Multiple Sclerosis — New Developments

Circa 2005

What Is Multiple Sclerosis (MS)?

The term multiple sclerosis actually means many scars. In multiple sclerosis the body’s immune system repeatedly attacks the protective covering (myelin) of nerve tracks in the brain and spinal cord, causing the characteristic plaques that can be identified on MRI (demyelination). In addition to attacks by the immune system, other processes may contribute to the disease in some people.

The symptoms of multiple sclerosis vary widely among those affected, depending on the speed and pattern of damage. Common symptoms include poor muscle coordination, dropping things, falling, weakness of the arms or legs, difficulty with handwriting, pain, numbness, double vision, and changes in bowel or bladder habits (incontinence, difficulty emptying the bladder or constipation).

Eighty percent of people with MS are diagnosed with the relapsing-remitting type, where episodes occur only intermittently, with near-complete recovery in between. Some people continue with this type of MS indefinitely, but if untreated about 50 percent convert to what is termed secondary progressive MS within 10 years. In secondary progressive MS, some function loss remains permanently in between episodes. A smaller number of individuals (about 15 percent) have primary progressive MS, where instead of having on-and-off exacerbations they experience a steadily increasing loss of function over a period of years. A very small number of people with MS have a benign course, with very infrequent, mild episodes, sometimes many years apart, and almost no associated disability.

Because MS is a disease of the brain, it can cause other brain-related problems. About 50 percent of people with MS notice some memory problems or reduced thinking speed. MS is also associated with major depression onefourth to one-third of the time, a higher rate than among either the general population or individuals with other chronic illnesses.

There are many theories about what causes MS, but most experts believe that a combination of factors is involved. Individuals may inherit an increased tendency for the illness that is then set in motion by exposure to viruses, toxins or other environmental factors. Many claims have been made about odd potential causes of MS, such as consumption of the artificial sweetener aspartame or the presence of amalgam dental fillings, but scientific evaluations have revealed no evidence that these play any role. MS most often appears between ages 20 and 40, affects women more often than men, and is more common in Caucasians than other racial groups. It is also more common the further one lives away from the equator in the first 15 years of life.

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Treatment for MS can be divided into two categories— treatments to slow the progression of the illness and treatments to manage symptoms.

Different medications are used to slow the progression of MS depending on the stage. In relapsing-remitting illness, four drugs (called immunomodulating drugs) can be used to slow the development of plaques on MRI and reduce the frequency of attacks. Three of the drugs (Avonex, Betaseron, and Rebif) are forms of interferon beta, a protein that occurs naturally in the body, and one drug (Copaxone) is a synthetic compound. Together they are referred to as the ABC-R drugs. All must be given by injection, ranging from daily to once a week. Side effects can include pain, swelling, skin breakdown, bruising and rash at the injection site; flu-like symptoms (fever, chills and muscle aches); muscle stiffness; flushing; shortness of breath; menstrual disorders; abdominal and joint pain; liver or thyroid problems; blood cell abnormalities; and anxiety reactions. Evidence from long-term observational studies suggests, however, that when immunomodulating drugs are started early they are associated with better long-term outcomes and less disability over the course of the illness

Once MS has moved into the more progressive forms, the drugs used turn off the immune system more extensively, similar to drugs used to treat certain cancers. The most prominent of these drugs is Novantrone (mitoxantrone), which is given intravenously once every three months. Side effects can include nausea, hair thinning, loss of menstrual periods, mouth sores, certain heart problems and susceptibility to infections. Because of the risk of heart injury there is a lifetime limit on the amount of mitoxantrone a person may receive.

During flares, symptoms can be lessened with corticosteroids like prednisone, medications similar to hormones the body produces naturally to reduce inflammation and modulate stress. Most commonly given for only three to five days, these drugs can reduce the length and intensity of an exacerbation. The most frequent side effects are short-term agitation and mood swings.

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The MS community was disappointed this year when the new medication Tysabri (previously known as Antegren) was approved by the FDA and then almost immediately suspended from production by the manufacturer because of two reports of progressive multifocal leukoencephalopathy (PML), a rare but frequently fatal demyelinating disease, in two patients taking Tysabri in combination with the drug Avonex. It is not clear whether the PML cases were truly related to Tysabri or whether the association was coincidental; these two cases are the only cases identified among 8,000 patients who have taken Tysabri. Tysabri’s manufacturer, Biogen-IDEC, has convened a panel of experts on PML to assist in the investigation.

On the research front, there are some exciting discoveries providing more clues about the development of MS. Researchers at the Mayo Clinic have explored the role that supportive brain cells called oligodendrocytes may play in promoting myelin repair for MS lesions. Noticing that MS is characterized by increased rates of oligodendrocyte cell death as well as a loss of myelin, they have proposed that in the future therapies that help prevent oligodendrocyte cell death might prove a viable MS treatment.

In genetic research, an international team led by the Mayo Clinic has identified a genetic variation that may explain why women develop MS more frequently than men do. The team’s findings suggest those individuals who carry a gene causing them to produce greater amounts of the immune protein interferon gamma may be at higher risk of developing MS, and they hypothesize that women may develop MS more frequently than men because they have greater rates of this gene. In another genetic study, researchers from the United States and the United Kingdom discovered that the gene Olig1, which promotes the growth of certain nerve cells, is essential in the repair process for recoating nerves with myelin. Although these genetic studies do not provide any immediate treatments for MS, they are significant because they illuminate potential mechanisms for affecting the course of MS in the future.

On the treatment front, the drug company Genentech is currently recruiting patients with relapsing-remitting MS for phase II trials (the second of three steps toward FDA approval) of the drug rituximab (Rituxan), currently used in the treatment of B-cell non-Hodgkins lymphoma. The Olympus trial will evaluate the same medication in patients with primary progressive MS.

by Gillian Friedman, MD

The National Multiple Sclerosis Society, 800.FIGHT.MS

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