Introduction

Synonyms and keywords
MS, demyelinating disease, relapsing remitting, primary progressive, secondary progressive, progressive relapsing, devic’s syndrome, neuromyelitis optica, NMO, autoimmune disease, demyelination, plaques, disseminated sclerosis

Definition
Multiple sclerosis is a chronic, immune-mediated disease of the brain, spinal cord, and optic nerve.

Overview
Multiple sclerosis (MS) was first described in detail in 1868 by a French neurologist, Jean-Martin Charcot.  MS affects the central nervous system (CNS) which includes the brain, spinal cord, and optic nerve, in multiple locations and causes scarring or sclerosis.  Although MS affects males and females in all age groups, it is typically diagnosed in women between the ages of 20 and 40 years. 

The exact cause of the disease is unknown.  Many experts believe that it is related to an attack on the central nervous system by the patient’s own immune system, which is referred to as an autoimmune disease.  In MS, the immune system attacks the fatty coating around the nerves, called myelin.  When this occurs, electric impulses cannot properly travel from the brain to the spinal cord and vice versa.  MS is thought to be due to both environmental and genetic causes.

The injury to the central nervous system is extremely variable in MS.  Symptoms can vary dramatically from person-to-person and over time in an individual.  In addition, there is much variability in the course of the disease.  There are four types of expected courses and these include relapsing-remitting, secondary progressive, primary progressive and progressive relapsing.  Of these, relapsing-remitting is by far the most common type.

Significant advances have been made recently in the treatment of MS.  Therapies may treat the underlying disease process or the symptoms of the disease, such as fatigue or weakness.  For treating the underlying disease, multiple medications have been proven to change the course of the disease.  Steroids are used to treat episodes of worsening symptoms, known as attacks or exacerbations.  For the symptoms of multiple sclerosis, there are many treatment options, which include medications as well as non-medication approaches, such as physical therapy, occupational therapy, speech therapy, and psychotherapy.

The Distribution of MS (Epidemiology)
Specific people appear to be at higher risk for developing multiple sclerosis.  The disease is more common in people from certain geographical areas, particular racial and ethnic groups, and women.
 
Multiple sclerosis has a specific geographical distribution.  The risk of developing multiple sclerosis is higher is those who spend their childhood years farther from the equator—in other words, multiple sclerosis is most common in those who grow up in the northern parts of the northern hemisphere and the southern parts of the southern hemisphere (see figure). 

The geographical distribution of multiple sclerosis indicates that environmental factors contribute to the risk of developing the disease.  The specific environmental factors are not known, but may relate to viruses or sunlight exposure.  The age of 15 seems to be an important milestone for the development of multiple sclerosis with regards to where that individual grew up.  If the individual moves before the age of 15, they then share the same risk for developing multiple sclerosis as all individuals who live in that area to which they moved.  In contrast, if they move after the age of 15, they keep the same risk as the other individuals in the area where they spent their first 15 years.

In North America, multiple sclerosis is much more common in Caucasians of northern European ancestry than in Hispanics, Native-Americans, African-Americans, and Asian-Americans.  Multiple sclerosis is rare or non-existent in Inuits, pure Africans, and specific isolated populations around the world.

A gender discrepancy exists in the risk of developing multiple sclerosis.  Women are about twice as likely to develop multiple sclerosis in comparison to men, with all other factors being equal.  This probably relates to hormonal effects on the immune system.

Anatomy
The brain functions as the information control center for the entire body.  The spinal cord begins at the base of the brain and functions to relay messages to and from the brain to the rest of the body.  The spinal cord is about the width of a human finger and transmits information in both directions.

The central nervous system (CNS) is made up of the brain and the spinal cord.  The peripheral nervous system (PNS) includes the nerves that leave the spinal cord and travel to various parts of the body.

Nerve cells that make up the nervous tissue of the brain and spinal cord are more specifically referred to as neurons (see figure).  Neurons conduct electrical current between the brain and spinal cord and peripheral nerves.  They function to interpret and process complex information and transmit that information to the appropriate location in the body.  Neurons consist of three main parts: the soma or cell body, dendrite, and axon.  The dendrites are finger-like extensions projecting off of the cell body--they usually receive information from other neurons.  The soma is the control center of the neuron.  Information is electrically transmitted from the soma to the axon, which allows the information to travel to the appropriate location or tissue.  Axons may synapse, or communicate with another neuron, to continue the relay of information throughout the nervous system.  Some neurons have one axon that extends for over one meter (about three feet) in length.  An example of this is the axon that travels from the spinal cord to the foot.

When discussing multiple sclerosis, myelin is a key component of the anatomy that must be understood.  Myelin is a fatty substance (phospholipid) that also contains protein and acts to insulate the axon.  Myelin has a white appearance, which is responsible for the white matter description of the nervous system as compared to the grey matter, which is largely composed of the cell bodies.  In the brain, the grey matter is generally on the outer surface, and the white matter is inside.  In contrast, in the spinal cord, the white matter is generally found on the outside surface and grey matter is in the center.

Myelin's main function is to increase the conduction speed of electrical impulses down the axon of the nerve.  Myelin is organized on the axon similar to beads on a necklace.  Axons that are covered with myelin cause the electrical impulses to jump over each myelin section (bead), which causes the electrical impulse to spend less time actually on the nerve. To understand this, imagine that it takes less time for an electrical impulse to travel through the air as opposed to staying on the nerve the entire time.  This jumping over the myelin sections dramatically increases the speed of the electrical transmission down the axon. 

Myelin is produced by oligodendrocyte cells in the central nervous system and Schwann cells in the peripheral nervous system.  These cells wrap around the axons and produce myelin. The area on the nerve that is not covered by myelin is referred to as the node of Ranvier.  This is the area where the electrical impulse actually travels on the nerve as it jumps over the myelin section. If an axon does not have myelin, the electrical impulses travel continuously down the entire length of the axon—the speed of conduction in these types of nerves is slower than that with axons with myelin. 

The Disease Process of MS
Multiple sclerosis is characterized by chronic inflammation and injury to the central nervous system’s myelin.  Inflammation may lead to damage to the axons and oligodendrocytes.

This inflammation and destruction of myelin is thought to occur by the individual’s own immune system.  It is not known exactly why this occurs or what triggers this abnormal reaction.  When the individual’s own immune system begins to attack itself, this is referred to as an autoimmune disease.  Other diseases that are categorized as autoimmune include rheumatoid arthritis and type I diabetes.  In multiple sclerosis, there are other factors that likely contribute to this autoimmune disease, and these include genetics, environmental factors, ethnicity, and age of exposure.

The normal functioning immune response is very important and beneficial to maintaining our health.  When foreign substances, such as viruses, bacteria, and fungi, enter the body, our immune system begins to fight off and kill the potentially harmful invaders. In multiple sclerosis, there is confusion about what is self and what is a harmful foreign invader.  The immune system begins to recognize the myelin as a harmful foreign invader and mounts an attack which causes destruction and subsequent neurological difficulties. 

The exact reason why the immune system turns against itself is an area of debate and current research.  Some have proposed that there was a previous infection with an organism or virus that has a structure that is similar to that of the myelin.  The immune system keeps memory of the structure of the infectious agent in a manner that is similar to that of a lock and key (see figure), in which the lock is the infectious agent and the key is the immune system.  If myelin happens to have a structure that resembles the lock on the infectious agent, then the key of the immune system will into that lock and destruction of the myelin will begin.

 

A characteristic feature of multiple sclerosis is a demyelinating plaque.  Demyelination means that the nerve, which once was covered with myelin, has completely or partially lost this covering.  The term plaque is used to describe an area in the central nervous system that has suffered demyelination.

Initially, in the early stages of multiple sclerosis, the myelin is attacked and destroyed in multiple areas throughout the nervous system.  The most common initial involvement includes:
• the white matter around the inner portion of the brain (the ventricles)
• the coordination part of the brain (the cerebellum)
• the base of the brain (the brainstem)
• the nerves from the eyes to the brain (the optic nerves)
• the spinal cord.

Remyelination is the process of repairing the nervous system by adding myelin back to the areas that suffered demyelination during the autoimmune process.  Oligodendrocytes are the cells in the central nervous system that are responsible for producing myelin that covers the axon. Axons may also be damaged in MS.  Once an axon in the central nervous system is damaged, it can never be repaired.  This damage to axons is likely responsible for the eventual progressive decline in neurological function that is seen later in the disease process.  Studies have looked into why remyelination does or does not occur on the axons.  There is some evidence that the axon that has chronically suffered inflammation loses its ability to accept myelin.

At a cellular level, multiple sclerosis usually includes an initial demyelination, followed by complete or partial remyelination, injury to the axon, and eventual scar formation.  These areas of demyelination are responsible for the initial symptoms of multiple sclerosis.  Areas of the nerve that are demyelinated prevent normal conduction and may partially or completely block transmission of electrical signals.  The axonal injury is irreversible and prevents transmission of electrical conduction throughout the nerve.  This decrease in transmission along the nerve may occur in the nerves involved in strength, sensation, coordination, or vision.  Therefore, depending on the degree of involvement, people with multiple sclerosis may have weakness, abnormal sensation, incoordination, or visual difficulties.  As remyelination takes place, or inflammation decreases, these symptoms may improve.

Clinical course

Subtypes of MS
There are four major subtypes of MS (see figure):

• Relapsing-Remitting:  At the time of diagnosis, about 85% of patients have relapsing-remitting MS.  In this condition, the individual suffers from unpredictable exacerbations (also known as relapses, attacks, or flares) which then can be followed by improvement to baseline or permanent signs and symptoms to varying degrees. 

• Secondary Progressive:  Approximately 50% of individuals who previously were diagnosed with relapsing-remitting MS develop secondary progressive MS within 10 years if not treated.  These individuals start out with exacerbations followed by remissions, but later develop a progressive declining neurological course with increasing disability.

• Primary Progressive:  Approximately 10% of those with multiple sclerosis are diagnosed with primary progressive MS at the time of initial presentation of symptoms.  These individuals do not experience exacerbations and have a progressive declining neurological course, which typically affects leg strength and walking ability.  

• Progressive-Relapsing: This is the least common category of multiple sclerosis.  These individuals initially have a progressive declining course, like primary progressive MS, but then experience exacerbations as well.  

 

A New Direction in Classifying MS
MS has typically been thought of as a single disease.  However, recent research indicates that it may in fact be multiple diseases.  A research program, the “MS Lesion Project” (MSLP), is investigating this concept.  This international project includes a US component led by Dr. Claudia Lucchinetti at the Mayo Clinic.  Other MSLP research centers are in Germany and Austria.  In this research project, MS brain tissue is examined microscopically.   It has been found that there are four patterns of nervous system injury in MS.  Patterns I and II have characteristics of immune system involvement that would typically be expected with MS.  Pattern I has immune cell involvement, while Pattern II has both immune cell and antibody involvement.  In Pattern III, immune cells are present and there is an abnormality of the cells that make myelin, the insulation-like coating on nerve fibers.  Pattern IV exhibits loss, or degeneration, of oligodendrocytes, the myelin-producing cells. 

Through the work of the MSLP, there have been several important observations.  First,   our current MS classification scheme (such as relapsing-remitting and secondary progressive) does not correlate well with the microscopic patterns of pathology.  Also, it all of the lesions from a single person exhibit the same pattern.

These studies suggest that the underlying pathology, and thus the optimal treatment, may be different for different people with MS.  In the future, it may be possible to individualize treatment based on a specific type of pathology.  For example, immune-based therapies may be most effective for those with lesions that contain immune cells, such as Pattern I.  A blood-filtering process that can remove antibodies (plasmapheresis) may be particularly effective for Pattern II, while Pattern IV may be especially amenable to therapies that decrease degeneration.

Quantifying disability
The Expanded Disability Status Scale (EDSS) is used to quantify the level of disability in multiple sclerosis.  For researchers, the EDSS is an objective measurement that makes it possible to know how an intervention affects the level of function.   For healthcare providers, the EDSS may be used to give a general description of how the person is functioning.
The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. The Functional Systems are:
• cerebellar
• brainstem
• sensory
• bowel and bladder
• visual
• cerebral
• pyramidal
• other
EDSS score of 1.0 to 4.5 refer to people with MS who are able to walk with little or no limitations. EDSS score 5.0 to 9.5 are defined by the impairment to walking. 
  
Kurtzke Expanded Disability Status Scale

 

.0>/p>	Normal neurological examination
1.0	No disability, minimal signs in one FS
1.5	No disability, minimal signs in more than one FS
2.0	Minimal disability in one FS
2.5	Mild disability in one FS or minimal disability in two FS
3.0	Moderate disability in one FS, or mild disability in three or four FS. Fully ambulatory
3.5	Fully ambulatory but with moderate disability in one FS and more than minimal disability in several others
4.0	Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively severe disability; able to walk without aid or rest some 500 meters
4.5	Fully ambulatory without aid, up and about much of the day, able to work a full day, may otherwise have some limitation of full activity or require minimal assistance; characterized by relatively severe disability; able to walk without aid or rest some 300 meters.
5.0	Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily activities (work a full day without special provisions)
5.5	Ambulatory without aid or rest for about 100 meters; disability severe enough to preclude full daily activities
6.0	Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 meters with or without resting
6.5	Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters without resting
7.0	Unable to walk beyond approximately five meters even with aid, essentially restricted to wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair some 12 hours a day
7.5	Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels self but cannot carry on in standard wheelchair a full day; may require motorized wheelchair
8.0	Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself much of the day; retains many self-care functions; generally has effective use of arms
8.5	Essentially restricted to bed much of day; has some effective use of arms retains some self-care functions
9.0	Confined to bed; can still communicate and eat
9.5	Totally helpless bed patient; unable to communicate effectively or eat/swallow
10.0	Death due to multiple sclerosis.