What is MS?

Multiple sclerosis (MS) is a disease that involves an immune system attack against the central nervous system (brain, spinal cord, and optic nerves). The disease is thought to be triggered in a genetically susceptible individual by a combination of one or more  environmental factors. Although MS is thought by some scientists to be an autoimmune disease, others disagree strongly because the specific target of the immune attack in MS has not yet been identified. For this reason, MS is referred to as an immune-mediated disease.

As part of the immune attack on the central nervous system, myelin (the fatty substance that surrounds and protects the nerve fibers in the central nervous system) is damaged, as well as the nerve fibers themselves. The damaged myelin forms scar tissue (sclerosis), which gives the disease its name. When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing the variety of symptoms that can occur.

What causes MS?

While the cause (etiology) of MS is still not known, scientists believe that a combination of several factors may be involved. Studies are ongoing in the areas of immunology (the science of the body’s immune system), epidemiology (that looks at patterns of disease in the population), and genetics in an effort to answer this important question. Understanding what causes MS will be an important step toward finding more effective ways to treat it and—ultimately—cure it, or even prevent it from occurring in the first place.

The major scientific theories about the causes of MS include the following:

Immunologic

It is now generally accepted that MS involves an immune-mediated response—an abnormal response of the body’s immune system that is directed against the myelin (the fatty sheath that surrounds and insulates the nerve fibers) in the central nervous system (CNS—the brain, spinal cord and optic nerves). The exact antigen, or target that the immune cells are sensitized to attack, remains unknown -- which is why MS is considered by most experts to be immune-mediated rather than autoimmune. In recent years, however, researchers have been able to identify which immune cells are mounting the attack, some of the factors that cause them to attack, and some of the sites, or receptors, on the attacking cells that appear to be attracted to the myelin to begin the destructive process. Ongoing efforts to learn more about the immune-mediated process in MS—what sets it in motion, how it works, and how to slow or stop it—are bringing us closer to understanding the cause of MS.

 

Environmental

MS is known to occur more frequently in areas that are farther from the equator. Epidemiologists—scientists who study disease patterns—are looking at many factors, including variations in geography, demographics (age, gender, and ethnic background), genetics, infectious causes, and migration patterns, in an effort to understand why. Studies of migration patterns have shown that people born in an area of the world with a high risk of MS who then move to an area with a lower risk before the age of 15, acquire the risk of their new area. Such data suggest that exposure to some environmental agent that occurs before puberty may predispose a person to develop MS later on.

Some scientists think the reason may have something to do with vitamin D, which the human body produces naturally when the skin is exposed to sunlight. People who live closer to the equator are exposed to greater amounts of sunlight year-round. As a result, they tend to have higher levels of naturally-produced vitamin D, which is thought to have a beneficial impact on immune function and may help protect against autoimmune diseases like MS.

Infections

Since initial exposure to numerous viruses, bacteria and other microbes occurs during childhood, and since viruses are well recognized as causes of demyelination and inflammation, it is possible that a virus or other infectious agent is the triggering factor in MS. More than a dozen viruses and bacteria, including measles, canine distemper, human herpes virus-6, Epstein-Barr, and Chlamydia pneumonia have been or are being investigated to determine if they are involved in the development of MS, but none have been definitively proven to trigger MS.

Genetic

While MS is not hereditary in a strict sense, having a first-degree relative such as a parent or sibling with MS increases an individual's risk of developing the disease several-fold above the risk for the general population. Studies have shown that there is a higher prevalence of certain genes in populations with higher rates of MS. Common genetic factors have also been found in some families where there is more than one person with MS. Some researchers theorize that MS develops because a person is born with a genetic predisposition to react to some environmental agent that, upon exposure, triggers an autoimmune response.

Pathopysiology of MS

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. In pathologic specimens, the demyelinating lesions of MS, called plaques (see the image below), appear as indurated areas—hence the term sclerosis.

Demyelination in multiple sclerosis. Luxol fast blue (LFB)/periodic acid-Schiff (PAS) stain confers an intense blue to myelin. Loss of myelin is demonstrated in this chronic plaque. Note that absence of inflammation may be demonstrated at the edge of chronic lesions.

Examination of the demyelinating lesions in the spinal cord and brain of patients with MS shows myelin loss, destruction of oligodendrocytes, and reactive astrogliosis, often with relative sparing of the axon cylinder. In some MS patients, however, the axon is also aggressively destroyed.

The location of lesions in the CNS usually dictates the type of clinical deficit that results. As neural inflammation resolves in MS, some remyelination occurs, but some recovery of function that takes place in a patient could be due to nervous system plasticity. MS is also characterized by perivenular infiltration of lymphocytes and macrophages, as demonstrated in the image below. Infiltration of inflammatory cells occurs in the parenchyma of the brain, brainstem, optic nerves, and spinal cord.

Inflammation in multiple sclerosis. Hematoxylin and eosin (H&E) stain shows perivascular infiltration of inflammatory cells. These infiltrates are composed of activated T cells, B cells, and macrophages.

One of the earliest steps in lesion formation is the breakdown of the blood-brain barrier. Enhanced expression of adhesion molecules on the surface of lymphocytes and macrophages seems to underlie the ability of these inflammatory cells to penetrate the blood-brain barrier.

The elevated immunoglobulin G (IgG) level in the cerebrospinal fluid, which can be demonstrated by an oligoclonal band pattern on electrophoresis, suggests an important humoral (ie, B-cell activation) component to MS. In fact, variable degrees of antibody-producing plasma cell infiltration have been demonstrated in MS lesions. 

The image below provides an overview of demyelination.

The mechanism of demyelination in multiple sclerosis may be activation of myelin-reactive T cells in the periphery, which then express adhesion molecules, allowing their entry through the blood-brain barrier (BBB). T cells are activated following antigen presentation by antigen-presenting cells such as macrophages and microglia, or B cells. Perivascular T cells can secrete proinflammatory cytokines, including interferon gamma and tumor necrosis factor alpha. Antibodies against myelin also may be generated in the periphery or intrathecally. Ongoing inflammation leads to epitope spread and recruitment of other inflammatory cells (ie, bystander activation). The T cell receptor recognizes antigen in the context of human leukocyte antigen molecule presentation and also requires a second event (ie, co-stimulatory signal via the B7-CD28 pathway, not shown) for T cell activation to occur. Activated microglia may release free radicals, nitric oxide, and proteases that may contribute to tissue damage.

Immune cells in MS

Molecular studies of white matter plaque tissue have shown that interleukin (IL)-12, a potent promoter of inflammation, is expressed at high levels in lesions that form early in MS. B7-1, a molecule required to stimulate lymphocytes to release proinflammatory cytokines, is also expressed at high levels in early MS plaques.Evidence exists of elevated frequencies of activated myelin-reactive T-cell clones in the circulation of patients with relapsing-remitting MS and higher IL-12 production in immune cells of patients with progressive MS.

Decreased function of T-lymphocytes with a regulatory role (Tregs) has been implicated in MS.These Tregs are CD4+ CD25+ T cells that can be identified by their expression of a transcription factor known as Foxp3.

Conversely, the cytokine IL-23 has been shown to drive cells to commit to a pathogenic phenotype in autoimmune diseases, including MS. These pathogenic CD4+ T cells act reciprocally to counteract Treg function and can be identified by their high expression of the proinflammatory cytokine IL-17; they are therefore referred to as TH 17 cells.

Tregs and TH 17 cells are not the only critical immune cells in the pathogenesis of MS. Immune cells such as microglia (resident macrophages of the CNS), dendritic cells, natural killer (NK) cells, and B cells are gaining increased attention by MS researchers. In addition, nonimmune cells (ie, endothelial cells) have also been implicated in mechanisms that lead to CNS inflammation.

Signs and Symptoms of MS

• Most Common Symptoms
  Some symptoms of MS are much more common than others.

  Fatigue

  Numbness

  Walking (Gait), Balance, & Coordination Problems

  Bladder Dysfunction

  Bowel Dysfunction

  Vision Problems

  Dizziness and Vertigo

  Sexual Dysfunction

  Pain

  Cognitive Dysfunction

  Emotional Changes

  Depression

  Spasticity

  Less Common Symptoms
  These symptoms also occur in MS, but much less frequently.

  Speech Disorders

  Swallowing Problems

  Headache

  Hearing Loss

  Seizures

  Tremor

  Respiration / Breathing Problems

  Itching

  
  

  
  

  
  

  
  

  
  

  
  

  
  

  
  

  
  

Who is at risk ?

MS is thought to affect more than 2.1 million people worldwide. While the disease is not contagious or directly inherited, epidemiologists—the scientists who study patterns of disease—have identified factors in the distribution of MS around the world that may eventually help determine what causes the disease. These factors include gender, genetics, age, geography, and ethnic background.

Patterns in the Distribution of MS

-As in other autoimmune diseases, MS is significantly more common (at least 2-3 times) in women than men. This gender difference has stimulated important research initiatives looking at the role of hormones in MS. 

-MS is not directly inherited, but genetics play an important role in who gets the disease. While the risk of developing MS in the general population is 1/750, the risk rises to 1/40 in anyone who has a close relative (parent, sibling, child) with the disease. In families in which several people have been diagnosed with MS, the risk may be even higher. Even though identical twins share the same genetic makeup, the risk for an identical twin is only 1/4—which means that some factor(s) other than genetics are involved.

-While most people are diagnosed between the ages of 20 and 50, MS can appear in young children and teens as well as much older adults. Studying the disease in different age groups may help scientists determine the cause of MS and explain why the disease course differs from one person to another. Important questions include why the disease appears so early in some children and why people who are diagnosed after age 50 tend to have a more steadily progressive course that primarily affects their ability to walk.

-In all parts of the world, MS is more common at northern latitudes that are farther from the equator and less common in areas closer to the equator. Researchers are now investigating whether increased exposure to sunlight and the vitamin D it provides may have a protective effect on those living nearer the equator.

-MS occurs in most ethnic groups, including African-Americans, Asians and Hispanics/Latinos, but is more common in Caucasians of northern European ancestry. However some ethnic groups, such as the Inuit, Aborigines and Maoris, have few if any documented cases of MS regardless of where they live. These variations that occur even within geographic areas with the same climate suggest that geography, ethnicity, and other factors interact in some complex way.

Occurence and Prevalence of MS?

  Worldwide, approximately 2.1 million people are affected by MS. The disease is seen in all parts of the world and in all races, but rates vary widely. In general, the prevalence of MS tends to increase with latitude (eg, lower rates in the tropics, higher rates in northern Europe), but there are many exceptions to this gradient (eg, low rates among Chinese, Japanese, and African blacks; high rates among Sardinians, Parsis, and Palestinians).

The presence of these exceptions implies that racial and ethnic differences affect risk. In addition, a substantial increase in MS incidence has been reported from different regions, suggesting that environmental factors, as well as geographic and genetic ones, play an important role in MS.

Epidemiologic studies indicate an increase in MS prevalence in Latin America. Susceptibility to MS and clinical behavior of the disease varies genetically in Latin America; for example, MS apparently does not occur in Amerindians with Mongoloid genes.

Prevalence estimates for MS in the United States vary from 58 to 95 per 100,000 population. According to the National Multiple Sclerosis Society, 400,000 individuals in the United States are affected by MS. Misdiagnosis is common, however.

As is true of autoimmune diseases in general, MS is more common in women. The female-to-male ratio of MS incidence has increased since the mid-20th century, from an estimated 1.4 in 1955 to 2.3 in 2000. MS is usually diagnosed in persons aged 15-45 years; however, it can occur in persons of any age. The average age at diagnosis is 29 years in women and 31 years in men.

The Criteria for a Diagnosis of MS

A common misconception is that any attack of CNS demyelination means a diagnosis of acute multiple sclerosis (MS). When a patient has a first attack of demyelination, the physician should not rush to diagnose MS, because the differential diagnosis includes a number of other diseases.

In order to make a diagnosis of MS, the physician must:

Find evidence of damage in at least two separate areas of the central nervous system (CNS), which includes the brain, spinal cord and optic nerves AND

Find evidence that the damage occurred at least one month apart AND

Rule out all other possible diagnoses.

In 2001, the International Panel on the Diagnosis of Multiple Sclerosis updated the criteria to include specific guidelines for using magnetic resonance imaging (MRI), visual evoked potentials (VEP) and cerebrospinal fluid analysis to speed the diagnostic process. Other tools to be considered in diagnosing MS are medical history and neurological exam and blood tests. These tests can be used to look for a second area of damage in a person who has experienced only one attack (also called a relapse or an exacerbation) of MS-like symptoms — referred to as a clinically-isolated syndrome (CIS). A person with CIS may or may not go on to develop MS.  

The Four Courses of MS

People with MS can typically experience one of four disease courses, each of which might be mild, moderate, or severe.

Relapsing-remitting MS

"Relapsing remitting" MS is the most common type of MS, affecting around 85 per cent of everyone diagnosed with MS. It means that symptoms appear (a relapse), and then fade away, either partially or completely (remitting).
The relapsing remitting label can help to explain MS to others and help you to find the best treatments. But it can't predict exactly how MS will affect you.
For most people with MS, this is the way their MS begins, except for the small group of people who have primary progressive MS (about 15 per cent of all people with MS).
People with this type of MS experience clearly defined attacks of worsening neurologic function. These attacks—which are called relapses, flare-ups, or exacerbations —are followed by partial or complete recovery periods (remissions), during which no disease progression occurs. Approximately 85% of people are initially diagnosed with relapsing-remitting MS.



Primary-Progressive MS

Primary progressive MS affects about 10 to 15 per cent of people diagnosed with MS.
It has this name because from the first (primary) symptoms it is progressive. Symptoms gradually get worse over time, rather than appearing as sudden attacks (relapses).
In primary progressive MS, early symptoms are often subtle problems with walking, which develop – often slowly – over time.
Whatever symptoms someone experiences, the way they progress can vary – from person to person and over time. So, although in the long-term symptoms might get gradually worse, there can be long periods of time when they seem to be staying level, with no noticeable changes.
This type of MS is usually diagnosed in people in their forties or fifties – older than the average age for relapsing remitting MS – but it can be diagnosed earlier or later than this.
Equal numbers of men and women have primary progressive MS. This is different to relapsing remitting MS, where more women than men have the condition.
People with primary progressive MS can experience many of the same symptoms as those with relapsing remitting MS.
This disease course is characterized by slowly worsening neurologic function from the beginning—with no distinct relapses or remissions. The rate of progression may vary over time, with occasional plateaus and temporary minor improvements. Approximately 10% of people are diagnosed with primary-progressive MS.



Secondary-Progressive MS

Secondary progressive MS (SPMS) is a stage of MS which comes after relapsing remitting MS in many cases. Neurologists generally agree secondary progressive MS is a "sustained build up of disability, independent of any relapses".
Most people with relapsing remitting MS will eventually develop secondary progressive MS. It varies widely from person to person, but on average, around 65 per cent of people with relapsing remitting MS will develop secondary progressive MS 15 years after being diagnosed.
It can be hard to diagnose. Most neurologists will look for at least six months of clear progression before they use the term secondary progressive.
It is possible to be diagnosed with this type of MS when you are first diagnosed with the condition - if the relapsing remitting phase of MS had never been identified - but this is rare.
It's different from primary progressive MS, which is progressive from the beginning.
Following an initial period of relapsing-remitting MS, many people develop a secondary-progressive disease course in which the disease worsens more steadily, with or without occasional flare-ups, minor recoveries (remissions), or plateaus. Before the disease-modifying medications became available, approximately 50% of people with relapsing-remitting MS developed this form of the disease within 10 years. Long-term data are not yet available to determine if treatment significantly delays this transition.



Progressive-Relapsing MS



In this relatively rare course of MS (5%), people experience steadily worsening disease from the beginning, but with clear attacks of worsening neurologic function along the way. They may or may not experience some recovery following these relapses, but the disease continues to progress without remissions.
Since no two people have exactly the same experience of MS, the disease course may look very different from one person to another. And, it may not always be clear to the physician—at least right away—which course a person is experiencing.