Multiple sclerosis: an update

Multiple sclerosis: an update

Linda Bren

This article was revised in April 2005 to include information about the suspension of marketing of the multiple sclerosis drug Tysabri due to reports of serious adverse reactions.

Shari Ferko feared the worst when she was diagnosed with multiple sclerosis in 1990. Her ability to walk was declining and she might soon need a cane and eventually a wheelchair, she thought. She wasn’t even sure she’d be around to see her children grow up.

“It was a scary prospect,” says the Dallas mother of two, whose children were 7 and 8 at the time. “I thought, ‘These kids need their Mom. Will I even see them graduate from high school?'”

But Ferko did see her children graduate, and today, at age 48, she chases after a grandchild when she isn’t working at a desk job as a nurse three days a week. “I’m still not using a cane and I only use a wheelchair for long distances,” says Ferko, who didn’t let her disease keep her from touring Europe last year.

Ferko takes medications to help relieve fatigue, spasms, blurred vision, and bowel and bladder problems, all common symptoms of multiple sclerosis (MS).

An estimated 400,000 Americans have MS, according to the National Multiple Sclerosis Society (NMSS). Every week, about 200 people in the United States are diagnosed with the disease. But many are managing their symptoms and staving off debilitation with medications.

Today, five FDA-approved treatments to lessen the likelihood of MS attacks are on the market. Three of them also slow the progression of disability in this often- incapacitating disease.

A Prime-of-Life Disease

MS is a non-contagious, lifelong chronic disease that causes symptoms such as weakness, muscle stiffness, poor coordination and balance, tingling, numbness, tremors, blurred vision, and slurred speech. According to the National Institute of Neurological Disorders and Stroke (NINDS), about half of all people with MS also experience memory and concentration problems.

“It’s a disease that strikes people typically in the prime of their life,” says Susan McDermott, M.D., an FDA neurologist. In rare instances, it can develop in children or older adults, but MS is diagnosed most frequently in people between the ages of 20 and 50, according to the NMSS.

Ferko’s first symptom–loss of vision in one eye–appeared when she was 23. She was diagnosed with inflammation of the optic nerve (optic neuritis), and treatment with steroids restored her sight, she says. It wasn’t until five years later that her second symptom appeared–numbness and tingling in one leg. More bouts with optic neuritis and bowel and bladder problems followed, along with mobility problems. “I had a slow, progressive decline in my ability to walk long distances, decreased sensation in my hands, and I would tire easily,” says Ferko.

Experts recognize three main forms of MS. In its most common form–relapsing-remitting–an attack, or relapse, is followed by a period of decreased or no symptoms (remission) until the next flare-up. “A relapse can leave some residual disability, or it can resolve completely over the course of weeks or months,” says Marc Walton, M.D., Ph.D., a neurologist and director of the FDA’s Division of Therapeutic Biological Internal Medicine Products.

A second form of MS–primary-progressive–brings on a gradual decline and disability without specific attacks. In the third form–secondary-progressive–MS starts out as relapsing-remitting but eventually takes on a course of gradual progressive disability with few or no relapses.

MS ranges from a very mild, hardly noticeable disease in some people to a very severe, paralyzing disease in others. About 20 percent of people with MS have a benign form of the disease, according to the NINDS. After the first attack, they show minimal, if any, progression and remain fully functional for long periods of time. “However, a majority of people with MS will go on to eventually have significant disability,” says Walton.

Research indicates that despite disability, most people with MS have a life expectancy only a few years shorter than normal.

Communication Breakdown

The exact cause of MS is unknown. “So many things have been implicated,” says McDermott. “The general consensus is that most people who have MS have a genetic predisposition to it, but something in the environment triggers it,” such as a virus, bacteria, a toxic chemical, or some other agent. “Gender also seems to play a role,” says McDermott, “as women are more commonly affected than men.”

Although the disease trigger still eludes researchers, they do know that MS interrupts the body’s intricate communication network of nerves. In a healthy individual, nerve fibers act like electrical cables, transmitting electrical impulses, or messages, at high speeds between the brain, the spinal cord, and the rest of the body. The fibers are insulated by a fatty coating called myelin.

In a person with MS, experts say the immune system appears to attack the brain and spinal cord. This attack inflames random patches of plaques, causing lesions that destroy the nerve-protecting myelin. Scar tissue replaces the myelin, a process known as demyelination. When electrical impulses zip through the nerve fibers and reach the scarred areas, they “short circuit,” slowing or preventing communication.

The loss of myelin “disrupts the way we receive signals, the way we give commands to our muscles to allow us to move, and the integrating activity that the brain and spinal cord needs to process sensory and motor movement information to allow us to function normally,” says Stephen Reingold, Ph.D., research counselor and former vice president for research programs at the NMSS. Continued scarring combined with damage to the nerve fibers may result in permanent disability.

Diagnosing MS

MS is “notoriously difficult to diagnose,” says Reingold. There is no single test to detect it.

Until recently, to meet the diagnostic criteria for MS, a person must have had two separate attacks at least a month apart and in different parts of the body. But early on in the disease process, some people have infrequent relapses or symptoms so mild that they might not recognize a second attack, says Walton.

In Ferko’s case, her eye doctor told her “not to worry about it” after her first symptom, optic neuritis, cleared up. Five years later, another doctor diagnosed her second symptom, leg numbness, as a pinched nerve.

Recent advances in technology, particularly magnetic resonance imaging (MRI), a non-invasive form of taking pictures of the brain to detect MS lesions, have aided physicians in diagnosing people with MS. “Now patients can come in with a single clinical episode and a neurologist can use an assortment of lab tools, including MRI, to determine more rapidly than waiting for a second clinical attack if there is a second lesion in the brain or spinal cord,” says Reingold.

“This has led to people being given the diagnosis sooner than otherwise,” says Walton. “We may now be making diagnoses of MS in more people with the least severe forms. In addition, it is possible that by treating patients earlier, the course of their disease may be less severe.”

Highly Variable

One of the frustrations for newly diagnosed patients is the uncertainty of living with a potentially debilitating disease. Dennis Bourdette, M.D., chairman of the neurology department at Oregon Health & Science University in Portland, Ore., describes MS as “highly variable.” “In the first few years of the condition, we don’t have any way of confidently identifying individuals who may have a benign course and who will have a more active course.”

“There is a series of clues that can help guide us in understanding more about what might happen,” says Reingold, “but the variability of the disease from person to person makes giving an individual prognosis for multiple sclerosis very, very uncertain. Most physicians still are uncomfortable with sitting down with a newly diagnosed individual and saying we believe that this may be what is going to be the course of your disease over the next 20 to 30 years.”

Relapses also are variable. When they strike, how long they last, and what organs or functions they affect differ from person to person.

“Nobody really knows why relapses occur,” says McDermott. In some people, they seem to be triggered by certain events that cause trauma to the body, she says, such as an accident, surgery, viral infection, or other illness.

Temperature changes may trigger a worsening of symptoms in some individuals. This effect is usually reversible when the temperature returns to normal, but it can sometimes be confused for a clinical relapse. Some people are sensitive to heat, says Reingold, but others are more sensitive to cold. “You need to learn what your disease is like for you, and then you’ll learn to cope with it.”

Treatment

The FDA has approved six drugs to treat MS, all injections. They cannot reverse the damage already caused by the disease, but they can help prevent relapses and further damage. In addition, a number of oral drugs can help alleviate some of the symptoms, such as fatigue, bladder infections, constipation, pain, depression, and involuntary jerking movements (spasticity).

The most recently approved MS drug, Tysabri (natalizumab), was licensed by the FDA in November 2004 to reduce the frequency of multiple sclerosis (MS) attacks in people with relapsing forms of MS. In February 2005, the drug manufacturer, Biogen Idec Inc., voluntarily suspended marketing of Tysabri because of two serious adverse events, including one death, reported with its use. A rare brain disease, progressive multifocal leukoencephalopathy (PML), was confirmed in two people with MS who had been taking Tysabri for more than two years.

PML can occur in people whose immune systems are suppressed. It often results in irreversible neurologic deterioration and death. Although the relationship, if any, between Tysabri and PML is not clear, the FDA concurred with the manufacturer that it voluntarily withdraw the drug from the market because of the serious nature of PML. The FDA has also prohibited new clinical trials with Tysabri until more information is available.

No previous cases of PML had been reported in the roughly 3,000 people who took Tysabri in clinical trials. The two people who developed PML were taking the drug in post-marketing studies required by the FDA.

People who were being treated with Tysabri should contact their physicians to discuss other treatments that may be appropriate. The FDA is working with the manufacturer to determine the best methods for assessing those who have received Tysabri in order to assure their safety and understand the connection, if any, between Tysabri and PML.

Four other treatments for people with relapsing MS are approved for lifelong use by the FDA: Avonex, Betaseron, and Rebif (beta interferons), and Copaxone (glatiramer acetate), a synthetic drug. All of these drugs reduce the frequency of MS attacks by influencing the activity of the immune system. In addition, Avonex and Rebif may slow down the rate of physical disability.

Each of the four drugs can be injected by the patient at home and each is used at regular intervals, ranging from once a day to once a week. Common side effects of the three interferon drugs are flu-like symptoms and reactions at the area of injection. Copaxone may trigger a short-term reaction that includes flushing, chest pain, heart palpitations, anxiety, and shortness of breath.

Another drug, Novantrone (mitoxantrone), is approved for people with secondary-progressive MS or those with rapidly worsening relapsing-remitting MS. This IV cancer chemotherapy drug is given in a medical facility. By suppressing the immune system, the drug may reduce new lesions, decrease relapses, and slow down the rate of disability. Because of the serious side effect of heart damage, Novantrone is restricted to use in an individual no more than four times a year for up to three years.

When it comes to choosing a treatment, Reingold says that’s a decision for the patient to make with a physician, taking into account the patient’s goal, quality of life, lifestyle, and insurance coverage, combined with the physician’s perspective on what the best options might be.

“Each of these drugs is different,” says Reingold. “They may be different biological molecules. They are given in different doses, they are given at different frequencies, they have different side effect profiles, and they cost different amounts.

“You may or may not be responsive to one drug,” he adds, “and you may have allergic reactions or side effects to one drug or not to another drug. There’s a certain amount of trial and error. We cannot currently tell at the onset of treatment which drug is going to be best for which people.”

As yet, there are no approved treatments for primary-progressive MS. “The currently available drugs focus their actions on inflammation while the damage at this stage is caused from degeneration and not inflammation,” says Jack Burks, M.D., a clinical professor at the University of Nevada School of Medicine in Reno, and vice president and chief medical officer at the Multiple Sclerosis Association of America (MSAA). “Patients with progressive MS can often benefit from rehabilitation therapies such as exercise, nutritional guidance, and psychological support to increase coping and adapting skills plus deal better with depression. Most people learn to recognize that quality of life is more related to having good relationships and feeling productive than running a 100-yard dash.”

Doctors advise people with all forms of MS to get enough rest, eat healthily, not smoke, and to exercise regularly. “Every person with MS should be on a regular exercise program customized to their level of disability,” says Bourdette. “Several studies of people with MS have demonstrated that exercise will improve fatigue, cardiovascular health, quality of life, and doesn’t make their MS worse.”

Importance of Early Treatment

People who have frequent relapses or whose functioning is severely affected may willingly take one of the injectable drugs approved to treat MS. When symptoms are mild, however, some people are reluctant to go on medication, says Bourdette. But even if a person has just one attack and an abnormal MRI brain scan, “they are at high risk for developing MS,” he says, adding that 80 percent to 90 percent of such people will develop MS within five years. “The goal is to make a definite diagnosis as early as possible and go on therapy.”

Even without symptoms, “the disease marches on,” adds McDermott, noting that studies involving MRIs of the brain of MS patients have shown new lesions forming even when relapses are not occurring. “I’ve seen patients who say, ‘I had a mild attack five years ago and I don’t need to be on medication–I’m feeling great.’ But the MRI shows a couple new spots, indicating areas of demyelination.” It’s like hypertension, says McDermott. “You can’t feel high blood pressure, but the damage goes on every day.”

The patients taking a placebo in clinical trials in MS “never caught up to the functioning of the patients treated with immune therapies from the beginning,” says Burks. “What is lost is gone forever.”

Harriet Fridkin, 62, knows this all too well. Fridkin knew that something was wrong in 1971, at age 29, when she couldn’t hold a drinking glass and her knees buckled under her. She was diagnosed with an orthopedic problem and the symptoms went away after her doctor prescribed several anti-inflammatory drugs. Six years later, Fridkin developed optic neuritis, which cleared up with steroid treatment. It wasn’t until 1980, when she was taken by ambulance to a hospital with vomiting, vision problems, and loss of balance, that Fridkin was diagnosed with MS. Treatments at that time were limited and Fridkin was told to “forget about it–you might never get another attack.”

When the first interferon drug for MS was approved in 1993, Fridkin’s doctor didn’t recommend it for her. Looking back, Fridkin believes that earlier treatment may have changed the course of her disease, now in a progressive state. “On a good day, I can move my left arm,” says Fridkin, who is confined to a wheelchair.

“Make sure you get help early and are proactive,” Fridkin advises people with symptoms, even mild ones. “lf a doctor tells you there’s nothing you can do, don’t be afraid to get a second opinion. Read about the disease, educate yourself, and ask questions.”

Fridkin also stresses the importance of exercise but cautions not to overexert. “Don’t exercise until you overheat and are tired,” she says, “because with MS, you don’t recover as fast.” Exercising for short periods, more frequently, is less fatiguing, she says.

Drawing on the experiences of people who have had the disease for a long time can also be helpful, says Fridkin. “Join a support group and listen to what others say.” Local support groups and other assistance are available through the NMSS and the MSAA.

Ferko says she is pleased with her quality of life right now. “I haven’t been that significantly affected in comparison to many other patients,” she says, adding that planning is important. Knowing that early in the day is better for her than afternoons and evenings, Ferko does her physical activities, like grocery shopping, in the mornings and does activities that she can sit down for in the afternoon. “Once you understand your symptoms and how it works in you, you have to modify things a little.

“And one of the most important things you can do is to find a doctor who specializes in MS,” Ferko advises. “It made the difference for me.”

Future of MS Treatment

Researchers continue to work toward a better understanding of MS and to find safe and effective treatments for all forms of the disease. Current drugs can curtail relapses, but they don’t stop the body’s attack on its immune system or the degenerative aspect of MS in the more advanced stages. “A major research focus on neuroprotection to stop the degeneration is underway,” says Burks.

Another area of research centers on finding agents that not only stop the damage but also repair it, says Reingold. “We need to learn how to reverse the damage that has been done, and hopefully, to improve functioning on a day-to-day basis for people with MS.” Researchers are studying the repair and regeneration of the myelin coating on nerve fibers that is destroyed by MS. “Myelin does repair itself,” says Reingold, but myelin repair is then subject to myelin damage in a person with MS whose immune system is launching an attack.

Repairing damage from MS remains a hope for the future, but in the short term, Reingold says, “The general consensus is that no single therapy is going to prove completely efficacious for MS. We need to focus on safety and efficacy of combination therapies and try to capitalize on multiple modes of action.” Reingold expects to see more studies that combine drugs with different modes of action, and is encouraged by the explosion of clinical trials. “There are more clinical trials for more new drugs to be used on MS going on right now than ever before in history.”

FDA-Approved Drugs for the Treatment of Multiple Sclerosis

Brand Name Generic Name Manufacturer/

Distributor and

Year of FDA

Approval

Betaseron interferon beta-1b Berlex Laboratories

Inc., 1993

Avonex interferon beta-1a Biogen Idec, 1996

Copaxone glatiramer acetate TEVA Neuroscience

Inc., 1996

Novantrone mitoxantrone Serono Inc., 2000

Rebif interferon beta-1a Serono Inc., 2002

Tysabri natalizumab Biogen Idec and

Elan, 2004;

marketing

suspended Feb. 28,

2005, due to reports

of two serious

adverse events

Brand Name Indication (From Frequency of

FDA-Approved Injection

Labeling)

Betaseron Relapsing forms of Every other day

MS

Avonex Relapsing forms of Once a week

MS

Copaxone Relapsing forms of Every day

MS

Novantrone Worsening Four times a year;

relapsing-remitting lifetime limit of 8,12

MS and doses

progressive-

relapsing or

secondary-

progressive MS

Rebif Relapsing forms of Three times a week

MS

Tysabri Relapsing forms of Every four weeks

MS

National Multiple Sclerosis Society

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