As with many chronic medical conditions, there is a lot of guesswork involved in making a diagnosis of multiple sclerosis (MS). Lesions in the brain and spinal cord cause a wide range of neurological symptoms depending on where the damage occurs. These symptoms are initially experienced as a sudden "attack" that may last for hours or days. But not everyone who has experiences will go on to have additional attacks; and a diagnosis of MS is only definitive when an individual has two or more attacks. Although brain imaging is sometimes used after the first attack to try to predict a diagnosis by detecting lesions, a blood test might be a simpler way to identify people with the disease.

In a recent New England Journal of Medicine (NEJM) study, Austrian researchers found that a blood test measuring two antibodies, which are substances that the immune system produces, which, in MS, may attack the myelin, a protective coating that insulates the nerves. The test was given to 103 participants who had had one neurological episode, as well as brain imaging and spinal fluid tests that indicated that they had a high risk of MS. Researchers found that 95 percent of patients with both antibodies were eventually diagnosed with MS; 83 percent with one antibody were later diagnosed; and only 23 percent with neither antibodies went on to be diagnosed.

Amit Bar-Or, MD, FRCPC, an assistant professor in neurology and neurosurgery at the Montreal Neurological Institute and an associate in microbiology and immunology at McGill University in Montreal, Canada, contributed to an editorial that accompanied the NEJM article. Below, Dr. Bar-Or discusses the need for a reliable MS blood test and how it might affect treatment decisions.

How is MS is traditionally diagnosed?
Most patients will come to attention of their doctors when they have their first neurological episode, which may involve a range of different symptoms or signs. This first episode is called a clinically isolated syndrome.

The part of the nervous system that is involved in an attack will determine what kind of symptoms or signs a patient has. These may include loss of vision, problems with weakness, incoordination of the limbs, unsteadiness of gait, or a loss of sensation or a tingling sensation in the limbs, trunk or face.

A proportion of these patients will eventually end up with a diagnosis of multiple sclerosis and a proportion of them will end up having just that clinically isolated syndrome. The challenge of seeing a patient with a single episode is trying to help them understand how likely they are to end up with a diagnosis of MS.

What diagnostic tests are available for MS?
What has been most helpful in identifying people who will transition to an MS diagnosis is a type of brain imaging called magnetic resonance imaging (MRI). Research shows that if you look at an MRI of the brain at the time of the first episode, the presence or absence of lesions associated with demyelination can be helpful in predicting the likelihood of eventually having a second attack, and consequently a multiple sclerosis diagnosis.

If you have an isolated event, such as optic neuritis, which is an inflammation of the optic nerve, but your brain scan is quite normal looking, then you are at a relatively low risk of developing MS. Depending on the study, the risk may be as low as 10 percent. If you have an MRI with multiple lesions that suggest demyelination at the time of that same single episode, your likelihood of eventually developing MS is about 80 percent.

That difference is quite substantial in terms of trying to plan treatment, but it's still not as close to perfect prediction as one would like to get. So there is a great interest in identifying additional, easy-to-measure and reliable parameters early on that could predict who will end up with MS and who will not, or whether individuals are likely to have a more aggressive course of MS or a milder course of MS.

Why is a blood test such an attractive concept?
If it turns out to be validated, a blood test is a very simple thing to do. It's minimally invasive and relatively inexpensive. Theoretically, the test could be given to people when they have their first isolated syndrome and help guide the team in terms of predicting the eventual development of MS. It could also help in terms of considering instituting therapies early on, or following patients more proactively, as opposed to just waiting until they come back with another episode.

What are the blood tests measuring?
The blood tests are measuring antibodies that are produced by the immune system and recognize myelin. People have known for a long time that many MS patients have an unusual antibody response within the central nervous system. We've known about that because we measured what are called oligoclonal bands in the spinal fluid. Oligoclonal bands represent antibodies, yet it has been very difficult to understand whether these antibodies are actively participating in the disease process.

Myelin is one of the components thought to be a target of attack in the brain. In this study, the blood test measured antibodies that targeted two particular proteins within the myelin, one being myelin basic protein (MBP) and the other one being myelin oligodendrocyte glycoprotein (MOG). Those two proteins have been considered potential targets in MS for a long time.

This study showed that if you identify antibodies directed against these particular targets, you might have additional information in terms of predictive value. The study still doesn't tell us whether or not these antibodies are causing damage or whether they just represent a marker of immune system activity. It is also possible that someone could have these antibodies but not have MS, or neurological symptoms.

How could the test affect treatment?
Given that there are many countries where it is possible to prescribe immune modulators for MS when patients have only a single attack, this kind of information can be helpful in allowing people to have discussions about MS therapies early on.

This is important because we now recognize that people with MS have perhaps tenfold more underlying MS activity than what is apparent during clinical attacks. We believe that those attacks are likely to be associated with damage to the central nervous system. The reason that patients don't necessarily experience deficits early on is because there is reserve built into the nervous system, just as there is with any other organ of the body. So as you're waiting and considering the institution of therapy, more damage may be occurring, which is a reason for considering early intervention. And for that decision you want to have early and accurate diagnosis.

What questions still need to be addressed?
One would want to see these results validated in another study. I think it's important to mention that there are other publications out there, including some fairly recent ones, that suggest that antibodies against these same targets—the MBP and the MOG—are not likely to be important in MS. Part of our challenge is to understand how to reconcile these observations.

What these conflicting results may be reflecting is the involvement of these antibodies at different stages of MS. For instance, the antibodies may play more of a role earlier on, whereas later in MS, the antibodies may be harder to detect and not necessarily that helpful.

The other thing of interest is how this antibody test relates to the predictive value of magnetic resonance imaging. Is the combination of MRI and the antibody test going to be helpful? Or will they be overlapping in terms of their predictive ability?

I think that groups will start to apply a similar assay to their patient populations and follow them prospectively. And so there will be information coming out over the next couple of years. Obviously the longer you wait to confirm results, the more confident you feel. It will probably take two to three years to sort out whether this could be a test of predictive value.

Another initiative is prospectively following the pediatric population with MS. We are adding this blood test to other measures, such as MRI and comprehensive immunological studies. The pediatric population offers a unique opportunity to understand the predictive value of tests done early on in the disease process.

Are you aware of any other potential early detection methods that are being studied now?
There is an initiative that is driven by the Immune Tolerance Network, supported in part by the National Institutes of Health, which is trying to develop ways of looking at T cell and other responses in MS. This test would hopefully be able to discriminate between normal individuals and those with MS, and could potentially be used in patients with MS to follow their disease as well as response to therapies.