Finding the genetic source of the disease will help determine the most effective treatments.

The more complex the puzzle, the more patience is required for its completion. Thankfully, those working on the mystery of multiple sclerosis (MS) have endurance, which in recent years has been rewarded with advancements on all fronts: research, diagnosis, and treatment.

Exactly what causes MS is unclear. Women are more likely than men to develop the chronic neurological condition that causes damage to the myelin sheath, the protective material that surrounds nerve cells. This damage causes inflammation and scarring (or sclerosis), inciting the body’s natural immune reaction.

As a result, the speed at which nerve impulses travel throughout the body is slowed or interrupted entirely, leading to any number of symptoms, including weakness, tremors, spasms, or paralysis in one or more extremities; muscle atrophy, vision problems, or discomfort; decreases in memory, spontaneity, or judgment; as well as dizziness and vertigo.

Estimates are that as many as 500,000 people in the United States are living with MS. For some of those individuals, their disease is asymptomatic, which is why magnetic resonance imaging (MRI) has taken on an essential role in helping identify the disease, as well as in tracking its progress.

“What revolutionized the study of MS was the use of MRI. A person with MS may be feeling OK if the damage is taking place in a part of the brain that is not expressed dramatically,” says Patricia A O’Looney MD, director of Biomedical Research Programs for the National Multiple Sclerosis Society (NMSS) in New York City. “In the early 1990s when the MRI started becoming more mainstream in the clinical practice, it allowed the doctors to look into the brain. That has been extremely helpful in our understanding of MS.”

“These guidelines address some of the technical aspects of MRI use in MS. While there is no consensus on how MRI is used in following the person with MS, there is agreement on how the study is done,” says Ben W. Thrower, MD, medical director at the MS Institute at Shepherd, Atlanta. “Each slice should examine no more than 3 mm of brain, and no more than 1 mm should be skipped. This technique decreases the likelihood of missing small lesions.”

When using gadolinium, the Consortium of Multiple Sclerosis Centers advised allowing 5 minutes to pass between pushing the contrast agent intravenously and the start of the scan. Tests are currently under way to use this powerful imaging technology.

“Some people are now testing 3-Tesla magnets, and there is some experimental use with 8-Tesla magnets at Ohio State,” says Jack Burks, MD, chief medical officer and vice president, Multiple Sclerosis Association of America, Cherry Hill, NJ, and clinical professor of Urology at the Nevada School of Medicine, Reno, Nev. “There are individuals working with spectroscopy, magnetization transfer imaging, diffusion tensor imaging—these are all being looked at in the laboratory development phase.”

Eliminating Suspects
A diagnosis of MS is generally arrived at when all other likely causes of symptoms are eliminated. According to the International Panel Criteria (McDonald Criteria) for diagnosing MS, when a patient has had less than two attacks or displays less than two lesions, clinicians will order cerebrospinal fluid (CSF) electrophoresis or isoelectric focusing for CSF oligoclonal banding in addition to visualizing brain lesions using MRI.

After separation, a protein stain is applied to both the serum and the patient’s CSF so the banding patterns of the proteins in the two can be compared. If there are two or more IgG bands in the CSF that are not present in serum, it is a positive test for oligoclonal banding and generally a positive diagnosis of MS. The increased levels of CSF IgG is thought to be a result of the breakdown of myelin, which is composed of fats and proteins.

Most challenging in diagnosis is the lack of a definitive MS marker of any kind. There is also no indicator authoritatively identifying either the disease or how severe the case may be.

“What we’d like to find is a specific marker for the disease. That may be an immunologic marker, an antibody marker of some kind, or even some type of clinical marker, such as a specialized technique for looking in the eye to detect damage,” Burks says.

A Tremendous Difference
“In the MS clinical world we are desperately in need of a biomarker that will be a reflection not only of the diagnosis of MS, but which will also be able to measure the disease course,” O’Looney says. “This would help not only in the clinical role of diagnosis but also in clinical trials, because as we test new drugs a marker could tell us which drugs had efficacy.”

Giving hope that a biomarker for MS is on the horizon is a blood test developed at the Mayo Clinic in Rochester, NY, which identifies a biomarker called NMO-IgG. This test makes it possible to rule out neuromyelitis optica, also called Devic’s disease, which impairs the central nervous system and causes demyelination.

“It’s a blood test that is about 70% sensitive and over 90% specific; and it not only shows that Devic’s is a separate disease, but gives us a way of distinguishing it from MS,” Thrower says. “We want to sort out Devic’s because it is not only aggressive, but it doesn’t tend to respond to some of the traditional immune modulators we use with multiple sclerosis.”

Tackling Treatment
Just as the diagnostic techniques are growing, so are the options patients have for treatment of MS. One area generating a great deal of discussion is the role of neutralizing antibodies (NAb) and binding antibodies (BAb).

“Neutralizing antibodies can be seen with beta-interferon therapy in multiple sclerosis, but it is still controversial in terms of how important they are and whether we should give them routinely as part of screening,” Thrower says, adding that scientists have begun to use BAb as a screen for when to use a NAb. “We are moving toward doing the binding assay first, and if it’s negative then you don’t need to do the neutralizing antibodies; if it is positive, perform the neutralizing antibodies and see if those are also positive.”

With literally hundreds of clinical tests under way, there is much for authorities in the field to be excited about. Topping the list for many is the prospect of oral therapies for MS; currently, all treatments are administered intravenously.

A standout among this type of research is fingolimod (FTY720), which is currently being evaluated for the treatment of relapsing MS.

“It is an oral medication that takes activated lymphocytes from the blood and puts them back into the lymph nodes, taking them out of circulation,” Burks explains. Sequestering these cells might lessen the amount of inflammation patients experience. “They’ve already begun a Phase III trial, so we are hoping to see an update on some preliminary data that might be helpful.”

As research advances, the objective is becoming far more specific. Scientists are working on more selective treatments—for example, therapies designed to block only those immune cells doing the damage in MS. Such an approach is a significant change from the global type of immunosuppressive drug used just 20 years ago.

In the 1990s, efforts switched to creating pharmaceuticals to dampen the immune system in people with MS in a more natural way. The resulting interferons have been beneficial to MS patients. Work continues on designing even more specific therapies, tailor-made to block or destroy only immune cells that are causing the damage.

In addition to creating new medications, focus is being placed on adjusting the dosages of existing therapies as well as using them in combination.

Studies have been under way to examine the effects of doubling the dose of interferon beta-1b (sold under the brand name Betaseron), and another study recently began to look at doubling the dose of glatiramer acetate (branded as Copaxone) to see if there is any additional benefit.

No matter how promising the therapy, the lure of an additive effect is constantly balanced against the risk of increased toxicity over extended periods of time.

“The key thing that we are worried about right now is we’re seeing some very effective drugs, but the question is are they too toxic to use with a disease that is nonfatal,” Burks says. “You don’t want to get fatal treatments to a nonfatal disease, so we are trying to weigh the risks and benefits of some of this new exciting data that we are seeing.”

Diving Into Genetics
In the last few years a large international collaboration has been in place, centered on the genetic dissection of MS. The Multiple Sclerosis Genetics Group pulled together researchers from the University of California San Francisco, Duke University, Vanderbilt University, Harvard University, the Broad Institute of the Massachusetts Institute of Technology (MIT), as well as a team at the University of Cambridge in the United Kingdom.

“For the past 14 years the MS Society has put a major focus on genetics, because it holds promise to do things we wouldn’t even have imagined possible 20 years ago,” O’Looney says. “The scientists up at MIT are working side by side with the scientists who are investigating the entire human genome, and we’re very pleased that MS is one of the first diseases t

hat will be analyzed with any information that comes out of the Human Genome Project.”

Though still to be determined, the suspicion is that instead of isolating a solitary gene responsible for the development of MS, it is more likely that scientists will identify multiple genetic contributions that increase the odds someone will develop the disease.

“It is important to note that MS is not directly inherited, but there has been very clear evidence that the closer a person is in relationship to a member of the family with MS, the higher risk that person has,” O’Looney says. “I am convinced that not only will genetics help us to understand the disease, but it will also help us unravel one of the greatest mysteries of the disease, which is why when two people are diagnosed with MS, one person may have a relapse-remitting course and the other person has a much more progressive form.”

In addition to providing valuable insight into the origins and likely pathways of the disease, knowing the genetic source of MS could also impart valuable information about which treatments will be most effective in which patients.

“The information that could come out of the genetics research could be very helpful, for instance it might produce genetic profiles that predicted better responses to one class of drug versus another,” Thrower says. “Right now, there is guesswork and a lot of personal preference that goes into selecting an initial therapy. It would be nice if we could do some genetic profiling to predict a better response from one agent as compared to another.”

There is also an expectation that genetics can do more than just improve patient care.

“Certainly, the therapies we have now are very effective, and we are working on identifying even better or combination therapies,” O’Looney says. “But obviously, we are hoping this will eventually lead us to a cure as well.”

Dana Hinesly is a contributing writer for Clinical Lab Products.
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