What we know about multiple sclerosis now, and what we have yet to discover.

By Tom Scott

Jean-Martin Charcot, professor of Neurology at the University of Paris, was the first to complete a detailed study of multiple sclerosis (MS), an autoimmune disease that affects the central nervous system. In 1868, Charcot analyzed some unusual symptoms in a young female patient––tremor, slurred speech, and abnormal eye movements––comparing them to other patients with similar symptoms. He documented his observations and wrote a clinical-pathological defi nition of MS that is still accurate today. The three major signs of MS––diplopia (double vision), ataxia (disturbances of balance or co-ordination), and dysarthria (difficulties with, or slurred speech)––are called Charcot’s Triad, in recognition of his fi ndings.

Although Charcot could only identify the main features of MS, 20th and 21st century scientists have been more educated on the biology behind the disease and the role bacteria and viruses play in its etiology. This knowledge has opened the doors to more effective treatments and better prognoses for people diagnosed with MS.

River’s EAE Model

Just before World War II, Thomas Rivers of the Rockefeller Institute in New York City developed an animal model of MS called experimental allergic encephalomyelitis (EAE), which is now the best studied model of autoimmunity. While very little was understood about MS at this time, scientists knew that people vaccinated against viral illnesses such as rabies were sometimes prone to develop MS-like disease. They assumed this was because the virus within the vaccines was not completely inactivated.

In 1935, Rivers tested this theory by injecting virus-free myelin into laboratory animals. Under the appropriate conditions, he was able to induce the animals he injected to attack their own myelin, proving that nerve tissues, not viruses, were behind the MS-like symptoms. Although this discovery would play a signifi cant role in understanding immunology and how to treat diseases such as MS and was directly related to the development of two approved treatments for MS (Copaxone® and Tysabri®), it was largely ignored at the time.

In the past few decades, researchers have made tremendous advancements in formulating effective MS treatment strategies. Presently, six disease-modifying treatments have been approved for relapsing-remitting multiple sclerosis (RRMS): Three are interferons: two formulations of interferon beta-1a (Avonex® and Rebif®) and one of interferon beta-1b (Betaseron®); the rest are glatiramer acetate (Copaxone®), mitoxantrone (an immunosuppressant also used in cancer chemotherapy) and natalizumab (Tysabri®). Although these medications differ in their efficacy rate and studies of their long-term effects are still lacking, all six are proven modestly effective at decreasing the number of attacks and slowing progression.

Major Research Trends

The study of MS was greatly assisted by breakthroughs in the fields of cell biology, genetics, immunology, and virology. Some of the important findings that have resulted from this research are included below.

MS susceptibility is controlled by more than one gene. Family genetic linkage analysis has been performed in three large studies published over the past 10 years. Over 60 candidate genomic regions have been identified through these studies. The HLA DR2 region on Chromosome 6p21.3 is thought to explain 15% to 60% of MS susceptibility. Other candidate regions that may be involved in genetic risk include chromosome 19q13 and chromosome 17q21-23 (Wallin, M., 2006).

The chance of getting MS in the overall population is approximately less than one tenth of one percent. If you have one person in your immediate family with the disease, however, your risk increases by one to three percent. In the case of identical twins, the second twin will have a 30% chance of getting MS if the first twin has the disease.

Damage to myelin (which protects and insulate neurons) in MS appears to be the result of immune system reactions. Although it is still unclear what mechanisms are behind this, much more is understood about the immune system’s role in the formation of MS lesions. Scientists are now able to lessen the severity of these reactions through medications that control relapse, ease symptoms, and alter disease course. There is, however, no effective disease-modifying treatment for primary-progressive multiple sclerosis (PPMS), but clinical trials are ongoing.

An understanding of the role oligodendrocytes (oligos for short)––glial cells responsible for producing myelin––in MS has offered valuable information on the activity these cells exhibit in patients with varying forms of the disease. The job of oligos is to replace the myelin sheath if it is destroyed. In MS, however, these cells appear also to be destroyed. Depending on the type of MS lesion, oligos behave differently. In extremely aggressive forms of MS, oligos are abundant at the lesion site but seem to abort the remyelination (regeneration of the nerve’s myelin sheath) process, most likely due to the new myelin being destroyed faster than the oligos can finish producing it. In other less aggressive and more chronic lesions, immune system activity is minimal and there are fewer oligos at work around the center of the lesion site, but some remyelination does occur at its margins.

Recent studies show that the destruction of oligos may be partially caused by apoptosis (programmed cell death)—the process where cells “commit suicide” in response to receiving signaling compounds called cytokines (powerful chemicals produced by T cells). The cytokines Tumour Necrosis Factor-alpha (TNF-alpha), LymphoToxinalpha and -beta (LT-a and LT-b), and interferon-gamma (INF-g) all appear to be involved in the apoptosis of oligos in MS. One drug that has shown considerable potential in reducing the levels of some of these cytokines is the anti-inflammatory drug Rolipram®.

Researchers are also interested in finding agents that stimulate remyelination. Recent animal model studies show that monoclonmal antibodies and two immunosuppressant drugs––cyclophosophamide and azathioprine––may accelerate remyelination.

MS may be triggered by a specific virus or environmental factor. Similar to polio, MS may be precipitated by a widespread infection acquired in childhood or adolescence with the risk of acquiring disease increasing as the age of infection rises. A popular theory is that a viral infection or retroviral reactivation earlier in life prepares a susceptible immune system for an abnormal reaction later in life. This may occur if there is a structural similarity between the infectious virus and some component of the central nervous system on a molecular level, leading to confusion in the immune system that causes an attack on myelin.

There are also high concentrations of antibodies produced in the cerebrospinal fluid in patients with MS. While the target of these antibodies is still unclear, it suggests a response to an underlying infection. The Esptein-Barr virus (EBV) and Human Herpes virus 6 are two viruses within the Herpes family that have received recent attention in the literature; however, it is unclear what role, if any, they play. More research using more powerful molecular detection techniques and larger MS study populations will be needed to confirm the role some viruses play in MS. (Wallin, M., 2006).

The Road Ahead

Some of the major challenges that stand in the way of developing effective treatments to reverse or prevent the destruction of myelin in MS are:

1. Identifying genetic risk factors2. Identifying environmental triggers

3. Identifying the cellular and subcellular targets of the immune system in the brain and spinal cord

4. Identifying the subsets of T cells involved in the attack

5. Understanding how MS damages myelin and nerve fibers in the brain and spinal cord

Although this will be quite an undertaking, new advantages arise every day in finding a cure for MS. The large amount of clinical success that has occurred in the past 20 years within the field and the major scientific and technological advancements that have already taken place can only add to the optimism that scientists will one day crack the code behind this complex disease. According to the National MS Society, there are more potential therapies in the pipeline for MS than at any other time in history. The next 20 years should be very interesting.

Tom Scott is staff editor.

Further Reading

Wallin, M. (2006). An Update on MS Risk Factors. Multiple Sclerosis Quarterly Report, 25(3), 6-15.

Research Timeline––Multiple Sclerosis. (1993). Inside MS, Spring 1993.

Multiple Sclerosis: Hope Through Research. (1996). National Institute of Neurological Disorders and Stroke, Publication No. 96-75

Oligodendrocyte (n.d.). Retrieved January 2, 2008 from www.mult-sclerosis.org/oligodendrocyte.html.

Multiple Sclerosis (n.d.). Retrieved January 2, 2008 from en.wikipedia.org/wiki/Multiple_ sclerosis.