A Redefined Classification of Multiple Sclerosis

Robert J. Fox, MD: Traditionally, we have characterized MS [multiple sclerosis] into relapsing-remitting, secondary-progressive, and primary-progressive types. In relapsing-remitting MS, which makes up about 85% of patients at the start of MS, there are episodes of neurological dysfunction—blurry vision, double vision, coordination problems, weakness, or numbness.

These last several days to a few weeks and then resolve, although the episodes sometimes leave residual deficits. This is most common at the beginning of MS. After 10, 15, 20 years, the disease often transforms. The relapses and new lesions on MRI [magnetic resonance imaging] become less frequent and are replaced by a gradual, little-by-little decline. This is what we call secondary-progressive MS.

We call this secondary-progressive MS because it secondarily follows the relapsing-remitting stage. In the secondary-progressive phase, which is the gradual, little-by-little worsening, patients may sometimes have superimposed relapses or sometimes not. There are also some patients—about 10% to 15% of patients—who seem to skip the relapsing phase and go right to the gradual, little-by-little worsening over time at the beginning of their disease. We call that primary-progressive MS, because primarily it started as a progressive disease. The majority of those patients never have relapses, although there is certainly a subset who do develop relapses, and many of them will have new lesions on MRI.

Fred D. Lublin, MD: One of the great challenges in caring for patients with MS is our limited ability to prognosticate. We’re not very good at this. We can pick groups that are more likely or less likely to develop problems, such as the relapsing-remitting population. Women tend to have a better prognosis than men. At disease onset, younger individuals have a better prognosis than older individuals. People who have more attacks have a worse prognosis than people who have fewer attacks. Also, people with more disease on their MRI have a worse prognosis. People don’t recover as well.

In general, we have these courses. Clinically isolated syndrome obviously has the best prognosis because they’ve had only 1 attack. As a group, the next best would be relapsing-remitting. The patients who develop the most disability impairment are the people who have transitioned to either secondary-progressive MS or start out with primary-progressive MS. They carry a worse prognosis, but it’s still quite variable.

When we redid the phenotypes of MS—relapsing-remitting, secondary-progressive, primary-progressive—that you’ve already heard about, we also suggested subtyping disease by whether an individual was active or not active. A person who was active either had a relapse or had new activity on their MRI scan over some defined period of time. We also redefined them as having progression or not if they were in a progressive phase. In the 1996 phenotype paper, we described progressive-relapsing MS as patients who started out as primary-progressive and then have an acute attack. When we added on for the 2013 criteria, when we added on the measure for activity, that subsumed what was being called progressive-relapsing. That was primary-progressive with activity. That’s essentially the same as what was considered old progressive-relapsing MS.