Years
ago treatments were often based upon false hypotheses of what was thought
to take place in a person with MS during the progression of the disease.
First mentions of an MS-like disease have been traced back to the 1300s,
when the disease was often thought to be religious in nature. In this context,
people might be suffering for the sins of others, and remissions could be
viewed as miracles.
By the 1800s, treatments for this illness included such procedures as flesh-brush rubs, leeches, and skin plasters. Courses of electrical therapy were sometimes given, and prescriptions would include a host of unusual and toxic ingredients, such as mercury, quinine, and strychnine.
Jean-Martin Charcot, a clinician in Paris in the mid-to-late 1800s, provided doctors and patients with the first clinical and pathologic description of the disease. Charcot studied medicine at the University of Paris, where he developed the ability to combine patient experiences and doctors' descriptions, with the autopsy patterns of disease pathology.
By pairing clinical science with a pathologic correlation, Charcot was able to advance the understanding of several chronic diseases, including MS. In his 1868 description of the disease, Charcot describes plaques of demyelination and suggests the involvement of myelin in the development of MS. Charcot is also responsible for giving MS a name: "sclerose en plaque." Although doctors at that time were familiar with this illness, Charcot provided a clear definition of the disease - so other doctors could more readily recognize and understand the condition.
Since this time, researchers have made significant progress in identifying a number of the processes that appear to lead to the development and worsening of MS, with several important findings occurring only within the past decade. Current treatments are based on the cellular changes that are believed to take place within the body of a person with MS. And although many details still remain a mystery, researchers appear to be getting much closer to a cause and cure.
Nerve impulses serve as messages between the brain and other parts of the body (via the brainstem and spinal cord), delivering instructions on how to perform. Nerve impulses travel along connecting nerve fibers, called axons, which are thin
projections from the nerve cells. These vary in length from less than an
inch to several feet.
Axons are similar to electrical wires that carry electrical impulses to the objects they are powering. Axons need a protective covering of insulation, just like the wires within your home. Without such insulation, electricity leaks or "shorts" out along the way and is unable to complete its trip to supply power.
Axons are covered with a protective layer called myelin.
Composed of fat and protein, myelin acts as insulation for the axons
and allows for optimum, uninterrupted flow of nerve impulses. Impulses
normally travel at speeds of 225 mph along these axons.
MS affects the central nervous system (CNS), which consists of the brain
and spinal cord. This neurological disorder has traditionally been termed
a demyelinating disease, which means that the myelin protecting the nerve
fibers is damaged or destroyed.
Without insulation surrounding an axon, the nerve flow can slow down, become garbled, or "short-circuit" and discontinue entirely. When this happens, messages from the brain arrive at their destination late, confused, or not at all. Activities easily performed in the past may now require more time and may become difficult or even impossible to accomplish.
Until a few years ago, the focus of MS research was primarily on the loss of myelin. Research now shows that the axons in a person with MS appear to become damaged as well. This finding allows researchers to investigate other strategies for treating MS, such as using drugs that can prevent nerve cell death (known as neuroprotective agents) or procedures that may repair damaged nerves.
In RRMS, the myelin
and axons may not experience permanent or severe damage, and symptoms
normally disappear or greatly diminish once the inflammation subsides
and the relapse goes into remission. Slight changes to the myelin
or axons may occur, slowing down the nerve impulses, but these changes
are often not enough to cause symptoms. Nerve impulses traveling
along the axons at a reduced speed, however, are thought to contribute
to the fatigue often experienced by people with MS.
With the progressive forms of MS, the myelin and axons appear to experience steady damage. Inflammation is not thought to be involved (where cells attack other cells), but instead the cells appear to die on their own, which is known as apoptosis. Sometimes, the MRI shows ongoing axon damage and brain atrophy early in MS. These findings support the idea of considering MS treatments as soon as possible, and according to the advice of an individual's physician.
Evidence suggests that cells needed to rebuild these axons and myelin may possibly still be present in the areas of damage - and treatments may be found to activate these cells.
Although researchers have yet to confirm which agents initiate the process leading to myelin and axonal damage, many of the factors involved have been identified. An MS exacerbation begins when the myelin becomes inflamed and swollen. This inflamed area is referred to as a lesion. Tiny vessels in the area dilate and leak activated white blood cells into the tissues of the brain. These inflammatory cells stimulate the secretion of chemicals called cytokines, which activate certain cells (called macrophages) to damage myelin.
White blood cells are essential units of the immune system and are produced by the body to fight foreign substances, which may cause infection or disease. Most researchers believe MS is an "autoimmune disease" - one in which white blood cells are misguided to target and fight the body's own cells.
White blood cells originate from the thymus, spleen, and lymph nodes. Two types of white blood cells are relevant to MS: larger cells known as macrophages (Greek for "big eaters") and smaller cells called lymphocytes.
Macrophages, also known as "scavenger cells," clean up areas by surrounding and consuming debris -- in this case, myelin. Macrophages secrete proteases, and these can destroy myelin. Macrophages also produce prostaglandins, some of which promote inflammation and immune functions, while others suppress the same functions. Additionally, macrophages secrete free oxygen radicals. These can also significantly affect immune functions by promoting inflammation and cell destruction.
Among the many types of lymphocytes are B-lymphocytes and T-lymphocytes. B-lymphocytes are processed in bone marrow and produce immunoglobulins (also called gammaglobulins) - which are usually antibodies (cells that fight disease and infection). Antibodies are now thought to be able to damage myelin. Treatments aimed at these B-cells and antibodies may be another option for future drug development.
The majority of T-lymphocytes are processed in the thymus gland. Increased numbers of T-lymphocytes may be found in the cerebrospinal fluid (CSF) of a person with MS during an exacerbation. CSF is the fluid that circulates through and nourishes the brain and spinal canal. The many categories of T-lymphocytes include three types of "T-cells."
(1) T-helper cells - whose numbers increase in cerebrospinal fluid during an exacerbation, modulate the immune response, and are considered "regulatory T-cells" along with T-suppressor cells.
(2) T-suppressor cells - researchers find decreased T-suppressor cell activity in blood early in new exacerbations, and as their name suggests, these cells suppress an immune response. T-suppressor cell activity returns to normal following an exacerbation.
(3) T-killer cells - are sent to attack and destroy whatever
the immune system interprets as being a foreign substance.
In conjunction with macrophages, T-lymphocytes are activated when
exposed to a certain stimulus. Once this occurs, T-lymphocytes become
metabolically more active, grow in size, and secrete a group of chemicals
called cytokines. These are protein molecules that facilitate communication
between cells and act as mediators for immune responses through interaction
with specific cell-surface receptors. The four types of cytokines
include:
The functions of the cytokines are to (1) increase inflammation and damage (pro-inflammatory) or (2) reduce inflammation (anti-inflammatory). The pro-inflammatory cytokines work by:
Th-1 (T-helper 1) cells produce pro-inflammatory cytokines. These are the cells that appear to worsen MS, potentially causing injury to the myelin and axons. These include interferon gamma (IFN-gamma), tumor necrosis factor (TNF-alpha), interleukin 12 (IL-12), IL-6, IL-2, and IL-1. Th-1 cells are thought to increase during an exacerbation.
Th-2 (T-helper 2) cells produce anti-inflammatory cytokines. These may work to stop the inflammation associated with the damaging lesions in MS. They include interleukin 4 (IL-4), IL-10, and transforming growth factor beta (TGF-b). Th-2 cells may decrease during a relapse and increase at the conclusion of the flare-up. Treatments that switch the T-cells from Th-1 to Th-2, such as Copaxone®, are effective in MS.
Some lymphocytes entering the brain become plasma cells, which produce large numbers of immunoglobulins (antibodies). They also remain in the CNS for a long time following an
exacerbation.
Glial cells are non-neuronal brain cells, which provide support to neurons. (Neurons are the "thinking cells" of the brain, also known as gray matter.) One type of glial cell relevant to MS is the oligodendrocyte (oligo). Oligos are the cells which produce and nourish myelin. Myelin may sometimes be repaired by the oligos, a process known as "remyelination." When remyelination occurs, a person with MS may experience a recovery or remission. Unfortunately, in most cases of MS, the oligos eventually decrease or are depleted. This results in myelin loss as well as the loss of the ability to make more myelin.
New myelin is normally produced by young oligos. These new myelin cells develop in stages from another type of cell called a stem cell. As a person ages, these stem cells are less able to transform into oligos. Older oligos do not divide or replace themselves. Without young oligos or stem cells to develop myelin, remyelination is often slow and incomplete, if at all.
Researchers are presently working with mechanisms to transplant young oligos or stem cells into people with MS in order to promote remyelination along damaged areas. Although this process would not affect the underlying disease, it does hold the potential for the recovery of nerve function to disabled patients, as well as possible applications for individuals who suffer from spinal cord injuries or other nerve-related afflictions.
In a previous study, glial cells were transplanted into dogs with myelin disorders. These transplants resulted in large-scale remyelination, and for one dog, the remyelination continued to grow and spread for several months to follow.
Another possibility exists in the lesions around the damaged axons
of a person with MS. As mentioned earlier, studies suggest that cells
capable of remyelination may still exist in these areas, and researchers
may be able to find ways to activate these cells.
Insulating myelin may also be found in the two other systems aside
from the CNS -- the peripheral nervous system (PNS), which consists
of the nerves connecting the spinal cord to the arms and legs, and
the autonomic nervous system (ANS), which controls involuntary body
functions such as breathing, sweating, and beating of the heart.
These
systems appear to be unaffected by MS. A few people with MS, however, may
experience symptoms related to ANS dysfunction. A phase I trial has taken
myelin-building cells from the PNS (known as "Schwann cells")
and transplanted them into the brain of an MS patient, to see if these
cells will produce new myelin in the CNS. More studies are planned depending
on the outcome of this groundbreaking trial.
Another type of glial cell playing a role in MS is the astrocyte, a cell that normally supports the axons. Astrocytes increase in number and size when they arrive at the damaged myelin, possibly attaching themselves to the axons and preventing remyelination from taking place. Gliosis is the overgrowth of astrocytes, and this forms scars around the axon.
Astrocyte function includes regulating the passage of soluble substances between the blood vessels and other CNS cells. To reach CNS tissue, cells must pass through the blood-brain barrier (BBB). Under normal conditions, the ability of substances to pass through the walls of the blood vessels into the CNS is very limited. This means that many cells, including those that cause harm, are normally unable to pass through the vessel wall and attack CNS cells.
With MS, white blood cells are able to pass through the BBB and target myelin for destruction. Research has shown that the BBB must be altered in order for MS to initially begin and for demyelination to ultimately take place.
Adhesion molecules are protein structures which are believed to assist the white blood cells of the immune system to pass through the BBB. These molecules lie on the surface of white blood cells as well as the cells lining the blood vessels. White blood cells must first adhere (or stick) to the blood vessel lining with the aid of adhesion molecules, before passing through the BBB into the CNS.
Researchers are testing new agents that block these adhesion molecules,
thereby preventing the immune system cells from going through the BBB
and reaching the myelin. Factors thought to possibly increase BBB permeability
include viral infection
and vaccination.
Once the myelin becomes inflamed and blood leaks into the area (carrying macrophages and lymphocytes), some important changes take place.
Known as plaques, these areas of thick tissue formed by the astrocytes show up as white patches on MRI exams. The changes in size, number, and location of these plaques may determine the type and severity of the patient's symptoms as well as give the physician a visual chart by which to measure the progression of the disease.
Plaques may affect one axon or span across several. They vary in size from that of a pinhead to more than an inch in length. As plaques accumulate or increase in size, the functioning of the CNS deteriorates.
Interestingly, plaques are often widely distributed throughout the brain and spinal cord, many of which causing no apparent problems. The term "multiple sclerosis" originates from the discovery of these plaques. Multiple refers to many; sclerosis refers to scars.
Keep in mind, however, that inflammation does not always result in damage to the myelin and the forming of plaques. Some completely recover with no signs of any interference. What instructs the cells to form the plaque is still unknown. What keeps the plaque from forming in other instances is equally puzzling. Th-2 cells appear and release anti-inflammatory cytokines, which may be one factor in stopping the damage.
Inflammation only occurs in the early stages of SPMS, and later, primary degeneration causes the myelin and axons to become damaged. At this time apoptosis takes place, and cells simply die off. The latter is true for the other types of progressive MS as well.
Causes for any disease fall under one or more of the following categories: toxic, vascular, metabolic, heredity, congenital, degenerative, psychogenic, tumors, trauma, infection, and allergy. Many of these categories appear to be unrelated to MS. Of the categories that do appear to play a role in the acquisitionof MS, most research supports that MS may result from a
combination of these factors rather than from a single cause.
The most likely conditions associated with the development of MS are:
Other possible factors may include:
Although heredity is not the cause of MS, i.e., 50 percent of one's children do not get MS, genetic susceptibility may be passed along. As mentioned earlier, certain nationalities are more susceptible than others. This tendency increases for an individual if a family member has MS. For instance, the chances of an American developing MS is one in 1000 (one-tenth of one percent). When one family member has MS, the risk of MS is increased to between three and four percent for other family members.
Technically,
for a disorder to be deemed hereditary, 25 percent or more of a patient's
siblings and 50 percent or more of one's children would need to also
be afflicted. While MS does not qualify as being hereditary, research
shows that five percent of people with MS have a sibling with the same
disease and 15 percent have a close relative with MS - certainly far
greater odds than that of the general public.
The study of twins further supports genetic susceptibility. The incidence of fraternal twins both having MS is five percent compared to 31 percent of identical twins. Additionally, the discovery of MS lesions without symptoms in the "healthy" identical twin occurs in more than half of the remaining sets of twins.
Researchers have identified an immune response gene on the sixth chromosome called HLA DR2. Common to northern Europeans, most people with MS have a closely related gene. Finding a single common HLA antigen in all individuals with MS and those most susceptible is not likely. Research strongly suggests the involvement of multiple genetic factors.
For more than 100 years, infection (involving a virus or bacteria) has been suspected as one of the major players in the development of MS. A "slow-acting" virus - one which may remain dormant for years before triggering an illness - could well be involved. Three important findings support the idea of viruses causing or playing a role in MS.
(#1) The first finding involves the relationship between a higher incidence of MS and environment (specifically the distance from the equator) during a person's first 15 years. This could suggest childhood exposure to a virus followed by a long dormant period. Other chronic illnesses, such as Parkinson's Disease, have been known to follow the same geographic pattern as MS.
Moving to a lower-risk area does not seem to lessen a person's risk of MS unless he or she moves as a child. The area where a person's first 15 years are spent appears to determine the likelihood of later being diagnosed with MS.
Other theories related to latitude and an increased number of cases include those related to:
The highest incidence of MS is in the wealthiest, most sterile countries. Poorer, less sanitary countries have the lowest percentage of cases. This supports the theory that early exposure to a virus or bacteria, not present in cleaner areas, may allow a person to develop an immunity to MS.
(#2) The second finding concerns finding traces of a virus present. For example, abnormal levels of viral antibodies are consistently found in people with MS, as well as various viral particles and other signs of viral infection. Although a specific virus directly associated with MS has not been identified, studies conducted over the past 50 years have revealed more than 10 types of antibodies in the cerebrospinal fluid of those with MS.
Most people with MS have at least one type of viral antibody, if not more. Of particular interest are the measles, herpes, human T-cell lymphoma, and Epstein-Barr viruses. The idea of more than one virus causing or contributing to the development of MS is also a strong possibility.
Earlier research had shown an interesting correlation between dramatic rises in canine distemper virus (CDV) among an area's dog population and similar rises in MS cases 10 years later. This was documented both in Iceland and on islands near Great Britain.
Possibly tying in the environmental and latitudinal aspects is the fact that CDV thrives in cold, damp weather (where people and dogs are likely to be indoors and close). CDV is rapidly inactivated in warm weather (as found near the equator). Subsequent studies, however, failed to show any association, so CDV is no longer considered as a plausible factor in the development of MS.
Researchers agree that MS is not transmissible. In other words, it
is not believed to be contagious, so it may not be passed from one
person to another (except genetically). Spouses of people with MS
are not at an increased risk, and an elevated
incidence is not found among adopted children.
Researchers have found evidence of a herpes virus possibly being
involved with the development of MS. Concentrated
portions of the virus were found at the edges of plaques from autopsied
brains of people with MS, whereas brains from people without MS did
not have enough of the virus to be visible. This virus, human herpesvirus-6
(HHV-6), is the same one that causes childhood roseola. An estimated
90 percent of all Americans are infected with this illness, which
usually strikes infants and causes a mild fever.
A recent study found cells that were actively infected with HHV-6
in CNS tissue from eight of 11 (73 percent) people with MS. Ninety
percent of the tissue sections with active demyelination were positive
for HHV-6 infected cells. Compared to tissue
sections without active disease, only 13 percent were infected with
the virus. In CNS tissue from 28 individuals without MS, only two
were HHV-6 infected, and both were diagnosed with HHV-6 leukoencephalitis.
Active
HHV-6 infections were also found in blood samples from
54 percent of the 41 people with MS tested. None of the blood samples
from the 61 healthy controls tested positive.
Comparing those with MS who did have active HHV-6 infections in their blood to those who did not, no difference was found in terms of disease types. Those testing positive, however, were much younger and had MS for a shorter time versus those with MS who tested negative, possibly indicating a change in the pathology of MS over time. Nonetheless, a causative link between MS and HHV-6 has yet to be established.
The Epstein-Barr virus (EBV) has also been associated with MS and is postulated by some scientists to play a role in the etiology or development of the disease. This virus belongs to the herpes family and is known primarily as the cause of mononucleosis. The EBV is linked to other illnesses, including cancers and disorders affecting the nerves.
The EBV is very common and may infect up to 95 percent of US adults by the age of 40. Results of two Harvard University Nurses' Health Studies found that women with high levels of EBV antibodies in their blood were four times more likely to develop MS than women without these high levels. Other research has shown that people without EBV antibodies are rarely diagnosed with MS.
These findings are not conclusive of a viral involvement with the pathology of MS. While these studies show increased evidence of active viruses or viral antibodies in those with MS as compared to those without MS, researchers do not know whether this suggests the cause or an effect. With the immune system of people with MS appearing to be overactive, a person may react more to a dormant virus than those with a more regulated immune system. Either way, these findings will lead to further trials and perhaps the use of antiviral medications in the treatment of MS.
(#3) The third finding is that studies show how viruses can cause similar relapsing-remitting and demyelinating diseases in animals. Initial testing is often performed on laboratory animals that have been given a disease known as experimental allergic encephalomyelitis (EAE).
EAE is an autoimmune disease which is developed when researchers inject healthy animals with myelin or certain myelin proteins containing killed tuberculosis organisms. EAE behaves similarly to MS and allows researchers to study many aspects of demyelinating disease. Differences do exist between the two diseases, however, and while many drugs affect EAE in animals, few have the same impact on MS.
Another experimental model of MS is Theiler's murine encephalomyelitis virus (TMEV). Through intracerebral inoculation, susceptible mice may be given this disease that mimics the inflammation and demyelination found with MS.
These experimental models for MS give researchers much insight into the cellular processes that occur in MS. They are also vital for the development of new treatments, enabling researchers to study safety, efficacy, and responses to various new agents before they are tested in humans.
Technically, MS can fall under the heading of allergy, but this does not refer to a traditional allergy that one would associate with an external substance such as pollen or dust. Instead, this refers to autoimmunity, which occurs when a person becomes "allergic" to his or her own body tissue and produces antibodies that attack healthy cells.
MS appears to cause the production of antibodies to attack myelin and axons. Other autoimmune diseases include rheumatic fever, rheumatoid arthritis, lupus, and myasthenia gravis.
The idea of an injury or even stress precipitating the onset of MS or initiating an exacerbation has long been a controversial subject among researchers, physicians, and patients. Numerous studies have been conducted in an attempt to gain more insight into this theory. In most cases, results have been inconclusive, although many people with MS will attest to certain traumatic or stressful events occurring near the onset or worsening of their MS.
Relating to blood circulation, a vascular cause had been considered unlikely until recently. One study showed that as many as 50 percent of people with MS report migraine headaches, while another study found that migraine headaches are more than twice as common among people with MS versus matched controls. Up to one-third of patients report having had migraines before being diagnosed, and 20 percent of patients report a family history of migraines, versus 10 percent of controls.
This new information may possibly lead to a vascular connection in a subset of patients. One explanation, however, may be that genetic factors associated with MS are also associated with migraines, in which case, no causal link would exist.
MS may be a disease initially begun by a slow-acting virus and then resulting in an autoimmune disorder within a genetically susceptible person. A portion of new clinical MS attacks may begin shortly after a common viral illness, such as a cold or influenza. If the immune system is already burdened by a slow-acting virus, a recently acquired viral illness may perhaps contribute to the development or worsening of MS.
One theory considers the idea of the immune system incorrectly identifying a portion of myelin that is structurally similar to a virus (molecular mimicry). The immune system then mistakenly destroys the myelin. Another theory begins with a viral infection damaging the myelin, then releasing small amounts of myelin into the bloodstream, resulting in an autoimmune response to fight the "foreign" substance.
Additionally, viral infections activate T-lymphocytes, which in turn release interferon-gamma (IFN-gamma). IFN-gamma is a cytokine that stimulates the immune system to target cells for destruction. Clinical studies have shown that IFN-gamma treatment worsens MS.
Interferon-beta (IFN-beta) is also made within the body, but instead helps to slow MS by reducing target recognition, repairing the damaged BBB, and reducing pro-inflammatory cytokines. Three IFN-beta drugs, Betaseron®, Avonex®, and Rebif®, have all been approved for long-term treatment for people with RRMS in the US.