Fred D. Lublin, MD, and Patricia K. Coyle, MD, outline and elucidate the core phenotypes of multiple sclerosis, including the reclassification of progressive-relapsing multiple sclerosis into further subtypes.
Fred D. Lublin, MD, and Patricia K. Coyle, MD
PUBLISHED October 29, 2018
Current Series: Multiple Sclerosis: A Disease of an Immune System Gone Awry
Fred D. Lublin, MD: We characterize multiple sclerosis [MS] into different subtypes or phenotypes, if you will. The most common is relapsing-remitting, and this is where you have an attack from something affecting the central nervous system. It comes on acutely or subacutely, lasts for days or weeks, and then stops. Now, it may resolve anywhere from 0% to 100%, meaning that you may fully recover, or you may be left with some residual deficit: a limp, numbness, tingling, or change in vision. It stays stable over time until the next attack, and that’s what makes it relapsing-remitting.
The period between those attacks, the time between those attacks, is extremely variable. It could be weeks, months, years, or decades. This is why prognostication in MS is so difficult. Because of serious neurologic diseases, this phenotype is the most variable. From extremely mild to very severe, relapsing-remitting disease can follow that entire course.
Sometimes, in some people, the relapsing-remitting phase will then enter a progressive phase where between attacks, there will be gradual worsening. It’s not inexorable worsening, so it could fluctuate. Patients gradually worsen and may or may not have superimposed attacks, but that gradual worsening between attacks is progressive disease. If they start out with a relapse, then it’s secondary-progressive disease. Some individuals, maybe 10% to 15% of MS cases, have what’s called primary-progressive MS. In primary-progressive MS, patients don’t have an acute attack to start with. Instead, they start with a gradual worsening. Usually, it involves the legs or spastic paraparesis and progresses from there at a variable rate. The 2 progressive phases both carry a worsening prognosis in that most of the disability that we see, the lasting disability, is in patients with progressive disease.
Now, when someone who starts out as primary-progressive has an attack after they’ve already started progression, we used to call that progressive-relapsing MS. But more recently, we reviewed these phenotypes and decided to subtype them further regarding whether there’s activity or no activity and whether you are progressing or you are stable. What that does is if you take a relapsing-remitting patient and they come in to see you, you assess them for activity. Activity would either be an acute attack or a change in the MRI [magnetic resonance imaging], with a new T2 lesion or a gadolinium-enhancing lesion, that occurred over some fixed time period. You can pick whatever period you want, but we recommended 1 year.
When someone comes in, I’ll make an assessment 1 year down the road as to whether they had any activity or not. They become relapsing-remitting active if they’d had an attack or if they had had a change in their MRI. That holds for progressive patients, too. If you were a primary-progressive patient and you had an acute attack, which can happen—what used to be progressive-relapsing—you now will have primary-progressive active disease.
Now, if you’re primary-progressive or secondary-progressive already, then you may be characterized as either active or not active over say a 1-year period, but we also check whether you progressed or didn’t progress. That is, did you get worse? Some progressive patients stay stable for long periods of time. And so, progressive individuals can be active and progressing, active but not progressing, progressing but not active, or neither active nor progressing, and therefore stable. That’s the modern characterization of the disease types. We think it’s more helpful now because we need to know what people are doing within a timeframe to get a better idea on prognostication, which is not one of our strengths. We also need to develop means of better gauging how people respond to our therapies.
Patricia K. Coyle, MD: When they revised the MS phenotypes in 2013 and published them in 2014, they did away with one of the MS phenotypes, the so-called progressive-relapsing disease. Previously, in the unusual MS patient who showed gradual worsening and slow progression from the onset, we considered them either primary-progressive or progressive-relapsing. The only way we differentiated them was that the progressive relapsing patient subsequently had a superimposed acute attack, or acute relapse. If that happened, they were no longer considered primary-progressive and were switched from primary-progressive to progressive-relapsing.
After a number of years, it’s become apparent that was an artificial division. If you’re progressive from the onset, you fall into a unique group, and we know that about 1.5% of primary-progressive patients will have a clinical attack each year. It’s not 100% confirmed that they can’t have a clinical relapse. They really combined primary-progressive and progressive-relapsing and did away with progressive-relapsing. And so, primary-progressive is the unusual 10% to 15% of MS cases that show a gradual, slow worsening from onset; about a decade later age of onset, often in the mid-40s; and an equal sex ratio, men as likely affected as women. It’s the only MS phenotype that does not show a female predominance.