History

Multiple sclerosis is the most common neurological disorder, but has only been a recognized illness for a little over a century. The condition known as multiple sclerosis (MS) was given the name by French physician Jean Charcot in 1868. By that time, there had been numerous reports throughout Europe of persons with symptoms we now understand to be MS, but Charcot was the scientist to pull all the threads together. Thus, he described the characteristic condition and is credited with "discovering" MS, according to MS specialist and medical historian T. Jock Murray, MD, Professor of Medicine at Dalhousie University, Halifax, Nova Scotia.

What is interesting to physicians and scientists today is the degree to which Charcot was able to describe MS in such remarkable detail, Dr. Murray says. Not only did he characterize its symptoms, but he also understood something about the disease pathologically. He noticed, for example, that patients who died had evidence of inflammation in the brain-today, this inflammation is known to be part of the basic underlying nature of MS. His report triggered a flurry of similar accounts by other physicians, who soon occupied themselves with looking for the cause of MS-a challenge that still plagues researchers today.

The first known case of MS, however, probably predates Charcot by many centuries. In 1390, a young Dutch woman known as Saint Lidwina fell while ice skating and subsequently displayed a progressive neurological disorder that kept her confined to bed until her death 34 years later. Prominent physicians of the day prescribed a variety of "medicines" and herbs, however, the Duke of Holland's physician recognized Saint Lidwina's condition as one that could not be cured. "The disease," he said, "comes from the hand of God." He advised no treatment, predicting it would only "impoverish her father."

The next reported case of what appears to be MS occurred in the illegitimate grandson of King George III, Augustus Frederick d'Este. In the 1790s, d'Este developed as a young man what was probably optic neuritis, a hallmark symptom of MS onset. He charted his personal struggle with the progressive disease in a diary that now resides at the Royal College of Physicians in London.

D'Este was encouraged by his physicians to drink plenty of water and sherry, to douche his eyes, and to feast on beefsteak. In addition, he was prescribed the medicinals of the day: silver, mercury, iron, arsenic, and opium-these served as the backbone of general neurologic treatment into the 20th century, along with such things as "nervine tonics," spa therapy, massage, and even electricity applied over the skull.

Around the turn of this century, physicians made dedicated attempts to determine the actual cause of MS and endeavored to treat the suspected causes more specifically. In 1908, for example, MS was thought to be due to toxins such as copper, lead, and mercury; methods were devised, therefore, to rid the body of these elements. Another hypothesis proposed infection as the root of MS, and yet another claimed an organism called a spirochete was responsible. Some researchers even claimed to have isolated this spirochete from the brains of sufferers and to have developed a vaccine that would prevent MS.

By the 1930s, the treatment arsenal was broad but still ineffective: antimalarial drugs, typhoid vaccines, milk injections, arsenic, intramuscular mercury, X-rays. In this decade another popular theory took hold, that of MS as a disorder of the blood, which might respond to anticoagulants and special diets.

"The point, from all of these various treatments, is that the popular theories of the causes of MS are what directed the treatments at the time," Dr. Murray said.

Today, the same applies, he pointed out. The concept of inflammation is the focus of research, and drugs that improve the working of the immune system-the "immunomodulating drugs"-constitute first-line management.

The Present and Future

Current treatment with these agents-Avonex® (interferon beta-1a), Betaseron® (interferon beta-1b), and Copaxone® (glatiramer acetate), also called the "ABC drugs"- stave off relapses and may indeed keep patients functioning well for years. Their long- term success, however, has not yet been proven, and they appear not to work as well when patients reach a steadily progressive stage of illness. There is the general feeling that for therapy to have a long-lasting effect, it should be aimed at correcting the most basic damage-not only to the myelin sheath that insulates nerve cells and helps them send signals rapidly, but also to the brain's axons, which are the long extensions of the nerve cells through which these signals are transmitted.

Ian McDonald, MD, MS specialist and Harverian Librarian at the Royal College of Physicians and Surgeons, London, says future therapies will be based upon the insights currently evolving as to the pathology underlying MS. For example, researchers have recently discovered that demyelination-the destruction of the protective myelin sheath-occurs very early in MS; in fact, it can be demonstrated within 24 hours of the first onset of symptoms. Without the presence of the myelin sheath, nerve endings apparently "learn how" to continue conducting nerve impulses. The brain seems to compensate for injury and loss to certain areas by using multiple, new areas for its tasks. This has been shown by functional MRI studies-in which a dye "lights up" in areas of the brain that are being called upon, he says.

This "recovery and compensation" is what is responsible for the complete remissions that occur between MS attacks in the relapsing-remitting stage. But down the road, the recovery process becomes less successful, and a more progressive form of disability ensues. Future therapies that address disease at these levels, doing more than suppressing inflammation, should give MS patients an even better chance at maintaining function, he predicts.

Meanwhile, new approaches to using current therapies are being explored, especially using combinations of different types of agents when one agent alone is not effective. Investigative trials are now evaluating the safety and efficacy of combining cyclophosphamide (Cytoxan®) and methylprednisolone (Medrol®) in persons who do not respond to the ABC drugs, and of adding mitoxantrone (Novantrone®), prednisone (Prelone®), azathioprine (Imuran®), or methotrexate (Rheumatrex®) to beta-interferon for further benefit.

Investigators are especially anxious to learn final results from an ongoing trial combining two of the ABC drugs-Avonex®, which is administered weekly, and Copaxone®, which is given daily. Since these two immunomodulating agents work by different mechanisms, it is hoped that their combination will be more effective than a single agent alone (all ABCs reduce relapses by over 30 percent). First, however, they must be judged safe in this small trial of 32 persons.

George Kaufman, MD, Director of the MS Center at Carolinas Healthcare System, Charlotte, North Carolina, commented that there is not enough information regarding combination therapy yet to change the current practice of simply starting with an ABC drug. However, he and other investigators remain hopeful that better treatment is just around the corner.