of MS will help us understand the answers to these question

Studies of the natural history of MS suggest that there are different patterns of disease activity. Some patients have rare attacks, some have frequent attacks, and others gradually but steadily worsen without experiencing attacks. Patients who have rare attacks and are minimally disabled ten years after being diagnosed with MS are said to have benign MS. This group constitutes only about 10-15% of the total MS patient population, although there is some evidence suggesting that this course may be more common than is currently appreciated. Patients who have attacks with full or partial recovery and are otherwise stable between attacks are defined as having relapsing-remitting MS. Approximately 80-90% of patients with MS initially experience a relapsing-remitting course. Of these, approximately 50% will have difficulty walking 15 years after onset and 80% will ultimately (after 25 years) experience gradual progression of disability with or without attacks. Patients who first experience exacerbations and later experience gradual progression of disability have secondary progressive MS. Approximately 10-15% of MS patients do not experience an initial attack. Those patients who gradually worsen after the appearance of the first symptom have primary progressive MS. A few patients with primary progressive MS will later experience an exacerbation. These patients have progressive-relapsing MS.

The clinical course of MS is unpredictable. Neurologists are not able to foresee which newly diagnosed patients will have a benign course, who will have attacks, or who will gradually progress. Nonetheless, studies of large numbers of MS patients suggest that some disease-related factors do have some predictive value. The following factors are more likely to be associated with a favorable prognosis: (1) female gender, (2) age of disease onset earlier than 40 years, (3) a first attack consisting of optic neuritis or other sensory symptoms, (4) lack of significant disability 5 years after onset, and (4) minor abnormalities of brain MRI scan at the time of diagnosis. As a general rule, patients who have either difficulty walking or with sustained impairment in coordination after their first attack has resolved, and patients with a large number of MRI lesions have a less favorable prognosis.

Disability resulting from the first five years of the disease tends to predict the level of disability 15-20 years after diagnosis. Thus, it is often said that patients who have little or no disability five years after their diagnosis have the most favorable prognosis. Fifteen years after diagnosis, approximately 50% of patients will use a cane or other assistance to ambulate. Twenty years following diagnosis, approximately 60% of MS patients are still capable of ambulation, 20-30% maintain employment, and less than 15% require custodial care. Life span is shortened only slightly compared to the general population.

Pregnancy
There is evidence that the frequency of exacerbations is reduced during the third trimester of pregnancy, but increased during the 3-6 months following birth. Although the short-term increase in exacerbation rate is a concern, the long-term prognosis of MS does not appear to be worse for patients who have been pregnant. Decisions regarding pregnancy are personal and each patient has individual circumstances that may bear on that decision. We encourage you to speak with your neurologist about the relationship between pregnancy and MS disease activity.
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