Medicine & Research

The Search For A Cause of MS

By Dr. T. Jock Murray

Anyone who has been diagnosed with MS must have wondered about what causes the disease. In medicine, the search for the cause of a disease has been central to the process of understanding the nature of the disorder, and an important step towards discovering effective therapies and prevention. Occasionally, medicine has found a treatment or cure for a disease before really understanding the cause of the disease, but that usually depends on luck and serendipity.

Searching for a cause is more difficult than it may initially seem. For instance, even if we found the mechanism for how the disease proceeds, questions would remain about what started the process. Then, if we discovered the factors that started the process, that would lead to questions about why it happened to this person, and at this time. Answering questions in research usually leads to more questions, and that is how research progresses.

Physicians wondered about the cause of multiple sclerosis even before it had a name or they had a clear understanding of its characteristics. It was known for hundreds of years that there were disorders that caused a progressive disability, which were referred to as paraplegia, and there were theories about why this happened to young people. These theories fitted the concepts of how diseases developed in that era. For instance, the prominent physician to Lidwina of Schiedam, Holland, in the early 1400s, thought her increasing weakness was a disease sent by God. Therefore, seeking treatments would be of little help and just impoverish her father. Convinced that God had brought her the disease to suffer for the sins of others, Lidwina was later beatified by the Church. Because the first sign of her disease was a fall while skating on the canals in Holland, she is now the patron saint of illness and also of figure skating. The American Figure Skating Association has a medal featuring the picture of St. Lidwina. Because of the recurrent and progressive features of her disease, some modern writers have suggested that she suffered from the illness we now know as MS.

Up to the 19th century, it was believed that diseases were because of an imbalance in the four humors (blood, phlegm, black bile, and yellow bile, which relate to the earlier concept of the four elements of earth, air, fire, and water) in the body, so this would seem to explain disorders of the nervous system. If a humor were out of balance, the appropriate treatment would be a process or agent that would rid the body of the offending humor, such as by bleeding, cupping, or encouraging vomiting, or frequent bowel movements.

In the early 1800s, clinicians began to study the lesions in young adults who had paraplegia and noted scattered areas of degeneration (plaques) throughout the central nervous system. One of the first to postulate an explanation was Eduard Rindfleisch. In 1863, he noted that there was a blood vessel in the center of each plaque, so he thought it was most likely due to some inflammation of the vessels.

In 1868 in Paris, Jean-Martin Charcot gave a series of famous lectures that clarified the clinical and pathological picture of MS. He thought the cause was a derangement of the supporting glial cells in the nervous system that damaged the neurons. As Charcot’s description became widely known to other physicians, cases were reported all over the world, sometimes with suggestions of what may have caused the disorder in the individual patient. For instance, (and this commonly occurs today) if a person had a stress, trauma, or illness, and later developed the first signs of MS, it was natural to suppose that these events were the cause of the subsequent MS. By the beginning of the 20th century, it was thought that stress, fright, exposure to heat or cold, infection, dampness, or some toxin in the environment, like mercury, copper or zinc, might be the cause of MS.

Pierre Marie, a student of Charcot, was convinced that MS was because of an infection. Since Pasteur and others had recently developed vaccines against many infections, Marie believed there would soon be a vaccine that would eliminate MS. But the search for a specific infection that would be consistently related to MS has never been found and most neurologists believed that an infection could precipitate an attack or even initiate the onset in a person who already had the disease.

In the 20th century, other causes were postulated as more was learned about the disease. Some researchers thought they could transmit the disease to animals in experiments, again raising the concept of an infectious agent as the cause. When other laboratories were unable to reproduce the results, the transmission experiments were discredited. When anticoagulants (blood thinners) were discovered, the old observation of a blood vessel in the plaque again became of interest. Consequently, for a few decades those who believed MS was caused by small vessel blockage treated their patients with warfarin (Coumadin®).

After World War II, the research on immunology rapidly advanced and it was noted that there was an immunological reaction around the plaques in MS. This led to the idea that this was an immunological disease. Since then, treatments have mainly focused on drugs that alter the immune system. The current disease-modifying therapies (i.e., the interferons and glatiramer acetate) are immune-modulating agents. A century earlier, Charcot indicated that such explanations simply demand other explanations. If MS is an immunological disease, what caused the abnormality in the immune system? And why in this patient? And why at this time?

Other information added other explanations. MS was noted to be of higher incidence in more northern, temperate climates. Could different infections in different climes,or differing exposure to temperatures,ultraviolet light or vitamin D be part of the cause?

Although the earliest observers of MS noted that they sometimes saw more than one case in the same family, for a long time this was thought to be a coincidence. But it is now recognized that there is a genetic factor involved, leading to a predisposition to the disease. In other words, you may inherit something that heightens your risk for the disease. Is MS caused by a genetic abnormality transmitted through the family? This predisposition is a complex genetic factor, and not a simple gene defect, and most people with MS do not know of another person with MS in their family. It is also evident that some other factor is likely needed to precipitate the disease in a predisposed individual, and research is continuing to find the external trigger or triggers that are involved.

Finding a cause is more difficult than it may seem. This is not only because the cause may be very complex, but there may also be many causes. It is also possible that there are different types of MS with different factors involved, which would lead to different approaches to treatment.

While certainly complex, this is a major focus of research today. The neurologists who first described the disease recognized that effective treatments would be developed only when we had an understanding of the causes and underlying mechanisms involved. That is why multi-directional research is important and why we are learning so much more about the disease. With increased understanding will come better and beter treatments and in the future, effective prevention and cure.

Dr. T. Jock Murray is Emeritus Professor of Medicine at Dalhousie University in Halifax, Nova Scotia. Twenty-five years ago, he founded the Dalhousie MS Research Unit. He has written over 200 medical articles and books, including Multiple Sclerosis: A Guide for the Newly Diagnosed. Most recently, he published Multiple Sclerosis: The History of a Disease (Demos Medical Publishing, 2005), and co-authored Multiple Sclerosis The Guide to Treatment and Management (6th edition, Demos, 2006).

(Last reviewed 7/2009)